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Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior
Open accessAbstract
A large number of studies have demonstrated that the nucleus accumbens (NAC) is a critical site in the neuronal circuits controlling reward responses, motivation, and mood, but the neuronal cell type(s) underlying these processes are not yet known. Identification of the neuronal cell types that regulate depression-like states will guide us in understanding the biological basis of mood and its regulation by diseases like major depressive disorder. Taking advantage of recent findings demonstrating that the serotonin receptor chaperone, p11, is an important molecular regulator of depression-like states, here we identify cholinergic interneurons (CINs) as a primary site of action for p11 in the NAC. Depression-like behavior is observed in mice after decrease of p11 levels in NAC CINs. This phenotype is recapitulated by silencing neuronal transmission in these cells, demonstrating that accumbal cholinergic neuronal activity regulates depression-like behaviors and suggesting that accumbal CIN activity is crucial for the regulation of mood and motivation.
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“Mice lacking p11 [162], p11 reductions in NAc [163], or p11 knockout in NAc ChIs [158] is sufficient to reduce sucrose preference and increase forced-swim immobility (Fig. 2, top).”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [158]
In the citing paper
“Silencing NAc cholinergic interneurons (ChIs) results in anhedonia and increases immobility in the forced-swim and tail-suspension tests [158].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [158]
In the citing paper
“a recent study has shown that decreasing striatal cholinergic tone in the mouse can lead to depression-like symptoms, likely through interneuron-dependent disinhibition of striatal neurons (Warner-Schmidt et al., 2012)”
From Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior (2012) · cites this paper as Warner-Schmidt et al., 2012
In the citing paper
“decreasing cholinergic transmission in the striatum can induce depression-like effects in mice through disinhibition of medium spiny neurons (Warner-Schmidt et al., 2012)”
From Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states (2015) · cites this paper as Warner-Schmidt et al., 2012
In the citing paper
“numerous studies have now demonstrated that alterations of neuronal activity in the mesolimbic system can result in antidepressant-like effects (Nestler, 2014; Nestler and Carlezon, 2006; Warner-Schmidt et al., 2012)”
From Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states (2015) · cites this paper as Warner-Schmidt et al., 2012
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Marche, K., Martel, A., & Apicella, P. (2017) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2017.00052 · Cited by 39
“Inactivation studies on rodents have pointed to the involvement of the cholinergic system of the ventral striatum in mood control and emotional behavior (Witten et al., 2010; Warner-Schmidt et al., 2012).”
BackgroundZhang, Y. F., Wu, J., Wang, Y., Johnson, N. L., Bhattarai, J. P., Li, G., Wang, W., Guevara, C., Shoenhard, H., Fuccillo, M. V., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-42662-z · Cited by 37
“Activation of OTD3neuronsmayspeci fi callyimprove “ thedecreasedmotivationfor activity ” in CRS mice, while anhedonic phenotypes might be mediated by other neuronal subtypes such as cholinergic neurons 25,71 and/or otherbrainregions.”
Alterations in Striatal Circuits Underlying Addiction-Like Behaviors
Kim, H. J., Lee, J. H., Yun, K., & Kim, J. (2017) · Molecules and Cells · doi:10.14348/molcells.2017.0088 · Cited by 36
“Thus, the physiological roles of the accumbal ChINs could contribute to the altered emotional and motivational states that occur during drug (Warner-Schmidt et al., 2012).”
BackgroundAntidepressant-Like Effects of CX717, a Positive Allosteric Modulator of AMPA Receptors
Gordillo-Salas, M., Pascual-Antón, R., Ren, J. T., Greer, J. J., & Adell, A. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-01954-x · Cited by 40
“overexpression of p11 in the nucleus accumbens [62].”
