@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 {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 {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} }