한빛사논문
- 조회1,897
Joo Han Lee1, Efrain A. Ribeiro2, Jeongseop Kim3,4, Bumjin Ko1, Hope Kronman2, Yun Ha Jeong3, Jong Kyoung Kim5, Patricia H. Janak6,7,8, Eric J. Nestler2,∗, Ja Wook Koo3,4,∗,#, Joung-Hun Kim1,∗,#
1Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk, Republic of Korea
2Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu, Republic of Korea
4Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea
5Department of New Biology, DGIST, Daegu, Republic of Korea
6Department of Psychological and Brain Sciences, Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD, USA
7The Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, USA
8Kavli Neuroscience Discovery Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA
*These authors contributed equally.
#Corresponding author
Abstract
Background
Cholinergic interneurons (ChINs) in the nucleus accumbens (NAc) play critical roles in processing information related to reward. However, the contribution of ChINs to emergence of addiction-like behaviors and its underlying molecular mechanisms remain elusive.
Methods
We employed cocaine self-administration to identify two mouse subpopulations: susceptible and resilient to cocaine seeking. We compared the subpopulations for physiological responses with single-unit recording of NAc ChINs, and for gene expression levels with RNA-sequencing of FACS-sorted ChINs. To provide evidence for a causal relationship, we manipulated the expression level of dopamine D2 receptor (DRD2) of ChIN in a cell-type specific manner. Using optogenetic activation combined with a double whole-cell recording, the effect of ChIN-specific DRD2 manipulation on each synaptic inputs were assessed in NAc medium spiny neurons (MSNs) in a pathway-specific manner.
Results
Susceptible mice showed higher levels of nosepoke responses under progressive ratio schedule, and impairment in extinction and punishment procedures. DRD2 was highly abundant in NAc ChIN of susceptible mice. Elevated abundance of DRD2 in NAc ChINs was sufficient and necessary to express high cocaine motivation, putatively through reduction of ChIN activity during cocaine exposure. DRD2 overexpression in ChINs mimicked cocaine-induced effects on the dendritic spine density and the ratios of excitatory inputs between two distinct MSN cell-types, while DRD2 depletion precluded cocaine-induced synaptic plasticity.
Conclusions
These findings provide a molecular mechanism for dopaminergic control of NAc ChINs that can control the susceptibility to cocaine-seeking behavior.
논문정보
TOP52020년 후보
- Research article
- 2020년 05월 (BRIC 등록일 2020-05-13)
- 국내(교신)+국외 연구진
- 생명과학 > 신경생물학
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