Dentate gyrus activin signaling mediates the antidepressant response

Mark M Gergues,Christine N Yohn,Marjorie R Levinstein,Anusha Bharadia,Benjamin Adam Samuels

doi:10.1038/s41398-020-01156-y

Abstract

Antidepressants that target monoaminergic systems, such as selective serotonin reuptake inhibitors (SSRIs), are widely used to treat neuropsychiatric disorders including major depressive disorder, several anxiety disorders, and obsessive-compulsive disorder. However, these treatments are not ideal because only a subset of patients achieve remission. The reasons why some individuals remit to antidepressant treatments while others do not are unknown. Here, we developed a paradigm to assess antidepressant treatment resistance in mice. Exposure of male C57BL/6J mice to either chronic corticosterone administration or chronic social defeat stress induces maladaptive affective behaviors. Subsequent chronic treatment with the SSRI fluoxetine reverses these maladaptive affective behavioral changes in some, but not all, of the mice, permitting stratification into persistent responders and non-responders to fluoxetine. We found several differences in expression of Activin signaling-related genes between responders and non-responders in the dentate gyrus (DG), a region that is critical for the beneficial behavioral effects of fluoxetine. Enhancement of Activin signaling in the DG converted behavioral non-responders into responders to fluoxetine treatment more effectively than commonly used second-line antidepressant treatments, while inhibition of Activin signaling in the DG converted responders into non-responders. Taken together, these results demonstrate that the behavioral response to fluoxetine can be bidirectionally modified via targeted manipulations of the DG and suggest that molecular- and neural circuit-based modulations of DG may provide a new therapeutic avenue for more effective antidepressant treatments.

Highlights

32–35 million adults in the US population (16%) experience an episode of major depression in their lifetime[1], and commonly used treatments, such as selective serotonin reuptake inhibitors (SSRIs), are not ideal since only a subset of patients (~33%) achieves remission with initial treatment[2,3]
To better understand the treatment resistance phenotype following chronic stress and antidepressant treatment, we began by exposing a cohort (n = 70) of group housed 8-week-old male C57BL/6J mice to chronic administration with either vehicle or corticosterone (CORT, 5 mg/kg/day via drinking water)
Chronic CORT administration at this dosage induces several maladaptive avoidance behaviors, including increased latency to feed in Novelty Suppressed Feeding (NSF) and decreased open arm entries and duration in the elevated plus maze (EPM)[13]

Summary

Introduction

32–35 million adults in the US population (16%) experience an episode of major depression in their lifetime[1], and commonly used treatments, such as selective serotonin reuptake inhibitors (SSRIs), are not ideal since only a subset of patients (~33%) achieves remission with initial treatment[2,3]. Despite this large population of non-remitters, the reasons why some individuals remit to antidepressant treatments while others do not remain unknown. Direct peptide infusions of brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), or Activin A into DG yield an antidepressant-like behavioral response[21,22,23,24,25]

Methods

Results

Conclusion