@article{3369c71f02e641b2b57f2d6f0d29ebb6,
title = "Nucleus Accumbens D1 Receptor–Expressing Spiny Projection Neurons Control Food Motivation and Obesity",
abstract = "Background: Obesity is a chronic relapsing disorder that is caused by an excess of caloric intake relative to energy expenditure. There is growing recognition that food motivation is altered in people with obesity. However, it remains unclear how brain circuits that control food motivation are altered in obese animals. Methods: Using a novel behavioral assay that quantifies work during food seeking, in vivo and ex vivo cell-specific recordings, and a synaptic blocking technique, we tested the hypothesis that activity of circuits promoting appetitive behavior in the core of the nucleus accumbens (NAc) is enhanced in the obese state, particularly during food seeking. Results: We first confirmed that mice made obese with ad libitum exposure to a high fat diet work harder than lean mice to obtain food, consistent with an increase in food motivation in obese mice. We observed greater activation of D1 receptor–expressing NAc spiny projection neurons (NAc D1SPNs) during food seeking in obese mice relative to lean mice. This enhanced activity was not observed in D2 receptor–expressing neurons (D2SPNs). Consistent with these in vivo findings, both intrinsic excitability and excitatory drive onto D1SPNs were enhanced in obese mice relative to lean mice, and these measures were selective for D1SPNs. Finally, blocking synaptic transmission from D1SPNs, but not D2SPNs, in the NAc core decreased physical work during food seeking and, critically, attenuated high fat diet–induced weight gain. Conclusions: These experiments demonstrate the necessity of NAc core D1SPNs in food motivation and the development of diet-induced obesity, establishing these neurons as a potential therapeutic target for preventing obesity.",
keywords = "Accumbens, Direct-pathway, Electrophysiology, Food seeking, Motivation, Obesity",
author = "Matikainen-Ankney, {Bridget A.} and Legaria, {Alex A.} and Yiyan Pan and Vachez, {Yvan M.} and Murphy, {Caitlin A.} and Schaefer, {Robert F.} and McGrath, {Quinlan J.} and Wang, {Justin G.} and Bluitt, {Maya N.} and Ankney, {Kevin C.} and Norris, {Aaron J.} and Creed, {Meaghan C.} and Kravitz, {Alexxai V.}",
note = "Funding Information: This work was supported by funding provided by Washington University School of Medicine (to AVK and MCC), Washington University Diabetes Research Center (Grant No. DK020579 [to AVK]), Nutrition Obesity Research Center (Grant No. DK056341 [to AVK]), McDonnell Centers for Systems and Cellular Neuroscience (to AVK), The Brian and Behavior Research Foundation (Grant Nos. 27461 [to AVK] and 27197 [to MCC]), the NIDDK (Grant No. DK126355 [to BAM-A]), NIDA (Grant Nos. R21-DA047127 and R01-DA049924 [to MCC]), the American Heart Association (to AAL), NIGMS (Grant No. T32-GM108539 [to CM]), and Rita Allen Scholar Award in Pain (to MCC). Funding Information: This work was supported by funding provided by Washington University School of Medicine (to AVK and MCC), Washington University Diabetes Research Center (Grant No. DK020579 [to AVK]), Nutrition Obesity Research Center (Grant No. DK056341 [to AVK]), McDonnell Centers for Systems and Cellular Neuroscience (to AVK), The Brian and Behavior Research Foundation (Grant Nos. 27461 [to AVK] and 27197 [to MCC]), the NIDDK (Grant No. DK126355 [to BAM-A]), NIDA (Grant Nos. R21-DA047127 and R01-DA049924 [to MCC]), the American Heart Association (to AAL), NIGMS (Grant No. T32-GM108539 [to CM]), and Rita Allen Scholar Award in Pain (to MCC). BAM-A and AVK wrote the paper. BAM-A, AJN, MCC, and AVK designed experiments. BAM-A, AAL, YMV, CAM, YP, RFS, QJM, JGW, MNB, and MCC conducted experiments. BAM-A, AAL, and AVK analyzed data. AJN and MCC edited the manuscript. We thank the Howard Hughes Medical Institute Genetically Encoded Neuronal Indicator and Effector project for GCaMP reagents. A previous version of this article was published as a preprint on bioRxiv: https://doi.org/10.1101/2022.01.12.476057, The authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: {\textcopyright} 2022 Society of Biological Psychiatry",
year = "2023",
month = mar,
day = "15",
doi = "10.1016/j.biopsych.2022.10.003",
language = "English",
volume = "93",
pages = "512--523",
journal = "Biological Psychiatry",
issn = "0006-3223",
number = "6",
}