iBet uBet web content aggregator. Adding the entire web to your favor.
iBet uBet web content aggregator. Adding the entire web to your favor.



Link to original content: https://pubmed.ncbi.nlm.nih.gov/23401542/
Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety- and depression-like behavior - PubMed Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Feb 26;110(9):3573-8.
doi: 10.1073/pnas.1219731110. Epub 2013 Feb 11.

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

Yann S Mineur  1 , Adetokunbo Obayemi, Mattis B Wigestrand, Gianna M Fote, Cali A Calarco, Alice M Li, Marina R Picciotto
Affiliations

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

Yann S Mineur et al. Proc Natl Acad Sci U S A. .

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Time spent immobile in the tail suspension test after administration of the cholinesterase antagonist physostigmine 30 min before testing (A, Right). AChE activity in whole brain after administration of physostigmine (A, Left). Locomotor activity over 20 min following physostigmine injection (B). Time spent immobile in the tail suspension test after treatment with physostigmine with, or without, a nicotinic (mecamylamine) and/or muscarinic (scopolamine) antagonist (C). n = 8–12 per group. **P < 0.01; ***P < 0.001. All data are expressed as mean ± SEM.
Fig. 2.
Fig. 2.
(A) Time spent immobile in the tail suspension test after physostigmine-induced immobility and its reversal by fluoxetine; n = 9–12 per group. (B) AChE activity in microdissected brain regions following chronic treatment with fluoxetine; n = 5 per group. (C) Time spent immobile in the tail suspension test following an acute bilateral infusion of physostigmine into the hippocampus; n = 7–12 per group. #P = 0.07; *P < 0.05; ***P < 0.001. All data are expressed as mean ± SEM.
Fig. 3.
Fig. 3.
AAV2-mediated delivery of AChE shRNAs (AAV-shAChE) into the hippocampus of mice. Representative photomicrograph showing hippocampus-specific decrease in AChE activity after hippocampal infusion of AAV-shRNA by stereotaxic surgery (A). Real-time PCR showed knockdown of AChE mRNA levels in shAChE-infected hippocampus compared with scrambled controls; n = 6 per group (B). GFP expression after infusion of AAV in the hippocampus demonstrating the specificity of the localization and the spread of infusion (C). Representative activity-based staining of AChE showing hippocampal AChE overexpression following infusion of the AAV-hAChE construct (D). A control group infused with AAV-GFP shows baseline AChE activity (D, Top), whereas the group infused with the human esterase construct shows increased AChE activity (D, Middle), and the overexpression is not decreased by coinfusion of the AAV-shRNA (D, Bottom). Data are expressed as mean ± SEM. *P < 0.05.
Fig. 4.
Fig. 4.
AChE knockdown in the hippocampus promotes anxiety-like behavior in mice. Infusion of shAChE into the hippocampus (n = 10 per group) decreased both time spent in open arms in the elevated plus maze test (A, Left) and time spent in the light compartment of the light–dark box (A, Right). AChE knockdown in the hippocampus increased depression-like behavior in mice. Infusion of shAChE into the hippocampus increased immobility time in the tail suspension (B, Left) and forced-swim (B, Right) tests, with no effects on locomotor activity (C). AChE knockdown in the hippocampus promotes stress susceptibility in mice. Ten days of social defeat stress decreased social interaction in WT mice (D). Infusion of shAChE into the hippocampus decreased social interaction after submaximal defeat stress compared with mice receiving scrambled shRNA infusion (E). Expression of hAChE in the hippocampus prevents AChE knockdown and rescues the behavioral effect of shAChE infusion in mice. Infusion of AAV-hAChE in the hippocampus prevented prodepressive effects of hippocampal shAChE delivery in the tail suspension and forced-swim tests, as well as in the submaximal social defeat paradigm. Fluoxetine reversed the behavioral effects of hippocampal shRNA-mediated AChE knockdown. Acute administration of fluoxetine (10 mg/kg) reversed the effects of AChE knockdown in the hippocampus in the tail suspension test (F, Left). Chronic administration of fluoxetine (10 mg/kg) reversed the effects of shAChE infusion in the social defeat paradigm (F, Right); n = 8–10 per group. All data are expressed as mean ± SEM. *P < 0.05; **P < 0.01, ***P < 0.001.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Saricicek A, et al. Persistent β2*-nicotinic acetylcholinergic receptor dysfunction in major depressive disorder. Am J Psychiatry. 2012;169(8):851–859. - PMC - PubMed
    1. Furey ML, Drevets WC. Antidepressant efficacy of the antimuscarinic drug scopolamine: A randomized, placebo-controlled clinical trial. Arch Gen Psychiatry. 2006;63(10):1121–1129. - PMC - PubMed
    1. Janowsky DS. Serendipity strikes again: Scopolamine as an antidepressant agent in bipolar depressed patients. Curr Psychiatry Rep. 2011;13(6):443–445. - PubMed
    1. Mineur YS, Picciotto MR. Nicotine receptors and depression: Revisiting and revising the cholinergic hypothesis. Trends Pharmacol Sci. 2010;31(12):580–586. - PMC - PubMed
    1. Janowsky DS, el-Yousef MK, Davis JM, Sekerke HJ. A cholinergic-adrenergic hypothesis of mania and depression. Lancet. 1972;2(7778):632–635. - PubMed

Publication types

MeSH terms