@article {157496, title = {Social dominance in rats is a determinant of susceptibility to stress.}, journal = {Proc Natl Acad Sci U S A}, volume = {122}, year = {2025}, month = {2025 May 13}, pages = {e2412314122}, abstract = {

Establishing a dominance hierarchy in social organisms is important for access to resources. Stress has been proposed as a major factor influencing an animal{\textquoteright}s likely position in a social hierarchy. Although individual differences in vulnerability to stress are increasingly recognized, how social hierarchy affects vulnerability remains relatively understudied. Here, we examined how the social dominance status of adult male Sprague-Dawley rats influences their response to stress in interactions with a familiar animal living in the same cage, and separately when confronting an unfamiliar rat of uncertain dominance status from another cage, using the tube test. Having determined the relatively stable within-cage social dominance status of animals, half were subjected to a single episode of 2-h immobilization stress. Cagemates, both control and stressed rats, again faced one another 1 d and 10 d after stress. First, the predetermined hierarchical rank among familiar cagemates was relatively unaffected by stress. However, second, the same stress had a differential impact in competitions between unfamiliar rats. Socially dominant control rats continued to win competitions but subordinate control rats, that had previously lost, sometimes started to win against previously dominant rats that had been stressed. Strikingly, subordinate stressed rats displayed consistent submissive-like behavior and they alone showed differential effects on dendritic spine density in the amygdala. Thus, an individual{\textquoteright}s social rank can influence its response to stress, an effect that is detectable in interactions with unfamiliar animals. These findings provide an additional dimension to animal models of stress used for exploring facets of social anxiety and withdrawal in stress-related psychiatric disorders.

}, keywords = {dominance; stress; structural plasticity; susceptibility; tube test.}, issn = {1091-6490}, doi = {10.1073/pnas.2412314122}, url = {https://www.pnas.org/doi/10.1073/pnas.2412314122?url_ver=Z39.88-2003\&rfr_id=ori\%3Arid\%3Acrossref.org\&rfr_dat=cr_pub++0pubmed}, author = {Srinivasan, Durga J and Kapgal, Vijayakumar and Morris, Richard G M and Chattarji, Sumantra} } @article {129502, title = {Administration of the glutamate-modulating drug, riluzole, after stress prevents its delayed effects on the amygdala in male rats.}, journal = {PNAS Nexus}, volume = {2}, year = {2023}, month = {2023 Jun}, pages = {pgad166}, abstract = {

Extracellular glutamate levels are elevated across brain regions immediately after stress. Despite sharing common features in their genesis, the patterns of stress-induced plasticity that eventually take shape are strikingly different between these brain areas. While stress causes structural and functional deficits in the hippocampus, it has the opposite effect on the amygdala. Riluzole, an FDA-approved drug known to modulate glutamate release and facilitate glutamate clearance, prevents stress-induced deficits in the hippocampus. But whether the same drug is also effective in countering the opposite effects of stress in the amygdala remains unexplored. We addressed this question by using a rat model wherein even a single 2-h acute immobilization stress causes a delayed expression of anxiety-like behavior, 10 days later, alongside stronger excitatory synaptic connectivity in the basolateral amygdala (BLA). This temporal profile-several days separating the acute stressor and its delayed impact-allowed us to test if these effects can be prevented by administering riluzole in drinking water acute stress. Poststress riluzole not only prevented the delayed increase in anxiety-like behavior on the elevated plus maze but also blocked the increase in spine density on BLA neurons 10 days later. Further, stress-induced increase in the frequency of miniature excitatory postsynaptic currents recorded in BLA slices, 10 days later, was also blocked by the same poststress riluzole administration. Together, these findings underscore the importance of therapeutic strategies, aimed at glutamate uptake and modulation, in correcting the delayed behavioral, physiological, and morphological effects of stress on the amygdala.

}, issn = {2752-6542}, doi = {10.1093/pnasnexus/pgad166}, author = {Datta, Siddhartha and Rashid, Zubin and Naskar, Saptarnab and Chattarji, Sumantra} } @article {126685, title = {Astrocytes mediate cell non-autonomous correction of aberrant firing in human FXS neurons.}, journal = {Cell Rep}, volume = {42}, year = {2023}, month = {2023 Apr 04}, pages = {112344}, abstract = {

Pre-clinical studies of fragile X syndrome (FXS) have focused on neurons, with the role of glia remaining largely underexplored. We examined the astrocytic regulation of aberrant firing of FXS neurons derived from human pluripotent stem cells. Human FXS cortical neurons, co-cultured with human FXS astrocytes, fired frequent short-duration spontaneous bursts of action potentials compared with less frequent, longer-duration bursts of control neurons co-cultured with control astrocytes. Intriguingly, bursts fired by FXS neurons co-cultured with control astrocytes are indistinguishable from control neurons. Conversely, control neurons exhibit aberrant firing in the presence of FXS astrocytes. Thus, the astrocyte genotype determines the neuronal firing phenotype. Strikingly, astrocytic-conditioned medium, and not the physical presence of astrocytes, is capable of determining the firing phenotype. The mechanistic basis of this effect indicates that the astroglial-derived protein, S100β, restores normal firing by reversing the suppression of a persistent sodium current in FXS neurons.

}, issn = {2211-1247}, doi = {10.1016/j.celrep.2023.112344}, author = {Sharma, Shreya Das and Reddy, Bharath Kumar and Pal, Rakhi and Ritakari, Tuula E and Cooper, James D and Selvaraj, Bhuvaneish T and Kind, Peter C and Chandran, Siddharthan and Wyllie, David J A and Chattarji, Sumantra} } @article {108403, title = {FMRP protects the lung from xenobiotic stress by facilitating the Integrated Stress Response.}, journal = {J Cell Sci}, year = {2022}, month = {2022 Mar 23}, abstract = {

Stress response pathways protect the lung from the damaging effects of environmental toxicants. Here we investigate the role of the Fragile X Mental Retardation Protein (FMRP), a multifunctional protein implicated in stress responses, in the lung. We report that FMRP is expressed in murine and human lungs, in the airways and more broadly. Analysis of airway stress responses in mice and in a murine cell line ex vivo, using the well-established Naphthalene (Nap) injury model, reveals that FMRP-deficient cells exhibit increased expression of markers of oxidative and genotoxic stress and increased cell death. Further inquiry shows that FMRP-deficient cells fail to actuate the Integrated Stress Response Pathway (ISR) and upregulate the transcription factor ATF4. Knockdown of ATF4 expression phenocopies the loss of FMRP. We extend our analysis of the role of FMRP to human bronchial BEAS-2B cells, using a 9, 10-Phenanthrenequinone air pollutant model, to find FMRP-deficient BEAS-2B also fail to actuate the ISR and exhibit greater susceptibility. Taken together, our data suggest that FMRP has a conserved role in protecting the airways by facilitating the ISR.

}, issn = {1477-9137}, doi = {10.1242/jcs.258652}, author = {Basu, Deblina Sain and Bhavsar, Rital and Gulami, Imtiyaz and Chavda, Saraswati and Lingamallu, Sai Manoz and Muddashetty, Ravi and Veeranna, Chandrakanth and Chattarji, Sumantra and Thimmulappa, Rajesh and Bhattacharya, Aditi and Guha, Arjun} } @article {115033, title = {Imbalance of flight-freeze responses and their cellular correlates in the Nlgn3 -/y rat model of autism}, journal = {Mol Autism.}, volume = {13}, year = {2022}, month = {07/2022}, pages = {34}, abstract = {

Background: Mutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied in models of these disorders, however differences in fear response behaviours are often overlooked. We aim to examine fear behaviour and its cellular underpinnings in a rat model of ASD/ID lacking Nlgn3.

Methods: This study uses a range of behavioural tests to understand differences in fear response behaviour in Nlgn3-/y rats. Following this, we examined the physiological underpinnings of this in neurons of the periaqueductal grey (PAG), a midbrain area involved in flight-or-freeze responses. We used whole-cell patch-clamp recordings from ex vivo PAG slices, in addition to in vivo local-field potential recordings and electrical stimulation of the PAG in wildtype and Nlgn3-/y rats. We analysed behavioural data with two- and three-way ANOVAS and electrophysiological data with generalised linear mixed modelling (GLMM).

Results: We observed that, unlike the wildtype, Nlgn3-/y rats are more likely to response with flight rather than freezing in threatening situations. Electrophysiological findings were in agreement with these behavioural outcomes. We found in ex vivo slices from Nlgn3-/y rats that neurons in dorsal PAG (dPAG) showed intrinsic hyperexcitability compared to wildtype. Similarly, stimulating dPAG in vivo revealed that lower magnitudes sufficed to evoke flight behaviour in Nlgn3-/y than wildtype rats, indicating the functional impact of the increased cellular excitability.

Limitations: Our findings do not examine what specific cell type in the PAG is likely responsible for these phenotypes. Furthermore, we have focussed on phenotypes in young adult animals, whilst the human condition associated with NLGN3 mutations appears during the first few years of life.

Conclusions: We describe altered fear responses in Nlgn3-/y rats and provide evidence that this is the result of a circuit bias that predisposes flight over freeze responses. Additionally, we demonstrate the first link between PAG dysfunction and ASD/ID. This study provides new insight into potential pathophysiologies leading to anxiety disorders and changes to fear responses in individuals with ASD.

