Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety- and depression-like behavior
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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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Increasing acetylcholine signaling in the hippocampus via local knockdown of AChE results in increased avoidance of anxiogenic environments, increased immobility in response to inescapable stress, and decreased threshold for social defeat.
“Increasing acetylcholine signaling in the hippocampus via local knockdown of acetylcholine esterase (AChE) results in increased avoidance of anxiogenic environments, in-creased immobility in response to inescapable stress, and decreased threshold for social defeat (Mineur et al. 2013).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Mineur et al. 2013
Increased ACh transmission can increase behaviors related to depression in humans and rodents, but the type of circuits/cell types modulated by ACh or nAChRs can have opposite effects on mood regulation, and the outcome depends on the sum of these effects.
“while increased ACh transmission can increase behaviors related to depression in humans (Risch et al., 1980) and rodents (Mineur et al., 2013), the type of circuits/cell types that are modulated by ACh or nAChRs can have opposite effects on mood regulation, and the outcome on behavior depends on the sum of these effects.”
From Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states (2015) · cites this paper as Mineur et al., 2013
Abnormal nicotinic signaling may underlie depression symptoms.
“These results indicate that abnormal nicotinic signaling may underlie depression symptoms (Mineur et al., 2013; Tizabi et al., 2000)”
From Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states (2015) · cites this paper as Mineur et al., 2013
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“The hippocampus is involved in contextual memory and associated with anxiety and depression (Nunn et al., 2008; Mineur et al., 2013).”
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- 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
- 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
- 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 › 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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