@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 {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 {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 {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 {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} }