223. SEX DIFFERENCES IN THE AMYGDALA AND BED NUCLEUS OF THE STRIA TERMINALIS CIRCUIT INVOLVING IN MEMORY RETRIEVAL OF VICARIOUS FEAR CONDITIONING

Abstract Background Due to its value of survival, vicarious fear learning becomes a germane paradigm studying the transmission of threat information between individuals. In the context of literature on fear- and anxiety-like behaviors, the status quo is male animal models outnumber female ones. Obviously, it remains a paucity of empirical studies addressing sex differences in vicarious fear learning and memory. Understanding the neural circuits orchestrating sex-dimorphic vicarious fear learning is expected to dovetail the development of precision medicine on one hand. Showcasing the respective molecular underpinnings of vicarious learning may shed light on sex-specific behavioral and/or pharmacological treatments of choice on the other. Aims & Objectives This study was undertaken to identify the neural circuits mediating retrieval phase of vicarious fear memory by using observers’ and demonstrators’ fear conditioning paradigms and chemogenetic tools in both male and female mice. Method Intersectional viral strategy and virus-carrying hM3Dq and hM4Di DREADDs were employed to selectively modulate GABAergic and glutamatergic neuronal activity in basolateral amygdala (BLA) and posteroventral medial amygdala (MePV). Mice received intra-BLA or -MePV infusions with AAV9-hSyn-DIO-hM3Dq-mCherry or AAV5-hSyn-DIO-hM4Di-mCherry and intra-bed nucleus of the stria terminalis (BNST) infusions of AAV2/9-mDlx-Cre or AAV5-CamKII-Cre. Mouse observers were individually subjected to an observational compartment next to the demonstrators’ training compartment wherein three demonstrators received 3 consecutive days of daily fear training, consisting of presence of vanilla odors contingent on the delivery of 30 pseudo-randomly-arranged footshocks (0.5 mA, 2 s in duration per shock) in 30 minutes. And vanilla odors-induced freezing response (FR) was used to indicate observers’ vicarious fear learning magnitude. Approximately 24 hours after the conclusion of such vicarious fear learning regimen, all observers received vanilla odors-induced FR test and a designer drug, compound 21 (C21), was given 40 min prior to the FR test. Results Inactivating MePV-BNST glutamatergic neuron was found to produce a decrease in their FR magnitudes in male and female observers, while exciting BLA-BNST GABAergic neuron rendered a decline in vanilla-induced FR magnitudes in male, but not female, observers. Notably, presentation of conditioned auditory responses (acoustic sound from demonstrators receiving odors and footshocks) resulted in escalated FR magnitude in male mice while no such changes in female mice. Moreover, activating BLA-BNST GABAergic neuron, not inhibiting MePV-BNST glutamatergic neuron, dampened demonstrators’ sound-induced FR in male mice. Discussion & Conclusions These results, taken together, suggest that 1) MePV-BNST glutamatergic hyperactivity is necessary for memory retrieval of such vicarious fear conditioning in both male and female mouse observers, while BLA-BNST GABAergic hypoactivity is permissive only for male, but not female mouse observers; 2) mouse demonstrators’ auditory cues seem to be as important as olfactory cues in facilitating such vicarious fear learning in male, but not in female, mouse observers. 3) BLA-BNST GABA neuronal activity plays a role in mediating such fear-conditioned memory retrieval in male observers.