}, doi = {10.1186/s13229-022-00511-8}, author = {Anstey, NJ and Kapgal, V. and Tiwari, S. and Watson, TC and Toft, AKH and Dando, OR and Inkpen, FH and Baxter, PS and Kozi{\'c}, Z and Jackson, AD and He, X and Nawaz, MS and Kayenaat, A and Bhattacharya, A and Wyllie, DJA and Chattarji, Sumantra and Wood, ER and Hardt, O and Kind, PC} } @article {108404, title = {Riluzole prevents stress-induced spine plasticity in the hippocampus but mimics it in the amygdala.}, journal = {Neurobiol Stress}, volume = {18}, year = {2022}, month = {2022 May}, pages = {100442}, abstract = {

Stress elicits divergent patterns of structural plasticity in the amygdala and hippocampus. Despite these contrasting effects, at least one of the immediate consequences of stress - elevated levels of extracellular glutamate - is similar in both brain areas. This raises the possibility that the contrasting effects of stress on neuronal plasticity is shaped by differences in astrocytic glutamate clearance in these two brain areas. Although astrocytes play a key role in glutamate reuptake, past analyses of, and interventions against, stress-induced plasticity have focused largely on neurons. Hence, we tested the impact of riluzole, which potentiates glutamate clearance by astrocytic glutamate transporters, on principal neurons and astrocytes in the basal amygdala (BA) and hippocampal area CA1. Chronic immobilization stress reduced spine-density on CA1 pyramidal neurons of male rats. Riluzole, administered in the drinking water during chronic stress, prevented this decrease; but, the drug by itself had no effect. In contrast, the same chronic stress enhanced spine-density on BA principal neurons, and this effect, unlike area CA1, was not reversed by riluzole. Strikingly, riluzole treatment alone also caused spinogenesis in the BA. Thus, the same riluzole treatment that prevented the effect of stress on spines in the hippocampus, mimicked its effect in the amygdala. Further, chronic stress and riluzole alone decreased the neuropil volume occupied by astrocytes in both the BA and CA1 area. Riluzole treatment in stressed animals, however, did not reverse or further add to this reduction in either region. Thus, while the effects on astrocytes were similar, neuronal changes were distinct between the two areas following stress, riluzole and the two together. Therefore, similar to the impact of repeated stress, pharmacological potentiation of glutamate clearance, with or without stress, also leads to differential effects on dendritic spines in principal neurons of the amygdala and hippocampus. This highlights differences in the astrocytic glutamate reuptake machinery that are likely to have important functional consequences for stress-induced dysfunction, and its reversal, in two brain areas implicated in stress-related psychiatric disorders.

}, issn = {2352-2895}, doi = {10.1016/j.ynstr.2022.100442}, author = {Naskar, Saptarnab and Datta, Siddhartha and Chattarji, Sumantra} } @article {109679, title = {The same stress elicits different effects on anxiety-like behavior in rat models of Fmr1 and Pten.}, journal = {Behav Brain Res}, year = {2022}, month = {2022 Apr 15}, pages = {113892}, abstract = {

Individuals affected by autism spectrum disorders (ASDs) exhibit affective symptoms such as enhanced anxiety, which has been seen in rodent models of ASDs as well. Exposure to stress is also known to be anxiogenic. However, the effects of stress on animal models of ASDs remains less explored. Hence, in the present study we examined the impact of acute foot shock stress on anxiety-like behavior in two monogenic rat models of ASDs, fragile X mental retardation 1 knockout (Fmr1) and phosphatase and tensin homolog heterozygous (Pten). Before exposure to stress, the basal levels of anxiety-like behavior in both Fmr1 and Pten rats were comparable to that seen in wild-type (WT) control rats in an open-field arena. After exposure to the foot shock stress, however, Fmr1 rats showed the highest levels of anxiety-like behavior. WT animals also showed enhanced anxiety-like behavior but not as robustly as the Fmr1 animals. In Pten animals, on the other hand, the same stressor did not elicit any anxiogenic effects. In a separate group of rats, the efficacy of the acute foot shock in triggering a stress response was confirmed wherein a comparable surge in circulating corticosterone was seen in all three experimental groups. Thus, the same acute stress led to different effects on anxiety-like behavior in different rodent models of ASDs, suggesting that vulnerability to stress-induced changes in anxiety may vary with the underlying genetic mutations.

}, issn = {1872-7549}, doi = {10.1016/j.bbr.2022.113892}, author = {Dey, Rohit and Chattarji, Sumantra} } @article {111038, title = {Stress Elicits Contrasting Effects on Rac1-Cofilin Signaling in the Hippocampus and Amygdala.}, journal = {Front Mol Neurosci}, volume = {15}, year = {2022}, month = {2022}, pages = {880382}, abstract = {

There is accumulating evidence for contrasting patterns of stress-induced morphological and physiological plasticity in glutamatergic synapses of the hippocampus and amygdala. The same chronic stress that leads to the formation of dendritic spines in the basolateral amygdala (BLA) of rats, leads to a loss of spines in the hippocampus. However, the molecular underpinnings of these divergent effects of stress on dendritic spines are not well understood. Since the activity of the Rho GTPase Rac1 and the actin-depolymerizing factor cofilin are known to play a pivotal role in spine morphogenesis, we investigated if alterations in this signaling pathway reflect the differential effects of stress on spine plasticity in the hippocampus and amygdala. A day after the end of chronic immobilization stress (2 h/day for 10 days), we found a reduction in the activity of Rac1, as well as its effector p21-activated kinase 1 (PAK1), in the rat hippocampus. These changes, in turn, decreased cofilin phosphorylation alongside a reduction in the levels of profilin isoforms. In striking contrast, the same chronic stress increased Rac1, PAK1 activity, cofilin phosphorylation, and profilin levels in the BLA, which is consistent with enhanced actin polymerization leading to spinogenesis in the BLA. In the hippocampus, on the other hand, the same stress caused the opposite changes, the functional consequences of which would be actin depolymerization leading to the elimination of spines. Together, these findings reveal a role for brain-region specific differences in the dysregulation of Rac1-to-cofilin signaling in the effects of repeated stress on two brain areas that are implicated in the emotional and cognitive symptoms of stress-related psychiatric disorders.

}, issn = {1662-5099}, doi = {10.3389/fnmol.2022.880382}, author = {Bose, Mihika and Nawaz, Mohammad Sarfaraz and Pal, Rakhi and Chattarji, Sumantra} } @article {94540, title = {Brain circuits at risk in psychiatric diseases and pharmacological pathways.}, journal = {Therapie}, volume = {76}, year = {2021}, month = {2021 Mar-Apr}, pages = {75-86}, abstract = {

The multiple brain circuits involved in psychiatric diseases may appear daunting, but we prefer to concentrate on a select few, with a particular sensitivity to stress and neurodevelopmental issues, with a clear pharmacotherapy. This review is structured around 1. the key circuits, their role in health and disease, and the neurotransmitters maintaining them, 2. The influence of upbringing, stress, chronobiology, inflammation and infection, 3. The genetic and epigenetic influence on these circuits, particularly regarding copy number variants and neuronal plasticity, 4. The use and abuse of pharmacological agents with the particular risks of stress and chronobiology at critical periods. A major emphasis is placed on the links between hippocampus, prefrontal cortex and amygdala/periaqueductal grey which control specific aspects of cognition, mood, pain and even violence. Some of the research findings were from the innovative medicine initiative (IMI) NEWMEDS, a 22M{\texteuro} academic/industrial consortium on the brain circuits critical for psychiatric disease.

}, issn = {1958-5578}, doi = {10.1016/j.therap.2020.12.005}, author = {Spedding, Michael and Chattarji, Sumantra and Spedding, Charlotte and Jay, Th{\'e}r{\`e}se M} } @article {100749, title = {Correction of amygdalar dysfunction in a rat model of fragile X syndrome}, journal = {Cell Reports}, volume = {37}, year = {2021}, month = {10/2021}, pages = {109805}, chapter = {2}, abstract = {

Fragile X syndrome (FXS), a commonly inherited form of autism and intellectual disability, is associated with emotional symptoms that implicate dysfunction of the amygdala. However, current understanding of the pathogenesis of the disease is based primarily on studies in the hippocampus and neocortex, where FXS defects have been corrected by inhibiting group I metabotropic glutamate receptors (mGluRs). Here, we observe that activation, rather than inhibition, of mGluRs in the basolateral amygdala reverses impairments in a rat model of FXS. FXS rats exhibit deficient recall of auditory conditioned fear, which is accompanied by a range of in\ vitro and in\ vivo deficits in synaptic transmission and plasticity. We find presynaptic mGluR5 in the amygdala, activation of which reverses deficient synaptic transmission and plasticity, thereby restoring normal fear learning in FXS rats. This highlights the importance of modifying the prevailing mGluR-based framework for therapeutic strategies to include circuit-specific differences in FXS pathophysiology.

}, doi = {10.1016/j.celrep.2021.109805}, author = {Fernandes, Giselle and Mishra, Pradeep K. and Nawaz, Mohammad Sarfaraz and Donlin-Asp, Paul G. and Rahman, Mohammed Mostafizur and Hazra, Anupam and Kedia, Sonal and Kayenaat, Aiman and Songara, Dheeraj and Wyllie, David J A and Schuman, Erin M. and Kind, Peter C and Chattarji, Sumantra} } @article {84577, title = {Decreased dendritic spine density in posterodorsal medial amygdala neurons of proactive coping rats.}, journal = {Behav Brain Res}, volume = {397}, year = {2021}, month = {2020 Oct 27}, pages = {112940}, abstract = {

There are large individual differences in the way animals, including humans, behaviorally and physiologically cope with environmental challenges and opportunities. Rodents with either a proactive or reactive coping style not only differ in their capacity to adapt successfully to environmental conditions, but also have a differential susceptibility to develop stress-related (psycho)pathologies when coping fails. In this study, we explored if there are structural neuronal differences in spine density in brain regions important for the regulation of stress coping styles. For this, the individual coping styles of wild-type Groningen (WTG) rats were determined using their level of offensive aggressiveness assessed in the resident-intruder paradigm. Subsequently, brains from proactive (high-aggressive) and reactive (low-aggressive) rats were Golgi-cox stained for spine quantification. The results reveal that dendritic spine densities in the dorsal hippocampal CA1 region and basolateral amygdala are similar in rats with proactive and reactive coping styles. Interestingly, however, dendritic spine density in the medial amygdala (MeA) is strikingly reduced in the proactive coping rats. This brain region is reported to be strongly involved in rivalry aggression which is the criterion by which the coping styles in our study are dissociated. The possibility that structural differences in spine density in the MeA are involved in other behavioral traits of distinct coping styles needs further investigation.

