Volume 9 - 2017 | https://doi.org/10.3389/fnagi.2017.00284 Memory decline during aging or accompanying neurodegenerative diseases Neurotrophins have long been considered relevant to the mechanisms of aging-associated cognitive decline and neurodegeneration Mature Brain-Derived Neurotrophic Factor (BDNF) and its precursor (proBDNF) can both be secreted in response to neuronal activity and exert opposing effects on neuronal physiology and plasticity biochemical analyses revealed that increased levels of proBDNF are present in the aged mouse hippocampus relative to young and that the level of hippocampal proBDNF inversely correlates with the ability to perform in a spatial memory task To ascertain the role of increased proBDNF levels on hippocampal function and memory we performed infusions of proBDNF into the CA1 region of the dorsal hippocampus in male mice trained in the WRAM paradigm: In well-performing aged mice intra-hippocampal proBDNF infusions resulted in a progressive and significant impairment of memory performance This impairment was associated with increased p-cofilin levels an important regulator of dendritic spines and synapse physiology a peptide which blocks the interaction between the p75 Neurotrophin Receptor (p75NTR) and RhoGDI significantly improved learning and memory Our results support a role for proBDNF and its receptor p75NTR in aging-related memory impairments neuronal activity controls the ratio of extracellular proBDNF to mature BDNF which may be crucial for synapse physiology and function Despite the wealth of data gathered through in vitro or ex-vivo studies little is known about proBDNF production across the lifespan and consequences of over- or under-expression of proBDNF on learning and memory processes We hypothesized that aging is associated with a decrease in proBDNF processing to the mature form which induces alterations in structural and functional plasticity with detrimental effects upon learning and memory: Thus increasing proBDNF levels in well-performing mice by local infusions into the CA1 region of the hippocampus would impair spatial memory recall while blocking the p75NTR effects on RhoA activity in poorly performing aged mice would rescue spatial memory by improving consolidation and recall n = 21) C57BL/6 male mice served as subjects in Experiment 1 n = 36) C57BL/6 male mice served as subjects in Experiment 2; 18 months old mice were chosen in Experiment 2 so that they would be closer to gene expression patterns in the aged subjects from Experiment 1 (reduced enzymes for processing yet they would be more resilient when subjected to surgical procedures Mice were housed in a temperature-controlled room under a 12-h light-dark cycle This study was carried out in accordance with the recommendations of National Institutes of Health and the Guide for the Care and Use of Laboratory Animals The protocol was approved by the Utah State University IACUC committee mice were split into three groups based on their performance (unimpaired/impaired) and henceforth infused with different drugs (saline behavioral training/testing in the water radial arm maze task; SAL so effects of drug manipulations are generally evaluated in a mixed population of poor and good performers one has to take into account a possible “floor effect” in memory errors (when starting with a good performance learning can hardly be improved further) and a “ceiling effect” (an animal with poor learning and memory rather than injecting all drugs in both poor and good performers in Experiment 2 good performers (unimpaired aged mice) received proBDNF infusions in the hippocampus in order to assess its role in decreasing performance while poor performers (memory-impaired aged mice) were infused with TAT-Pep5 to evaluate the role of p75 signaling downstream proneurotrophin in possibly improving their performance The platform set-up was chosen randomly for each mouse at the beginning of testing then maintained constant throughout the experiment mice were implanted with stainless steel double cannula guides (28GA bilaterally aimed at the dorsal hippocampus using a stereotactic apparatus under aseptic conditions and anesthesia Guides were fixed with dental cement and covered with caps Mice were allowed to recover for 1 week before being retested and locally infused as described below Infusions were performed using a gear-driven infusion pump (Harvard Apparatus, Hollistone, MA, USA) with Hamilton syringes connected to the internal cannulae via polyethylene tubing. Internal double cannulae (33GA) extended 0.5 mm beyond the cannula guides and tips were directed at the CA1 subfield of the dorsal hippocampus (AP −2.1, ML ±1.5, DV −1.5) and (AP −2.7, ML ±2.1, DV −1.5; Franklin and Paxinos, 2008) on d19 all mice received intra-hippocampal infusions of saline to test stable performance before and after surgery On d20–22 unimpaired mice in group “unimpaired + proBDNF” were injected with “uncleavable” mouse proBDNF (proBDNF mut-mouse “Uncleavable” proBDNF differs from wildtype proBDNF at the site of cleavage by plasmin and was used in order to delay in vivo processing of proBDNF underperforming mice in group “impaired + TAT-Pep5” were injected with a solution of TAT-Pep5 (EMD Millipore while underperforming mice in “group impaired + SAL” were injected with saline 0.4 μL/side All drug solutions were infused at a speed of 0.1 μL/min Cannulae were left in place an extra 2 min post infusion Patency of cannulae was tested after each injection mice were sacrificed and brains collected for histological analyses to ascertain the placement of cannulae Mice were deeply anesthetized with isoflurane and transcardially perfused with 4% paraformaldehyde solution Brains were collected and sectioned at 50 μm thickness on a vibrating microtome (Leica VT1200S Sections were placed on positively charged glass slides rehydrated and stained with a 0.1% cresyl violet solution then cleared and coverslipped with Permount Sections were examined for cannula placement on a Zeiss AxioImager M2 motorized research microscope with an imaging system Only animals with cannulae correctly placed were used for analyses Two mice in group impaired + SAL and one mouse in group unimpaired + proBDNF were eliminated for improper cannula placement and/or clogged cannula guides Equal protein loading was verified using an HRP-conjugated anti-GAPDH antibody (ABCAM USA); major products were quantified (relative to GAPDH and to a standard brain lysate) using a FluorChem9900 system (Alpha Innotech Memory impairment in aged mice positively correlates with increases in hippocampal proBDNF levels (A) Average (±SEM) reference memory (RM) and working memory (WM) errors over four 4-session blocks of a WRAM task in 24-month old aged mice and 4-month old young mice RM and WM errors positively correlate with proBDNF levels but not brain-derived neurotrophic factor (BDNF) in 24-month old aged mice relative to young 4-month old mice aged 24-month old mice show increased p75 Neurotrophin Receptor (p75NTR) and decreased p-trk140 and trk140 aged 24-month old mice show decreased Tissue Plasminogen Activator (tPA) In Experiment 1, WM errors (entries in previously visited arms) and RM errors (entries in arms that never contained platforms; Jarrard et al., 1984) were subjected to mixed ANOVAs with between-subjects variable age (aged young) and within-subjects variable block (four blocks) CPE and tPA relative to GAPDH in hippocampal lysates were normalized to the average levels found in young mice baseline memory performance (WM and RM errors) was evaluated in mixed ANOVAs with between-subjects variable group (three groups) and within-subjects variable session (before surgery: average performance in the last block of three daily sessions before surgery and after surgery: d19 first session after surgery) Memory performance (WM and RM errors) in the impaired + SAL group was further evaluated in repeated-measures ANOVAs with within-subjects variable session (four local SAL infusion sessions: d19–d22) followed by post hoc analyses Memory performance (WM and RM errors) in the unimpaired + proBDNF group relative to the impaired + SAL group was evaluated in mixed ANOVAs with between-subjects variable group (two groups) and within-subjects variable session (four drug infusion sessions: d19–d22) followed by post hoc analyses Memory performance (WM and RM errors) in the impaired + TAT-Pep5 group relative to the impaired + SAL group was evaluated in mixed ANOVAs with between-subjects variable group (two groups) and within-subjects variable session (four drug infusion sessions: d19–d22) followed by post hoc analyses Levels of p-cofilin to total cofilin ratio were normalized to the average ratio found in unimpaired mice and subjected to a one-way ANOVA with factor group (three groups) Statistical analyses were performed in STATISTICA (StatSoft All statistical analyses were conducted at an alpha level 0.05 Plots indicate a relative diversity of the pattern at both ages proBDNF levels correlated significantly both with RM errors (R2 = 0.33 p < 0.01) and WM errors (R2 = 0.27 these results suggest that proBDNF processing and receptor levels in the hippocampus changed with age and that manipulating proBDNF levels and receptor activation may alter both RM and WM spatial performance in the WRAM task This hypothesis was tested by observing the effects of local hippocampal infusions of proBDNF and TAT-Pep5 on performance in the WRAM task in aged mice Intra-hippocampal infusion of proBDNF impairs memory in well-performing (unimpaired) mice while TAT-Pep5 infusion improves memory in poorly-performing (impaired) mice (A) Average (±SEM) RM and WM errors in memory impaired 18-month old mice receiving intra-hippocampal saline infusions (impaired + SAL open triangles) and well-performing 18-month old aged mice receiving uncleavable proBDNF intra-hippocampal infusions (unimpaired + proBDNF open circles) over four daily sessions of a WRAM task (B) Average (± SEM) RM and WM errors in memory impaired 18-month old mice infused with saline (impaired + SAL open triangles) and memory impaired 18-month old mice receiving intra-hippocampal infusions of TAT-Pep5 (impaired + TAT-Pep5 closed circles) over four daily sessions of a WRAM task (C) Representative images indicating the locations of drug infusions at two levels of the hippocampus ns not significant; *p < 0.05; **p < 0.01 WM and RM errors for the memory impaired mice infused with saline (impaired + SAL, n = 8, open triangles) are shown in Figure 3A analyses failed to indicate an effect of session for either RM (F(3,21) = 0.98 suggesting that memory impaired mice receiving intra-hippocampal infusions with saline failed to improve reliably over the four sessions The performance of memory impaired mice infused with TAT-Pep5 and of unimpaired (well-performing) mice infused with proBDNF was evaluated relative to that of memory impaired mice infused with saline as discussed below we have analyzed p-cofilin levels as a neuronal plasticity marker in mice showing memory impairments in the WRAM well-performing mice and well-performing mice receiving proBDNF infusions in the hippocampus Intra-hippocampal infusion of proBDNF increases p-cofilin levels in memory-unimpaired mice to levels seen in memory-impaired mice (A) p-Cofilin to total cofilin ratio in memory-unimpaired mice and memory-unimpaired mice infused with proBDNF (B) Representative p-cofilin and cofilin blots The current study evaluated the role of proBDNF and of the p75NTR neurotrophin receptor in aging-associated learning and memory deficits Our results revealed that proBDNF was increased in the aged mouse hippocampus possibly as a result of decreased tPA and plasmin activation; proBDNF levels negatively correlated with good performance (RM and WM) in a water radial maze task Infusions of “uncleavable” proBDNF into the CA1 region of the dorsal hippocampus significantly impaired memory recall in mice that previously learned the task while blocking p75NTR association with RhoGDI using the TAT-Pep5 peptide improved performance in memory-impaired aged mice These effects were gradual (over daily sessions) rather than immediate; this suggests that TAT-Pep5 affected not solely memory recall but also learning we have found an increase in p75NTR in the aged mouse hippocampus Although these studies point to an important role of BDNF in hippocampal learning and memory since the genetically-modified animals have chronically (life-long) reduced BDNF levels it is unclear whether the deficits in learning found in these animals are linked directly to the BDNF deficit or to subsequent changes in multiple gene expression levels Theoretical model of the role of proBDNF in learning in memory in aged individuals maturation of proBDNF to BDNF is controlled by plasmin and tPA Aged individuals show decreased levels of tPA and plasmin associated with increased spine remodeling and memory deficits as in the current study) leads to spine growth we cannot exclude that the improvement of spatial learning and memory in TAT-Pep5 infused mice reflects positive effects on basal forebrain cholinergic neurons and their hippocampal projections additional experiments need to clarify whether similar changes occur in aged females The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest This 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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) distribution or reproduction in other forums is permitted provided the original author(s) or licensor are credited and that the original publication in this journal is cited in accordance with accepted academic practice distribution or reproduction is permitted which does not comply with these terms *Correspondence: Mona Buhusi, bW9uYS5idWh1c2lAdXN1LmVkdQ== †Present address: Ann-Charlotte Granholm Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher 94% of researchers rate our articles as excellent or goodLearn more about the work of our research integrity team to safeguard the quality of each article we publish Health & Wellness By Allyson Myers | January 23 stands with undergrad researchers Madison Treasure Areno a Utah State University associate professor in psychology who specializes in neuroscience our ability to learn and remember can decline which can affect our ability to accomplish daily tasks Buhusi has spent much of her research career studying how cognitive decline happens and how it can be reduced and she does this with the help of some unlikely research partners: swimming mice To learn about the effects of cognitive decline on learning and memory Buhusi’s lab in the Emma Eccles Jones College of Education & Human Services studies mice as they swim through a maze to an exit platform young mice are more able to quickly and efficiently remember the correct route to get out of the maze Older mice do not learn or remember as well as the young mice and do not perform as well This difference in performance based on age is due to the fact that older brains have less neuroplasticity or ability to adapt and change in response to experiences Older brains have smaller amounts of mature BDNF (brain derived neurotrophic factor) a key molecule involved in learning and memory a precursor molecule that contributes to synapse remodeling and cell death Buhusi has determined that certain drugs can modify the effects of proBDNF enabling older mice to learn and remember the mazes better This research could contribute to interventions to reduce or prevent cognitive decline in humans affected by aging “It is always easier to prevent than to treat,” Buhusi said maybe we can learn what to do so they don't go wrong in the first place.” In addition to her primary research focuses Buhusi and some of her graduate students also study how BDNF plays a role in depression and schizophrenia Buhusi is now embarking on research focusing on the role of astrocytes Glial cells provide physical and chemical support to neurons.In the aging brain astrocytes become impaired and affect our ability to recall or to update our memories Buhusi will examine if and how drugs that target astrocytes can have a positive effect on cognitive impairment Buhusi’s lab includes undergraduates collecting and analyzing behavioral data and photographing brain cells will receive a research assistantship from the Alzheimer’s Disease and Dementia Research Center at USU to work with a mouse model of Alzheimer’s disease has received an Undergraduate Research and Creative Opportunities grant to study a model of depression Comments and questions regarding this article may be directed to the contact person listed on this page For Luke Hayes the decision to attend Utah State University came through seemingly small but momentous experiences Whether you consider yourself a cat or a dog person research shows caring for a pet can positively impact your physical and mental health UNIVERSITY AFFAIRS SCIENCE & TECHNOLOGY HEALTH & WELLNESS Old Main Hill,Logan, UT 84322(435) 797-1000 Volume 18 - 2024 | https://doi.org/10.3389/fnbeh.2024.1373556 The neuronal cell adhesion molecule (NrCAM) is widely expressed and has important physiological functions in the nervous system across the lifespan from axonal growth and guidance to spine and synaptic pruning to organization of proteins at the nodes of Ranvier NrCAM lies at the core of a functional protein network where multiple targets (including NrCAM itself) have been associated with schizophrenia Here we investigated the effects of chronic unpredictable stress on latent inhibition a measure of selective attention and learning which shows alterations in schizophrenia in NrCAM knockout (KO) mice and their wild-type littermate controls (WT) Under baseline experimental conditions both NrCAM KO and WT mice expressed robust latent inhibition (p = 0.001) but not NrCAM KO mice (F < 1) Analyses of neuronal activation (c-Fos positive counts) in key brain regions relevant to latent inhibition indicated four types of effects: a single hit by genotype in IL cortex (p = 0.0001) a single hit by stress in Acb-shell (p = 0.031) a dual hit stress x genotype in mOFC (p = 0.008) and no effect in PrL cortex (p > 0.141) These results indicating a pattern of differential effects of genotype and stress support a complex stress × genotype interaction model and a role for NrCAM in stress-induced pathological behaviors relevant to schizophrenia and other psychiatric disorders Weinberger (1987) proposed a ‘neurodevelopmental model’ of SZ suggesting that alterations in normal brain development lead to an altered brain developmental trajectory that is sensitive to factors associated with development and