Dynamically Timed Stimulation of Corticolimbic Circuitry Activates a Stress-Compensatory Pathway

Abstract Background The prefrontal cortex plays a critical role in regulating emotional behaviors, and dysfunction of prefrontal cortex–dependent networks has been broadly implicated in mediating stress-induced behavioral disorders including major depressive disorder. Methods Here we acquired multicircuit in vivo activity from eight cortical and limbic brain regions as mice were subjected to the tail suspension test (TST) and an open field test. We used a linear decoder to determine whether cellular responses across each of the cortical and limbic areas signal movement during the TST and open field test. We then performed 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 and medial dorsal thalamus, and to 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-naive mice, while stimulating above the carrier frequency of this circuit suppressed movement. This demonstrates that the adaptations in infralimbic cortex–medial dorsal thalamus circuitry observed after stress reflect a compensatory mechanism whereby the brain drives neural systems to counterbalance stress effects. Conclusions 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.