}, issn = {1872-7549}, doi = {10.1016/j.bbr.2020.112940}, author = {Anilkumar, Shobha and Patel, Deepika and de Boer, Sietse F and Chattarji, Sumantra and Buwalda, Bauke} } @article {96751, title = {Distinct temporal expression of GW182 (TNRC6A) in neurons regulates dendritic arborization.}, journal = {J Cell Sci}, year = {2021}, month = {2021 Jul 30}, abstract = {

Precise development of the dendritic architecture is a critical determinant of mature neuronal circuitry. MicroRNA-mediated regulation of protein synthesis plays a crucial role in dendritic morphogenesis but the role of miRISC protein components in this process is less studied. Here, we show an important role of a key miRISC protein GW182 paralog TNRC6A in the regulation of dendritic growth. We have identified a distinct brain region specific spatio-temporal expression pattern of GW182 during rat postnatal development. We found that the window of peak GW182 expression coincides with the period of extensive dendritic growth, both in the hippocampus and cerebellum. Perturbation of GW182 function during a specific temporal window resulted in reduced dendritic growth of cultured hippocampal neurons. Mechanistically, we show that GW182 modulates dendritic growth by regulating global somato-dendritic translation, and actin cytoskeletal dynamics of developing neurons. Furthermore, we found that GW182 affects dendritic architecture by regulating the expression of actin modulator LIMK1. Taken together, our data reveal a previously undescribed neurodevelopmental expression pattern of GW182 and its role in dendritic morphogenesis, through both translational control and actin cytoskeletal rearrangement.

}, issn = {1477-9137}, doi = {10.1242/jcs.258465}, author = {Nawalpuri, Bharti and Sharma, Arpita and Chattarji, Sumantra and Muddashetty, Ravi S} } @article {96750, title = {Reciprocal regulation of spontaneous synaptic vesicle fusion by Fragile X mental retardation protein and group I metabotropic glutamate receptors.}, journal = {J Neurochem}, year = {2021}, month = {2021 Jul 29}, abstract = {

Fragile X mental retardation protein (FMRP) is a neuronal protein mediating multiple functions, with its absence resulting in one of the most common monogenic causes of autism, Fragile X syndrome (FXS). Analyses of FXS pathophysiology have identified a range of aberrations in synaptic signaling pathways and plasticity associated with group I metabotropic glutamate (mGlu) receptors. These studies, however, have mostly focused on the postsynaptic functions of FMRP and mGlu receptor activation, and relatively little is known about their presynaptic effects. Neurotransmitter release is mediated via multiple forms of synaptic vesicle (SV) fusion, each of which contribute to specific neuronal functions. The impacts of mGlu receptor activation and loss of FMRP on these SV fusion events remains unexplored. Here we combined electrophysiological and fluorescence imaging analyses on primary hippocampal cultures prepared from a Fmr1 knockout (KO) rat model. Compared to wild-type (WT) hippocampal neurons, KO neurons displayed an increase in the frequency of spontaneous excitatory postsynaptic currents (sEPSCs), as well as spontaneous SV fusion events. Pharmacological activation of mGlu receptors in WT neurons caused a similar increase in spontaneous SV fusion and sEPSC frequency. Notably, this increase in SV fusion was not observed when spontaneous activity was blocked using the sodium channel antagonist tetrodotoxin. Importantly, the effect of mGlu receptor activation on spontaneous SV fusion was occluded in Fmr1 KO neurons. Together, our results reveal that FMRP represses spontaneous presynaptic SV fusion, whereas mGlu receptor activation increases this event. This reciprocal control appears to be mediated via their regulation of intrinsic neuronal excitability.

}, issn = {1471-4159}, doi = {10.1111/jnc.15484}, author = {Subrahmanyam, Rohini and Dwivedi, Deepanjali and Rashid, Zubin and Bonnycastle, Katherine and Cousin, Michael A and Chattarji, Sumantra} } @article {91137, title = {Repeated victorious and defeat experiences induce similar apical dendritic spine remodeling in CA1 hippocampus of rats.}, journal = {Behav Brain Res}, volume = {406}, year = {2021}, month = {2021 Mar 13}, pages = {113243}, abstract = {

In this study, apical dendritic spine density of neurons in hippocampal, amygdalar and prefrontal cortical areas was compared in rats that were repeatedly winning or losing social conflicts. Territorial male wild-type Groningen (WTG) rats were allowed multiple daily attacks (\>20 times) on intruder males in the resident-intruder paradigm. Frequent winning experiences are known to facilitate uncontrolled aggressive behavior reflected in aggressive attacks on anesthetized males which was also observed in the winners in this study. Both winners and losers were socially housed during the experiments; winners with females to stimulate territorial behavior, and losers with two other losing male rats. Twenty-four hours after the last social encounter, brains from experienced residential winners and repeatedly defeated intruder rats were collected and neuronal morphology in selected brain regions was studied via Golgi-Cox staining. Results indicate that spine density in the apical dendrites of the hippocampal CA1 reduced similarly in both winners and losers. In addition, winners showed increased spine densities at the proximal segments (20-30 μm) of the basolateral amygdala neurons and losers tended to show a decreased spine density at the more proximal segments of the infralimbic region of prefrontal cortex neurons. No effect of winning and losing was observed in the medial amygdala. The atrophic effect of repeated defeats in hippocampal and prefrontal regions was anticipated despite the fact that social housing of the repeatedly losing intruder males may have played a protective role. The reduction of hippocampal spine density in the winners seems surprising but supports previous findings in hierarchical dominant males in rat colonies. The dominants showed even greater shrinkage of the apical dendritic arbors of hippocampal CA3 pyramidal neurons compared to the stressed subordinates.

}, issn = {1872-7549}, doi = {10.1016/j.bbr.2021.113243}, author = {Patel, Deepika and Anilkumar, Shobha and Chattarji, Sumantra and de Boer, Sietse F and Buwalda, Bauke} } @article {102565, title = {A salience hypothesis of stress in PTSD.}, journal = {Eur J Neurosci}, year = {2021}, month = {2021 Nov 11}, abstract = {

Attention to key features of contexts and things is a necessary tool for all organisms. Detecting these salient features of cues, or simply, salience, can also be affected by exposure to traumatic stress, as has been widely reported in individuals suffering from Post-Traumatic Stress Disorder (PTSD). Interestingly, similar observations have been robustly replicated across many animal models of stress as well. By using evidence from such rodent stress paradigms, in the present review we explore PTSD through the lens of salience processing. In this context, we propose that interaction between the neurotrophin BDNF and glucocorticoid determines the long lasting cellular and behavioural consequences of stress salience. We also describe the dual effect of glucocorticoid therapy in the amelioration of PTSD symptoms. Finally, by integrating in vivo observations at multiple scales of plasticity, we propose a unifying hypothesis that pivots on a crucial role of glucocorticoid signalling in dynamically orchestrating stress salience.

}, issn = {1460-9568}, doi = {10.1111/ejn.15526}, author = {Chakraborty, Prabahan and Chattarji, Sumantra and Jeanneteau, Freddy} } @article {88402, title = {Sex differences in the delayed impact of acute stress on the amygdala.}, journal = {Neurobiol Stress}, volume = {14}, year = {2021}, month = {2021 May}, pages = {100292}, abstract = {

There is accumulating evidence that stress triggers specific temporal patterns of morphological plasticity in the amygdala, a brain area that plays a pivotal role in the debilitating emotional symptoms of stress-related psychiatric disorders. Acute immobilization stress is known to cause a delayed increase in the density of dendritic spines on principal neurons in the basolateral amygdala (BLA) of rats. These neuronal changes are also accompanied by a delayed enhancement in anxiety-like behavior. However, these earlier studies used male rats, and the delayed behavioral and synaptic effects of acute stress on the BLA of female rats remain unexplored. Here, using whole-cell recordings in rat brain slices, we find that a single exposure to 2-h immobilization stress leads to an increase, 10 days later, in the frequency of miniature excitatory postsynaptic currents (mEPSCs) recorded from lateral amygdala (LA) principal neurons in male rats. Further, acute stress also causes a reduction in the frequency of miniature inhibitory postsynaptic currents (mIPSCs) in LA neurons 10 days after acute stress. In striking contrast, excitatory and inhibitory synaptic transmission in the LA of female rats does not exhibit any delayed change despite exposure to the same acute stress. Finally, we examined the functional impact of these contrasting synaptic changes at the behavioral level. Male rats exhibit a delayed increase in anxiety-like behavior on the elevated plus-maze 10 days after acute stress. However, the same stress does not lead to a delayed anxiogenic effect in female rats. Together, these results demonstrate that the delayed modulation of the balance of synaptic excitation and inhibition in the amygdala, as well as anxiety-like behavior, differ between males and females. These findings provide a framework, across biological scales, for analyzing how affective symptoms of stress disorders vary between the sexes.

}, issn = {2352-2895}, doi = {10.1016/j.ynstr.2020.100292}, author = {Gupta, Kanika and Chattarji, Sumantra} } @article {93057, title = {Stress enhances hippocampal neuronal synchrony and alters ripple-spike interaction.}, journal = {Neurobiol Stress}, volume = {14}, year = {2021}, month = {2021 May}, pages = {100327}, abstract = {

Adverse effects of chronic stress include anxiety, depression, and memory deficits. Some of these stress-induced behavioural deficits are mediated by impaired hippocampal function. Much of our current understanding about how stress affects the hippocampus has been derived from post-mortem analyses of brain slices at fixed time points. Consequently, neural signatures of an ongoing stressful experiences in the intact brain of awake animals and their links to later hippocampal dysfunction remain poorly understood. Further, no information is available on the impact of stress on sharp-wave ripples (SPW-Rs), high frequency oscillation transients crucial for memory consolidation. Here, we used tetrode recordings to analyze the dynamic impact of 10 days of immobilization stress on neural activity in area CA1 of mice. While there was a net decrease in pyramidal cell activity in stressed animals, a greater fraction of CA1 spikes occurred specifically during sharp-wave ripples, resulting in an increase in neuronal synchrony. After repeated stress some of these alterations were visible during rest even in the absence of stress. These findings offer new insights into stress-induced changes in ripple-spike interactions and mechanisms through which chronic stress may interfere with subsequent information processing.