BackgroundMolecular neuroanatomy: a generation of progress
Pollock, J. D., Wu, D.-Y., & Satterlee, J. S. (2014) · Trends in Neurosciences · doi:10.1016/j.tins.2013.11.001 · Cited by 36
Nucleus accumbens in the pathogenesis of major depressive disorder: A brief review
Yajie, J., Zou, M., Wang, Y., & Wang, Y. (2023) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2023.03.004 · Cited by 41
“Silencing neurotransmission in accumbal choline acetyl transferase (ChAT) neurons would prevent the release of ACh and modulate downstream cellular responses to glutamate, dopamine and other transmitters in NAc, ultimately affecting the activity of D1/2-MSNs and the efferent projections of NAc (Warner-Schmidt et al.,…”
InfluentialImaging Habenula Volume in Schizophrenia and Bipolar Disorder
Schafer, M., Kim, J.-W., Joseph, J., Xu, J., Frangou, S., & Doucet, G. E. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00456 · Cited by 36
“Additionally, inactivation of cholinergic input from the MHb to the nucleus accumbens (NAc) via the IPN has been linked to fear (44) and anhedonia (43, 45).”
BackgroundReduced Kv3.1 Activity in Dentate Gyrus Parvalbumin Cells Induces Vulnerability to Depression
Medrihan, L., Umschweif, G., Sinha, A., Reed, S., Lee, J., Gindinova, K., Sinha, S. C., Greengard, P., & Sagi, Y. (2020) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.02.1179 · Cited by 36
Self-citationG Protein-Coupled Receptors: What a Difference a ‘Partner’ Makes
Roux, B. T., & Cottrell, G. S. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms15011112 · Cited by 37
“Protein S100-A10 is mainly expressed in regions of the brain that are involved in the pathophysiology of depression, such as the nucleus accumbens, cerebral cortex and hippocampus [68–70].”
van Calker, D., Serchov, T., Normann, C., & Biber, K. P. H. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.03.014 · Cited by 35
A mismatch between striatal cholinergic pauses and dopaminergic reward prediction errors
Duhne, M., Mohebi, A., Kim, K., Pelattini, L., & Berke, J. D. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2410828121 · Cited by 37
Cell type–specific translational profiling in the Xenopus laevis retina
Watson, F. L., Mills, E. A., Wang, X., Guo, C., Chen, D. F., & Marsh-Armstrong, N. (2012) · Developmental Dynamics · doi:10.1002/dvdy.23880 · Cited by 32
“Since the 2008 description of TRAP, relatively few studies have used this method in mice (Doyle et al., 2008; Dougherty et al., 2010; Fomchenko et al., 2011; Okaty et al., 2011; Schmidt et al., 2012; Warner-Schmidt et al., 2012).”
MethodAldrin-Kirk, P., Davidsson, M., Holmqvist, S., Li, J., & Björklund, T. (2014) · PLoS ONE · doi:10.1371/journal.pone.0100869 · Cited by 32
“reward processing [49], depression [50] and dyskinesias in PD”
BackgroundInsertional effect following electrode implantation: an underreported but important phenomenon
Hamani, C., Davidson, B., Lipsman, N., Abrahão, A., Nestor, S. M., Rabin, J. S., Giacobbe, P., Pagano, R. L., & Campos, A. C. P. (2024) · Brain Communications · doi:10.1093/braincomms/fcae093 · Cited by 32
“137 p11 is a protein expressed in brain regions implicated in the pathophysiology of depression 150-152 that co-localizes with 5-HT 1B and other serotonergic receptors.”
BackgroundHanada, Y., Kawahara, Y., Ohnishi, Y. N., Shuto, T., Kuroiwa, M., Sotogaku, N., Greengard, P., Sagi, Y., & Nishi, A. (2018) · eNeuro · doi:10.1523/eneuro.0332-18.2018 · Cited by 30
“2018 eNeuro.org that silencing CIN activity induces depression-like behaviors and that p11 in NAc CINs shows antidepressant effects (Warner-Schmidt et al., 2012).”
