Decoding Secondary Motor Cortex Neuronal Activity During Cocaine Self-Administration: Insights From Longitudinal In Vivo Calcium Imaging
Background: We recently reported that cocaine relapse risk is linked to hyperexcitability in the secondary motor cortex (M2) after prolonged withdrawal following intravenous self-administration (IVSA). However, the neuronal mechanisms underlying drug-taking behaviors and the response of M2 neurons t...
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Elsevier
2025-09-01
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| Series: | Biological Psychiatry Global Open Science |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667174325000850 |
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| author | Yingying Chen Haoying Fu Amith Korada Michal A. Lange Chandrashekar Rayanki Tao Lu Dongbing Lai Shiaofen Fang Changyong Guo Yao-Ying Ma |
| author_facet | Yingying Chen Haoying Fu Amith Korada Michal A. Lange Chandrashekar Rayanki Tao Lu Dongbing Lai Shiaofen Fang Changyong Guo Yao-Ying Ma |
| author_sort | Yingying Chen |
| collection | DOAJ |
| description | Background: We recently reported that cocaine relapse risk is linked to hyperexcitability in the secondary motor cortex (M2) after prolonged withdrawal following intravenous self-administration (IVSA). However, the neuronal mechanisms underlying drug-taking behaviors and the response of M2 neurons to contingent drug delivery remain poorly understood. Methods: Mice received cocaine as reinforcement (reinforcers [RNFs]) following active lever presses (ALPs) but not inactive lever presses (ILPs). Using miniScopes for in vivo calcium imaging during cocaine IVSA, we tracked M2 neuronal activity with single-cell resolution. Then we analyzed Ca2+ transients in the M2 at the early versus late stages during the 1-hour daily sessions on day 1 and day 5. Results: M2 neurons adapted to both operant behaviors and drug exposure history. Specifically, saline mice showed a reduction in both saline-taking behaviors and Ca2+ transient frequency with the 1-hour session. In contrast, cocaine mice maintained high ALP and RNF counts, with increased Ca2+ transient frequency and amplitude on day 1, persisting through day 5. Compared with saline control mice, cocaine mice exhibited a lower percentage of positively responsive neurons and a higher percentage of negatively responsive neurons before ALPs and after RNFs, a difference not seen before ILPs. Furthermore, as drug-taking behaviors progressed during the daily session, cocaine mice showed greater neuronal engagement with a larger population, particularly linked to ALPs and RNFs, with reduced overlap in neurons associated with ILPs. Conclusions: The M2 undergoes dynamic neuronal adaptations during drug-taking behaviors, supporting its role as a potential substrate mediating the persistence of drug-seeking behaviors in cocaine relapse. |
| format | Article |
| id | doaj-art-686f49c6f18b48e08fc27cea3aac5a4b |
| institution | DOAJ |
| issn | 2667-1743 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biological Psychiatry Global Open Science |
| spelling | doaj-art-686f49c6f18b48e08fc27cea3aac5a4b2025-08-20T02:39:59ZengElsevierBiological Psychiatry Global Open Science2667-17432025-09-015510053110.1016/j.bpsgos.2025.100531Decoding Secondary Motor Cortex Neuronal Activity During Cocaine Self-Administration: Insights From Longitudinal In Vivo Calcium ImagingYingying Chen0Haoying Fu1Amith Korada2Michal A. Lange3Chandrashekar Rayanki4Tao Lu5Dongbing Lai6Shiaofen Fang7Changyong Guo8Yao-Ying Ma9Department of Biochemistry, Molecular Biology, and Pharmacology, Indiana University School of Medicine, Indianapolis, IndianaDepartment of Biochemistry, Molecular Biology, and Pharmacology, Indiana University School of Medicine, Indianapolis, IndianaDepartment of Biochemistry, Molecular Biology, and Pharmacology, Indiana University School of Medicine, Indianapolis, IndianaDepartment of Biochemistry, Molecular Biology, and Pharmacology, Indiana University School of Medicine, Indianapolis, IndianaDepartment of Biochemistry, Molecular Biology, and Pharmacology, Indiana University School