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Cited by 101Neurotransmitter Receptor Influence on BehaviorStress Responses and CortisolNeuroscience and Neuropharmacology Research

Androgen-Dependent Excitability of Mouse Ventral Hippocampal Afferents to Nucleus Accumbens Underlies Sex-Specific Susceptibility to Stress

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Williams, Elizabeth S., Manning, Claire E., Eagle, Andrew L., Swift-Gallant, Ashlyn, Duque-Wilckens, Natalia, Chinnusamy, Sadhana, Moeser, Adam, Jordan, Cynthia +2 more·2020·Biological Psychiatry
DOI 10.1016/j.biopsych.2019.08.006PMC PMC7035179
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Abstract

Background Depression affects women nearly twice as often as men, but the neurobiological underpinnings of this discrepancy are unclear. Preclinical studies in male mice suggest that activity of ventral hippocampus (vHPC) neurons projecting to the nucleus accumbens (NAc) regulates mood-related behavioral responses to stress. We sought to characterize this circuit in both sexes and to investigate its role in potential sex differences in models of depression. Methods We used male and female adult C57BL/6J mice in the subchronic variable stress model to precipitate female-specific reduction in sucrose preference and performed gonadectomies to test the contributions of gonadal hormones to this stress response. In addition, ex vivo slice electrophysiology of transgenic Cre-inducible Rosa-eGFP-L10a mice in combination with retrograde viral tracing to identify circuits was used to test contributions of gonadal hormones to sex differences in vHPC afferents. Finally, we used an intersecting viral DREADD (designer receptor exclusively activated by designer drugs) strategy to manipulate vHPC-NAc excitability directly in awake behaving mice. Results We show a testosterone-dependent lower excitability in male versus female vHPC-NAc neurons and corresponding testosterone-dependent male resilience to reduced sucrose preference after subchronic variable stress. Importantly, we show that long-term DREADD stimulation of vHPC-NAc neurons causes decreased sucrose preference in male mice after subchronic variable stress, whereas DREADD inhibition of this circuit prevents this effect in female mice. Conclusions We demonstrate a circuit-specific sex difference in vHPC-NAc neurons that is dependent on testosterone and causes susceptibility to stress in female mice. These data provide a substantive mechanism linking gonadal hormones to cellular excitability and anhedonia-a key feature in depressive states.

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Authors
Williams, E. S., Manning, C. E., Eagle, A. L., Swift-Gallant, A., Duque-Wilckens, N., Chinnusamy, S., Moeser, A., Jordan, C., Leinninger, G., & Robison, A. J.
Affiliations
Michigan State University (US)
Corresponding author
Robison, Alfred Jay
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2020-03
Volume
87
Issue
6
Pages
492-501
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2019.08.006
PMC
PMC7035179
OpenAlex
W2969901945
Cited by
101
References
9
Citations by year
2026: 12 · 2025: 13 · 2024: 16 · 2023: 14 · 2022: 13 · 2021: 23 · 2020: 9 · 2019: 1
FWCI
5.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Mental Health (MH111604)
  • National Institutes of Neurological Disease and Stroke (NS085171)
  • National Institutes of Drug Abuse (DA040621, DA040621-03S1)
  • Avielle Foundation
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
sex differences in depression, ventral hippocampus, nucleus accumbens, testosterone, gonadal hormones, neuronal excitability, anhedonia, stress vulnerability, gonadectomy, depression in women
MeSH terms
Androgens, Animals, Female, Hippocampus, Male, Mice, Inbred C57BL, Mice, Transgenic, Nucleus Accumbens, Mice

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