environmental experience consequently leading to the emergence of schizophrenia in early adulthood If the original neurodevelopmental model of SZ was based mostly on epidemiological evidence linking the disorder to prenatal and early postnatal life recent analyses have revealed that many genes associated with SZ influence early neurodevelopmental processes such as neuronal migration These findings support roles for NrCAM in both developmental vulnerability and altered responses to environmental stressors making it an intriguing target for SZ research The subjects were forty 3–4 month-old male NrCAM-deficient (Sakurai et al., 2001) (KO n = 20) mice and their wild-type littermate controls (WT n = 20) obtained from breeding heterozygote NrCAM mice in a colony maintained on C57BL/6 J background for at least 10 generations Genotypes were confirmed by PCR amplification from tail biopsy samples The mice were further divided into Stress (S Mice were housed in a temperature-controlled room under a 12-h light–dark cycle Mice were maintained at 85% of their ad libitum weights by restricting access to food (Purina 5001 Rodent Diet All experimental procedures were conducted in accordance with the standards for the ethical treatment and approved by Utah State University IACUC Committee C57Bl/6 J mice do show changes in anxiety The apparatus consisted of 8 standard mouse operant chambers housed inside sound-attenuating cubicles (Med Associates two nosepokes on the front wall and one nosepoke on the back wall The pre-exposed (PE) and non-pre-exposed (NPE) conditioned stimuli were a 80-dB tone and a 10-Hz click The unconditioned stimulus was a 1-s 0.5 mA footshock To evaluate neuronal activation, we performed c-Fos immunostaining using standard procedures (Buhusi et al., 2016, 2017a,b, 2023) Ninety min after the start of the test session mice were deeply anesthetized and transcardially perfused with a paraformaldehyde solution (4% in 0.1 M Phosphate buffer Brains were collected and sectioned on a vibrating microtome (VT1200S Free-floating brain sections (50 μm) were permeabilized and incubated overnight at 4°C with the c-Fos primary antibody (Cell Signaling Technologies The next day sections were rinsed and incubated with Alexa488-conjugated goat anti-rabbit secondary antibody and NeuroTrace 530/615 (Fisher Scientific / Invitrogen NeuroTrace neuronal labeling was used to identify the neuroanatomical regions of interest Sections were rinsed in PBS before mounting with Prolong Diamond (Fisher Scientific/Invitrogen by independent observers unaware of genotype and LI performance Neuronal activation in each region was subjected to statistical analyses The estimated duration of freezing behavior in the first 60 s of the presentation of the PE and NPE stimuli during the conditioning and test sessions was subjected to mixed ANOVAs with between-subjects variables stress (S and within-subjects variable pre-exposure (PE The latency to freeze (to the context) during the conditioning and test sessions was subjected to mixed ANOVAs with between-subjects variables stress (S and within-subjects variable session (conditioning The difference in freezing between NPE and PE the number of rewards earned during the test session and the neuronal activation (c-Fos+ cell counts) in each brain region were subjected to 2-way ANOVAs with factors stress (S The average freezing duration during the first 60s of the presentation of the PE and NPE stimuli in the test session is shown in Figure 1 Analyses indicated a main effect of pre-exposure (F(1,36) = 37.239 suggesting that mice froze longer during the NPE stimulus than during the PE stimulus (LI) LI was not expressed equally in all groups: Analyses indicated a significant pre-exposure x stress interaction (F(1,36) = 5.244 suggesting that NS mice showed more LI—larger difference in freezing between NPE and PE stimuli—than S mice analyses indicated a significant pre-exposure x stress x genotype interaction (F(1,36) = 4.280 suggesting that stressed KO mice were particularly impaired in LI relative to the other groups Planned comparisons indicated a significant difference in freezing between NPE and PE in No-Stress mice irrespective of genotype NS-WT mice (F(1,36) = 12.223 p = 0.001) and NS-KO mice (F(1,36) = 23.974 Planned comparisons also indicated a significant difference in freezing between NPE and PE in stressed S-WT mice (F(1,36) = 10.724 but not in stressed S-NrCAM KO mice (F(1,36) < 1) indicating that all mice showed LI except stressed NrCAM KO mice these results provide support for a model under which environmental factors (stress) potentiate the effect of genotype to reveal the disruption of LI in stressed NrCAM KO mice but not in the other groups Average duration of freezing (±SEM) to the pre-exposed (PE) and non-pre-exposed (NPE) stimuli in NrCAM knockout (KO) and wild type littermate controls (WT) under no-stress (left) and chronic unpredictable stress (right) A significant latent inhibition (significantly larger freezing to NPE than PE) was observed in all groups except in stressed NrCAM KO mice *p < 0.05; **p < 0.01 To evaluate the hypothesis that the difference in freezing to PE and NPE stimuli in Figure 1 may be due to the intrinsic (unconditioned) differences in freezing to the two stimuli we performed analyses of freezing behavior to the PE and NPE stimuli in the conditioning session before these stimuli were paired with footshock These analyses failed to indicate any main effects of stimulus (PE/NPE) (F(1,36) < 1) or any interactions with the stimulus: stimulus x genotype (F(1,36) = 1.606 stimulus x stress (F(1,36) = 2.344 and stimulus x genotype x stress (F(1,36) = 3.163 suggesting no differences in unconditioned freezing to the PE and NPE stimuli irrespective of genotype and stress condition analyses of the latency to freeze in the conditioning session (before exposure to shock) and in the test session (after exposure to shock) failed to indicate any effects of session or any interactions (all Fs(1,36) < 2.342 suggesting that the propensity to freeze in the given context did not change after exposure to shock thus making it unlikely that mice differed in their reactivity to shock analyses of the number of rewards earned during the pre-exposure session (before the shock) and during rebaseline and test sessions (after the shock) indicated an effect of session (F(3,108) = 456.304 p = 0.0001) suggesting that rewards differed by session Planned comparisons indicated more rewards during both pre-exposure and rebaseline than during both conditioning and test sessions (ps < 0.0001) analyses failed to indicate any significant main effects or interactions with genotype and stress variables (Fs(3,108) < 1.752 suggesting that mice earned food similarly irrespective of stress and genotype thus making it unlikely that the absence of LI in stressed NrCAM KO mice is due to these mice being more reactive to shock than WT mice analyses of the number of nosepokes during the pre-exposure session (before the shock) and during rebaseline and test sessions (after the shock) indicated an effect of session (F(3,108) = 29.981 p = 0.0001) suggesting that nosepoking differed by session Planned comparisons indicated more nosepoking during both pre-exposure and rebaseline than during both conditioning and test sessions (ps < 0.0001) analyses failed to indicate any significant main effects or interactions with genotype and stress variables (Fs(3,108) < 1.664 suggesting that nosepoking was not affected by genotype or stress thus making it unlikely that the absence of LI in stressed NrCAM KO mice is due to these mice being more reactive to shock than the WT mice a dual hit stress x genotype interaction in mOFC analyses indicated a main effect of genotype in IL cortex (F(1,23) = 24.267 but no other main effects or interactions (Fs(1,23) < 2.495 analyses indicated a main effect of stress in Acb-shell (F(1,23) = 5.307 but no other main effects or interactions (Fs(1,23) < 1) analyses indicated stress x genotype interactions in mOFC (F(1,23) = 8.428 and Acb-core (F(1,23) = 5.199 but no other main effects (Fs(1,23) < 1.852 LSD post-hoc analyses failed to indicate differences in neuronal activation between KOs and WTs in the no-stress condition in either mOFC (p = 0.296) or Acb-core (p = 0.255); differences between KOs and WTs emerged only under stress: mOFC (p = 0.005) indicating that NrCAM KO mice are vulnerable to stress (neuronal activation in NrCAM KO mice becomes different from WT’s only under stress) analyses of c-Fos counts in PrL cortex failed to indicate any main effects or interactions (Fs(1,23) < 2.325 These results indicating a pattern of differential effects of genotype and stress support a complex stress x genotype interaction model Neuronal activation during latent inhibition testing Average c-Fos+ cell counts (±SEM) in prelimbic cortex (PrL) and nucleus accumbens shell (Acb-shell) in no-stress (NS) and stress (S) NrCAM-deficient mice (KO) and wild-type littermate controls (WT) *p < 0.05; **p < 0.01; ***p < 0.001 Using an “on baseline” within-subject CER LI procedure developed in our lab (Buhusi et al., 2017a,b, 2023), the current study found that C57BL/6 J WT mice showed LI, irrespective of stress, consistent with previous findings (Gould and Wehner, 1999; Buhusi et al., 2017a) results indicated that NrCAM KO mice showed LI under baseline These results were not due to differences in unconditioned freezing to the two stimuli these results were not due to differences in reactivity to shock as all mice froze similarly to the two stimuli (before they were paired with shock) nosepoked similarly with the other mice both before and after being exposed to shock learned similarly about the NPE stimulus and context irrespective of exposure to shock and were rewarded similarly during the task Further studies are required to evaluate whether altered LI as a consequence of the stress x NrCAM-deficit interaction reflects anomalies in either acquisition (stimulus pre-exposure) or expression of LI and suggest an increased vulnerability of NrCAM mice to the effect of stress in LI the disruption in LI in NrCAM KO relative to WTs may have been mediated by (opposing) changes in freezing to the PE and NPE stimuli that Acb-shell is vulnerable to the effect of stress irrespective of genotype and that OFC and ACb-core are vulnerable to the stress only in NrCAM KO mice (two hit genotype x stress interaction) PrL cortex does not show vulnerabilities to either genotype or stress in our LI paradigm Figure 3. Model of the impact of NrCAM and stress on a latent inhibition circuit (modified from Schmajuk et al., 1997; Weiner and Arad, 2009) IL cortex was found to be vulnerable to the NrCAM genotype irrespective of stress Acb-shell was found to be vulnerable to the effect of stress irrespective of genotype and ACb-core were found to be vulnerable to stress only in NrCAM KO mice (two hit PrL cortex was not found to be affected by either genotype or stress in the present LI paradigm Rodent models of chronic stress exhibit alterations of dendrite morphology, including reductions in dendrite complexity and spine density in the hippocampus and prefrontal cortex but increases in the basolateral amygdala and nucleus accumbens. Alterations of spine density and synapse connectivity in these regions may contribute to disruption of cognition, emotion, motivation, and reward in animal models and humans (Duman and Duman, 2015) In our current study only stressed NrCAM KO mice these findings support a role for NrCAM in neurodevelopment and vulnerability to environmental stressors and support the significance of our current study linking NrCAM to a cognitive endophenotype relevant to SZ or departures of this study from the literature while traditional CER LI paradigms measure the effect of pre-exposure on a behavioral response (e.g. in the current study nosepoking in FR1 task was only used as a “masking” task the current study directly measured freezing from video recordings using a computer program To better align our protocol with traditional CER protocols future studies could measure both the direct effect of pre-exposure on freezing (measured from video recordings) as well as its indirect effect on nosepoking and estimate whether these two measures correlate this investigation was conducted in homozygote NrCAM KO mice as an animal model of SZ which are more likely to be heterozygotes for NrCAM gene alterations future studies could also investigate the effect of stress on LI in NrCAM heterozygote mice which may align our protocol with future human studies The current study adds to this list that NrCAM is linked to a vulnerability to chronic unpredictable stress associated with impaired latent inhibition a phenotype relevant to acute schizophrenia-like symptoms The raw data supporting the conclusions of this article will be made available by the authors The animal study was approved by Utah State University IACUC Committee The study was conducted in accordance with the local legislation and institutional requirements The author(s) declare financial support was received for the research This work was supported by a Utah State University URCO Fellowship to CKB and a Brain and Behavior Research Foundation Independent Investigator Award to CVB MB and CVB were supported by grants AG075587 and NS123824 from the National Institutes of Health Daniel Griffin for assistance with behavioral procedures and all reviewers for thoughtful comments that helped improve our manuscript The author(s) declared that they were an editorial board member of Frontiers This had no impact on the peer review process and the final decision All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher Stress abnormalities in individuals at risk for psychosis: a review of studies in subjects with familial risk or with "at risk" mental state American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders Google Scholar Convergent functional genomics of 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2024; Accepted: 12 March 2024; Published: 27 March 2024 Copyright © 2024 Buhusi, Brown and Buhusi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited *Correspondence: Mona Buhusi, TW9uYS5CdWh1c2lAdXN1LmVkdQ==; Catalin V. Buhusi, Q2F0YWxpbi5CdWh1c2lAdXN1LmVkdQ== Metrics details Temporal information is crucial for goal reaching and the survival of humans and other animals and requires multiple biological mechanisms to track time over multiple scales the circadian clock is located in the suprachiasmatic nucleus which is responsible for automatic motor control in the millisecond range cognitively-controlled timer that operates in the seconds-to-hours range involves the activation thalamo-cortico-striatal circuits The hallmark of interval timing is that the error in estimating a duration is proportional to the duration to be timed represented and estimated has traditionally been explained using a pacemaker–accumulator model which is not only straightforward but also surprisingly powerful in explaining behavioural and biological data Pharmacological studies support a dissociation of the clock stage which is affected by dopaminergic manipulations which is affected by cholinergic manipulations the relevance of the pacemaker–accumulator model to the brain mechanisms that are involved in interval timing is unclear New models will require investigation of recent neurobiological evidence An impaired ability to process time is found in patients with disorders of the dopamine system the failure of a neurological disorder — such as cerebellar injury — to affect interval timing is taken to indicate that the affected structures are not essential for temporal processing in the seconds-to-hours range Because interval timing depends on the intact striatum the cerebellum is usually charged with millisecond timing and the basal ganglia with interval timing Recent findings suggest that separate timing circuits can be dissociated when continuity motor demands and attentional set are manipulated prefrontal cortex and posterior parietal cortex are activated in both interval-timing tasks and tasks that require integration of somatosensory signals or quantity/number processing Electrophysiological data are consistent with the involvement of these structures in number sequence or magnitude representation as well as in interval timing thereby supporting a mode-control model of counting and timing in which number and time are processed by the same neural circuits Functional MRI shows that two clusters of foci are activated during millisecond and interval timing tasks The 'automatic timing' cluster is activated by tasks that require repetitive movements and involve short timing intervals and includes the supplementary motor area and primary somatosensory cortex The 'cognitively controlled timing' cluster is activated when the durations are longer and the amount of movement required is limited and includes the dorsolateral prefrontal cortex The basal ganglia and the cerebellum are not specific to either cluster The striatal beat-frequency model describes interval timing as an emergent activity in the thalamo-cortico-striatal loops timing is based on the coincidental activation of medium spiny neurons in the basal ganglia by cortical neural oscillators The activity of the striatal neurons increases before the expected time of reward The model demonstrates the scalar property and incorporates features that would allow the integration of a number of lines of evidence into one vision of interval timing in the brain It is crucial for decisions about quantity represented and estimated has been explained using a pacemaker–accumulator model that is not only straightforward but also surprisingly powerful in explaining behavioural and biological data recent advances have challenged this traditional view It is now proposed that the brain represents time in a distributed manner and tells the time by detecting the coincidental activation of different neural populations Prices may be subject to local taxes which are calculated during checkout New roles for synaptic inhibition in sound localization (ed.) 