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Cited by 55Neurotransmitter Receptor Influence on BehaviorTreatment of Major DepressionStress Responses and Cortisol

Chronic social defeat stress impairs goal-directed behavior through dysregulation of ventral hippocampal activity in male mice

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Yoshida, Keitaro, Drew, Michael R., Kono, Anna, Mimura, Masaru, Takata, Norio, Tanaka, Kenji F.·2021·Neuropsychopharmacology
DOI 10.1038/s41386-021-00990-yPMC PMC8280175
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Abstract

Chronic stress is a risk factor for a variety of psychiatric disorders, including depression. Although impairments to motivated behavior are a major symptom of clinical depression, little is known about the circuit mechanisms through which stress impairs motivation. Furthermore, research in animal models for depression has focused on impairments to hedonic aspects of motivation, whereas patient studies suggest that impairments to appetitive, goal-directed motivation contribute significantly to motivational impairments in depression. Here, we characterized goal-directed motivation in repeated social defeat stress (R-SDS), a well-established mouse model for depression in male mice. R-SDS impaired the ability to sustain and complete goal-directed behavior in a food-seeking operant lever-press task. Furthermore, stress-exposed mice segregated into susceptible and resilient subpopulations. Interestingly, susceptibility to stress-induced motivational impairments was unrelated to stress-induced social withdrawal, another prominent effect of R-SDS in mouse models. Based on evidence that ventral hippocampus (vHP) modulates sustainment of goal-directed behavior, we monitored vHP activity during the task using fiber photometry. Successful task completion was associated with suppression of ventral hippocampal neural activity. This suppression was diminished after R-SDS in stress-susceptible but not stress-resilient mice. The serotonin selective reuptake inhibitor (SSRI) escitalopram and ketamine both normalized vHP activity during the task and restored motivated behavior. Furthermore, optogenetic vHP inhibition was sufficient to restore motivated behavior after stress. These results identify vHP hyperactivity as a circuit mechanism of stress-induced impairments to goal-directed behavior and a putative biomarker that is sensitive to antidepressant treatments and that differentiates susceptible and resilient individuals.

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  • Chronic social stress, particularly cSDS, is one of the most potent environmental risk factors precipitating depressive symptoms, as shown in human epidemiological data and animal models.

    “Chronic social stress, particularly paradigms like chronic social defeat stress (cSDS), stands out as one of the most potent environmental risk factors precipitating depressive symptoms, as demonstrated in both human epidemiological data and well - established animal models of depression [4–6].”

    From A nucleus accumbens-projecting prefrontal cortex circuit underlies chronic social stress-induced depression-like behaviors (2026) · cites this paper as [6]

    The Introduction calls stress a major risk factor for mood disorders and describes chronic social defeat stress as an animal model; the Results report stress-related behavioral changes in mice. The paper does not establish that chronic social stress is one of the most potent environmental risk factors, or present human epidemiological data demonstrating that specific claim. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Yoshida, K., Drew, M. R., Kono, A., Mimura, M., Takata, N., & Tanaka, K. F.
Affiliations
  • Keio University (JP)
  • The University of Texas at Austin (US)
Corresponding author
Tanaka, Kenji F.
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2021-03-10
Volume
46
Issue
9
Pages
1606-1616
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/s41386-021-00990-y
PMC
PMC8280175
OpenAlex
W3134927269
Cited by
55
References
11
Citations by year
2026: 9 · 2025: 12 · 2024: 10 · 2023: 17 · 2022: 5 · 2021: 1 · 2019: 1
FWCI
3.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuropsychopharmacology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • MEXT | Japan Society for the Promotion of Science (19H05027, 20J00643)
  • Japan Agency for Medical Research and Development (JP20dm0207069)
  • Keio University (Grant-in-Aid for Program for the Advancement of Next Generation Research Projects)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
chronic social defeat stress, goal-directed behavior, ventral hippocampus, depression, motivation, stress vulnerability, stress resilience, serotonin, escitalopram, ketamine, optogenetic inhibition, fiber photometry, appetitive motivation, biomarkers
MeSH terms
Social Defeat, Animals, Behavior, Animal, Goals, Hippocampus, Humans, Male, Mice, Inbred C57BL, Motivation, Social Behavior, Stress, Psychological, Mice

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