BackgroundMethodInfluentialSelf-citationRecent Advances in Molecular and Cellular Functions of S100A10
Okura, G. C., Bharadwaj, A. G., & Waisman, D. M. (2023) · Biomolecules · doi:10.3390/biom13101450 · Cited by 30
“Some identified areas include the hippocampus [45,102], amygdala [102], cerebral cortex [103], anterior cingulate cortex [40], and nucleus accumbens [104].”
BackgroundS100A10 and its binding partners in depression and antidepressant actions
Chen, M. X., Oh, Y., & Kim, Y. D. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.953066 · Cited by 32
“Presynaptic 5-HTR1B in CINs in the NAc are involved in inhibiting acetylcholine release in a p11-dependent manner, and CINs-specific deletion of 5-HTR1B (ChAT-Cre line crossed with floxed 5-HTR1B) induces an anhedonia-like phenotype in the SPT, cookie test, and social approach test (Virk et al., 2016).”
BackgroundMethodInfluentialCell-Type Specific Expression of p11 Controls Cocaine Reward
Arango-Lievano, M., Schwarz, J. T., Vernov, M., Wilkinson, M. B., Bradbury, K. R., Feliz, A., Marongiu, R., Gelfand, Y. J., Warner‐Schmidt, J. L., Nestler, E. J., et al. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.02.012 · Cited by 29
“Moreover, we identified the NAc as the key brain region sensitive to p11 homeostasis in which p11 loss exerts prodepressive effect, most specifically, through the cholinergic (ChAT positive) interneuron population that are the only source of acetylcholine for MSNs of the ventral striatum (17,21).”
Self-citationCholinergic system in sleep regulation of emotion and motivation
Mu, P., & Huang, Y. H. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.03.013 · Cited by 30
The role of enkephalinergic systems in substance use disorders
Rysztak, L. G., & Jutkiewicz, E. M. (2022) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2022.932546 · Cited by 34
“In the NAc, cholinergic interneurons are the only source of acetylcholine and act locally to regulate efferents, particularly glutamate and dopamine (Warner-Schmidt et al., 2012).”
BackgroundFocusing on the Opioid System for Addiction Biomarker Discovery
Belzeaux, R., Lalanne, L., Kieffer, B. L., & Lutz, P.-E. (2018) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.12.004 · Cited by 28
Han, Y., Sun, C.-Y., Meng, S., Tabarak, S., Yuan, K., Cao, L., Yan, W., Xu, L., Deng, J., Zhu, W., et al. (2019) · Molecular Psychiatry · doi:10.1038/s41380-019-0470-9 · Cited by 25
Endocannabinoid Modulation of Nucleus Accumbens Microcircuitry and Terminal Dopamine Release
Covey, D. P., & Yocky, A. G. (2021) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2021.734975 · Cited by 28
P11 deficiency increases stress reactivity along with HPA axis and autonomic hyperresponsiveness
Sousa, V. C., Mantas, I., Stroth, N., Hager, T., Pereira, M., Jiang, H., Jabre, S., Pasławski, W., Stiedl, O., & Svenningsson, P. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-00887-0 · Cited by 25
Enhanced cholinergic-tone during the stress induce a depressive-like state in mice
Fernandes, S. S., Koth, A. P., Parfitt, G. M., Cordeiro, M. F., Peixoto, C. S., Soubhia, A., Moreira, F. P., Wiener, C. D., Oses, J. P., Kaszubowski, E., et al. (2018) · Behavioural Brain Research · doi:10.1016/j.bbr.2018.02.044 · Cited by 26
“The activity cholinergic neurons in the nucleus accumbens regulates depression-like behaviors, suggesting that it is crucial for the regulation of mood and motivation [32].”