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declare no competing financial interests A network of artificial satellite transmitters that provide highly accurate position fixes for Earth-based The activation of neurons not by single inputs but by the simultaneous activity of several inputs coincidental activation or inactivation of specific dendritic inputs might trigger a neuron to fire thereby transforming a time code into a rate code coincidental activation that results from hearing a sound with a specific interaural time difference is used to transform a time code into a spatial code The difference in the time of arrival of a sound wave at an animal's two ears It ranges from 100 μs in gerbils to about 650 μs in humans and is one of the sources of information used by various species to make a topographic representation of space estimation and discrimination of durations in the range of seconds-to-minutes-to-hours Repetition of certain phenomena in living organisms at about the same time each day The most thought of circadian rhythm is sleep but other examples include body temperature and the production of hormones and digestive secretions estimation and discrimination of durations in the sub-second range Formulated by Ernst Weber in 1831 to explain the relationship between the physical intensity of a stimulus and the sensory experience that it causes Weber's Law states that the increase in a stimulus needed to produce a just-noticeable difference is constant Gustav Fechner (1801–1887) generalized Weber's law by proposing that sensation increases as the logarithm of stimulus intensity: S = k logI To signal the end of the to-be-timed duration to the participant the feedback is usually an appetitive stimulus (for example In experiments that involve human participants A parameter in the scalar expectancy theory that is responsible for producing scalar transforms of sensory input taken from an internal clock and stored in temporal memory It is used to explain systematic discrepancies in the accuracy of temporal memory The intrinsic mechanisms that control the period of the oscillator (the interval between two neuronal spikes) range from fast ion currents (for example 40 Hz oscillations in sparsely spiny neurons in the frontal cortex) to slow transcriptional feedback loops (for example Set of to-be-attended features that are primed for use in a specific task such that participants would be more likely to attend to the features in the attentional set than to other features of the task Sets of to-be-activated motor programs that are primed for use in a specific task such that participants would be more likely to respond using one of the motor programs in the motor set than using other responses Presentation of a stimulus is followed by a delay after which a choice is offered and the originally presented stimulus must be chosen such tasks are most readily solved by short-term or working memory rather than by long-term memory mechanisms An enduring increase in the amplitude of excitatory postsynaptic potentials as a result of high-frequency (tetanic) stimulation of afferent pathways It is measured both as the amplitude of excitatory postsynaptic potentials and as the magnitude of the postsynaptic-cell population spike LTP is most frequently studied in the hippocampus and is often considered to be the cellular basis of learning and memory in vertebrates An enduring weakening of synaptic strength that is thought to interact with LTP in the cellular mechanisms of learning and memory in structures such as the hippocampus and cerebellum which is produced by brief high-frequency stimulation Download citation Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. In the summer of 1947, a telegram arrived at the movement headquarters, with a notification about the organization of a group of children for immigration to Eretz Israel via the Netherlands.  Eliyahu decided to join the group.  Initially, the children were gathered in Bucharest. Eliyahu recalls: Some three weeks later, the children arrived at "Ilania" children's village in Apeldoorn, the Netherlands. Eliyahu recalls: We reached Apeldoorn on Yom Kippur Eve.  We were welcomed very warmly.  I was one of the first to arrive at the place, and they put us in a brightly lit hall with 15 bathtubs, a volunteer nurse next to each one.  They replaced all our clothes.  In October 1948, 16-year-old Eliyahu boarded the "Negba" together with the other "Ilania" children, on their way to Israel.  His parents, sisters and brother also immigrated to Israel. Volume 13 - 2019 | https://doi.org/10.3389/fnhum.2019.00009 Previous research has shown that schizophrenia (SZ) patients exhibit impairments in interval timing The cause of timing impairments in SZ remains unknown but may be explained by a dysfunction in the fronto-striatal circuits Although the current literature includes extensive behavioral data on timing impairments there is limited focus on the neural correlates of timing in SZ The neuroimaging literature included in the current review reports hypoactivation in the dorsal-lateral prefrontal cortex (DLPFC) supplementary motor area (SMA) and the basal ganglia (BG) Timing deficits and deficits in attention and working memory (WM) in SZ are likely due to a dysfunction of dopamine (DA) and gamma-aminobutyric acid (GABA) neurotransmission in the cortico-striatal-thalamo-cortical circuits which are highly implicated in executive functioning and motor preparation Neuroimaging and behavioral paradigms used to assess time perception (TP) in schizophrenia (SZ) patients Cortical oscillations generate oscillatory beat patterns detected and encoded by BG medium spiny neurons The onset of a timed duration initiates a phasic release in dopamine (DA) from the SN and VTA that synchronizes cortical oscillations in order to encode the to-be-timed duration in the BG whereas variability in time estimation in SZ may be due to abnormalities in neurotransmission/activation along the cortico-striato-thalamo-cortical loop As SZ patients exhibit both impairments in cognitive functioning and TP it is unclear whether cognitive deficits in attention and WM are responsible for timing deficits in SZ or disruption of TP is responsible for greater cognitive dysfunction The current review will address this issue by examining the neural network involved in TP and highlighting abnormalities in these regions in SZ patients and proposes that both TP and cognitive deficits in SZ patients are a result of a malfunction of neurotransmission in the cortico-striatal-thalamo-cortical network Decreased DLPFC activation during these tasks typically correlate with worse performance in patients indicating that SZ patients exhibit less SMA activation relative to controls and suggesting dysfunction of the right SMA and prefrontal areas in SZ patients which may reflect a failure in early time processing related to attentional deficits it is possible that the SMA encodes a distorted duration before sending it to the BG to be stored in reference memory Patients exhibited activity in the DLPFC that was negatively correlated with presynaptic DA activity; the less activation observed in the DLPFC This finding is compatible with the finding that increases in striatal DA are associated with a faster internal clock speed This research suggests that timing deficits in SZ may be due to an interaction of increased DA activity in the BG and dysfunction of the DLPFC showing brain regions where activation was greater in controls compared to SZ group (light blue = greater contrast) A large contrast is shown in the caudate nucleus where patients exhibited hypofunction relative to controls Functional connectivity between the PFC and striatum was also reduced resulting from hyperactivity in the mesolimbic DA pathway DA activity is typically increased in the striatum in SZ and decreased in the frontal regions which suggests less DA is released to the DLPFC during tasks involving WM and attention reflecting an inability to actively recruit these regions during task performance These results suggest that temporal integration of events may lead to misrepresentations of events that are lost (e.g. inability to identify the beginning or end of an action sequence) as explicit timing tasks were not employed in all studies suggesting that this region is critical for time prediction during salient events As many studies report a correlation between a faster clock and positive symptoms in SZ patients the nature of the relationship between TP and positive symptoms in SZ should be further investigated neuroimaging studies may be used to assess dysfunction in this circuit correlated with TP in first-degree relatives of SZ patients to assess timing deficits as a potential biomarker for SZ Authors contributed equally to all aspects of developing and writing this manuscript This work was supported by a National Institutes of Health (NIH) grant MH073057 and an Independent Investigator Award from the Brain & Behavior Research Foundation (formerly National Alliance for Research on Schizophrenia and Depression Functional architecture of basal ganglia circuits: neural substrates of parallel processing Parallel organization of functionally segregated circuits linking basal ganglia and cortex Meta-analysis of functional neuroimaging and cognitive control studies in schizophrenia: preliminary elucidation of a core dysfunctional timing network Selective deficits in prefrontal cortex function in medication-naive patients with schizophrenia “Dopaminergic mechanisms of interval timing and attention,” in Functional and Neural Mechanisms of Interval Timing Google Scholar Time and number: the privileged status of small values in the brain Functional and neural mechanisms of interval timing “Timing behavior,” in Encyclopedia of Psychopharmacology Google Scholar Time-scale invariance as an emergent property in a perceptron with realistic Clocks within clocks: timing by coincidence detection Inactivation of the medial-prefrontal cortex impairs interval timing precision but not timing accuracy or scalar timing in a peak-interval procedure in rats Impaired interval timing and spatial-temporal integration in mice deficient in CHL1 Timing dysfunctions in schizophrenia as measured by a repetitive finger tapping task Timing dysfunctions in schizophrenia span from millisecond to several-second durations Explicit time deficit in schizophrenia: systematic review and meta-analysis indicate it is primary and not domain specific The basal ganglia in perceptual timing: timing performance in multiple system atrophy and Huntington’s disease doi: 10.1016/j.neuropsychologia.2013.09.039 Persistent activity in the prefrontal cortex during working memory Circuits and circuit disorders of the basal ganglia Planning dysfunction in schizophrenia: impairment of potentials preceding fixed/free and single/sequence of self-initiated finger movements The initiation of voluntary movements by the supplementary motor area Altered subjective time of events in schizophrenia The positive and negative symptoms of schizophrenia reflect impairments in the perception and initiation of action Rhythm and beat perception in motor areas of the brain “Timing in neurogenerative disorders of the basal ganglia,” in Time Distortions in Mind: Temporal Processing in Clinical Populations Google Scholar Dedicated and intrinsic models of time perception The right dorsolateral prefrontal cortex is essential in time reproduction: an investigation with repetitive transcranial magnetic stimulation High-frequency rTMS improves time perception in Parkinson disease Underestimation of time perception after repetitive transcranial magnetic stimulation Fronto-striatal hypoactivation during correct information retrieval in patients with schizophrenia: an fMRI study Time perception and its neuropsychological correlates in patients with schizophrenia and in healthy volunteers Cognitive control deficits in schizophrenia: mechanisms and meaning Cortical inhibitory neurons and schizophrenia Lošák Predictive motor timing and the cerebellar vermis in schizophrenia: an fMRI study Timing functions of the supplementary motor area: an event-related fMRI study Fragile temporal prediction in patients with schizophrenia is related to minimal self disorders Dissociation of the role of the prelimbic cortex in interval timing and resource allocation: beneficial effect of norepinephrine and dopamine reuptake inhibitor nomifensine on anxiety-inducing distraction Meyer-Lindenberg Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia Interval time coding by neurons in the presupplementary and supplementary motor areas Processing of temporal information and the basal ganglia: new evidence from fMRI Atypical audiovisual temporal function in autism and schizophrenia: similar phenotype Modeling pharmacological clock and memory patterns of interval timing in a striatal beat-frequency model with realistic Dysfunctional supplementary motor area implication during attention and time estimation tasks in schizophrenia: a PET-O15 water study Schizophrenia: overview and treatment options PubMed Abstract | Google Scholar Dipole source analysis suggests selective modulation of the supplementary motor area contribution to the readiness potential Impaired temporal discrimination in Parkinson’s disease: temporal processing of brief durations as an indicator of degeneration of dopaminergic neurons in the basal ganglia The evolution of brain activation during temporal processing Time perception disorders are related to working memory impairment in schizophrenia Schröder Sensorimotor cortex and supplementary motor area changes in schizophrenia A study with functional magnetic resonance imaging Time perception and motor timing: a common cortical and subcortical basis revealed by fMRI Meta-analysis of time perception and temporal processing in schizophrenia: differential effects on precision and accuracy Time estimation by healthy subjects and schizophrenic patients: a methodological study Üstün Neural networks for time perception and working memory In and out of control: brain mechanisms linking fluency of action selection to self-agency in patients with schizophrenia Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia: I Impaired prefrontal-basal ganglia functional connectivity and substantia nigra hyperactivity in schizophrenia Citation: Snowden AW and Buhusi CV (2019) Neural Correlates of Interval Timing Deficits in Schizophrenia Received: 30 September 2018; Accepted: 09 January 2019; Published: 29 January 2019 Copyright © 2019 Snowden and Buhusi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) *Correspondence: Catalin V. Buhusi, Y2F0YWxpbi5idWh1c2lAdXN1LmVkdQ== By Allyson Myers | March 08 The Alzheimer’s Disease and Dementia Research Center (ADRC) at Utah State has extended support totaling over $350,000 to multiple USU researchers studying Alzheimer’s disease and related dementia Researchers from the Emma Eccles Jones College of Education and Human Services and the College of Engineering are studying many facets of Alzheimer’s disease from biological markers of Alzheimer’s to its prevalence in specific populations and impacts on caregivers “We’re thrilled to partner with so many researchers from different disciplines,” said Beth Fauth “Supporting research like this is central to our mission and marks an important milestone for the center In our first funding cycle we focused on supporting research at USU and in the future this program will expand to support researchers across the state.” Research is the primary mission of the ADRC These projects will advance the current understanding of Alzheimer’s disease and create opportunities for future research and the development of treatments and support for individuals living with dementia Learn about the researchers and their projects below will study the disruptions in sleep cycles in people living with Alzheimer’s disease using mice that model Alzheimer’s and cognitive decline Humans typically follow a diurnal sleep cycle meaning we are awake during the day and sleep at night aging and neuropsychiatric disorders can disrupt these cycles and can affect health in significant ways which can increase cognitive and behavioral deficits have been reported in individuals with Alzheimer’s disease and related dementia this research aims to identify new options for improving cognitive function in individuals with Alzheimer’s disease and related dementia Buhusi is joined in this research by Psychology Associate Professor Mona Buhusi and Psychology Professor JoAnn Tschanz By examining cognitive impairment in mice at different ages the researchers hope to identify ways of slowing down Alzheimer's disease and preserving cognitive abilities for a longer period of time Buhusi will also receive support to purchase an Odyssey XF Dual-Mode Imaging system which is essential equipment for quantifying changes in protein expression in neurodegeneration studies The new system will help the researchers move past the use of X-ray film and developing chemicals and it will allow them to conduct their studies more quickly and effectively will extend a yearlong research assistantship to neuroscience Ph.D student Olivia Ewing to work on a project entitled “Aging and Numerical Quantity Estimation.” Jordan’s lab studies numerical and mathematical abilities which play a role in many aspects of life such as counting Ewing’s project will focus on general quantity estimation an ability that begins to develop in childhood and changes throughout the lifespan the main question addressed in this study is whether a sample of aging individuals maintain the more precise numerical representation of numbers exhibited by young adults child-like pattern in their quantity estimations A previous study from Jordan's lab in collaboration with JoAnn Tschanz and USU undergraduate student Brett Campbell found that a sample population of older adults did maintain a young adult-like pattern of numerical representation; however this study did not account for factors such as level of cognitive ability Ewing will be able to analyze these previous data and draw conclusions that can be published and disseminated This study will help researchers understand which cognitive abilities are left intact during the process of typical aging compared to dementia is working to develop a program to help with pain management for individuals suffering from dementia The program will involve dementia patients as well as their caregivers and it will be especially tailored to needs of community-dwelling patients residing in rural areas Along with Psychology Professor Susan Crowley and Psychology Assistant Professor Sara Boghosian Kleinstaeuber will first gather information about the needs of patients with dementia and chronic pain The team will then examine how feasible it is to implement a caregiver-assisted program over seven sessions Kleinstaeuber and her colleagues are interested in establishing a clinic at the USU Behavioral Health Clinic that offers psychological interventions for individuals with persistent somatic symptoms Kleinstaeuber and Crowley have clinical and research