Cited by 375Neurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology ResearchTreatment of Major Depression

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Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety- and depression-like behavior

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Mineur, Yann S., Obayemi, Adetokunbo, Wigestrand, Mattis B., Fote, Gianna M., Calarco, Cali A., Li, Alice M., Picciotto, Marina R.·2013·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1219731110PMC PMC3587265

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Abstract

Symptoms of depression can be induced in humans through blockade of acetylcholinesterase (AChE) whereas antidepressant-like effects can be produced in animal models and some clinical trials by limiting activity of acetylcholine (ACh) receptors. Thus, ACh signaling could contribute to the etiology of mood regulation. To test this hypothesis, we administered the AChE inhibitor physostigmine to mice and demonstrated an increase in anxiety- and depression-like behaviors that was reversed by administration of nicotinic or muscarinic antagonists. The behavioral effects of physostigmine were also reversed by administration of the selective serotonin reuptake inhibitor fluoxetine. Administration of fluoxetine also increased AChE activity throughout the brain, with the greatest change in the hippocampus. To determine whether cholinergic signaling in the hippocampus could contribute to the systemic effects of cholinergic drugs, we infused physostigmine or virally delivered shRNAs targeting AChE into the hippocampus. Both pharmacological and molecular genetic decreases in hippocampal AChE activity increased anxiety- and depression-like behaviors and decreased resilience to repeated stress in a social defeat paradigm. The behavioral changes due to shRNA-mediated knockdown of AChE were rescued by coinfusion of an shRNA-resistant AChE transgene into the hippocampus and reversed by systemic administration of fluoxetine. These data demonstrate that ACh signaling in the hippocampus promotes behaviors related to anxiety and depression. The sensitivity of these effects to fluoxetine suggests that shRNA-mediated knockdown of hippocampal AChE represents a model for anxiety- and depression-like phenotypes. Furthermore, abnormalities in the cholinergic system may be critical for the etiology of mood disorders and could represent an endophenotype of depression.

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BindingDB Entry 50045100: Recent developments in novel antidepressants targetinga4ß2-nicotinic acetylcholine receptors.
BindingDB (2016) · UC San Diego · doi:10.7270/q2kw5hpx

Authors: Mineur, Y. S., Obayemi, A., Wigestrand, M. B., Fote, G. M., Calarco, C. A., Li, A. M., & Picciotto, M. R.
Affiliations: Yale University (US)
ORCID: Mineur, Yann S.
Obayemi, Adetokunbo
Fote, Gianna M.
Calarco, Cali A.
Li, Alice M.
Picciotto, Marina R.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2013-02-11
Volume: 110
Issue: 9
Pages: 3573-3578
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.1219731110
PMC: PMC3587265
OpenAlex: W2020386906
Cited by: 375
References: 46
Citations by year: 2026: 25 · 2025: 28 · 2024: 21 · 2023: 24 · 2022: 38 · 2021: 34 · 2020: 38 · 2019: 30 · 2018: 33 · 2017: 20 · 2016: 24 · 2015: 27 · 2014: 18 · 2013: 15
FWCI: 13.90
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (DA033945)
National Institute of Mental Health (MH077681, R01MH077681)
National Institute on Drug Abuse (P50DA033945, DA033945)
National Institute of General Medical Sciences (T32GM007205)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Keywords: cholinergic neurotransmission, hippocampus, acetylcholinesterase, physostigmine, anxiety-like behavior, depression-like behavior, social defeat, fluoxetine, nicotinic acetylcholine receptors, muscarinic receptors, shRNA knockdown, mood disorders
MeSH terms: Acetylcholinesterase, Dependovirus, Animals, Antidepressive Agents, Anxiety, Behavior, Animal, Depression, Fluoxetine, Hippocampus, Humans, Male, Mice, Inbred C57BL, Phenotype, Physostigmine, Receptors, Cholinergic, Stress, Psychological, Time Factors, Signal Transduction, Cholinergic Antagonists, Hindlimb Suspension, RNA, Small Interfering, Mice, Resilience, Psychological, Gene Knockdown Techniques, Cholinergic Neurons

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Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety- and depression-like behavior

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