Estefani Saint-Jour, Marie-Charlotte Allichon, Andry Andrianarivelo, Enrica Montalban, Claire Martin, Lisa Huet, Nicolas Heck, Anna M Hagenston, Aisha Ravenhorst, Mélanie Marias, Nicolas Gervasi, Faustine Arrivet, Adèle Vilette, Katleen Pinchaud, Sandrine Betuing, Thomas Lissek, Jocelyne Caboche, Hilmar Bading, Peter Vanhoutte
{"title":"Nuclear calcium signaling in D1 receptor-expressing neurons of the nucleus accumbens regulates molecular, cellular and behavioral adaptations to cocaine.","authors":"Estefani Saint-Jour, Marie-Charlotte Allichon, Andry Andrianarivelo, Enrica Montalban, Claire Martin, Lisa Huet, Nicolas Heck, Anna M Hagenston, Aisha Ravenhorst, Mélanie Marias, Nicolas Gervasi, Faustine Arrivet, Adèle Vilette, Katleen Pinchaud, Sandrine Betuing, Thomas Lissek, Jocelyne Caboche, Hilmar Bading, Peter Vanhoutte","doi":"10.1016/j.biopsych.2025.01.013","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The persistence of cocaine-evoked adaptations relies on gene regulations within the reward circuit, especially in the ventral striatum (i.e., nucleus accumbens (NAc)). Notably, activation of the extracellular signal-regulated kinase (ERK) pathway in the striatum is known to trigger a transcriptional program shaping long-term responses to cocaine. Nuclear calcium signaling has also been shown to control multiple forms of transcription-dependent neuroadaptations but the dynamics and roles of striatal nuclear calcium signaling in preclinical models of addiction remains unknown.</p><p><strong>Methods: </strong>A genetically-encoded cell-type-specific nuclear calcium probe has been developed to monitor calcium dynamics in the nuclei of striatal neurons, including in freely-moving mice. A cell-type-specific inhibitor of nuclear calcium signaling, combined with 3D imaging of neuronal morphology, immunostaining and behavior, was used to disentangle the roles of nuclear calcium in NAc medium-sized spiny neurons (MSN) expressing the dopamine D1 (D1R) or D2 (D2R) receptor on cocaine-evoked responses.</p><p><strong>Results: </strong>The D1R-mediated potentiation of calcium influx through glutamate N-methyl-D-aspartate receptors (NMDAR), which shapes cocaine effects, also drives nuclear calcium transients. Fiber photometry revealed that cocaine-treated mice display a sustained nuclear calcium increase in NAc D1R-MSN. Disrupting nuclear calcium in D1R-MSN, but not D2R-MSN, blocks cocaine-evoked morphological changes of MSN and gene expression, and blunts cocaine's rewarding effects.</p><p><strong>Conclusions: </strong>Our study unravels the dynamics and roles of cocaine-induced nuclear calcium signaling increases in D1R-MSN on molecular, cellular and behavioral adaptations to cocaine, and brings a significant breakthrough as it could contribute to the development of innovative strategies with therapeutic potential to alleviate addiction symptoms.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.6000,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biological Psychiatry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.biopsych.2025.01.013","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Nuclear calcium signaling in D1 receptor-expressing neurons of the nucleus accumbens regulates molecular, cellular and behavioral adaptations to cocaine.
Background: The persistence of cocaine-evoked adaptations relies on gene regulations within the reward circuit, especially in the ventral striatum (i.e., nucleus accumbens (NAc)). Notably, activation of the extracellular signal-regulated kinase (ERK) pathway in the striatum is known to trigger a transcriptional program shaping long-term responses to cocaine. Nuclear calcium signaling has also been shown to control multiple forms of transcription-dependent neuroadaptations but the dynamics and roles of striatal nuclear calcium signaling in preclinical models of addiction remains unknown.
Methods: A genetically-encoded cell-type-specific nuclear calcium probe has been developed to monitor calcium dynamics in the nuclei of striatal neurons, including in freely-moving mice. A cell-type-specific inhibitor of nuclear calcium signaling, combined with 3D imaging of neuronal morphology, immunostaining and behavior, was used to disentangle the roles of nuclear calcium in NAc medium-sized spiny neurons (MSN) expressing the dopamine D1 (D1R) or D2 (D2R) receptor on cocaine-evoked responses.
Results: The D1R-mediated potentiation of calcium influx through glutamate N-methyl-D-aspartate receptors (NMDAR), which shapes cocaine effects, also drives nuclear calcium transients. Fiber photometry revealed that cocaine-treated mice display a sustained nuclear calcium increase in NAc D1R-MSN. Disrupting nuclear calcium in D1R-MSN, but not D2R-MSN, blocks cocaine-evoked morphological changes of MSN and gene expression, and blunts cocaine's rewarding effects.
Conclusions: Our study unravels the dynamics and roles of cocaine-induced nuclear calcium signaling increases in D1R-MSN on molecular, cellular and behavioral adaptations to cocaine, and brings a significant breakthrough as it could contribute to the development of innovative strategies with therapeutic potential to alleviate addiction symptoms.
期刊介绍：
Biological Psychiatry is an official journal of the Society of Biological Psychiatry and was established in 1969. It is the first journal in the Biological Psychiatry family, which also includes Biological Psychiatry: Cognitive Neuroscience and Neuroimaging and Biological Psychiatry: Global Open Science. The Society's main goal is to promote excellence in scientific research and education in the fields related to the nature, causes, mechanisms, and treatments of disorders pertaining to thought, emotion, and behavior. To fulfill this mission, Biological Psychiatry publishes peer-reviewed, rapid-publication articles that present new findings from original basic, translational, and clinical mechanistic research, ultimately advancing our understanding of psychiatric disorders and their treatment. The journal also encourages the submission of reviews and commentaries on current research and topics of interest.
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