Razidlo, J. A., Fausner, S. M. L., Ingebretson, A. E., Wang, L. C., Petersen, C. L., Mirza, S. A., Swank, I. N., Alvarez, V. A., & Lemos, J. C. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.1424-21.2022 · Cited by 24
Fu, K., Miyamoto, Y., Sumi, K., Saika, E., Muramatsu, S., Uno, K., & Nitta, A. (2017) · PLoS ONE · doi:10.1371/journal.pone.0189006 · Cited by 23
Molecular Plasticity of the Nucleus Accumbens Revisited—Astrocytic Waves Shall Rise
Kardos, J., Dobolyi, Á., Szabó, Z. M., Simon, Á., Lourmet, G. S., Palkovits, M., & Héja, L. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-1641-z · Cited by 22
PET imaging of animal models with depressive-like phenotypes
Vazquez-Matias, D. A., de Vries, E. F. J., Dierckx, R., & Doorduin, J. (2023) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-022-06073-4 · Cited by 23
Marongiu, R., Arango-Lievano, M., Francardo, V., Morgenstern, P. F., Zhang, X., Cenci, M. A., Svenningsson, P., Greengard, P., & Kaplitt, M. G. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1524387113 · Cited by 20
“The small adaptor protein p11 has been identified as critical for the function of ventral striatum in models of depression and addiction (8, 14, 15).”
BackgroundSelf-citationBielczyk, N., Buitelaar, J. K., Glennon, J. C., & Tiesinga, P. H. E. (2015) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2015.00029 · Cited by 18
“Today, it is known that not only DA, NE, and 5HT, but also acetylcholine (AC) has a strong impact on mood (21).”
BackgroundAdult-born neurons maintain hippocampal cholinergic inputs and support working memory during aging
Kirshenbaum, G. S., Chang, C., Bompolaki, M., Bradford, V. R., Bell, J., Kosmidis, S., Shansky, R. M., Orlandi, J. G., Savage, L. M., Harris, A. Z., et al. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02167-z · Cited by 17
Gargouri, B., Bouchard, M., Saliba, S. W., Fetoui, H., & Fiebich, B. L. (2019) · Behavioural Brain Research · doi:10.1016/j.bbr.2019.04.012 · Cited by 16
Coss, A., Suaste, E., & Gutiérrez, R. (2022) · Neuroscience · doi:10.1016/j.neuroscience.2022.04.022 · Cited by 18
Schintu, N., Zhang, X., Alvarsson, A., Marongiu, R., Kaplitt, M. G., Greengard, P., & Svenningsson, P. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1524303113 · Cited by 16
Self-citation
Metadata
- Authors
- Warner-Schmidt, J. L., Schmidt, E. F., Marshall, J. J., Rubin, A. J., Arango-Lievano, M., Kaplitt, M. G., Ibañez-Tallon, I., Heintz, N., & Greengard, P.
- Affiliations
- Laboratories of aMolecular and Cellular Neuroscience and
- Howard Hughes Medical Institute (US)
- Weill Cornell Medicine (US)
- Molecular Biology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065;
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-06-25
- Volume
- 109
- Issue
- 28
- Pages
- 11360-11365
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3396525
- OpenAlex
- W2004051792
- Cited by
- 163
- References
- 37
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 8 · 2023: 11 · 2022: 14 · 2021: 20 · 2020: 11 · 2019: 13 · 2018: 9 · 2017: 14 · 2016: 11 · 2015: 13 · 2014: 11 · 2013: 11 · 2012: 5
- FWCI
- 5.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute on Aging (AG09464, P01AG009464)
- National Institute of Mental Health (P50MH090963, MH090963)
- National Institute on Drug Abuse (RC2DA028968)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- cholinergic interneurons, nucleus accumbens, depression-like behavior, p11, major depressive disorder, mood regulation, motivation, neuronal silencing, neural transmission
- MeSH terms
- S100 Calcium Binding Protein A10, Acetylcholine, Animals, Antidepressive Agents, Behavior, Animal, Depression, Immunohistochemistry, Interneurons, Male, Mice, Inbred C57BL, Models, Biological, S100 Proteins, Neurons, Nucleus Accumbens, Phenotype, Receptors, Cholinergic, Annexin A2, Mice, Knockout, Neurotransmitter Agents, Molecular Chaperones, Mice
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