experience in working with individuals with persistent somatic symptoms and associated emotional distress over many years Chronic pain in dementia has been neglected in previous research and psychological support for this specific patient group is challenging to access The researchers hope to have a positive impact on patients’ pain intensity and interference with quality of life as well as on caregivers’ self-efficacy assistant professor in Communicative Disorders and Deaf Education will study the effect of hearing aid use on cognition in older adults with hearing loss Age-related hearing loss is associated with a higher incidence of dementia poorer physical functioning and reduced quality of life Current evidence suggests that effective treatment of age-related hearing loss improves quality of life and is associated with a reduction in new dementia cases While studies have suggested that hearing aids improve social engagement and there is no neurophysiological evidence supporting these observations To assess the cognitive and neurophysiological benefits of hearing aids Nagaraj and his team will conduct a study using functional near-infrared spectroscopy and portable device for assessing brain activity The team will assess changes in neural connectivity between different parts of the brain as a function of wearing hearing aids Age-related hearing loss is recognized as one of the major risk factors for dementia so this project has high significance and a strong potential for guiding future research and practice in this area The team’s long-term plan is to understand the social cognitive and neural benefits of increased access to hearing aid interventions in rural areas Nagaraj is joined in this research by Ronald Gillam Raymond and Eloise Lillywhite Endowed Chair of Speech-Language Pathology; Tiffany Shelton clinical assistant professor of Audiology; Allison Hancock Premium hearing aids are provided by Oticon and WS Audiology to use in the study will collaborate with other researchers to increase the diversity of samples in the Cache County Study on Memory in Aging population-based study of Alzheimer’s disease and other dementias that has followed over 5,000 elderly residents of Cache Valley since 1995 The study has contributed to the research on genetic psychosocial and environmental risk factors for Alzheimer’s disease and the progression of dementia after its onset Because the CCSMA is a population-based study it is limited to the racial makeup of the area it came from Tschanz is partnering with Perry Ridge (BYU) students Justina Tavana and Anika Wallace to build on their efforts to recruit a cohort of Native Hawaiians and Pacific Islanders to examine difference in Alzheimer’s disease risk between the two cohorts Native Hawaiians and Pacific Islanders are largely absent from existing studies on Alzheimer’s disease and related dementias but limited research suggests these populations have higher rates of dementia than Caucasians and exhibit different genetic biomarkers By collecting and cataloging samples from these populations researchers hope to increase understanding of the genetic makeup of dementia and increase opportunities for research moving forward Tschanz will receive support to organize and catalogue existing biological samples from the CCSMA stored at Brigham Young University in collaboration with Ridge A central database with website access will be developed Completion of the database will allow researchers to look up specific information on around 5,000 samples and explore the relationship between genetics and co-morbidities of Alzheimer’s disease A similar effort to sort and catalog DNA and other biological samples from the CCSMA will also take place at USU These projects may facilitate research to use blood-based biomarkers to identify risk for Alzheimer’s and the organized repositories will facilitate future biomarker and genetics investigations of Alzheimer’s disease and related cognitive decline in older adults Tschanz has also received support for two Ph.D students to continue their research and studies at USU A major marker of Alzheimer’s disease is the presence of plaques that form when protein pieces called beta-amyloid clump together The connection between these clinical markers neuronal death and cognitive impairment has long been studied but the link between Alzheimer’s disease and abnormalities in organs other than the brain beta-amyloid aggregations similar to those in Alzheimer’s patients are found in patients with dilated cardiomyopathy a condition that affects the ability of the heart muscle to pump blood through the body Individuals diagnosed with Alzheimer’s disease tend to experience an increase in severity of heart and retinal diseases but mechanisms explaining how Alzheimer’s and markers like beta-amyloid relate to these diseases remain unclear associate professor of Biological Engineering aims to prevent the effects of Alzheimer’s disease in the heart and eye by investigating their impact on the heart muscle wall and outer retina using realistic models made of hagfish protein fibers These tissue-engineered models will mimic the characteristics of real heart and eye tissue allowing the researchers to evaluate the effect of beta-amyloid buildup on cardiac muscle and retinal cell health Understanding the impact of beta-amyloid plaques on heart and eye health will have a positive impacton research surrounding Alzheimer’s disease and related diseases Vargis is joined in this research by Justin Jones assistant professor of Biology; Biological Engineering master’s student Emilee Rickabaugh; and Biological Engineering Ph.D Volume 17 - 2023 | https://doi.org/10.3389/fnint.2023.1113238 This article is part of the Research TopicInsights in Integrative Neuroscience 2022View all 6 articles Neuroscience is ready to transcend the reductionist approach (Joyce and Shergill, 2018; Pessoa, 2022) The revolutionary integrative approach to synthesizing information from single neurons and whole brain imaging and manipulations using methods derived from multiple disciplines: chemistry is producing “big data” sets Here we explore several “big questions” posed by the integrative approach: How to integrate heterogeneous neuroscience information How to train the workforce for this approach What resources are needed for this integrative revolution Progress culminated in recent years with the development of integrative engram technologies capable of identifying Such groundbreaking manipulations could not have been possible without integration of multiple methods from varied sciences in the same study Several “big questions” are outstanding: Integrative neuroscience encompasses multiple levels of analyses (A) and integrates “big data” (B) collected using diverse methods (C) to uncover relationships and phenomena that transcend levels (D) Several solutions to the integration problem with the hope that soon they will integrate real data A more practical approach is to store raw data into databases, either local or “in the cloud” (Gordon, 2003) (Figure 1D second from top) One drawback is the level of detail optimal for integration similar to seeing the forest for the trees: Less detail helps integration but decreases accuracy; too much detail provides accuracy but prevents integration storing data in databases helps identifying correlations between phenomena at different levels but new theories or new levels of understanding are not expected to simply emerge and integrate “big data” one may need to use artificial intelligence a combination of artificial neural networks (ANNs) a handful of PhD programs around the world have started adding “integrative” to their designation aiming at training future neuroscientists in multiple methods in the skills that would allow them to work efficiently in a team analyzing the same problem at multiple levels and University of Cardiff are among the universities offering INS training The neuroscience curriculum of these institutions has been restructured to include courses on “Integrative Neuroscience” and on data analysis and computational modeling (e.g. “Bioinformatics,” and “Artificial Neural Networks”) and to also include student rotations through labs using various methods considerably more funding is needed to transform out-of-date “one-method” labs into modern “integrative” labs The general population already benefits from translating the INS revolution into the marketplace: self-driving vehicles and artificial intelligence software for various functions Age-related memory deficits are reversed by a CCR5 antagonist already approved by the FDA a possible game-changer in cognitive decline therapy Further integrative research regarding neuronal- astrocytic- and microglial-interactions will pave the way for new therapeutic approaches in cognitive aging and neurodegenerative disorders One thing is sure: Neuroscience is an exciting field in the midst of an “integrative” revolution in directions that are stretching the limits of our imagination CB and MB wrote the first draft of the manuscript All authors contributed to manuscript revision This work has been supported by NIH grants NS123824 to CB and AG075587 to MB Neuroscience training for the 21st century Non-invasive brain stimulation and neuroenhancement Google Scholar The across-fiber pattern theory and fuzzy logic: A matter of taste PubMed Abstract | Google Scholar Biological and cognitive frameworks for a mental timeline Imaging and optically manipulating neuronal ensembles doi: 10.1146/annurev-biophys-070816-033647 The use of representation and formalism in a theoretical approach to integrative neuroscience Electrophysiological recordings from behaving animals: going beyond spikes Claremont Mckenna College (2022). Preparing Future Leaders Through Integrated Sciences. Claremont: Claremont Mckenna College. Available online at: https://75.cmc.edu/integrated-sciences/ (accessed January 18 CrossRef Full Text | Google Scholar A synthetic biology approach to integrative high school STEM training PubMed Abstract | CrossRef Full Text | Google Scholar Integrative neuroscience: linking levels of analyses Back to basics: luring industry back into neuroscience PubMed Abstract | CrossRef Full Text | Google Scholar The BRAIN Initiative: developing technology to catalyse neuroscience discovery Integration is not necessarily at odds with reductionism PubMed Abstract | CrossRef Full Text | Google Scholar Neuroscience in the 21st century: circuits Integration of optogenetics with complementary methodologies in systems neuroscience “A real-time theory of Pavlovian conditioning: simple stimuli and occasion setters,” in Occasion Setting: Associative Learning and Cognition in Animals allocation to an engram and memory linking in the behavioral generation of a false memory in mice A logical calculus of the ideas immanent in nervous activity PubMed Abstract | CrossRef Full Text | Google Scholar A neuroscientist's guide to transgenic mice and other genetic tools Insight into the roles of CCR5 in learning and memory in normal and disordered states Ortega-De San Luis Understanding the physical basis of memory: molecular mechanisms of the engram CrossRef Full Text | Google Scholar Plimpton, S. H. (2020). Innovative Approaches to Science and Engineering Research on Brain Function. National Science Foundation (NSF). Available online at: https://www.nsf.gov/pubs/2020/nsf20609/nsf20609.htm (accessed January 18 PubMed Abstract | CrossRef Full Text | Google Scholar CCR5 closes the temporal window for memory linking Imaging human engrams using 7 Tesla magnetic resonance imaging PubMed Abstract | CrossRef Full Text | Google Scholar PubMed Abstract | CrossRef Full Text | Google Scholar Oprisan SA and Buhusi M (2023) The future of integrative neuroscience: The big questions Received: 01 December 2022; Accepted: 27 January 2023; Published: 23 February 2023 Copyright © 2023 Buhusi, Oprisan and Buhusi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) *Correspondence: Catalin V. Buhusi, Q2F0YWxpbi5CdWh1c2lAVVNVLmVkdQ== Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. 94% of researchers rate our articles as excellent or goodLearn more about the work of our research integrity team to safeguard the quality of each article we publish. We are extremely sad to report that our beloved Jerry has passed away.  Jerry was a magnificent lion and much loved by all at Born Free and the team at our big cat sanctuary at Shamwari Private Game Reserve, where he had lived since 2007. Born in Romania in 2001, Jerry’s early years were spent languishing inside a barren cage at a rundown zoo in Buhusi, worlds away from the vast African plains of his ancestral home. In 2007, Born Free rescued Jerry, along with his mother Jools and brother James, and gave them a permanent new home at our South African sanctuary. In March 2021, despite being in good physical condition for his age, Jerry suddenly stopped eating, and developed serious respiratory problems. Despite the best efforts of the veterinary team, Jerry was found to have a form of lung cancer. His condition deteriorated and he sadly passed away after 14 wonderful years at Shamwari. SHARE ON FACEBOOK     SHARE ON TWITTER Volume 10 - 2016 | https://doi.org/10.3389/fnbeh.2016.00114 Maladaptive reactivity to stress is linked to improper decision making Chronic unpredictable stress (CUS) alters dopaminergic function re-shapes dopaminergic circuits in key areas involved in decision making and impairs prefrontal-cortex dependent response inhibition and working memory Glial-derived neurotrophic factor (GDNF) is essential for regulating dopamine (DA) release in the basal ganglia and for the survival of dopaminergic neurons; GDNF-deficient mice are considered an animal model for aging-related Parkinsonism GDNF expression in the striatum has been linked to resilience to stress Here we investigated the effects of CUS on decision making in GDNF-heterozygous (HET) mice and their wild-type littermate controls (WT) Before CUS no differences in temporal discounting (TD) were found between genotypes showed increased impulsive choice indexed by a reduction in percent Larger-Later (LL) choices in the TD paradigm and a reduction in area under the TD curve showed decreased neuronal activation (number of cFos positive neurons) in the orbitofrontal cortex (OFC) suggestive of a maladaptive response to stress area under the TD curve positively correlated with cFos activation in the NA core These results provide further evidence of the differential involvement of the OFC and identify GDNF-deficient mice as a double-hit (gene × environment) model of stress-related executive dysfunction particularly relevant to substance abuse and Parkinson’s disease (PD) Nucleus accumbens (NA)-derived GDNF is a retrograde enhancer of dopaminergic tone in the mesocorticolimbic system (Wang et al., 2010). GDNF expression is increased in the mouse hippocampus during CUS as well as during recovery (Bian et al., 2012). Uchida et al. (2011) found that epigenetic regulation of GDNF expression in the NA influences vulnerability to CUS: individuals who cannot upregulate GDNF during stress exhibit anxiety anhedonia and avoidance of social interactions possibly due to the negative consequences of chronic stress on the dopaminergic circuits GDNF-deficient HET mice would be less able to increase levels of GDNF (due to having a single functional allele) than their WT littermates with negative consequences on dopaminergic function and decision making Here we investigated decision making in GDNF HET male mice and their WT littermate controls before and after exposure to CUS in the TD paradigm In order to evaluate functional alterations in corticolimbic circuits in stressed GDNF mice we also analyzed neuronal activation (measured by cFos expression) in the NA and their correlation with impulsive choice The behavioral setup consisted of 12 mouse operant chambers (Med Associates USA) equipped with a food cup and a white noise generator/speaker on the front wall and a house light (above the lever) on the opposing wall Noyes precision food pellets 20 mg (Research Diets USA) were delivered in the food cup according to the paradigm After being shaped to nose-poke and lever-press for food pellets, mice were trained in a TD paradigm modified after Adriani and Laviola (2003) and Isles et al. (2003) four pellets at progressively larger delays Sessions consisted of 40 trials broken up into five 8-trial blocks The beginning of a block was signaled by the house light flashing for 1 min; continuous illumination of the house light signaled that the mice can self-initiate a trial by pressing on the lever Each block consisted of six forced choice trials (3 pairs of forced-choice trials on the SS and LL alternatives) followed by two free-choice trials between alternatives one nosepoke was lit and the subject had to respond on that nosepoke to receive the appropriate reward For free-choice trials both nosepokes were lit and the subject was free to choose either nosepoke to receive the associated reward the nosepoke flashed during the delay period between choice and reward delivery (cued delay) If mice failed to initiate a trial within 30 s after the house light was turned on continuously or if no nosepoke was recorded within 30 s of nosepoke illumination the trial was terminated by a 2-s blackout (inter-trial interval) The position of the SS and LL nosepokes (to the left or to the right of the lever) was counterbalanced among subjects the five blocks of trials differed by the delay on the LL choice presented in increasing order of delay during each session Mice received five sessions with 0 s LL delays Mice were then tested during four sessions with the LL delays 0 s Data from these four pre-stress test TD sessions were subjected to data and statistical analyses After being tested in the TD paradigm, all mice were subjected to a CUS paradigm for 21 days as in Dias-Ferreira et al. (2009). Briefly, mice were exposed once daily to one of the following stressors (randomly chosen): 30 min restraint in a small container, 10 min forced swim, or 10 min exposure to an aggressive BALB/cJ male mouse (Brodkin, 2007) mice were re-tested for four sessions in the TD paradigm with the LL delays 0 s Data from these four post-stress TD sessions were subjected to data and statistical analyses To assess neuronal activation, 2 h after the start of the last TD test session mice were deeply anesthetized with isoflurane and transcardially perfused with a paraformaldehyde solution (4% in 0.1 M phosphate buffer, pH 7.4). Brains were collected and sectioned on a vibrating microtome (VT1200S, Leica, Germany). cFos