Circuit-specific hippocampal \u0394FosB underlies resilience to stress-induced social avoidance

Andrew L Eagle,Claire E Manning,Paula A Gajewski,Rachel L Neve,Seda Akguen,Ryan M Bastle,Wilson Endege,Yoshinori N Ohnishi,Alfred J Robison,Alexis J Wirtz,Frederick M Boyce,Katie Brandel-Ankrapp,Amber Garrison,Elizabeth S Williams,Michelle Mazei-Robison,Ian Maze

doi:10.1038/s41467-020-17825-x

Abstract

Chronic stress is a key risk factor for mood disorders like depression, but the stress-induced changes in brain circuit function and gene expression underlying depression symptoms are not completely understood, hindering development of novel treatments. Because of its projections to brain regions regulating reward and anxiety, the ventral hippocampus is uniquely poised to translate the experience of stress into altered brain function and pathological mood, though the cellular and molecular mechanisms of this process are not fully understood. Here, we use a novel method of circuit-specific gene editing to show that the transcription factor ΔFosB drives projection-specific activity of ventral hippocampus glutamatergic neurons causing behaviorally diverse responses to stress. We establish molecular, cellular, and circuit-level mechanisms for depression- and anxiety-like behavior in response to stress and use circuit-specific gene expression profiling to uncover novel downstream targets as potential sites of therapeutic intervention in depression.

Highlights

Chronic stress is a key risk factor for mood disorders like depression, but the stress-induced changes in brain circuit function and gene expression underlying depression symptoms are not completely understood, hindering development of novel treatments
Expanding upon our previous findings in the dHPC21,22, we found that ΔFosB was induced in all subregions of the ventral hippocampus (vHPC) following repeated treatment with the antidepressant fluoxetine (Fig. S1d, e), a selective serotonin reuptake inhibitor
ΔFosB is induced in vHPC by both stress and antidepressants, which strongly suggests that stress-induction of ΔFosB in vHPC is a compensatory response to counteract the effects of stress, i.e., mediating stress resilience as it does in NAc14

Summary

Introduction

Chronic stress is a key risk factor for mood disorders like depression, but the stress-induced changes in brain circuit function and gene expression underlying depression symptoms are not completely understood, hindering development of novel treatments. We use a novel method of circuit-specific gene editing to show that the transcription factor ΔFosB drives projection-specific activity of ventral hippocampus glutamatergic neurons causing behaviorally diverse responses to stress. Cellular, and circuitlevel mechanisms for depression- and anxiety-like behavior in response to stress and use circuit-specific gene expression profiling to uncover novel downstream targets as potential sites of therapeutic intervention in depression. ΔFosB is induced throughout HPC by stress and antidepressant treatment[13,21,22,23], and vHPC CA3 ΔFosB is critical for the prophylactic effects of ketamine on stress responses[23] This indicates that ΔFosB is a critical modulator of vHPC function and may orchestrate long-term alterations in gene expression underlying depressive and anxiety disorders. We show that ΔFosB regulates the excitability of this circuit and we identify potential downstream gene targets in this circuit that may underlie stress resilience

Methods

Results

Conclusion