The ventral hippocampus (vHPC) plays a crucial role in regulating emotional responses to stress, which can contribute to neuropsychiatric disorders like depression. Glutamatergic vHPC neurons project to brain regions involved in stress and mood, such as the nucleus accumbens (NAc) and basolateral amygdala (BLA). Previous research has linked the hyperexcitability of NAc-projecting vHPC neurons to stress-induced social avoidance and anhedonia. However, the underlying molecular mechanisms within the vHPC that modulate these target regions remain unclear. Stress affects gene expression in vHPC neurons, but the circuit-specific mechanisms are poorly understood. ΔFosB, a stable transcription factor induced by chronic neuronal activity, is implicated in mediating stress susceptibility in the NAc and regulating hippocampal function. This study investigates the role of ΔFosB in vHPC neurons projecting to the NAc in resilience to stress-induced social avoidance, aiming to uncover molecular mechanisms and potential therapeutic targets.

Existing literature highlights the role of the ventral hippocampus in stress response and mood regulation. Studies have shown that the hyperexcitability of ventral hippocampal neurons projecting to the nucleus accumbens is linked to stress-induced behavioral changes, including social avoidance and anhedonia. ΔFosB, a transcription factor, has been established as a key player in mediating stress susceptibility in the nucleus accumbens and its role in dorsal hippocampal function is also known. However, its role in the ventral hippocampus, specifically in mediating circuit-specific responses to stress, remained largely unexplored prior to this study. Previous research demonstrated that ΔFosB is induced in the hippocampus by both stress and antidepressant treatment, suggesting its potential involvement in the compensatory response to stress and the mechanisms of resilience.

This study employed a multi-faceted approach combining behavioral analysis, circuit-specific gene editing, and molecular techniques. Chronic social defeat stress (CSDS) was used to induce depressive-like behaviors in mice. To investigate the role of ΔFosB in vHPC-NAc projections, the researchers used a mouse line expressing Cre-dependent GFP, combined with retrograde viral vectors expressing Cre to label vHPC-NAc neurons. They then used circuit-specific CRISPR-Cas9 gene editing to manipulate ΔFosB expression within these projections, either silencing or overexpressing it. To further quantify the stress-induced changes, circuit-specific translating ribosome affinity purification (TRAP) was used to enrich for actively translating FosB and ΔFosB mRNA in vHPC-NAc neurons. Behavioral tests included social interaction tests, passive avoidance learning, and elevated plus maze to assess social avoidance, learning, and anxiety-like behaviors, respectively. Whole-cell patch-clamp electrophysiology was used to examine the effect of ΔFosB on the excitability of vHPC neurons. Finally, circuit-specific TRAP combined with RNA sequencing was used to identify downstream gene targets of ΔFosB in vHPC-NAc neurons. The researchers also conducted experiments to examine vHPC-BLA projections using similar methods and validated findings in cultured Neuro2a cells.

Chronic social defeat stress increased ΔFosB expression in vHPC neurons projecting to the NAc. Inhibition of ΔFosB in vHPC, but not dHPC, reduced resilience to stress-induced social avoidance. Circuit-specific CRISPR-Cas9-mediated knockout (KO) of FosB in vHPC-NAc neurons enhanced stress-induced social avoidance without affecting baseline anxiety or passive avoidance learning. However, FosB KO in vHPC-BLA neurons impaired passive avoidance learning and reduced anxiety-like behavior. ΔFosB overexpression in vHPC-NAc neurons rescued the stress-induced social avoidance phenotype in FosB KO mice, indicating that ΔFosB is both necessary and sufficient for resilience to stress-induced social avoidance. Electrophysiological recordings showed that ΔFosB overexpression reduced the excitability of vHPC neurons, while FosB KO increased their excitability. Circuit-specific TRAP-Seq identified hundreds of potential ΔFosB target genes, including *Adra2a* (encoding the α2a adrenergic receptor), which was confirmed to be downregulated by ΔFosB both in vitro and in vivo. The study demonstrated that ΔFosB acts to reduce excitability and enhance resilience to stress through this regulation of downstream gene targets in vHPC.

This study provides strong evidence for a circuit-specific role of ΔFosB in mediating resilience to stress-induced social avoidance. The findings highlight the importance of considering not only cell type heterogeneity but also circuit-specific projections when investigating the complex role of brain regions in behavioral responses to stress. The identification of downstream gene targets, such as *Adra2a*, offers potential therapeutic targets for interventions aimed at enhancing stress resilience. The results contribute significantly to our understanding of the molecular mechanisms underlying depression and anxiety disorders and could pave the way for the development of novel treatments targeting specific brain circuits.

This study demonstrates that ΔFosB in vHPC neurons projecting to the NAc is crucial for resilience to stress-induced social avoidance. The use of circuit-specific gene editing and RNA sequencing identified potential downstream targets of ΔFosB that could serve as therapeutic avenues. Future research should focus on further investigating the identified gene targets and exploring the potential for circuit-specific interventions to treat depression and anxiety.

The study primarily used male mice, limiting the generalizability to females. While the researchers validated their findings in cultured cells, further in vivo validation of identified gene targets is warranted. The use of a chronic stress paradigm may not fully capture the complexity of stress in humans, and individual variation in stress responses was not explicitly addressed. The study focused on a limited set of behaviors; further research is necessary to determine the full scope of ΔFosB's role in other stress-related behaviors.