immunostaining was performed using standard procedures similar to Bertran-Gonzalez et al. (2008) Free-floating brain sections (50 μm) were incubated with a blocking and permeabilization solution (10% donkey serum 0.3% Triton X-100 in PBS) for 2 h and then incubated overnight at 4°C with the cFos primary antibody (Cell Signaling Technologies 0.1% Tween-20 and incubated for 2 h with Alexa 488 conjugated donkey anti rabbit secondary antibody and Neurotrace 530/615 (Life Technologies) Neurotrace neuronal labeling was used to identify the neuroanatomical regions of interest Sections were rinsed in PBS before mounting with Prolong Gold (Life Technologies) was also computed and submitted to statistical analyses: the smaller the %AUC by two independent observers unaware of genotype; Pearson’s r correlation (inter-reliability) between observers was r = 0.32 Neuronal activation in each region was averaged over observers and subjected to statistical analyses The %LL choices were submitted to mixed ANOVAs with between-subjects variable genotype (HET WT) and within-subject variables stress (pre and post) and delay (0 s The %AUC was subjected to mixed ANOVAs with between-subjects variable genotype (HET WT) and within-subject variables stress (pre and post) The individual average neuronal activation (cFos+ counts) for each region of interest was submitted to t-tests with between-subjects variable genotype (HET Pearson’s r correlation coefficient was estimated between %AUC and neuronal activation (cFos+ counts) in each region of interest Analyses were conducted in STATISTICA 6.0 (StatSoft GDNF HET mice made fewer LL choices at the longest 64 s delay (F(1,25) = 5.51 but not at shorter delays (all Fs(1,25) < 3.3 these analyses failed to identify discounting differences between genotypes before stress but suggest that after stress GDNF-HET mice discounted more than WT controls Increased temporal discounting (TD) in GDNF-deficient mice after chronic stress Average % larger-later (LL) choices (± SEM) in GDNF-deficient heterozygous (HET n = 12) and wild-type (WT) controls (n = 15) before (left) and after chronic unpredictable stress (CUS; right) GDNF HET mice discounted reliably more than before stress at all delays (all Fs(1,25) > 6.43 while WT controls were unaffected by stress (all Fs(1,25) < 0.85 were sensitive to the effect of chronic stress GDNF HET mice made fewer LL choices at the maximal delay (100% normalized delay but not at shorter delays (all Fs(1,25) < 0.26 these analyses failed to find discounting differences between genotypes before stress but suggest that after stress GDNF HET mice discounted at a higher rate than WT controls Decreased %AUC in GDNF-deficient mice after chronic stress (A) Average normalized %LL choices (± SEM) in GDNF-deficient (HET n = 12) and WT controls (n = 15) before (left) and after CUS (right) (B) Average %AUC (± SEM) in GDNF-deficient mice (HET) and WT controls in the Pre- and Post-Stress conditions Figure 2B shows the %AUC in GDNF HET and WT mice in the Pre- and Post-Stress conditions. Analyses indicated a main effect of stress (F(1,25) = 8.16, p < 0.01), although the effect of stress seemed to be prominent in the GDNF HET mice but not in the WT controls (Figure 2B) %AUC decreased reliably Post-Stress in HET mice (F(1,25) = 8.81 these results suggest an increased vulnerability to stress (reduced %LL choices and increased impulsivity) in GDNF HET mice NA core and NA shell in GDNF HET mice (right) relative to their WT controls (left) Decreased neuronal activity during post-stress TD in GDNF-deficient mice relative to controls (A) Representative orbitofrontal cortex (OFC) and prelimbic cortex (PrL) cFos expression in GDNF-deficient mice (HET) and WT controls in the Post-Stress condition Images were converted to grayscale for better contrast The Neurotrace stain used to identify neurons and neuroanatomical regions is shown in gray; cFos immunostaining appears as black dots (B) Representative nucleus accumbens (NA) core and NA shell cFos expression in GDNF HET and WT controls in the Post-Stress condition (see A for details) (C) OFC and PrL neuronal activity (average cFos+ cell counts ± SEM) in GDNF HET (n = 7) and WT controls (n = 7) in the Post-Stress condition (D) NA core and NA shell neuronal activity (average cFos+ cell counts ± SEM) in GDNF HET (n = 7) and WT controls (n = 7) in the Post-Stress condition ns p > 0.05; *p < 0.05; **p < 0.01 These results suggest that the decrease in neuronal activation in GDNF HET mice is specific to regions previously shown to be involved in the TD task rather than being a general brain-wide effect Pearson’s r correlation coefficient between %AUC and neuronal activation (cFos+ cell counts) in OFC NA core and NA shell was estimated in GDNF mice over both genotypes (n = 14) in the Post-Stress condition Analyses indicated that %AUC positively correlated with neural activation in NA core (r(12) = 0.57 p < 0.05) and NA shell (r(12) = 0.68 while no correlation was observed with orbitofrontal (r(12) = 0.05 p > 0.05) or prelimbic activity (r(12) = 0.03 These results suggest that in our TD task Post-stress impulsivity (reduced %AUC) negatively correlated with neuronal activation in the accumbens Using a cued-delay within-session TD procedure we evaluated whether exposure to CUS alters executive function in GDNF-deficient mice (GDNF HET) and their WT littermate controls Analyses indicated a reliable effect of stress on TD (indexed by %LL choices and %AUC) in GDNF HET but not WT mice suggesting that impulsivity increased Post-Stress in GDNF HET but not in WT mice Analysis of neuronal activation (cFos+ cell counts) in the OFC and NA shell during TD in the Post-Stress condition revealed a significant decrease in activation in OFC suggesting that the decrease in OFC and NA activation in GDNF HET mice relative to controls is specific to the TD task Post-Stress %AUC positively correlated with accumbens activity As impulsivity is indexed by a reduced %AUC in our study impulsivity was negatively correlated with activity in these brain regions abnormal regulation/maintenance of dopaminergic tone in stressed GDNF-deficient mice may underlie both their observed deficits in neuronal activation and their executive dysfunction This possibility is supported by our observations that neuronal activation in NA core and NA shell was positively correlated with %AUC (negatively correlated with impulsivity) which may explain their increased vulnerability to stress manifested in alterations in their executive functions Epigenetic alterations in GDNF expression could underlie both reactivity to stress and vulnerability to substance abuse One obvious concern regarding using GDNF-deficient mice in our studies is the possibility for motor impairment interfering with the TD testing. However, in our study, GDNF mice were about 8–10 months old at the end of testing. At this age, GDNF-deficient mice do not show signs of motor impairment, motor symptoms appearing after 12 months of age, as previously documented by Boger et al. (2006) GDNF-deficient mice were equivalent to pre-symptomatic Parkinsonian patients Our results identify stress-induced executive dysfunction in a pre-symptomatic model of aging-related Parkinsonism as a potential predictive marker Further studies are required to investigate whether the results obtained in GDNF-deficient mice can be found in other models of PD and are relevant to pre-symptomatic human carriers of PD-related gene mutations This work was supported by National Institutes of Health grant NS090283 to MB The authors would like to thank Brooke Hansen for excellent assistance with mouse colony management and genotyping untreated Parkinson disease: the Norwegian ParkWest study Elevated levels of impulsivity and reduced place conditioning with d-amphetamine: two behavioral features of adolescence in mice Alterations in monoamine levels and oxidative systems in frontal cortex striatum and hippocampus of the rat brain during chronic unpredictable stress GDNF is a novel 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when it comes to making decisions Mesolimbic dopamine dynamically tracks and is causally linked to discrete aspects of value-based decision making Acute stress induces selective alterations in cost/benefit decision-making Potentiation of in vivo neuroprotection by BclX(L) and GDNF co-expression depends on post-lesion time in deafferentiated CNS neurons Dopaminergic modulation of risky decision-making Decision making under stress: a selective review Frontal lobe dysfunction in Parkinson’s disease Selective activation of mesocortical DA system by stress Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo Chronic corticosterone exposure during adolescence reduces impulsive action but increases impulsive choice and sensitivity to yohimbine in male Sprague-Dawley rats Valencia-Torres Fos expression in the prefrontal cortex and ventral striatum after exposure to a free-operant timing schedule Population coding of reward magnitude in the orbitofrontal cortex of the rat CRF acts in the midbrain to attenuate accumbens dopamine release to rewards but not their predictors Nucleus accumbens-derived glial cell line-derived neurotrophic factor is a retrograde enhancer of dopaminergic tone in the mesocorticolimbic system Chronic mild stress-induced changes of risk assessment behaviors in mice are prevented by chronic treatment with fluoxetine but not diazepam Cognitive deficits and psychosis in Parkinson’s disease: a review of pathophysiology and therapeutic options Parkinson’s disease-related disorders in the impulsive-compulsive spectrum Contributions of the orbitofrontal cortex to impulsive choice: interactions with basal levels of impulsivity dopamine signalling and reward-related cues Yang BZ and Buhusi CV (2016) Stress-Induced Executive Dysfunction in GDNF-Deficient Mice Received: 14 March 2016; Accepted: 24 May 2016; Published: 21 June 2016 Copyright © 2016 Buhusi, Olsen, Yang and Buhusi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) distribution and reproduction in other forums is permitted *Correspondence: Mona Buhusi, bW9uYS5idWh1c2lAdXN1LmVkdQ==; Catalin V. Buhusi, Y2F0YWxpbi5idWh1c2lAdXN1LmVkdQ== Volume 12 - 2018 | https://doi.org/10.3389/fnins.2018.00377 This article is part of the Research TopicScience of Mental Time and Experimental Time PerceptionView all 12 articles Animals are molded by natural forces they do not comprehend To their minds there is no past and no future… only the everlasting present of a single generation its hidden pathways in the air and in the sea… There is nothing in the Universe more alone than Man He has entered into the strange world of history… – Loren Eiseley (1960) content etc.) are stored in memory and recalled when needed But how is the order of events assessed when events are recalled from memory to be placed on the timeline we discuss several classes of models of timing and time perception and their capability of ordering events in time Because the mental time includes all durations our discussion will freely mix time scales: milliseconds here we do not discuss in depth the scalar property—the increase in timing errors with the criterion time—because almost all models of timing can reproduce the scalar property making it a weak criterion for selecting among these models Cognitive models of time perception readily implement the “mental timeline” paradigm even when they use an internal representation of time which is very much not timeline-like Temporal order within the framework of cognitive (A–C) and biological (D–F) models of timing and time perception Panels indicate how models assess temporal order of two events at times t1 and t2 (see text for details) (A) Subjective time is a monotonic function of objective time (linear—black such that the objective order of events can be inferred from the subjective representation of time (B) Multiple monotonic (exponentially-decaying) memory traces can convey temporal order (C) Multiple non-monotonic traces that evolve at different speeds can also convey temporal order (D) An internal representation of time based on patterns of firing neurons cannot in itself convey temporal order time could be considered a parameter of a system that follows a trajectory in a state-based coordinate system {s1 Such systems can equally follow the same state trajectory toward the future or toward the past they have difficulty ordering events in time (F) The pattern of activity of a population of neurons varies in time as the model accumulates evidence; evidence / activity / patterns correlate with time but are not solely representing time Biological models (D–F) need extra assumptions / transformations / information to map activity / states / evidence / patterns to order of events; such information may be provided by chemical and circuit level constraints rather than time itself Because time is coded by (one or many) monotonically decaying functions these models can order events in time simply by comparing the numbers/patterns corresponding to the events In this model events are represented by distinct non-monotonic patterns of memory traces they can be correctly ordered on a time line in a manner similar to comparing the pattern of the hands on the wristwatch with a desired time despite using an internal representation of time which is very much not timeline-like While cognitive models readily order events on a time line biologically-inspired models have difficulties ordering events because they process and store events in memory as neural patterns these models have difficulty assessing the order of events as there is no predetermined order of neural patterns These models need extra information to order of events in time which may be provided by circuit level constraints such as the unidirectionality of action potentials Another way real physical systems code for time is in their (distributed) state. For example, winter is different from summer in all the changes in foliage, temperature, precipitation etc. Similarly, in the State Dependent Timing Model (Buonomano and Maass, 2009) the system follows a trajectory along which states (events) are coded in time (Figure 1E) When events (states) are recalled from memory pretty much like one has difficulty saying whether summer follows winter or rather winter follows summer state dependent models can follow the same trajectory “forward” in time as well as “backward” in time since time is a parameter rather than a coordinate in these models state dependent models are physically- and biologically-inspired but need extra information to implement a unidirectional timeline Extra information to order events in time may be provided by chemical reactions as not all chemical reactions are bi-directional; this type of information may limit the trajectory of the system The latter assume that time is stored in memory as (ordered) numbers while the former store in memory the patterns of neural activation/evidence Not only Evidence Accumulation Models work with patterns but the nature of the information manipulated/stored (activation or evidence) is different than in Pacemaker-Accumulator Models (pulses or numbers) Evidence Accumulation Models can compare events in terms of evidence/patterns of activation It would require an extra assumption (transformation) to map activation or evidence into order of events For example one could assume that more activity/evidence represents a later event but whether the brain follows this assumption or not it is not known at this time The brain seems to need extra sources of information—at the chemical, electrical, circuit level—than time itself to order memory patterns in a time line. This idea is consistent with recent experimental evidence suggesting that time and order of events are coded by different processes in the brain (D'argembeau et al., 2015) Future research should differentiate and integrate a “sense of time passage” with “a sense of order” of events and their biological substrates that enable the (re)construction of a mental time line All authors listed have made a substantial direct and intellectual contribution to the work The writing of this article was supported by NIH grants MH073057 to CB Differential encoding of time by prefrontal and striatal network dynamics State-dependent computations: spatiotemporal processing in cortical networks “The internal clock,” in Cognitive Processes in Animal Behavior Dallérac Updating temporal expectancy of an aversive event engages striatal plasticity under amygdala control D'argembeau The neural basis of temporal order processing in past and future thought Time cells in the hippocampus: a new dimension for mapping memories The long loneliness: man and the porpoise: two solitary destinies Google Scholar Scalar expectancy theory and Weber's law in animal timing CrossRef Full Text | Google Scholar CrossRef Full Text | Google Scholar A neural mechanism for sensing and reproducing a time interval Representation of time by neurons in the posterior parietal cortex of the macaque An adaptive drift-diffusion model of interval timing dynamics CrossRef Full Text | Google Scholar How noise contributes to time-scale invariance of interval timing Why noise is useful in functional and neural mechanisms of interval timing What is all the noise about in interval timing Timing in the visual cortex and its investigation A model of interval timing by neural integration Time and memory: towards a pacemaker-free theory of interval timing Implications for a model of the “internal clock” Google Scholar Accumulation of neural activity in the posterior insula encodes the passage of time doi: 10.1016/j.neuropsychologia.2010.06.023 Representation of interval timing by temporally scalable firing patterns in rat prefrontal cortex biologically inspired cognitive architectures Oprisan SA and Buhusi M (2018) Biological and Cognitive Frameworks for a Mental Timeline Received: 24 February 2018; Accepted: 16 May 2018; Published: 11 June 2018 Copyright © 2018 Buhusi, Oprisan and Buhusi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited Volume 11 - 2017 | https://doi.org/10.3389/fnbeh.2017.00177 This article is part of the Research TopicThe Impact of Stress on Cognition and MotivationView all 11 articles Increased reactivity to stress is maladaptive and linked to abnormal behaviors and psychopathology Chronic unpredictable stress (CUS) alters catecholaminergic neurotransmission and remodels neuronal circuits involved in learning Glial-derived neurotrophic factor (GDNF) is essential for the physiology and survival of dopaminergic neurons in substantia nigra and of noradrenergic neurons in