Abstract

High emotional reactivity is associated with activation of a molecularly distinct hippocampal-amygdala circuit modulated by the glucocorticoid receptor

Kumar V, Wei Q, Moore SJ, Li F, Murphy GG, Watson SJ, Akil H
51st Annual Meeting of the Society for Neuroscience. 2022.

Abstract

Background: Altered emotional reactivity, as clinically observed in mood and affective disorders, is typically characterized by magnitudes of valence, intensity, duration and speed of shifting. The molecular and neural circuitry which regulate the dynamic nature of emotionality is yet to be fully understood. Our previous work showed that glucocorticoid receptor overexpression in the forebrain (GRov) leads to the development of a unique mouse model of high emotional reactivity with increased anxiety behavior and greater shifts in the emotional responses. In the present study, we sought to understand the neural circuitry associated with this lifelong increased emotional lability which gets established early in the development phase. Methods: The ventral dentate gyrus (vDG) of wild-type (WT) and GRov mice were selectively stimulated through optogenetics and anxiety responses were measured using elevated plus maze test. Neuronal activity as indexed by the c-Fos and cell type specificity patterns were analyzed through fluorescence in situ hybridization chain reaction (HCR-FISH) methods. Results: Our findings showed that the optogenetic stimulation in the vDG of GRov mice leads to a greater range and a prolonged duration of anxiety behavior relative to WT, and this amplified behavioral response was found to be associated with cFos-based increased neuronal activity in specific brain regions, particularly the ventral CA1 and the basal posterior amygdala complex. HCR-FISH studies provided evidence for altered glutamatergic/GABAergic activation balance within these sub-regions. Furthermore, we identified increased activation of molecularly distinct subpopulations: calbindin1+ glutamatergic neurons in the vCA1 and DARPP-32/Ppp1r1b+ glutamatergic neurons in the posterior basolateral amygdala. Conclusion: We propose that a molecularly distinct hippocampal-amygdala circuit is shaped during early life by the stress system, and in particular the glucocorticoid receptors, and tunes the dynamics of emotional responses.