Prefrontal-Accumbens Neurocircuits Mediating Response to Social Stress

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PROJECT SUMMARY/ABSTRACT (revised) Mal-adaptations to stress often leads to impaired social behavior, a shared domain across many neuropsychiatric conditions. While it is well-established that environmental factors, such as stress, play an etiology role, the brain mechanisms, particularly the role of specific neural circuits mediating the maladaptive responses, remain to be elucidated. Chronic social defeat stress (cSDS) in mice is a highly relevant, validated model to study brain circuit mechanisms related to stress. cSDS has been shown to induce morphological and functional changes in multiple brain regions including the medial prefrontal cortex (mPFC), which contains heterogeneous cell types and is interconnected with other limbic brain regions. Using recently developed neuronal activity reporter mouse lines, termed fosTRAP and TRAP2, the applicants’ laboratories have determined that acute (aSDS) and chronic (cSDS) social defeat stress activate distinct populations of projection neurons in the mPFC. The goal of this study is to determine whether specific circuit connectivity is pertinent to stress-induced social impairment and if novel therapeutic intervention strategies could be devised to selectively target the relevant circuits to combat the social deficits and alleviate off target effects. The expertise of two laboratories (Ferguson- mouse behavior, molecular biology and bioinformatics; Qiu-neurophysiology and functional circuit mapping, optogenetics) will be combined to test the hypothesis that cSDS-induced, impaired social behaviors are encoded within a specific neural circuit in the mPFC. The PIs will employ a TRAP2 reporter mouse line to gain genetic access to the mPFC neurons that are activated by cSDS, followed by investigation of: Aim 1) whether disrupted synaptic homeostasis selectively occurs in NAc-projecting mPFC neuronal populations that are activated by the cSDS, and whether disrupted synaptic homeostasis occurs selectively in the mice susceptible to social impairment. In Aim 2, this team will use targeted optogenetic manipulation of neural activity in the cSDS-activated mPFC projection neurons that also selectively express excitatory or inhibitory opsins. The investigators will test the novel hypothesis that optogenetic inhibition of this specific neuron ensemble during the cSDS confers resilience, while repeated activation of these neurons leads to susceptibility to social impairments. Aim 3 will investigate potential dysregulated gene networks in cSDS-activated mPFC neurons and to what extent such changes depend on SIRT1, a major human genetic risk factor for depression, through an innovative combination of cSDS in TRAP2 and RiboTag mice and bioinformatics analyses on RNAseq data collected from both male and female mice. Impact: Successful completion of these aims could reveal a paradigm-shifting practice in circuit-based therapeutics aimed at restoring prefrontal synaptic homeostasis and could establish a specific corticolimbic circuit as a lead intervention target for preventing the development of stress induced circuit pathology, which is otherwise not possible by previous studies examining an indiscriminate wholesale population of PFC neurons.