the locus coeruleus Up-regulation of GDNF expression during stress is linked to resilience; on the other hand the inability to up-regulate GDNF in response to stress as a result of either genetic or epigenetic modifications GDNF-deficient mice exposed to chronic stress exhibit alterations of executive function Here we investigated the effects of CUS on latent inhibition (LI) a measure of selective attention and learning in GDNF-heterozygous (HET) mice and their wild-type (WT) littermate controls No differences in LI were found between GDNF HET and WT mice under baseline experimental conditions showed decreased neuronal activation (number of c-Fos positive neurons) in the nucleus accumbens shell and increased activation in the nucleus accumbens core Our results add LI to the list of behaviors affected by chronic stress and support a role for GDNF deficits in stress-induced pathological behaviors relevant to schizophrenia and other psychiatric disorders A recent study (Knapman et al., 2010) revealed that mice highly reactive to stress exhibit reversal learning and latent inhibition (LI) deficits. LI is defined as the loss of future associability by a stimulus that has been repeatedly presented without consequence (Lubow and Moore, 1959) LI results in slower learning of a new conditioned stimulus (CS)—unconditioned stimulus (US) association when the pre-exposed (PE) stimulus is afterwards presented with consequences Given that LI is a process highly dependent on DA (Young et al., 2005; Weiner and Arad, 2009; Arad and Weiner, 2010), which in turn is regulated by GDNF levels, here we tested the hypothesis that stressed GDNF-deficient (heterozygous, HET) mice would be less able to increase levels of GDNF (due to having a single functional allele, Griffin et al., 2006) than their wild-type (WT) littermates with negative consequences on DA function and deficits in LI We also comparatively evaluated neuronal activation (c-Fos+ cell counts) in brain regions known to be important for LI expression—Acb and ventral hippocampus (vHipp)—in GDNF HET mice and their WT littermates The subjects were 52 3–4 month-old male GDNF-deficient (HET, n = 26) mice and their WT (n = 26) littermate controls from a GDNF colony (Granholm et al., 1997) maintained on C57BL/6J background for at least 10 generations Mice were maintained at 85% of their ad libitum weights by restricting access to food (Teklad Diet 8604 The apparatus consisted in eight standard mouse operant chambers housed inside sound-attenuating cubicles (Med Associates To evaluate neuronal activation, we performed c-Fos immunostaining using standard procedures (Buhusi et al., 2016) Two hours after the start of the test session 5–9 mice in each group were deeply anesthetized and transcardially perfused with a paraformaldehyde solution (4% in 0.1 M phosphate buffer Free-floating brain sections (50 μm) were incubated with a blocking and permeabilization solution (5% donkey serum 0.3% Triton X-100 in PBS) for 2 h and then incubated overnight at 4°C with the c-Fos primary antibody (Cell Signaling Technologies 0.1% Tween-20 and incubated for 2 h with Alexa488-conjugated donkey anti rabbit secondary antibody and NeuroTrace 530/615 (Fisher Scientific/Invitrogen The sections were rinsed in PBS before mounting with Prolong Gold (Fisher Scientific/Invitrogen by two independent observers unaware of genotype The estimated duration of freezing behavior in the first 60 s of the presentation of the PE and NPE stimuli during the conditioning and test sessions was subjected to mixed ANOVAs with between-subjects variables stress (S the number of rewards and nosepokes during the test session and the neuronal activation (c-Fos+ cell counts in each brain region) were subjected to two-way ANOVAs with factors stress (S results were collapsed over stress and/or genotype (to yield larger groups) and correlational analyses were conducted between LI (the difference in freezing to the NPE and PE stimuli) and neuronal activation (c-Fos+ cell counts) for Acb-shell and Acb-core The average freezing duration during the PE and NPE stimuli during the test session is shown in Figure 1 Analyses indicated a main effect of pre-exposure (F(1,48) = 52.96 LI was not expressed equally in all groups: Analyses indicated a significant main effect of stress (F(1,48) = 5.51 suggesting that NS mice showed more LI than S mice analyses indicated a significant pre-exposure × stress interaction (F(1,48) = 5.34 suggesting that stress increased freezing to the PE stimulus A post hoc LSD test indicated a significant difference in freezing between NPE and PE in all NS mice (all ps < 0.01) and in the stressed WT mice (p < 0.05) but not in stressed GDNF HET mice (p > 0.05) indicating that all mice showed LI except stressed GDNF HET mice Latent inhibition (LI) by stress and genotype Average duration of freezing (±SEM) to the pre-exposed (PE) and non-pre-exposed (NPE) stimulus in glial-derived neurotrophic factor (GDNF) heterozygotes (HET) and wild type (WT) littermate controls under no-stress (left) and chronic unpredictable stress (CUS; right) A significant LI (significantly larger freezing to NPE than PE) was observed in all groups except in stressed GDNF HET mice the difference in freezing between NPE to PE supported the above results: a factorial ANOVA with factors stress and genotype indicated a significant main effect of stress (F(1,48) = 5.34 LI was large in NS mice (13.5 ± 3.9 s in WTs but it decreased in stressed mice (10.3 ± 2.9 s in WTs A post hoc LSD test indicated that LI did not change with stress in WT mice (p > 0.05) but was significantly decreased in stressed GDNF HET mice relative to no-stress mice (p < 0.05) these results provide support for a “two-hit” model under which environmental factors (stress) potentiate the effect of genotype to reveal the disruption of LI in stressed GDNF HET mice but not in the other groups but reflect differences in conditioned freezing (associability/learning) these analyses suggest that all mice learned similarly about the NPE stimuli thus making it unlikely that they had different reactivity to shock analyses of the latency to freeze in the conditioning session (before exposure to shock) and in the test session (after exposure to shock) failed to indicate any effects of session (F(1,48) = 0.74 or any interactions (all Fs(1,48) < 3.27 during the test session failed to indicate any effects of genotype (all Fs(1,48) < 0.02 or stress × genotype interaction (all Fs(1,48) < 0.18 These results indicate that stressed GDNF HET mice nosepoked and were rewarded similarly with the other mice thus making it unlikely that the absence of LI in stressed GDNF HET mice is due to these mice being more reactive to shock than the other mice but increased (to levels not significantly different than freezing to the NPE stimulus) only in the stressed GDNF HET mice neuronal activation in vHipp was affected only by stress (F(1,22) = 5.39 Acb-shell was independently affected by stress (F(1,22) = 4.55 p < 0.05) and genotype (F(1,22) = 5.06 but not by the stress × genotype interaction (F(1,22) = 1.08 Acb-core activation was not affected by neither stress alone (F(1,23) = 1.14 p > 0.05) nor genotype alone (F(1,23) = 0.83 but was significantly affected by a stress × genotype interaction (F(1,23) = 4.80 A post hoc LSD test indicated that Acb-core activation was significantly increased in GDNF-HET mice relative to the other groups (p < 0.05) PrL neuronal activation was not affected by either stress or their interaction (all Fs(1,27) < 0.31 These results indicate that various brain regions relevant to LI are differentially affected by stress thus supporting a complex “two-hit” stress × genotype model (A) Average c-Fos+ cell counts (±SEM) in ventral hippocampus (vHipp) and nucleus accumbens core (Acb-core) in the stress (S) and no-stress (NS) GDNF-deficient mice (HET) and WT littermate controls Analyses indicated different patterns of effects of stress and genotype on neuronal activation in these brain regions: vHipp activation was affected only by stress (one-hit) Acb-shell activation was independently affected by stress and genotype (independent two-hit) while Acb-core activation was affected by the interaction stress × genotype (two-hit interaction) (B–D) Correlations between LI (difference in freezing duration to the NPE stimuli) and neuronal activation (number of c-Fos+ cells) in Acb-shell (B) and Acb-core (C,D) when data are collapsed across stress (B,C) or genotype (D) Using an “on baseline” within-subject CER LI procedure developed in our lab (Buhusi et al., 2017), the current study found that WT mice showed LI, consistent with previous findings (Gould and Wehner, 1999) results indicated that GDNF HET mice in C57BL/6J background showed LI under baseline These results are unlikely to be due to differences in unconditioned freezing to the two stimuli learned similarly about the NPE stimulus and context nosepoked similarly and were rewarded similarly in the FR1 task Further studies are required to evaluate whether altered LI as a consequence of the stress × GDNF-deficit interaction reflects anomalies in either acquisition or expression of LI suggesting that the hippocampus may be important for detecting the mismatch Figure 3. Modulation of a putative LI circuit by stress or the GDNF genotype. A putative circuit for LI (modified after Schmajuk et al., 1997; Weiner, 2003) indicating the brain regions where activity was affected by stress and/or genotype Interestingly, the results of our study support a computational model suggesting that LI is affected by the interaction between environmental stimuli and brain insults (Schmajuk et al., 1997; Buhusi et al., 1998; see Figure 3) In this neural network model LI depends on the novelty of the PE and NPE stimuli relative to the context (computed in the VTA and modulating activity in the accumbens) which relies on learned associations between stimuli (which in turn depend on normal hippocampal function) current data could be explained by genetically-induced alterations in brain function combined with environmental factors (e.g. decreased expression of GDNF and inability to up-regulate GDNF expression in the hippocampus during stress) which interact to alter novelty computation and activity in the accumbens thus possibly addressing the data from the current study As suggested by the above theories, multiple studies have shown that the Acb and the hippocampus are indeed key structures in LI acquisition and expression. Lesion studies revealed opposing roles of Acb-shell and core in LI: lesions of the Acb-shell impair LI (Weiner et al., 1999), while lesions of Acb-core or Acb-shell+core are associated with persistent LI (Weiner et al., 1999; Gal et al., 2005) Our results showing that stressed GDNF HET mice which have impaired LI also have decreased c-Fos+ cell counts in the Acb-shell and increased neuronal activation in the Acb-core are consistent with these previous findings Hippocampal lesions revealed maintenance of LI, but loss of context specificity of the CR and LI (Good and Honey, 1991; Honey and Good, 1993; Coutureau et al., 1999), however LI is disrupted after ventral hippocampal (vHipp)/ventral subiculum (vSub) NMDA receptor activation (Pouzet et al., 2004; Lodge and Grace, 2008) Our findings that stress increases c-Fos+ cell counts in the ventral hippocampus in the LI procedure also support a role for the increased vHipp activity in the disruption of LI The absence of differences in the prelimbic cortex activation between experimental groups in the LI task further suggests that in our study the changes in neuronal activity were not general but were rather specific to certain brain areas possibly by modifying neuronal activation threshold in specific brain areas as well as evidence for GFRA2 variants modulating the therapeutic response to clozapine Our results support a role for the GDNF signaling pathway and its interaction with stress in the development of abnormal behaviors relevant to SZ and other mental disorders This study identifies a disruption of LI in stressed GDNF-deficient mice providing strong evidence for a role of chronic stress in LI alterations in individuals with particular genetic vulnerabilities The disruption of LI may be the result of small changes in neuronal function or connectivity related to genotype which is potentiated as a result of chronic stress MB: experimental design and immunostaining and imaging MB and CVB: data analysis and wrote the article This work was supported by grant NS090283 from the National Institutes of Health to MB a Utah State University URCO Fellowship to CKB and an Independent Investigator Award from the Brain & Behavior Research Foundation (formerly National Alliance for Research on Schizophrenia and Depression and hippocampus of the rat brain during chronic unpredictable stress Contrasting effects of increased and decreased dopamine transmission on latent inhibition in ovariectomized rats and their modulation by 17β-estradiol: an animal model of menopausal psychosis GDNF induces a dystonia-like state in neonatal rats and stimulates dopamine and serotonin synthesis Braunstein-Bercovitz GDNF as a candidate striatal target-derived neurotrophic factor for the development of substantia nigra dopamine neurons Entorhinal but not hippocampal or subicular lesions disrupt latent inhibition in rats Stress-induced neuroplasticity: (mal)adaptation to adverse life events in patients with PTSD—a critical overview Conditioning and contextual retrieval in hippocampal rats Glial cell line-derived neurotrophic factor is essential for postnatal survival of midbrain dopamine neurons Latent inhibition in drug naive schizophrenics: relationship to duration of illness and dopamine D2 binding using SPET The relevance of irrelevance to schizophrenia Interaction of tail-pressure stress and d-amphetamine in disruption of the rat’s ability to ignore an irrevelant stimulus A simple (or simplistic?) cognitive model for schizophrenia Selective hippocampal lesions abolish the contextual specificity of latent inhibition and conditioning Effects of stress on behavioral flexibility in rodents Deficits in cognitive flexibility induced by chronic unpredictable stress are associated with impaired glutamate neurotransmission in the rat medial prefrontal cortex Too much of a good thing: blocking noradrenergic facilitation in medial prefrontal cortex prevents the detrimental effects of chronic stress on cognition Glial cell line-derived neurotrophic factor (GDNF) gene and schizophrenia: polymorphism screening and association analysis Effects of typical and atypical antipsychotics on prepulse inhibition and latent inhibition in chronic schizophrenia and dendritic spines: what are the connections Stress and the brain: solving the puzzle using microdialysis Hippocampal dysfunction and disruption of dopamine system regulation in an animal model of schizophrenia Google Scholar PubMed Abstract | CrossRef Full Text The context effect: the relatioship between stimulus preexposure and environmental preexposure determines subsequent learning Sculpting the hippocampus from within: stress The brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course Chronic stress increases prefrontal inhibition: a mechanism for stress-induced prefrontal dysfunction Enhancement of latent inhibition by chronic mild stress in rats submitted to emotional response conditioning 3′ UTR (AGG)n repeat of glial cell line-derived neurotrophic factor (GDNF) gene polymorphism in schizophrenia Impact of chronic stress protocols in learning and memory in rodents: systematic review and meta-analysis Catecholaminergic depletion within the prelimbic medial prefrontal cortex enhances latent inhibition PubMed Abstract | CrossRef Full Text GDNF and protection of adult central catecholaminergic neurons A model for Pavlovian learning: variations in the effectiveness of conditioned but not of unconditioned stimuli Glial cell line-derived neurotrophic factor is essential for neuronal survival in the locus coeruleus-hippocampal noradrenergic pathway Clinical features of latent inhibition in schizophrenia Increased serum glial cell line-derived neurotrophic factor immunocontent during manic and depressive episodes in individuals with bipolar disorder Selective modifications in the nucleus accumbens of dopamine synaptic transmission in rats exposed to chronic stress Latent inhibition in conditioned emotional response: c-fos immunolabelling evidence for brain areas involved in the rat Genetic association of the GDNF alpha-receptor genes with schizophrenia and clozapine response Strömberg Glial cell line-derived neurotrophic factor is expressed in the developing but not adult striatum and stimulates developing dopamine neurons in vivo Chronic stress may facilitate the recruitment of habit- and addiction-related neurocircuitries through neuronal restructuring of the striatum Age-associated decrease in serum glial cell line-derived neurotrophic factor levels in patients with major depressive disorder Diverse glial cell line-derived neurotrophic factor (GDNF) support between mania and schizophrenia: a comparative study in four major psychiatric disorders Epigenetic status of Gdnf in the ventral striatum determines susceptibility and adaptation to daily stressful events The “two-headed” latent inhibition model of schizophrenia: modeling positive and negative symptoms and their treatment The switching model of latent inhibition: an update of neural substrates Association analysis of the glial cell line-derived neurotrophic factor (GDNF) gene in schizophrenia Reduced latent inhibition in people with schizophrenia: an effect of psychosis or of its treatment The role of dopamine in conditioning and latent inhibition: what The nigrostriatal dopamine system of aging GFRα-1 heterozygous mice: neurochemistry The noradrenergic system of aged GDNF heterozygous mice Effect of treatment on serum glial cell line-derived neurotrophic factor in depressed patients Brown CK and Buhusi CV (2017) Impaired Latent Inhibition in GDNF-Deficient Mice Exposed to Chronic Stress Received: 12 June 2017; Accepted: 07 September 2017; Published: 10 October 2017 Copyright © 2017 Buhusi, Brown and Buhusi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) Volume 6 - 2012 | https://doi.org/10.3389/fnint.2012.00111 Emotional distracters impair cognitive function Emotional processing is dysregulated in affective disorders such as depression Among the processes impaired by emotional distracters and whose dysregulation is documented in affective disorders is the ability to time in the seconds-to-minutes range Presentation of task-irrelevant