Background The prefrontal cortex (PFC) plays a critical role in regulating emotional behaviors, and dysfunction of PFC-dependent networks has been broadly implicated in mediating stress-induced behavioral disorders including major depressive disorder (MDD). Methods Here we acquire multi-circuit in vivo activity from eight cortical and limbic brain regions as mice are subjected to the tail suspension test (TST) and an open field test (OFT). We use a linear decoder to determine whether cellular responses across each of the cortical and limbic areas signal movement during the TST and OFT. We then perform repeat behavioral testing to identify which brain areas show cellular adaptations that signal the increase in immobility induced by repeat TST exposure. Results The increase in immobility observed during repeat TST exposure is linked to a selective functional upregulation of cellular activity in infralimbic cortex (IL) and medial dorsal thalamic (Thal), and an increase in the spatiotemporal dynamic interaction between these structures. Inducing this spatiotemporal dynamic using “closed-loop” optogenetic stimulation is sufficient to increase movement in the TST in stress-naïve mice, while stimulating above the carrier frequency of this circuit suppressed movement. This demonstrates that the adaptations in IL-Thal circuitry observed after stress reflect a compensatory mechanism whereby the brain drives neural systems to counterbalance stress effects. Conclusion Our findings provide evidence that targeting endogenous spatiotemporal dynamics is a potential therapeutic approach for treating stress-induced behavioral disorders, and that dynamics are a critical axis of manipulation for causal optogenetic studies.

A B S T R A C TAnti-HIV-1 drug design has been notably challenging due to the virus' ability to mutate and develop immunity against commercially available drugs. The aims of this project were to develop a series of fleximer base analogues that not only possess inherent flexibility that can remain active when faced with binding site mutations, but also target a non-canonical, highly conserved target: the nucleocapsid protein of HIV (NC). The compounds were predicted by computational studies not to function via zinc ejection, which would endow them with significant advantages over non-specific and thus toxic zinc-ejectors. The target fleximer bases were synthesized using palladium-catalyzed cross-coupling techniques and subsequently tested against NC and HIV-1. The results of those studies are described herein.

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