}, issn = {2352-2895}, doi = {10.1016/j.ynstr.2021.100327}, author = {Tomar, Anupratap and Polygalov, Denis and Chattarji, Sumantra and McHugh, Thomas J} } @article {103404, title = {Stressed rats fail to exhibit avoidance reactions to innately aversive social calls.}, journal = {Neuropsychopharmacology}, year = {2021}, month = {2021 Nov 30}, abstract = {

Disruptions in amygdalar function, a brain area involved in encoding emotionally salient information, has been implicated in stress-related affective disorders. Earlier animal studies on the behavioral consequences of stress-induced abnormalities in the amygdala focused on learned behaviors using fear conditioning paradigms. If and how stress affects unconditioned, innate fear responses to ethologically natural aversive stimuli remains unexplored. Hence, we subjected rats to aversive ultrasonic vocalization calls emitted on one end of a linear track. Unstressed control rats exhibited a robust avoidance response by spending more time away from the source of the playback calls. Unexpectedly, prior exposure to chronic immobilization stress prevented this avoidance reaction, rather than enhancing it. Further, this stress-induced impairment extended to other innately aversive stimuli, such as white noise and electric shock in an inhibitory avoidance task. However, conditioned fear responses were enhanced by the same stress. Inactivation of the basolateral amygdala (BLA) in control rats prevented this avoidance reaction evoked by the playback. Consistent with this, analysis of the immediate early gene cFos revealed higher activity in the BLA of control, but not stressed rats, after exposure to the playback. Further, in vivo recordings in freely behaving control rats exposed to playback showed enhanced theta activity in the BLA, which also was absent in stressed rats. These findings offer a new framework for studying stress-induced alterations in amygdala-dependent maladaptive responses to more naturally threatening and emotionally relevant social stimuli. The divergent impact of stress on defensive responses--impaired avoidance responses together with increased conditioned fear--also has important implications for models of learned helplessness and depression.

}, issn = {1740-634X}, doi = {10.1038/s41386-021-01230-z}, author = {Shukla, Ashutosh and Chattarji, Sumantra} } @article {77438, title = {Convolvulus pluricaulis extract can modulate synaptic plasticity in rat brain hippocampus.}, journal = {Neuroreport}, volume = {31}, year = {2020}, month = {2020 May 22}, pages = {597-604}, abstract = {

The memory-boosting property of Indian traditional herb, Convolvulus pluricaulis, has been documented in literature; however, its effect on synaptic plasticity has not yet been reported. Two important forms of synaptic plasticity known to be involved in the processes of memory formation are long-term potentiation (LTP) and long-term depression (LTD). In the present study, the effect of C. pluricaulis plant extract on LTP and LTD were evaluated. The adult male Wistar rats were fed orally with 250, 500 and 1000 mg/kg of this extract for 4 weeks and the effect was determined on LTP and LTD in the Schaffer collaterals of the hippocampal cornu ammonis region CA1. We found that the 500 mg/kg dose of the extract could significantly enhance LTP compared to the vehicle treated ones. Moreover, the same dose could also reduce LTD while used in a separate set of animals. Also, a fresh group of animals treated with the effective dose (500 mg/kg) of plant extract were examined for memory retention in two behavioral platforms namely, contextual fear conditioning (CFC) and novel object recognition test (NORT). Increased fear response to the conditioned stimulus and enhanced recognition of objects were observed in CFC and NORT, respectively, both indicating strengthening of memory. Following up, ex-vivo electrophysiology experiments were performed with the active single molecule scopoletin, present in C. pluricaulis extract and similar patterns in synaptic plasticity changes were obtained. These findings suggest that prolonged treatment of C. pluricaulis extract, at a specific dose in healthy animals, can augment memory functions by modulating hippocampal plasticity.

}, issn = {1473-558X}, doi = {10.1097/WNR.0000000000001446}, author = {Das, Rishi and Sengupta, Tathagata and Roy, Shubhrajit and Chattarji, Sumantra and Ray, Jharna} } @article {78161, title = {Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns.}, journal = {Mol Autism}, volume = {11}, year = {2020}, month = {2020 Jun 19}, pages = {52}, abstract = {

BACKGROUND: Fragile X syndrome (FXS), a neurodevelopmental disorder, is a leading monogenetic cause of intellectual disability and autism spectrum disorder. Notwithstanding the extensive studies using rodent and other pre-clinical models of FXS, which have provided detailed mechanistic insights into the pathophysiology of this disorder, it is only relatively recently that human stem cell-derived neurons have been employed as a model system to further our understanding of the pathophysiological events that may underlie FXS. Our study assesses the physiological properties of human pluripotent stem cell-derived cortical neurons lacking fragile X mental retardation protein (FMRP).

METHODS: Electrophysiological whole-cell voltage- and current-clamp recordings were performed on two control and three FXS patient lines of human cortical neurons derived from induced pluripotent stem cells. In addition, we also describe the properties of an isogenic pair of lines in one of which FMR1 gene expression has been silenced.

RESULTS: Neurons lacking FMRP displayed bursts of spontaneous action potential firing that were more frequent but shorter in duration compared to those recorded from neurons expressing FMRP. Inhibition of large conductance Ca-activated K currents and the persistent Na current in control neurons phenocopies action potential bursting observed in neurons lacking FMRP, while in neurons lacking FMRP pharmacological potentiation of voltage-dependent Na channels phenocopies action potential bursting observed in control neurons. Notwithstanding the changes in spontaneous action potential firing, we did not observe any differences in the intrinsic properties of neurons in any of the lines examined. Moreover, we did not detect any differences in the properties of miniature excitatory postsynaptic currents in any of the lines.

CONCLUSIONS: Pharmacological manipulations can alter the action potential burst profiles in both control and FMRP-null human cortical neurons, making them appear like their genetic counterpart. Our studies indicate that FMRP targets that have been found in rodent models of FXS are also potential targets in a human-based model system, and we suggest potential mechanisms by which activity is altered.

}, issn = {2040-2392}, doi = {10.1186/s13229-020-00351-4}, author = {Das Sharma, Shreya and Pal, Rakhi and Reddy, Bharath Kumar and Selvaraj, Bhuvaneish T and Raj, Nisha and Samaga, Krishna Kumar and Srinivasan, Durga J and Ornelas, Loren and Sareen, Dhruv and Livesey, Matthew R and Bassell, Gary J and Svendsen, Clive N and Kind, Peter C and Chandran, Siddharthan and Chattarji, Sumantra and Wyllie, David J A} } @article {79718, title = {Corticosterone after acute stress prevents the delayed effects on the amygdala.}, journal = {Neuropsychopharmacology}, year = {2020}, month = {2020 Jul 06}, abstract = {

Even a single 2-hour episode of immobilization stress is known to trigger anxiety-like behavior and increase spine-density in the basolateral amygdala (BLA) of rats 10 days later. This delayed build-up of morphological and behavioral effects offers a stress-free time window of intervention after acute stress, which we used to test a protective role for glucocorticoids against stress. We observed that post-stress corticosterone, given 1 day after acute stress in drinking water, reversed enhanced anxiety-like behavior 10 days later. Quantification of spine-density on Golgi-stained BLA principal neurons showed that the same intervention also prevented the increase in spine numbers in the amygdala, at the same delayed time-point. Further, stress elevated serum corticosterone levels in rats that received vehicle in the drinking water. However, when stress was followed 24 h later by corticosterone in the drinking water, the surge in corticosterone was prevented. Together, these observations suggest that corticosterone, delivered through drinking water even 24 h after acute stress, is capable of reversing the delayed enhancing effects on BLA synaptic connectivity and anxiety-like behavior. Strikingly, although the immobilization-induced surge in corticosterone by itself has delayed detrimental effects on amygdalar structure and function, there exists a window of opportunity even after stress to mitigate its impact with a second surge of exogenously administered corticosterone. This provides a framework in the amygdala for analyzing how the initial physiological and endocrine processes triggered by traumatic stress eventually give rise to debilitating emotional symptoms, as well as the protective effects of glucocorticoids against their development.

}, issn = {1740-634X}, doi = {10.1038/s41386-020-0758-0}, author = {Chakraborty, Prabahan and Datta, Siddhartha and McEwen, Bruce S and Chattarji, Sumantra} } @article {77437, title = {Distinct regulation of bioenergetics and translation by group I mGluR and NMDAR.}, journal = {EMBO Rep}, volume = {21}, year = {2020}, month = {2020 Jun 04}, pages = {e48037}, abstract = {

Neuronal activity is responsible for the high energy consumption in the brain. However, the cellular mechanisms draining ATP upon the arrival of a stimulus are yet to be explored systematically at the post-synapse. Here, we provide evidence that a significant fraction of ATP is consumed upon glutamate stimulation to energize mGluR-induced protein synthesis. We find that both mGluR and NMDAR alter protein synthesis and ATP consumption with distinct kinetics at the synaptic-dendritic compartments. While mGluR activation leads to a rapid and sustained reduction in neuronal ATP levels, NMDAR activation has no immediate impact on the same. ATP consumption correlates inversely with the kinetics of protein synthesis for both receptors. We observe a persistent elevation in protein synthesis within 5\ minutes of mGluR activation and a robust inhibition of the same within 2\ minutes of NMDAR activation, assessed by the phosphorylation status of eEF2 and metabolic labeling. However, a delayed protein synthesis-dependent ATP expenditure ensues after 15\ minutes of NMDAR stimulation. We identify a central role for AMPK in the correlation between protein synthesis and ATP consumption. AMPK is dephosphorylated and inhibited upon mGluR activation, while it is phosphorylated upon NMDAR activation. Perturbing AMPK activity disrupts receptor-specific modulations of eEF2 phosphorylation and protein synthesis. Our observations, therefore, demonstrate that the regulation of the AMPK-eEF2 signaling axis by glutamate receptors alters neuronal protein synthesis and bioenergetics.

