Hyperconnectivity of Two Separate Long-Range Cholinergic Systems Contributes to the Reorganization of the Brain Functional Connectivity during Nicotine Withdrawal in Male Mice
Creators
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1.
University of California, San Diego
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2.
Yale University
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3.
Cornell University
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4.
California Institute of Technology
Abstract
Chronic nicotine results in dependence with withdrawal symptoms on discontinuation of use, through desensitization of nicotinic acetylcholine receptors and altered cholinergic neurotransmission. Nicotine withdrawal is associated with increased whole-brain functional connectivity and decreased network modularity; however, the role of cholinergic neurons in those changes is unknown. To identify the contribution of nicotinic receptors and cholinergic regions to changes in the functional network, we analyzed the contribution of the main cholinergic regions to brain-wide activation of the immediate early-gene Fos during withdrawal in male mice and correlated these changes with the expression of nicotinic receptor mRNA throughout the brain. We show that the main functional connectivity modules included the main long-range cholinergic regions, which were highly synchronized with the rest of the brain. However, despite this hyperconnectivity, they were organized into two anticorrelated networks that were separated into basal forebrain-projecting and brainstem-thalamic-projecting cholinergic regions, validating a long-standing hypothesis of the organization of the brain cholinergic systems. Moreover, baseline (without nicotine) expression ofChrna2,Chrna3,Chrna10, andChrndmRNA of each brain region correlated with withdrawal-induced changes in Fos expression. Finally, by mining the Allen Brain mRNA expression database, we were able to identify 1755 gene candidates and three pathways (Sox2-Oct4-Nanog, JAK-STAT, and MeCP2-GABA) that may contribute to nicotine withdrawal-induced Fos expression. These results identify the dual contribution of the basal forebrain and brainstem-thalamic cholinergic systems to whole-brain functional connectivity during withdrawal; and identify nicotinic receptors and novel cellular pathways that may be critical for the transition to nicotine dependence.
Additional Information
© 2023 Carrette et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. Support was received from the Preclinical Addiction Research Consortium. This work was supported by National Institute on Drug Abuse Grant 1R21-DA-057694; Tobacco-Related Disease Research Program Grants 27IR0047 and 32IR5384 to O.G.; and Innovation Award 3901 from the International Rett Syndrome Foundation to L.L.G.C. National Institute of Mental Health Grant R01MH128217 to A.C.K.; National Institute on Drug Abuse Grant F30DA059437 to P.A.D. Publication fees were contributed by the UC San Diego library. Author Contributions. Author contributions: L.L.G.C. and O.G. designed research; L.L.G.C. and A.C. performed research; A.K., P.D., and A.C.K. contributed unpublished reagents/analytic tools; L.L.G.C. and O.G. analyzed data; L.L.G.C. and O.G. wrote the paper. The authors declare no competing financial interests.Attached Files
Published - ENEURO.0019-23.2023.pdf
Files
ENEURO.0019-23.2023.pdf
Additional details
Identifiers
- PMCID
- PMC10306126
- Eprint ID
- 122066
- Resolver ID
- CaltechAUTHORS:20230630-745340000.2
Related works
- Describes
- 10.1523/ENEURO.0019-23.2023 (DOI)
Funding
- Preclinical Addiction Research Consortium
- NIH
- 1R21-DA-057694
- California Tobacco-Related Disease Research Program
- 27IR0047
- California Tobacco-Related Disease Research Program
- T32IR5384
- International Rett Syndrome Foundation
- 3901
- NIH
- R01MH128217
- NIH Postdoctoral Fellowship
- F30DA059437
- University of California, San Diego
Dates
- Created
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2023-07-01Created from EPrint's datestamp field
- Updated
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2023-07-01Created from EPrint's last_modified field