distracters during a timing task results in a delay in responding suggesting a failure to maintain subjective time in working memory possibly due to attentional and working memory resources being diverted away from timing as proposed by the Relative Time-Sharing (RTS) model We investigated the role of the prelimbic cortex in the detrimental effect of anxiety-inducing task-irrelevant distracters on the cognitive ability to keep track of time using local infusions of norepinephrine and dopamine reuptake inhibitor (NDRI) nomifensine in a modified peak-interval procedure with neutral and anxiety-inducing distracters Given that some anti-depressants have beneficial effects on attention and working memory decreasing emotional response to negative events we hypothesized that nomifensine would improve maintenance of information in working memory in trials with distracters resulting in a decrease of the disruptive effect of emotional events on the timekeeping abilities Our results revealed a dissociation of the effects of nomifensine infusion in prelimbic cortex between interval timing and resource allocation and between neutral and anxiety-inducing distraction Nomifensine was effective only during trials with distracters Nomifensine reduced the detrimental effect of the distracters only when the distracters were anxiety-inducing Results are discussed in relation to the brain circuits involved in RTS of resources and the pharmacological management of affective disorders distracters result in a difference between the subjective (perceived) time and the objective time thus explaining why “time flies when you are having fun,” but also how food gets burnt when little attention is paid to cooking the specific roles of DA and NE in interval timing at various brain sites are less understood we anticipated that nomifensine would improve maintenance of information in working memory in trials with distracters resulting in a decrease in the disruptive effect of emotional events on the cognitive ability of timekeeping Twenty-two naïve Sprague-Dawley male rats 300–350 g (3 months old at the beginning of the experiment) were housed individually in a temperature-controlled room Rats were maintained at 85% of their ad libitum weight by restricting access to food (Rodent Diet 5001 All experimental procedures were conducted in accordance with the National Institutes of Health's Guide for the Care and Use of Laboratory Animals (1996) The apparatus consisted of 12 standard rat operant chambers (MED Associates of which four were used for fear conditioning and the other eight for interval timing An auditory stimulus was first used during fear conditioning in the fear conditioning chambers then later used as an anxiety-inducing distracter during the timing task in the timing chambers The fear conditioning chambers and the interval timing chambers were made distinctive as follows: the fear conditioning chambers contained a dipper entry space for a liquid dipper (not used in the experiment); no lever was inserted in the boxes at any time; no food was given inside these chambers; pine pellets (Feline Pine Cat Litter the interval timing chambers contained four nose pokes (not used in the experiment) and a lever; food was provided for lever-pressing at the right time; the bedding used in these boxes was cedar shavings (Grreat Choice In the fear conditioning chambers the grid floor was connected to shockers and scramblers controlled by a Med Associates interface The fear conditioning stimulus was an 85 dB white noise produced by a white-noise generator (MED Associates The intensity of the distracter was measured with a sound-level meter (Realistic Radio Shack Model 33–2050) from the center of the silent box The interval timing chambers were equipped with a single fixed lever situated on the front wall of the chamber 45 mg precision food pellets (PMI Nutrition International MO) were delivered in a food cup situated on the front wall The to-be-timed visual stimulus was a 28 V 100 mA house light mounted at the center-top of the front wall The auditory distracter was an 85 dB white noise produced by a white-noise generator (MED Associates VT) mounted on the opposite wall from the response levers A 66 dB background sound produced by a ventilation fan was present throughout the session For details of training and testing in the peak-interval timing procedure with distracters, see Buhusi and Meck (2006). For details of training and testing with emotional distracters in the peak-interval timing procedure, see Brown et al. (2007) All timing sessions were conducted in the eight timing chambers rats received five daily sessions of fixed-interval (FI) training during which the first lever press 40 s after the onset of the visual signal was reinforced by the delivery of a food pellet and turned off the house light for the duration of a random 120 ± 30 s inter-trial interval (ITI) rats received five sessions of peak-interval training during which FI trials were randomly intermixed with non-reinforced PI trials in which the visual signal was presented for a duration three times longer than the FI before being terminated irrespective of responding Trials were separated by a 120 ± 30 s random ITIs During aseptic surgery under isoflurane anaesthesia, 26-gauge bilateral cannula guides (PlasticsOne, Roanoke, VA) were implanted aiming at the prelimbic cortex (AP 2.5 mm, ML ± 0.6 mm, DV −3.5 mm) (Paxinos and Watson, 1998) and embedded in dental cement Rats were given at least 3 days to recover from surgery before retraining began again but not shown) indicated that rats responded reasonably well post-recovery Rats were given six sessions of PI re-training before any local infusions began Rats in the FEAR group were placed in the fear conditioning chambers where they received two presentations of the noise in extinction followed by two noise-shock pairings the white noise stimulus was not paired with the foot shock Behavior was recorded and freezing behavior was scored by two-independent observers in 2.5 s bins The percent agreement score between the two observers was 89.64 ± 1.25 percent Fear conditioning testing and re-training was followed by one session of PI re-training Cannulae injectors aiming at mPFC were lowered into the cannula guides Rats received intracranial injections of either saline or norepinephrine and dopamine reuptake inhibitor (NDRI) nomifensine (nomifensine maleate salt dissolved in 45% cyclodextrin (methyl-beta-cyclodextrin Rats received microinjections of 0.5 μL nomifensine solution (4 μg/side) or saline followed by a 2 min interval to allow the drug to infuse the tissue rats were placed into the timing chambers for testing in a timing sessions with noise (see next paragraph) Infusion sessions were separated by three no-drug sessions as follows: one post-drug PI re-training session one fear conditioning testing and re-training session and one post-fear conditioning PI re-training session The order of drug infusion (saline or nomifensine) was counterbalanced between animals rats received two consecutive 1.5 h sessions of interval timing testing during which rats received 20 FI and 14 PI trials randomly intermixed with 6 PI trials with noise (PI + N) PI + N trials were similar to PI trials except that the 5 s white noise was presented (during the uninterrupted visual to-be-timed stimulus) Rats were anesthetized with isoflurane overdose and transcardially perfused with formalin; their brains were collected and sectioned on a vibratome. Sixty-micron sections were placed on slides and stained with sky-blue for histological analyses. Three rats were eliminated due to incorrect cannula placement; two rats lost their cannulae before testing was completed and were eliminated from the study (CTRL n = 6, FEAR n = 11) (Figure 2) Cannula placements in the present experiment Only rats with injections in the prelimbic cortex were used in the experiment (CTRL n = 6 except for PI + N trials in the FEAR group: to accommodate for the disruption in response caused by the presentation of the noise in PI + N trials in the FEAR group analyses were conducted on data after the noise [in the interval-of-interest (20–120 s) same interval as for the curve fitting analysis see above] and there were no exclusion criteria for start time and the coefficient of variation (CV) of the start and stop times were submitted to mixed ANOVAs with independent between-subject variable group (FEAR CTRL) and within-subject variables trial type (PI Statistical tests were evaluated at a significance level of 0.05 and decreased slowly to baseline levels before the next presentation of the noise This long-lasting effect of the presentation of the emotionally charged event (FEAR group) explains the considerable delay in timing by the presentation of the same fear-inducing event in the timing context Long-lasting freezing behavior following the presentation of the auditory distracter in the FEAR Average percent freezing behavior (±SEM) in the fear conditioning context during freezing behavior testing and re-training sessions and after the presentation of the noise (in extinction but not before the presentation of the noise Empty symbols show time where emotional response (freezing behavior) did not differ reliably between FEAR and CTRL rats The gray bar indicates the presentation of the auditory distracter The average maximum percent response rate functions in PI and PI + N trials, with and without auditory distracter are shown in Figure 4 the variability in timing (width of the timing function) is not affected by either treatment a mixed ANOVA of the width of the timing functions with between-subject variable group (FEAR CTRL) and within-group variables drug (SAL failed to indicate any reliable main effects or interactions suggesting that neither nomifensine nor the distracter had any reliable effects on variability of response in either group the treatments simply shifted the timing functions without changing their width we will focus only on the effect of treatment on timing (i.e. Effect of nomifensine infusion on average timing functions Average maximum percent response (lever pressing) rate in rats trained to time a 40 s criterion signaled by a visual stimulus when presented with a neutral distracter (CTRL group upper panels) or an emotionally charged distracter (noise previously paired with foot shock Left panels: Peak interval (PI) trials (without noise): nomifensine has no reliable effects in either group Right panels: Peak interval with noise (PI + N) trials (with noise): when emotionally charged (FEAR group) the distracter shifts the response function rightward considerably relative to neutral events (CTRL); nomifensine reduces the delaying effect of the distracter only when the distracter is emotionally charged (FEAR group) The gray bars indicate the presentation of the auditory distracters The average maximum percent response rate functions in PI trials (without auditory distracter) are shown in the left panels of Figure 4 the PI timing functions peaked at 36.51 ± 2.21 s in FEAR rats and at 35.25 ± 1.46 s in CTRL rats the PI timing functions peaked at 34.69 ± 1.39 s in FEAR rats and at 36.92 ± 2.34 s in CTRL rats suggesting that nomifensine had no specific effects relative to saline Although reliably lower than 40 s for both saline and nomifensine the estimated peak times were relatively close to the criterion time indicating that rats acquired the timing task a mixed ANOVA of peak time with between-subject variable group (FEAR NOM) failed to indicate reliable effects of group suggesting that nomifensine had no reliable effects in trials without noise distracter (PI trials) in either group The top-right panel of Figure 4 indicates that the presentation of the noise has no effect on timing when the distracter was neutral (CTRL group). The PI + N timing functions peaked at 38.42 ± 3.38 s under saline, and at 32.44 ± 3.61 s under nomifensine, not significantly different from the 40 s criterion, all ts < 2.09, p > 0.05. In contrast, as seen in the bottom-right panel of Figure 4 responding was considerably delayed by the presentation of the fear-inducing distracter under both saline and nomifensine the PI + N timing functions peaked at 69.77 ± 5.50 s under saline The difference between groups was confirmed by a mixed ANOVA of peak time in PI + N trials NOM) which indicated a reliable main effect of group suggesting that the distracter has a reliably different effect when it is emotionally charged or neutral where an emotionally charged distracter resulted in an over-reset of timing Average delay for trials with and without noise distracter Average peak time delay (±SEM) in trials with distracters (PI + N) relative to trials without distracters (PI) Should the clock stop timing during the distracter the delay would be equal to the duration of the noise (stop Should the clock restart timing after the distracter the delay would be equal to the duration of the noise plus the duration of the pre-distracter interval rats over-reset when the distracter is emotionally charged (FEAR) Nomifensine reliably reduces the time delay The data from Figure 5 also indicates that nomifensine reduces the delay in peak time only when the noise is emotionally charged (FEAR group). A mixed ANOVA of the delay time between PI + N and PI trials with between-subject variable group (FEAR, CTRL) and within-subject variable drug (SAL, NOM), indicated a reliable effect of drug, F(1, 15) = 5.83, p < 0.05 (see Figure 5) Planned comparisons indicated that in PI + N trials nomifensine reliably decreases the delay in timing for the FEAR group the delay under nomifensine is reliably smaller than under saline Average estimated start and stop times (±SEM) in individual trials Nomifensine reliably reduced both start and stop times only in trials with distracter (PI + N) and only when the noise distracter is emotionally charged (FEAR rats) The lack of effect of nomifensine in trials without noise (PI) may have been due to large variations in response, for example, in trials before and after trials with auditory distracter (PI + N). Considering the relatively long-lasting freezing behavior following the presentation of the noise (see Figure 3) rats were expected to have large disruptions in response immediately after a PI + N trial but recover before the next PI + N trial These differences in responding before and after a PI + N trial may have resulted in large variations in response which may have obscured the effect of the drug in PI trials we extracted and contrasted the start and stop times in PI trials before and after PI + N trials analyses of start and stop times and their coefficients of variation failed to indicate main effects of the group suggesting that the response in PI trials were relatively stable before and after a PI + N trial the lack of effect of nomifensine in PI trials does not seem to be due to interference from trials with distracters and rats started and stopped timing earlier suggesting that nomifensine decreased the fear-inducing effect of the distracter and facilitated the return of resources from emotional processing back to interval timing we expected that increasing DA availability by nomifensine infusion to speed-up timing in PI trials which found that the delaying effect of the distracter is limited to trials with distracters and does not “spill” into PI trials our experiment indicates that nomifensine's modulation of NE and DA cortical activity could offset the increased fear caused by the distracter possibly by activating the cortical “high” road and reducing fear thus decreasing both the start and stop in responding right) provides support for a neurobiological RTS model by which resource allocation is dependent on the modulation of activity in brain regions dealing with working memory (dlPFC for humans mPFC for rodents) by both the circuits involved in timing and other processing (e.g. fronto-striatal circuits would engage working memory (dlPFC/mPFC) presentation of an emotionally charged distracter would also activate the amygdala which would engage the dlPFC/mPFC in emotional processing thus decreasing the relative activation on the fronto-striatal timing circuits When emotional processing ceases (which could be long after the offset of the distracter) the activation of dlPFC/mPFC by (emotional) amygdalar circuits would decrease relative to their activation by fronto-striatal (timing) circuits nomifensine would modulate activity within mPFC to either decrease the fear-inducing effect of the distracter and/or to reallocate resources toward timing by increasing maintenance of temporal information in working memory This may explain the “over-resetting” effect of the distracter and the fact that nomifensine was effective only in PI + N trials and only when distracters were fear-inducing The FS switch is flickering only during the interrupting event and is located before the accumulator; therefore it would at best predict a stop (no pulses accumulated.) On the other hand not only during the noise but possibly after the noise as well RTS can explain the over-reset behavior in the present experiment RTS is concurrent with timing (involves competition between the timer and other processes outside of the timer) while FS is a process inside the timer FS cannot predict an over-reset (since the timer itself cannot over-reset) while RTS is free from this restriction in that nomifensine decreases the fear-inducing effect of the distracter and/or affects reallocation of resources toward timing nomifensine treatment may be beneficial in disorders characterized by impaired working memory processing This research was supported by the National Institutes of Health through grants MH65561 and MH73057 to Catalin V Author contribution: conceived and designed the experiments: Mona Buhusi and Catalin V Buhusi; performed the experiments: Alexander R We would like to thank Daniel Morrison for excellent assistance with histology and Heather Matthews for comments on an early version of the manuscript Working memory capacity in generalized social phobia Pubmed Abstract | Pubmed Full Text | CrossRef Full Text The effects of concurrent task and gap events on peak time in the peak procedure Pubmed Abstract | Pubmed Full Text | CrossRef Full Text The effect of an intruded event on peak-interval timing in rats: isolation of a postcue effect Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Dopaminergic Mechanisms of Interval Timing and Attention Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Time-sharing in rats: effect of distracter intensity and discriminability Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Timing