}, issn = {1469-3178}, doi = {10.15252/embr.201948037}, author = {Ghosh Dastidar, Sudhriti and Das Sharma, Shreya and Chakraborty, Sumita and Chattarji, Sumantra and Bhattacharya, Aditi and Muddashetty, Ravi S} } @article {77390, title = {N-terminal variant Asp14Asn of the human p70 S6 Kinase 1 enhances translational signaling causing different effects in developing and mature neuronal cells.}, journal = {Neurobiol Learn Mem}, volume = {171}, year = {2020}, month = {2020 May}, pages = {107203}, abstract = {

The ribosomal p70 S6 Kinase 1 (S6K1) has been implicated in the etiology of complex neurological diseases including autism, depression and dementia. Though no major gene disruption has been reported in humans in RPS6KB1, single nucleotide variants (SNVs) causing missense mutations have been identified, which have not been assessed for their impact on protein function. These S6K1 mutations have the potential to influence disease progression and treatment response. We mined the Simon Simplex Collection (SSC) and SPARK autism database to find inherited SNVs in S6K1 and characterized the effect of two missense SNVs, Asp14Asn (allele frequency\ =\ 0.03282\%) and Glu44Gln (allele frequency\ =\ 0.0008244\%), on S6K1 function in HEK293, human ES cells and primary neurons. Expressing Asp14Asn in HEK293 cells resulted in increased basal phosphorylation of downstream targets of S6K1 and increased de novo translation. This variant also showed blunted response to the specific S6K1 inhibitor, FS-115. In human embryonic cell line Shef4, Asp14Asn enhanced spontaneous neural fate specification in the absence of differentiating growth factors. In addition to enhanced translation, neurons expressing Asp14Asn exhibited impaired dendritic arborization and increased levels of phosphorylated ERK 1/2. Finally, in the SSC families tracked, Asp14Asn segregated with lower IQ scores when found in the autistic individual rather than the unaffected sibling. The Glu44Gln mutation showed a milder, but opposite phenotype in HEK cells as compared to Asp14Asn. Although the Glu44Gln mutation displayed increased neuronal translation, it had no impact on neuronal morphology. Our results provide the first characterization of naturally occurring human S6K1 variants on cognitive phenotype, neuronal morphology and maturation, underscoring again the importance of translation control in neural development and plasticity.

}, issn = {1095-9564}, doi = {10.1016/j.nlm.2020.107203}, author = {Venkatasubramani, Janani Priya and Subramanyam, Prakash and Pal, Rakhi and Reddy, Bharath K and Srinivasan, Durga Jeyalakshmi and Chattarji, Sumantra and Iossifov, Ivan and Klann, Eric and Bhattacharya, Aditi} } @article {85903, title = {The same stress has divergent effects on social versus asocial manifestations of anxiety-like behavior over time.}, journal = {Stress}, year = {2020}, month = {2020 Nov 25}, pages = {1-21}, abstract = {

Stress may lead to augmented anxiety, which may, with time culminate in some form of anxiety disorder. Behavioral alterations related to increased anxiety can be broadly classified into two types - social, affecting interactions between individuals, and self-oriented, affecting the anxious individual only. While a growing body of literature now exists describing the effects of stress-induced anxiety on self-oriented behavior in animal models of anxiety disorders, the effects of such aberrant anxiety on social behavior has largely remained uncharacterized in these models. This study aims to fill this gap in our understanding by examining changes in social behavior following a single 2-hour episode of immobilization stress, which has been shown to cause delayed structural and functional changes in the amygdala. To this end, we examined social behavior, measured as active social interactions, anogenital sniffing, nose-to-nose contacts, allogrooming, actively following and crawling under, as well as self-oriented asocial behavior, manifested as self-grooming and rearing, in adult male rats. Stressed animals showed reduced social interaction 1 day after immobilization stress and this decrease was persistent for at least 10 days after stress. In contrast, individualistic behaviors were impaired only 10 days, but not 1 day later. Together, these results not only show that the same single episode of stress can elicit divergent effects on social and asocial measures of anxiety in the same animal, but also suggest that enhanced social anxiety soon after stress may also serve as an early indicator of its delayed behavioral effects.

}, issn = {1607-8888}, doi = {10.1080/10253890.2020.1855421}, author = {Saxena, Kapil and Chakraborty, Prabahan and Chattarji, Sumantra} } @article {70234, title = {Stress-induced modulation of endocannabinoid signaling leads to delayed strengthening of synaptic connectivity in the amygdala.}, journal = {Proc Natl Acad Sci U S A}, volume = {117}, year = {2020}, month = {2019 Dec 16}, pages = {650-655}, abstract = {

Even a brief exposure to severe stress strengthens synaptic connectivity days later in the amygdala, a brain area implicated in the affective symptoms of stress-related psychiatric disorders. However, little is known about the synaptic signaling mechanisms during stress that eventually culminate in its delayed impact on the amygdala. Hence, we investigated early stress-induced changes in amygdalar synaptic signaling in order to prevent its delayed effects. Whole-cell recordings in basolateral amygdala (BLA) slices from rats revealed higher frequency of miniature excitatory postsynaptic currents (mEPSCs) immediately after 2-h immobilization stress. This was replicated by inhibition of cannabinoid receptors (CBR), suggesting a role for endocannabinoid (eCB) signaling. Stress also reduced -arachidonoylethanolamine (AEA), an endogenous ligand of CBR. Since stress-induced activation of fatty acid amide hydrolase (FAAH) reduces AEA, we confirmed that oral administration of an FAAH inhibitor during stress prevents the increase in synaptic excitation in the BLA soon after stress. Although stress also caused an immediate reduction in synaptic inhibition, this was not prevented by FAAH inhibition. Strikingly, FAAH inhibition during the traumatic stressor was also effective 10 d later on the delayed manifestation of synaptic strengthening in BLA neurons, preventing both enhanced mEPSC frequency and increased dendritic spine-density. Thus, oral administration of an FAAH inhibitor during a brief stress prevents the early synaptic changes that eventually build up to hyperexcitability in the amygdala. This framework is of therapeutic relevance because of growing interest in targeting eCB signaling to prevent the gradual development of emotional symptoms and underlying amygdalar dysfunction triggered by traumatic stress.

}, issn = {1091-6490}, doi = {10.1073/pnas.1910322116}, author = {Yasmin, Farhana and Colangeli, Roberto and Morena, Maria and Filipski, Sarah and van der Stelt, Mario and Pittman, Quentin J and Hillard, Cecilia J and Teskey, G Campbell and McEwen, Bruce S and Hill, Matthew N and Chattarji, Sumantra} } @article {59741, title = {Differential effects of unipolar versus bipolar depression on episodic memory updating.}, journal = {Neurobiol Learn Mem}, volume = {161}, year = {2019}, month = {2019 05}, pages = {158-168}, abstract = {

Episodic memories, when reactivated, can be modified or updated by new learning. Since such dynamic memory processes remain largely unexplored in psychiatric disorders, we examined the impact of depression on episodic memory updating. Unipolar and bipolar depression patients, and age/education matched controls, first learned a set of objects (List-1). Two days later, participants in all three groups were either reminded of the first learning session or not followed by the learning of a new set of objects (List-2). Forty-eight hours later, List-1 recall was impaired in unipolar and bipolar patients compared to control participants. Further, as expected, control participants who received a reminder spontaneously recalled items from List-2 during recall of List-1, indicative of an updated List-1 memory. Such spontaneous intrusions were also seen in the unipolar and bipolar patients that received the reminder, suggesting that memory updating was unaffected in these two patient groups despite impaired recall of List 1. Unexpectedly, we observed a trend towards higher intrusions, albeit statistically insignificant, not only in the reminder but also in the no-reminder subgroups of bipolar patients. We probed this further in a second cohort by testing recall of List-2, which was also impaired in both depression groups. Again bipolar patients showed intrusions, but this time in the reverse order from List-1 into List-2, independent of a reminder. Taken together, despite impaired recall, updating of episodic memories was intact and unidirectional in unipolar depression. In contrast, indiscriminate updating, as evidenced by bidirectional interference between episodic memories, was seen in bipolar depression. These findings reveal a novel distinction between unipolar versus bipolar depression using a reactivation-dependent memory updating paradigm.

}, issn = {1095-9564}, doi = {10.1016/j.nlm.2019.04.008}, author = {Dongaonkar, Bhaktee and Hupbach, Almut and Nadel, Lynn and Chattarji, Sumantra} } @article {67835, title = {Impaired reliability and precision of spiking in adults but not juveniles in a mouse model of Fragile X Syndrome.}, journal = {eNeuro}, year = {2019}, month = {2019 Nov 04}, abstract = {

Fragile X Syndrome (FXS) is the most common source of intellectual disability and autism. Extensive studies have been performed on the network and behavioral correlates of the syndrome but our knowledge about intrinsic conductance changes is still limited. In this study we show a differential effect of FMRP Knock Out (KO) in different sub-sections of hippocampus using whole cell patch clamp in mouse hippocampal slices. We observed no significant change in spike numbers in the CA1 region of hippocampus but a significant increase in CA3, in juvenile mice. However, in adult mice we see a reduction in spike number in the CA1 with no significant difference in CA3. In addition, we see increased variability in spike number in CA1 cells following a variety of steady and modulated current step protocols. This effect emerges in adult (8 weeks) but not juvenile (4 weeks) mice. This increased spiking variability was correlated with reduced spike number and with elevated AHP. The increased AHP arose from elevated SK currents (small conductance calcium activated potassium channels) but other currents involved in mAHP, such as I and M, were not significantly different. We obtained a partial rescue of the cellular variability phenotype when we blocked SK current using the specific blocker apamin. Our observations provide a single cell correlate of the network observations of response variability and loss of synchronization, and suggest that elevation of SK currents in FXS may provide a partial mechanistic explanation for this difference. Fragile-X syndrome leads to a range of intellectual disability effects and autism. We have found differential effect of FMRP KO in different sub sections of hippocampus where it caused an increased spiking in CA3 in juveniles and reduced spiking in CA1, in adults. We have also found that even individual neurons with this mutation exhibit increased variability in their activity patterns. Importantly, this effect emerges after six weeks of age in mice. We showed that a specific ion channel protein, SK channel, was partially responsible, and blockage of these channels led to a partial restoration of cellular activity. This is interesting as it provides a possible molecular link between activity variability in single cells, and reported irregularity in network activity.