of Medicine, Indianapolis, IndianaDepartment of Biochemistry, Molecular Biology, and Pharmacology, Indiana University School of Medicine, Indianapolis, IndianaDepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IndianaLuddy School of Informatics, Computing and Engineering, Indiana University, Indianapolis, IndianaDepartment of Biochemistry, Molecular Biology, and Pharmacology, Indiana University School of Medicine, Indianapolis, IndianaDepartment of Biochemistry, Molecular Biology, and Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana; Address correspondence to Yao-Ying Ma, M.D., Ph.D.Background: We recently reported that cocaine relapse risk is linked to hyperexcitability in the secondary motor cortex (M2) after prolonged withdrawal following intravenous self-administration (IVSA). However, the neuronal mechanisms underlying drug-taking behaviors and the response of M2 neurons to contingent drug delivery remain poorly understood. Methods: Mice received cocaine as reinforcement (reinforcers [RNFs]) following active lever presses (ALPs) but not inactive lever presses (ILPs). Using miniScopes for in vivo calcium imaging during cocaine IVSA, we tracked M2 neuronal activity with single-cell resolution. Then we analyzed Ca2+ transients in the M2 at the early versus late stages during the 1-hour daily sessions on day 1 and day 5. Results: M2 neurons adapted to both operant behaviors and drug exposure history. Specifically, saline mice showed a reduction in both saline-taking behaviors and Ca2+ transient frequency with the 1-hour session. In contrast, cocaine mice maintained high ALP and RNF counts, with increased Ca2+ transient frequency and amplitude on day 1, persisting through day 5. Compared with saline control mice, cocaine mice exhibited a lower percentage of positively responsive neurons and a higher percentage of negatively responsive neurons before ALPs and after RNFs, a difference not seen before ILPs. Furthermore, as drug-taking behaviors progressed during the daily session, cocaine mice showed greater neuronal engagement with a larger population, particularly linked to ALPs and RNFs, with reduced overlap in neurons associated with ILPs. Conclusions: The M2 undergoes dynamic neuronal adaptations during drug-taking behaviors, supporting its role as a potential substrate mediating the persistence of drug-seeking behaviors in cocaine relapse.http://www.sciencedirect.com/science/article/pii/S2667174325000850Calcium transientCocaineDrug takingIn vivo Ca2+ imagingIntravenous self-administrationminiScope |
| spellingShingle | Yingying Chen Haoying Fu Amith Korada Michal A. Lange Chandrashekar Rayanki Tao Lu Dongbing Lai Shiaofen Fang Changyong Guo Yao-Ying Ma Decoding Secondary Motor Cortex Neuronal Activity During Cocaine Self-Administration: Insights From Longitudinal In Vivo Calcium Imaging Biological Psychiatry Global Open Science Calcium transient Cocaine Drug taking In vivo Ca2+ imaging Intravenous self-administration miniScope |
| title | Decoding Secondary Motor Cortex Neuronal Activity During Cocaine Self-Administration: Insights From Longitudinal In Vivo Calcium Imaging |
| title_full | Decoding Secondary Motor Cortex Neuronal Activity During Cocaine Self-Administration: Insights From Longitudinal In Vivo Calcium Imaging |
| title_fullStr | Decoding Secondary Motor Cortex Neuronal Activity During Cocaine Self-Administration: Insights From Longitudinal In Vivo Calcium Imaging |
| title_full_unstemmed | Decoding Secondary Motor Cortex Neuronal Activity During Cocaine Self-Administration: Insights From Longitudinal In Vivo Calcium Imaging |
| title_short | Decoding Secondary Motor Cortex Neuronal Activity During Cocaine Self-Administration: Insights From Longitudinal In Vivo Calcium Imaging |
| title_sort | decoding secondary motor cortex neuronal activity during cocaine self administration insights from longitudinal in vivo calcium imaging |
| topic | Calcium transient Cocaine Drug taking In vivo Ca2+ imaging Intravenous self-administration miniScope |
| url | http://www.sciencedirect.com/science/article/pii/S2667174325000850 |
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