for the absence of a stimulus: the gap paradigm reversed Pubmed Abstract | Pubmed Full Text Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Interval timing with gaps and distracters: evaluation of the ambiguity Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Effect of clozapine on interval timing and working memory for time in the peak-interval procedure with gaps Relative time sharing: new findings and an extension of the resource allocation model of temporal processing Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Relativity theory and time perception: single or multiple clocks Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Positive affect versus reward: emotional and motivational influences on cognitive control Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Application of scalar timing theory to individual trials Pubmed Abstract | Pubmed Full Text Neuroanatomical and neurochemical substrates of timing Pubmed Abstract | Pubmed Full Text | CrossRef Full Text National Research Council Guide for the Care and use of Laboratory Animals The functional neuroanatomy of emotion and affective style Pubmed Abstract | Pubmed Full Text | CrossRef Full Text The impact of anxiety-inducing distraction on cognitive performance: a combined brain imaging and personality investigation Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Brain systems mediating cognitive interference by emotional distraction Pubmed Abstract | Pubmed Full Text | CrossRef Full Text How emotions colour our perception of time Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Emotional processing in anterior cingulate and medial prefrontal cortex Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Cognitive inhibition and working memory in unipolar depression Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Antidepressant drug induced alterations in binding to central dopamine transporter sites in the Wistar Kyoto rat strain Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Regulation of the fear network by mediators of stress: norepinephrine alters the balance between cortical and subcortical afferent excitation of the lateral amygdala Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Inactivation of medial prefrontal cortex impairs time interval discrimination in rats Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Pubmed Abstract | Pubmed Full Text | CrossRef Full Text The attentional challenge in cognitive models of psychological time Systems-level integration of interval timing and reaction time Pubmed Abstract | Pubmed Full Text | CrossRef Full Text N algorithm for least-squares estimation of nonlinear parameters Selective enhancement of mesocortical dopaminergic transmission by noradrenergic drugs: therapeutic opportunities in schizophrenia Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Noradrenergic antidepressants increase cortical dopamine: potential use in augmentation strategies Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Single-trials analyses demonstrate that increases in clock speed contribute to the methamphetamine-induced horizontal shifts in peak-interval timing functions Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Amygdala inactivation reverses fear's ability to impair divided attention and make time stand still Pubmed Abstract | Pubmed Full Text | CrossRef Full Text MED Associates The role of mesoprefrontal dopamine neurons in the acquisition and expression of conditioned fear in the rat Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Pubmed Abstract | Pubmed Full Text Clonidine-induced antagonism of norepinephrine modulates the attentional processes involved in peak-interval timing On the relationship between emotion and cognition Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Effects of noradrenergic activity on temporal information processing in humans Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Nomifensine amplifies subsecond dopamine signals in the ventral striatum of freely-moving rats Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Pattern of impaired working memory during major depression Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Cellular mechanisms of infralimbic and prelimbic prefrontal cortical inhibition and dopaminergic modulation of basolateral amygdala neurons in vivo Pubmed Abstract | Pubmed Full Text Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Sierra-Mercado Dissociable roles of prelimbic and infralimbic cortices and basolateral amygdala in the expression and extinction of conditioned fear Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Functional neural circuits for mental timekeeping Pubmed Abstract | Pubmed Full Text | CrossRef Full Text The pattern of responding in the peak-interval procedure with gaps: an individual-trials analysis Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Amphetamine affects the start of responding in the peak interval timing task Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Strain-dependent modification of behavior following antidepressant treatment Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Differential projections of the infralimbic and prelimbic cortex in the rat Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Gating is a better model of prospective timing (a response to ‘switching or gating?' by Lejeune)(1) Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Buhusi M and Buhusi CV (2012) Dissociation of the role of the prelimbic cortex in interval timing and resource allocation: beneficial effect of norepinephrine and dopamine reuptake inhibitor nomifensine on anxiety-inducing distraction Received: 01 May 2012; Accepted: 05 November 2012; Published online: 03 December 2012 Copyright © 2012 Matthews, He, Buhusi and Buhusi. This is an open-access article distributed under the terms of the Creative Commons Attribution License distribution and reproduction in other forums provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc *Correspondence: Catalin V. Buhusi, Department of Psychology, USTAR BioInnovations Center, Utah State University, 2810 Old Main Hill, Logan, UT 84322-2810, USA. e-mail:Y2F0YWxpbi5idWh1c2lAdXN1LmVkdQ== Volume 7 - 2016 | https://doi.org/10.3389/fpsyg.2016.00224 This article is part of the Research TopicUnderstanding the role of the time dimension in the brain information processingView all 13 articles some hypotheses are supported by the literature on rhythmic entrainment Figure 1. Illustration of the main interval timing theories of interval timing that rely on the notion of neural oscillations. Panel (A) illustrates the idea that faster alpha rhythms results in longer estimates of time as more pulses could be accumulated in a given physical time interval (Treisman, 1963) The gray sinusoids depict oscillators in an example trial The amplitude of each oscillator is represented by the size of gray circle at t1 and t2 times Panel (C) illustrates the main brain regions engaged in interval timing (PFC PPC) and their presumed projections to the striatum as suggested by the SBF model Despite mechanistic attempts to link oscillatory processes with internal clock models, direct implementations of internal clock models still lack solid neural foundations whereas, more biologically grounded frameworks have been more plausible (Buhusi and Meck, 2005) something that would be in line with the SBF model This hypothesis awaits future tests and more compelling evidence have to be provided that different neural oscillations have the potentiality to track time instead of focusing on one single neural oscillation future studies should explore local trial-to-trial fluctuations across frequency bands and how subdominant frequencies vary as a function of subjectively perceived time intervals addressing the implications of such markers at different time scales and across sensory modalities may be desirable Interestingly, a recent review by Gu et al. (2015) proposes to unify interval timing and working memory models. Specifically, these authors proposed, that working memory and interval timing can originate from the same oscillatory processes such as gamma and theta oscillations, and phase-amplitude coupling between these frequency bands (Lisman, 2010) The proposed model largely focuses on oscillatory processes that could be shared between working memory and SBF the empirical ways to assess the principles of SBF model are still lacking As the gist of the SBF lies in the notion of communication between cortical areas and the striatum here we discuss the possibility of testing this hypothesis by investigating functional connectivity between the striatum and PFC the striatal-PFC synchrony enhancement should emerge at the time of a standard interval for example in the task where subjects compare a comparison interval that could vary in length to a fixed standard interval That is because striatal and PFC structures should become transiently synchronous due to previous learning enhancing sensitivity/tuning of striatum to the particular neural pattern exhibited at the time of standard interval This work has been supported by ERC-YSt-263584 to VW Increases in functional connectivity between prefrontal cortex and striatum during category learning Information processing in the primate basal ganglia during sensory-guided and internally driven rhythmic tapping duration and eccentricity on the visual gamma-band response Google Scholar Neuronal oscillations in cortical networks Prelude to and resolution of an error: EEG phase synchrony reveals cognitive control dynamics during action monitoring Endogenous modulation of low frequency oscillations by temporal expectations Dynamic representation of the temporal and sequential structure of rhythmic movements in the primate medial premotor cortex Dynamic causal modeling of subcortical connectivity of language The role of phase synchronization in memory processes Rhythms for cognition: communication through coherence Beta-band 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gamma-band activity distinguishes between sound durations and controlled access to stored information Dopamine-dependent oscillations in frontal cortex index ‘start-gun’ signal in interval timing Decoupling interval timing and climbing neural activity: a dissociation between CNV and N1P2 amplitudes Single trial beta oscillations index time estimation doi: 10.1016/j.neuropsychologia.2015.06.014 Encoding of event timing in the phase of neural oscillations Working memory: the importance of theta and gamma oscillations “Searching for the Holy Grail: temporally informative firing patterns in the Rat,” in Neurobiology of Interval Timing doi: 10.1002/(SICI)1521-1878(200001)22:1<94::AID-BIES14>3.0.CO;2-E and memory—A retrospective analysis A scalable population code for time in the striatum “Neurophysiology of timing in the hundreds of milliseconds: multiple layers of neuronal clocks in the medial premotor areas,” in Neurobiology of Interval Timing Google Scholar CrossRef Full Text | Google Scholar PubMed Abstract | CrossRef Full Text D1-dependent 4 Hz oscillations and ramping activity in rodent medial frontal cortex during interval timing Neurophysiology of implicit timing in serial choice reaction-time performance Alpha oscillations related to anticipatory attention follow temporal expectations Time is more than a sensory feature: attending to duration triggers specific anticipatory activity PubMed Abstract | CrossRef Full Text | Google Scholar Temporal discrimination and the indifference interval: implications for a model of the “internal clock.” Psychol The internal clock: electroencephalographic evidence for oscillatory processes underlying time perception The internal clock: evidence for a temporal oscillator underlying time perception with some estimates of its characteristic frequency van Wassenhove Minding time in an amodal representational space van Wassenhove Temporal Cognition and Neural Oscillations PubMed Abstract Frequency tuning for temporal perception and prediction CrossRef Full Text | Google Scholar Citation: Kononowicz TW and van Wassenhove V (2016) In Search of Oscillatory Traces of the Internal Clock Received: 08 November 2015; Accepted: 03 February 2016; Published: 23 February 2016 Copyright © 2016 Kononowicz and van Wassenhove. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) *Correspondence: Tadeusz W. Kononowicz, dC53Lmtvbm9ub3dpY3pAaWNsb3VkLmNvbQ==; Virginie van Wassenhove, dmlyZ2luaWUudmFuLndhc3NlbmhvdmVAZ21haWwuY29t Your brain is a time machine with three modes that control everything from instantaneous tasks like moving to maintaining long trains of thought and ultimately staying in synch with night and day But they have no clue how most of it works Focusing on the poorly understood middle time zone where the brain does some of its best work researchers at Duke University summarize this latest thinking in a new article in the journal Nature Reviews Neuroscience Scientists have long understood human and animal brains to be governed in part by a circadian clock which keeps us in synch with night and day The rhythm of this 24-hour clock encourages nighttime sleep and allows many people to awaken with no help from a rooster Another clock is thought to operate at the millisecond level among other vital functions that occur so quickly we don't really think about them there must be a third timekeeper of the mind to aid all the functions that require seconds to minutes of attention Get the world’s most fascinating discoveries delivered straight to your inbox Duke neuroscientists Warren Meck and Catalin Buhusi call the middle mode "interval timing." I not only have to process the millisecond intervals involved in voice onset time but also the duration of vowels and consonants," Meck said Friday to organize my thoughts coherently and to respond back to you in a timely manner." Interval timing has not been studied in detail In fact it may be very hard to look into it Meck has been pondering it since the 1980s but little progress has been made in pinning down how it works He suspects the interval-timing clock does not reside in a single location Even the circadian clock is located in one part of the brain But interval timing "has to be distributed so it can integrate information from all the senses," Meck said today Figuring out how it works may turn out to be more important in understanding the brain that the spatial connections between various parts of the brain "I would argue that time is more fundamental than space because one can just close one's eyes and relive memories "or prospectively go forward in time to predict something without actually changing your position in space." Theorists used to think interval timing was orchestrated by some sort of biological pacemaker that emitted timing pulses The new thinking is that the various parts of the brain oscillate and all these oscillations are monitored and integrated by certain circuits an area of the brain that controls basic functions such as movement "It's like a conductor who listens to the orchestra which is composed of individual musicians," Buhusi explains the conductor synchronizes the orchestra so that listeners hear a coordinated sound." The new paper by Meck and Buhusi lists the various challenges to cracking the interval timing mechanism and outlines techniques being employed As with many attempts to understand the brain researchers are looking at what happens when it stops working normally "When Parkinson's patients are on their medication we can see their clock slow down by recording their brain signals." covering how we age and how to optimize the mind and body through time. He has a journalism degree from Humboldt State University in California Colors are universal — even if our perception of them is subjective Scientists hijacked the human eye to get it to see a brand-new color May's full 'Flower Moon' will be a micromoon The ad-free version is ready for purchase on iOS mobile app today we couldn't find that page";var n=e.querySelector("h2");return n&&n.remove(),{staticContent:e,title:t}},d=function(e){var t=document.createElement("button");return t.innerText=e,t.classList.add("error-page-button"),t},f=function(e){var t=document.createElement("div");t.id="recirculation-404",t.classList.add("brand-hint-bg");var n="\n \n \n Tick here if you would like us to send you the author’s response Blinking with her one eye into the tropical sun Bella the lioness lifts a paw and cautiously puts it outside her crate she finally steps out and stands for the first time on African soil.. all thanks to Sunday Mirror readers who helped raise £80,000 to rescue her from a life of misery who 25 years ago set up a charity in its name to save wildlife around the world As Bella – who was discovered by the Born Free Foundation going slowly blind in a crumbling Romanian zoo  – looks at her new home she turns and stares at the woman who has spent a quarter of a century fighting for wild animals like her Virginia said later: “It was the most stirring thing She made eye contact and held it for a long time It was almost as though she knew all the effort so many people have made to get her here.” We first revealed seven-year-old Bella’s plight at Christmas As a cub she had been used as a tourist photographer’s prop at resorts on the Black Sea But when she grew too big she was dumped at a decaying Communist-era zoo where for six years she lived in a tiny concrete enclosure She had a mate and is thought to have given birth to several cubs her back legs never formed properly and all she she could do was stumble around her cell <p>When Born Free vet John Knight first saw her Bella’s left eye was so badly infected it had to be removed She had a cataract in the other which would eventually have left her completely blind.</p> <p>In a desperate race against time to save her sight an appeal was launched to pay for vital medical treatment and find a new home  her in Africa.</p> <p>Born Free needed to raise £22,000 – but animal-lovers were so touched by Bella’s story that they gave an astonishing £80,000 which will now help to pay for the costs of her lifetime care.</p> <p>After a flood of donations from Sunday Mirror readers a team of experts operated to remove the cataract and Bella was moved to a temporary home to recuperate.</p> <p>Meanwhile a two-acre enclosure was built for her at the Lilongwe Wildlife Centre in Malawi where she arrived this week.</p> <p>Virginia said: “She didn’t want to come out at first and then her paw.</p> <p>“She’s had a lot of suffering – her cubs dying To see her here – I’m just so grateful.”</p> Get email updates with the day's biggest stories