}, issn = {2373-2822}, doi = {10.1523/ENEURO.0217-19.2019}, author = {Dwivedi, Deepanjali and Chattarji, Sumantra and Bhalla, Upinder S} } @article {59702, title = {Interventions after acute stress prevent its delayed effects on the amygdala.}, journal = {Neurobiol Stress}, volume = {10}, year = {2019}, month = {2019 Feb}, pages = {100168}, abstract = {

Stress is known to elicit contrasting patterns of plasticity in the amygdala and hippocampus. While chronic stress leads to neuronal atrophy in the rodent hippocampus, it has the opposite effect in the basolateral amygdala (BLA). Further, even a single episode of acute stress is known to elicit delayed effects in the amygdala. For example, 2 h of immobilisation stress has been shown to cause a delayed increase in dendritic spine density on BLA principal neurons 10 days later in young rats. This is paralleled by higher anxiety-like behaviour at the same delayed time point. This temporal build-up of morphological and behavioural effects 10 days later, in turn, provides a stress-free time window of intervention after exposure to acute stress. Here, we explore this possibility by specifically testing the efficacy of an anxiolytic drug in reversing the delayed effects of acute immobilisation stress. Oral gavage of diazepam 1 h immobilisation stress prevented the increase in anxiety-like behaviour on the elevated plus-maze 10 days later. The same post-stress intervention also prevented delayed spinogenesis in the BLA 10 days after acute stress. Surprisingly, gavage of only the vehicle also had a protective effect on both the behavioural and synaptic effects of stress 10 days later. Vehicle gavage was found to trigger a significant rise in corticosterone levels that was comparable to that elicited by acute stress. This suggests that a surge in corticosterone levels, caused by the vehicle gavage 1 h after acute stress, was capable of reversing the delayed enhancing effects of stress on anxiety-like behaviour and BLA synaptic connectivity. These findings are consistent with clinical reports on the protective effects of glucocorticoids against the development of symptoms of post-traumatic stress disorder. Taken together, these results reveal strategies, targeted 1 h after stress, which can prevent the delayed effects of a brief exposure to a severe physical stressor.

}, issn = {2352-2895}, doi = {10.1016/j.ynstr.2019.100168}, author = {Chakraborty, Prabahan and Chattarji, Sumantra} } @article {62765, title = {NMDAR mediated translation at the synapse is regulated by MOV10 and FMRP.}, journal = {Mol Brain}, volume = {12}, year = {2019}, month = {2019 Jul 10}, pages = {65}, abstract = {

Protein synthesis is crucial for maintaining synaptic plasticity and synaptic signalling. Here we have attempted to understand the role of RNA binding proteins, Fragile X Mental Retardation Protein (FMRP) and Moloney Leukemia Virus 10 (MOV10) protein in N-Methyl-D-Aspartate Receptor (NMDAR) mediated translation regulation. We show that FMRP is required for translation downstream of NMDAR stimulation and MOV10 is the key specificity factor in this process. In rat cortical synaptoneurosomes, MOV10 in association with FMRP and Argonaute 2 (AGO2) forms the inhibitory complex on a subset of NMDAR responsive mRNAs. On NMDAR stimulation, MOV10 dissociates from AGO2 and promotes the translation of its target mRNAs. FMRP is required to form MOV10-AGO2 inhibitory complex and to promote translation of MOV10 associated mRNAs. Phosphorylation of FMRP appears to be the potential switch for NMDAR mediated translation and in the absence of FMRP, the distinct translation response to NMDAR\ stimulation is lost. Thus, FMRP and MOV10 have an important regulatory role in NMDAR mediated translation at the synapse.

}, issn = {1756-6606}, doi = {10.1186/s13041-019-0473-0}, author = {Kute, Preeti Madhav and Ramakrishna, Sarayu and Neelagandan, Nagammal and Chattarji, Sumantra and Muddashetty, Ravi S} } @article {56658, title = {Rodent models of social stress and neuronal plasticity: relevance to depressive-like disorders.}, journal = {Behav Brain Res}, year = {2019}, month = {2019 Apr 22}, abstract = {

Exposure to severe or persistent social stress may lead to the development of psychiatric disorders such as anxiety and depression. These mood disorders are associated with structural alterations of neural architecture in limbic brain regions that control emotion, mood and cognition. Structural remodeling may either be a sign of successful adaptation, or of failure to do so. In neuropsychiatric disorders like depression structural remodeling involves apoptosis, reduced neurogenesis, and structural remodeling of neuronal dendrites which most likely reflects the latter. Here we review key findings from animal models of psychosocial stress that have been used to gain insights into the relation between stress-related behavioral disorders like depression and structural plasticity. Specifically, we focus on models having a high face validity like social defeat stress in the resident-intruder paradigm and chronic stress of social subordination in social housing conditions. Moderate to severe social stress appears to stimulate plasticity and neuronal growth in regions of the amygdala, whereas the effects in the hippocampus and prefrontal cortex tend to be opposite. A major focus of the current review is to characterize social stress induced structural changes in these brain regions, aiming to provide insight in pathways and factors that underlie behavioral effects of stress and depression.

}, issn = {1872-7549}, doi = {10.1016/j.bbr.2019.111900}, author = {Patel, Deepika and Kas, Martien J and Chattarji, Sumantra and Buwalda, Bauke} } @article {53186, title = {Stress Elicits Contrasting Effects on the Structure and Number of Astrocytes in the Amygdala versus Hippocampus.}, journal = {eNeuro}, volume = {6}, year = {2019}, month = {2019 Jan-Feb}, abstract = {

Stress causes divergent patterns of structural and physiological plasticity in the hippocampus versus amygdala. However, a majority of earlier studies focused primarily on neurons. Despite growing evidence for the importance of glia in health and disease, relatively little is known about how stress affects astrocytes. Further, previous work focused on hippocampal astrocytes. Hence, we examined the impact of chronic immobilization stress (2 h/d, 10 d), on the number and structure of astrocytes in the rat hippocampus and amygdala. We observed a reduction in the number of glial fibrillary acidic protein (GFAP)-positive astrocytes in the basal amygdala (BA), 1 d after the end of 10 d of chronic stress. Detailed morphometric analysis of individual dye-filled astrocytes also revealed a decrease in the neuropil volume occupied by these astrocytes in the BA, alongside a reduction in the volume fraction of fine astrocytic protrusions rather than larger dendrite-like processes. By contrast, the same chronic stress had no effect on the number or morphology of astrocytes in hippocampal area CA3. We also confirmed previous reports that chronic stress triggers dendritic hypertrophy in dye-filled BA principal neurons that were located adjacent to astrocytes that had undergone atrophy. Thus, building on earlier evidence for contrasting patterns of stress-induced plasticity in neurons across brain areas, our findings offer new evidence that the same stress can also elicit divergent morphological effects in astrocytes in the hippocampus versus the amygdala.

}, issn = {2373-2822}, doi = {10.1523/ENEURO.0338-18.2019}, author = {Naskar, Saptarnab and Chattarji, Sumantra} } @article {45306, title = {Timing is everything: differential effects of chronic stress on fear extinction.}, journal = {Psychopharmacology (Berl)}, volume = {236}, year = {2019}, month = {2018 Oct 10}, pages = {73-86}, abstract = {

RATIONALE: Stress disorders cause abnormal regulation of fear-related behaviors. In most rodent models of these effects, stress was administered before fear conditioning, thereby assessing its impact on both the formation and extinction of fear memories, not the latter alone. Here, we dissociated the two processes by also administering stress after fear conditioning, and then compared how pre-conditioning versus post-conditioning exposure to chronic stress affects subsequent acquisition and recall of fear extinction.

METHODS: Male Wistar rats were subjected to chronic immobilization stress (2\ h/day, 10\ days); the morphological effects of which were analyzed using modified Golgi-Cox staining across brain areas mediating the formation and extinction of fear memories. Separate groups of rats underwent fear conditioning followed by acquisition and recall of extinction, wherein stress was administered either before or after fear conditioning.

RESULTS: When fear memories were formed after chronic stress, both acquisition and retrieval of extinction was impaired. Strikingly, these deficits were absent when fear memories were formed before the same stress. Chronic stress also reduced dendritic spine density in the infralimbic prefrontal cortex, but enhanced it in the basolateral amygdala.

CONCLUSION: Chronic stress, administered either before or after fear learning, had distinct effects on the acquisition and recall of fear extinction memories. Stress also strengthened the structural basis of synaptic connectivity in the amygdala, but weakened it in the prefrontal cortex. Thus, despite eliciting a specific pattern of brain region-specific morphological changes, the timing of the same stress gave rise to strikingly different behavioral effects on the extinction of fear.

}, issn = {1432-2072}, doi = {10.1007/s00213-018-5053-y}, author = {Chakraborty, Prabahan and Chattarji, Sumantra} } @article {33717, title = {Discovery biology of neuropsychiatric syndromes (DBNS): a center for integrating clinical medicine and basic science.}, journal = {BMC Psychiatry}, volume = {18}, year = {2018}, month = {2018 Apr 18}, pages = {106}, abstract = {

BACKGROUND: There is emerging evidence that there are shared genetic, environmental and developmental risk factors in psychiatry, that cut across traditional diagnostic boundaries. With this background, the Discovery biology of neuropsychiatric syndromes (DBNS) proposes to recruit patients from five different syndromes (schizophrenia, bipolar disorder, obsessive compulsive disorder, Alzheimer{\textquoteright}s dementia and substance use disorders), identify those with multiple affected relatives, and invite these families to participate in this study. The families will be assessed: 1) To compare neuro-endophenotype measures between patients, first degree relatives (FDR) and healthy controls., 2) To identify cellular phenotypes which differentiate the groups., 3) To examine the longitudinal course of neuro-endophenotype measures., 4) To identify measures which correlate with outcome, and 5) To create a unified digital database and biorepository.

METHODS: The identification of the index participants will occur at well-established specialty clinics. The selected individuals will have a strong family history (with at least another affected FDR) of mental illness. We will also recruit healthy controls without family history of such illness. All recruited individuals (N = 4500) will undergo brief clinical assessments and a blood sample will be drawn for isolation of DNA and peripheral blood mononuclear cells (PBMCs). From among this set, a subset of 1500 individuals (300 families and 300 controls) will be assessed on several additional assessments [detailed clinical assessments, endophenotype measures (neuroimaging- structural and functional, neuropsychology, psychophysics-electroencephalography, functional near infrared spectroscopy, eye movement tracking)], with the intention of conducting repeated measurements every alternate year. PBMCs from this set will be used to generate lymphoblastoid cell lines, and a subset of these would be converted to induced pluripotent stem cell lines and also undergo whole exome sequencing.

DISCUSSION: We hope to identify unique and overlapping brain endophenotypes for major psychiatric syndromes. In a proportion of subjects, we expect these neuro-endophenotypes to progress over time and to predict treatment outcome. Similarly, cellular assays could differentiate cell lines derived from such groups. The repository of biomaterials as well as digital datasets of clinical parameters, will serve as a valuable resource for the broader scientific community who wish to address research questions in the area.

}, issn = {1471-244X}, doi = {10.1186/s12888-018-1674-2}, author = {Viswanath, Biju and Rao, Naren P and Narayanaswamy, Janardhanan C and Sivakumar, Palanimuthu T and Kandasamy, Arun and Kesavan, Muralidharan and Mehta, Urvakhsh Meherwan and Venkatasubramanian, Ganesan and John, John P and Mukherjee, Odity and Purushottam, Meera and Kannan, Ramakrishnan and Mehta, Bhupesh and Kandavel, Thennarasu and Binukumar, B and Saini, Jitender and Jayarajan, Deepak and Shyamsundar, A and Moirangthem, Sydney and Vijay Kumar, K G and Thirthalli, Jagadisha and Chandra, Prabha S and Gangadhar, Bangalore N and Murthy, Pratima and Panicker, Mitradas M and Bhalla, Upinder S and Chattarji, Sumantra and Benegal, Vivek and Varghese, Mathew and Reddy, Janardhan Y C and Raghu, Padinjat and Rao, Mahendra and Jain, Sanjeev} } @article {43851, title = {Extinction recall of fear memories formed before stress is not affected despite higher theta activity in the amygdala.}, journal = {Elife}, volume = {7}, year = {2018}, month = {2018 Aug 13}, abstract = {

Stress is known to exert its detrimental effects not only by enhancing fear, but also by impairing its extinction. However, in earlier studies stress exposure preceded both processes. Thus, compared to unstressed animals, stressed animals had to extinguish fear memories that were strengthened by prior exposure to stress. Here, we dissociate the two processes to examine if stress specifically impairs the acquisition and recall of fear extinction. Strikingly, when fear memories were formed before stress exposure, thereby allowing animals to initiate extinction from comparable levels of fear, recall of fear extinction was unaffected. Despite this, we observed a persistent increase in theta activity in the BLA. Theta activity in the mPFC, by contrast, was normal. Stress also disrupted mPFC-BLA theta-frequency synchrony and directional coupling. Thus, in the absence of the fear-enhancing effects of stress, the expression of fear during and after extinction reflects normal regulation of theta activity in the mPFC, not theta hyperactivity in the amygdala.

}, issn = {2050-084X}, doi = {10.7554/eLife.35450}, author = {Rahman, Mohammed Mostafizur and Shukla, Ashutosh and Chattarji, Sumantra} } @article {47057, title = {FMRP Interacts with C/D Box snoRNA in the Nucleus and Regulates Ribosomal RNA Methylation.}, journal = {iScience}, volume = {9}, year = {2018}, month = {2018 Nov 07}, pages = {399-411}, abstract = {

FMRP is an RNA-binding protein that is known to localize in the cytoplasm and in the nucleus. Here, we have identified an interaction of FMRP with a specific set of C/D box snoRNAs in the nucleus. C/D box snoRNAs guide 2{\textquoteright}O methylations of ribosomal RNA (rRNA) on defined sites, and this modification regulates rRNA folding and assembly of ribosomes. 2{\textquoteright}O methylation of rRNA is partial on several sites in human embryonic stem cells, which results in ribosomes with differential methylation patterns. FMRP-snoRNA interaction affects rRNA methylation on several of these sites, and in the absence of FMRP, differential methylation pattern of rRNA is significantly altered. We found that FMRP recognizes ribosomes carrying specific methylation patterns on rRNA and the recognition of methylation pattern by FMRP may potentially determine the translation status of its target mRNAs. Thus, FMRP integrates its function in the nucleus and in the cytoplasm.

}, issn = {2589-0042}, doi = {10.1016/j.isci.2018.11.007}, author = {D{\textquoteright}Souza, Michelle Ninochka and Gowda, Naveen Kumar Chandappa and Tiwari, Vishal and Babu, Rosana Ottakandathil and Anand, Praveen and Dastidar, Sudhriti Ghosh and Singh, Randhir and Selvaraja, Bhuvaneish and Pal, Rakhi and Ramesh, Arati and Chattarji, Sumantra and Chandran, Siddharthan and Gulyani, Akash and Palakodeti, Dasaradhi and Muddashetty, Ravi S} } @article {32473, title = {Hippocampal and amygdalar cell-specific translation is similar soon after stress but diverge over time.}, journal = {Hippocampus}, year = {2018}, month = {2018 Apr 07}, abstract = {

Stress is known to cause contrasting patterns of morphological and physiological plasticity in the hippocampus and amygdala. An obligatory cellular process underlying such neural changes is de novo translation and alterations in protein expression. Yet the nature of the translational response to stress in neurons remains largely unexplored. Even less is known about how glia are affected. Using a click-chemistry-based method to label the de novo proteome in live brain slices, we monitored translation in neurons and astrocytes of the basolateral amygdala (BLA) and dorsal hippocampal area CA3 (dCA3) in rats at different time-points after a single 2-hour exposure to immobilization stress. We observed enhancements in neuronal translation in both brain regions 1 hour after stress. This initial increase persisted in the BLA up to 10 days afterwards. In contrast, dCA3 neuronal translation gradually decreased to below control levels 10 days later. Translation profiles of dCA3 astrocytes followed timelines similar to neurons, but in BLA astrocytes translation peaked 1day later and remained elevated 10 days later. Together our results demonstrate that stress causes an immediate upregulation of protein synthesis in both amygdalar and hippocampal neurons and astrocytes. However, these two areas eventually exhibit opposite temporal profiles of protein expression well after the end of stress. These findings identify new metrics of stress-induced plasticity at the level of cell-type specific proteomic landscape that may provide important insights into the molecular basis of the divergent temporal effects of stress across brain regions and biological scales. This article is protected by copyright. All rights reserved.

}, issn = {1098-1063}, doi = {10.1002/hipo.22845}, author = {Madan, Jesvin S and Gupta, Kanika and Chattarji, Sumantra and Bhattacharya, Aditi} } @article {18678, title = {Activation of the same mGluR5 receptors in the amygdala causes divergent effects on specific versus indiscriminate fear.}, journal = {Elife}, volume = {6}, year = {2017}, month = {2017 May 30}, abstract = {

Although mGluR5-antagonists prevent fear and anxiety, little is known about how the same receptor in the amygdala gives rise to both. Combining in vitro and in vivo activation of mGluR5 in rats, we identify specific changes in intrinsic excitability and synaptic plasticity in basolateral amygdala neurons that give rise to temporally distinct and mutually exclusive effects on fear-related behaviors. The immediate impact of mGluR5 activation is to produce anxiety manifested as indiscriminate fear of both tone and context. Surprisingly, this state does not interfere with the proper encoding of tone-shock associations that eventually lead to enhanced cue-specific fear. These results provide a new framework for dissecting the functional impact of amygdalar mGluR-plasticity on fear versus anxiety in health and disease.

}, issn = {2050-084X}, doi = {10.7554/eLife.25665}, author = {Rahman, Mohammed Mostafizur and Kedia, Sonal and Fernandes, Giselle and Chattarji, Sumantra} } @article {8203, title = {Chronic but not acute immobilization stress stably enhances hippocampal CA1 metabotropic glutamate receptor dependent Long-Term Depression.}, journal = {Neurosci Lett}, volume = {633}, year = {2016}, month = {2016 Sep 20}, pages = {101-105}, abstract = {

Acute stress has been shown to facilitate but not increase metabotropic glutamate receptor (mGluR) mediated Long-Term Depression (LTD) in the hippocampus. However, the effect of chronic stress on mGluR dependent LTD has not been investigated. Moreover, whether stress leads to a transient modification LTD threshold or a more stable change in synaptic plasticity needs to be addressed. In the present study, we have explored the effects of both a ten-day long and a single day immobilization stress protocol on mGluR-LTD at the CA3:CA1synapse in the hippocampus of adult male Sprague-Dawley rats, a day after applying stress. Bath application of the selective group 1 mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) promoted robust LTD in hippocampal slices from control (i.e. un-stressed) animals. Administration of immobility stress for two hours per day for ten days significantly elevated this LTD to a level almost twice that of control, when observed 24h following the last stress event. Acute stress i.e. a single day of two hours of immobilization, however, failed to significantly enhance LTD, 24h later. These results demonstrate for the first time, that repeated exposure to stress, but not a single stress event, is required to bring about a stable alteration in mGluR mediated synaptic plasticity.

}, issn = {1872-7972}, doi = {10.1016/j.neulet.2016.09.031}, author = {Sengupta, Tathagata and Das, Rishi and Chattarji, Sumantra} } @article {9605, title = {The delayed strengthening of synaptic connectivity in the amygdala depends on NMDA receptor activation during acute stress.}, journal = {Physiol Rep}, volume = {4}, year = {2016}, month = {2016 Oct}, abstract = {

There is growing evidence that stress leads to contrasting patterns of structural plasticity in the hippocampus and amygdala, two brain areas implicated in the cognitive and affective symptoms of stress-related psychiatric disorders. Acute stress has been shown to trigger a delayed increase in the density of dendritic spines in the basolateral amygdala (BLA) of rodents. However, the physiological correlates of this delayed spinogenesis in the BLA remain unexplored. Furthermore, NMDA receptors (NMDARs) have been known to underlie chronic stress-induced structural plasticity in the hippocampus, but nothing is known about the role of these receptors in the delayed spinogenesis, and its physiological consequences, in the BLA following acute stress. Here, using whole-cell recordings in rat brain slices, we find that a single exposure to 2-h immobilization stress enhances the frequency, but not amplitude, of miniature excitatory postsynaptic currents (mEPSCs) recorded from principal neurons in the BLA 10\ days later. This was also accompanied by faster use-dependent block of NMDA receptor currents during repeated stimulation of thalamic inputs to the BLA, which is indicative of higher presynaptic release probability at these inputs 10\ days later. Furthermore, targeted in\ vivo infusion of the NMDAR-antagonist APV into the BLA during the acute stress prevents the increase in mEPSC frequency and spine density 10\ days later. Together, these results identify a role for NMDARs during acute stress in both the physiological and morphological strengthening of synaptic connectivity in the BLA in a delayed fashion. These findings also raise the possibility that activation of NMDA receptors during stress may serve as a common molecular mechanism despite the divergent patterns of plasticity that eventually emerge after stress in the amygdala and hippocampus.

}, issn = {2051-817X}, doi = {10.14814/phy2.13002}, author = {Yasmin, Farhana and Saxena, Kapil and McEwen, Bruce S and Chattarji, Sumantra} } @article {5295, title = {Early hippocampal volume loss as a marker of eventual memory deficits caused by repeated stress.}, journal = {Sci Rep}, volume = {6}, year = {2016}, month = {2016}, pages = {29127}, abstract = {

Exposure to severe and prolonged stress has detrimental effects on the hippocampus. However, relatively little is known about the gradual changes in hippocampal structure, and its behavioral consequences, over the course of repeated stress. Behavioral analyses during 10 days of chronic stress pointed to a delayed decline in spatial memory, the full impact of which is evident only after the end of stress. In contrast, concurrent volumetric measurements in the same animals revealed significant reduction in hippocampal volumes in stressed animals relative to their unstressed counterparts, as early as the third day of stress. Notably, animals that were behaviorally the worst affected at the end of chronic stress suffered the most pronounced early loss in hippocampal volume. Together, these findings support the view that not only is smaller hippocampal volume linked to stress-induced memory deficits, but it may also act as an early risk factor for the eventual development of cognitive impairments seen in stress-related psychiatric disorders.

}, issn = {2045-2322}, doi = {10.1038/srep29127}, author = {Rahman, Mohammed Mostafizur and Callaghan, Charlotte K and Kerskens, Christian M and Chattarji, Sumantra and O{\textquoteright}Mara, Shane M} } @article {1017, title = {Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS.}, journal = {Hum Mol Genet}, volume = {24}, year = {2015}, month = {2015 Nov 1}, pages = {5977-84}, abstract = {

Recent advances in techniques for manipulating genomes have allowed the generation of transgenic animals other than mice. These new models enable cross-mammalian comparison of neurological disease from core cellular pathophysiology to circuit and behavioural endophenotypes. Moreover they will enable us to directly test whether common cellular dysfunction or behavioural outcomes of a genetic mutation are more conserved across species. Using a new rat model of Fragile X Syndrome, we report that Fmr1 knockout (KO) rats exhibit elevated basal protein synthesis and an increase in mGluR-dependent long-term depression in CA1 of the hippocampus that is independent of new protein synthesis. These defects in plasticity are accompanied by an increase in dendritic spine density selectively in apical dendrites and subtle changes in dendritic spine morphology of CA1 pyramidal neurons. Behaviourally, Fmr1 KO rats show deficits in hippocampal-dependent, but not hippocampal-independent, forms of associative recognition memory indicating that the loss of fragile X mental retardation protein (FMRP) causes defects in episodic-like memory. In contrast to previous reports from mice, Fmr1 KO rats show no deficits in spatial reference memory reversal learning. One-trial spatial learning in a delayed matching to place water maze task was also not affected by the loss of FMRP in rats. This is the first evidence for conservation across mammalian species of cellular and physiological hippocampal phenotypes associated with the loss of FMRP. Furthermore, while key cellular phenotypes are conserved they manifest in distinct behavioural dysfunction. Finally, our data reveal novel information about the selective role of FMRP in hippocampus-dependent associative memory.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddv299}, author = {Till, Sally M and Asiminas, Antonis and Jackson, Adam D and Katsanevaki, Danai and Barnes, Stephanie A and Osterweil, Emily K and Bear, Mark F and Chattarji, Sumantra and Wood, Emma R and Wyllie, David J A and Kind, Peter C} } @article {909, title = {The dynamic impact of repeated stress on the hippocampal spatial map.}, journal = {Hippocampus}, volume = {25}, year = {2015}, month = {2015 Jan}, pages = {38-50}, abstract = {

Stress alters the function of many physiological processes throughout the body, including in the brain. A neural circuit particularly vulnerable to the effects of stress is the hippocampus, a key component of the episodic and spatial memory system in both humans and rodents. Earlier studies have provided snapshots of morphological, molecular, physiological and behavioral changes in the hippocampus following either acute or repeated stress. However, the cumulative impact of repeated stress on in vivo hippocampal physiology remains unexplored. Here we report the stress-induced modulation of the spatially receptive fields of the hippocampal CA1 {\textquoteright}place cells{\textquoteright} as mice explore familiar and novel tracks after 5 and 10 days of immobilization stress. We find that similar to what has been observed following acute stress, five days of repeated stress results in decreased excitability of CA1 pyramidal cells. Following ten days of chronic stress, however, this decreased hippocampal excitability is no longer evident, suggesting adaptation may have occurred. In addition to these changes in neuronal excitability, we find deficient context discrimination, wherein both short-term and chronic stress impair the ability of the hippocampus to unambiguously distinguish novel and familiar environments. These results suggest that a loss of network flexibility may underlie some of the behavioral deficits accompanying chronic stress.

}, keywords = {Animals, Behavior, Animal, CA1 Region, Hippocampal, Discrimination (Psychology), Generalization (Psychology), Male, Mice, Mice, Inbred C57BL, Spatial Memory, Stress, Psychological, Time Factors}, issn = {1098-1063}, doi = {10.1002/hipo.22348}, author = {Tomar, Anupratap and Polygalov, Denis and Chattarji, Sumantra and McHugh, Thomas J} } @article {1016, title = {Neighborhood matters: divergent patterns of stress-induced plasticity across the brain.}, journal = {Nat Neurosci}, volume = {18}, year = {2015}, month = {2015 Oct}, pages = {1364-75}, abstract = {

The fact that exposure to severe stress leads to the development of psychiatric disorders serves as the basic rationale for animal models of stress disorders. Clinical and neuroimaging studies have shown that three brain areas involved in learning and memory--the hippocampus, amygdala and prefrontal cortex--undergo distinct structural and functional changes in individuals with stress disorders. These findings from patient studies pose several challenges for animal models of stress disorders. For instance, why does stress impair cognitive function, yet enhance fear and anxiety? Can the same stressful experience elicit contrasting patterns of plasticity in the hippocampus, amygdala and prefrontal cortex? How does even a brief exposure to traumatic stress lead to long-lasting behavioral abnormalities? Thus, animal models of stress disorders must not only capture the unique spatio-temporal features of structural and functional alterations in these brain areas, but must also provide insights into the underlying neuronal plasticity mechanisms. This Review will address some of these key questions by describing findings from animal models on how stress-induced plasticity varies across different brain regions and thereby gives rise to the debilitating emotional and cognitive symptoms of stress-related psychiatric disorders.

}, keywords = {Animals, Brain, Humans, Neuronal Plasticity, Stress, Psychological}, issn = {1546-1726}, doi = {10.1038/nn.4115}, author = {Chattarji, Sumantra and Tomar, Anupratap and Suvrathan, Aparna and Ghosh, Supriya and Rahman, Mohammed Mostafizur} } @article {907, title = {Neuronal encoding of the switch from specific to generalized fear.}, journal = {Nat Neurosci}, volume = {18}, year = {2015}, month = {2015 Jan}, pages = {112-20}, abstract = {

Fear memories are crucial for survival. However, excessive generalization of such memories, characterized by a failure to discriminate dangerous from safe stimuli, is common in anxiety disorders. Neuronal encoding of the transition from cue-specific to generalized fear is poorly understood. We identified distinct neuronal populations in the lateral amygdala (LA) of rats that signaled generalized versus cue-specific associations and determined how their distributions switched during fear generalization. Notably, the same LA neurons that were cue specific before the behavioral shift to generalized fear lost their specificity afterwards, thereby tilting the balance of activity toward a greater proportion of generalizing neurons. Neuronal activity in the LA, but not the auditory cortex, was necessary for fear generalization. Furthermore, targeted activation of cAMP-PKA signaling in the LA increased neuronal excitability of LA neurons and led to generalized fear. These results provide a cellular basis in the amygdala for the alteration of emotional states from normal to pathological fear.

}, keywords = {Animals, Auditory Cortex, Conditioning, Operant, Cyclic AMP-Dependent Protein Kinases, Discrimination (Psychology), Fear, GABA Agonists, Generalization (Psychology), Male, Mental Recall, Neuronal Plasticity, Neurons, Rats, Rats, Sprague-Dawley, Signal Transduction}, issn = {1546-1726}, doi = {10.1038/nn.3888}, author = {Ghosh, Supriya and Chattarji, Sumantra} }