Nucleus accumbens D1R expressing spiny projection neurons control food motivation and obesity.



      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.


      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.


      We first confirmed that mice made obese with ad libitum exposure to HFD (HFD) 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, 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 HFD-induced weight gain.


      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.

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        • Epstein L.H.
        • Carr K.A.
        Food reinforcement and habituation to food are processes related to initiation and cessation of eating.
        Physiology & Behavior. 2021 Oct 1; 239113512
        • Lee P.C.
        • Dixon J.B.
        Food for Thought: Reward Mechanisms and Hedonic Overeating in Obesity.
        Curr Obes Rep. 2017 Dec; 6: 353-361
        • Carr K.A.
        • Lin H.
        • Fletcher K.D.
        • Epstein L.H.
        Food reinforcement, dietary disinhibition and weight gain in nonobese adults.
        Obesity (Silver Spring). 2014 Jan; 22: 254-259
        • Mogenson G.J.
        • Jones D.L.
        • Yim C.Y.
        From motivation to action: functional interface between the limbic system and the motor system.
        Prog Neurobiol. 1980; 14: 69-97
        • Gendelis S.
        • Inbar D.
        • Kupchik Y.M.
        The role of the nucleus accumbens and ventral pallidum in feeding and obesity.
        Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2021 Dec 20; 111110394
      1. Dalton M, Finlayson G, Walsh B, Halseth AE, Duarte C, Blundell JE. Early improvement in food cravings are associated with long-term weight loss success in a large clinical sample. International journal of obesity (2005). 2017/04/05 ed. 2017 Aug;41(8):1232–1236.

        • la Fleur S.E.
        • Vanderschuren L.J.M.J.
        • Luijendijk M.C.
        • Kloeze B.M.
        • Tiesjema B.
        • Adan R.a.H.
        A reciprocal interaction between food-motivated behavior and diet-induced obesity.
        Int J Obes (Lond). 2007 Aug; 31: 1286-1294
        • Wang G.J.
        • Tomasi D.
        • Convit A.
        • Logan J.
        • Wong C.T.
        • Shumay E.
        • et al.
        BMI modulates calorie-dependent dopamine changes in accumbens from glucose intake.
        PLoS One. 2014; 9e101585
        • Willeumier K.C.
        • Taylor D.V.
        • Amen D.G.
        Elevated BMI is associated with decreased blood flow in the prefrontal cortex using SPECT imaging in healthy adults.
        Obesity (Silver Spring). 2011 May; 19: 1095-1097
        • Jastreboff A.M.
        • Sinha R.
        • Arora J.
        • Giannini C.
        • Kubat J.
        • Malik S.
        • et al.
        Altered Brain Response to Drinking Glucose and Fructose in Obese Adolescents.
        Diabetes. 2016; 65: 1929-1939
      2. Del Parigi A, Gautier JF, Chen K, Salbe AD, Ravussin E, Reiman E, et al. Neuroimaging and obesity: mapping the brain responses to hunger and satiation in humans using positron emission tomography. Annals of the New York Academy of Sciences. 2002/06/25 ed. 2002 Jun;967:389–397.

        • Stoeckel L.E.
        • Weller R.E.
        • Cook E.W.
        • Twieg D.B.
        • Knowlton R.C.
        • Cox J.E.
        Widespread reward-system activation in obese women in response to pictures of high-calorie foods.
        Neuroimage. 2008 Jun; 41: 636-647
      3. Bruce AS, Holsen LM, Chambers RJ, Martin LE, Brooks WM, Zarcone JR, et al. Obese children show hyperactivation to food pictures in brain networks linked to motivation, reward and cognitive control. International journal of obesity (2005). 2010/05/05 ed. 2010 Oct;34(10):1494–1500.

      4. Oginsky MF, Goforth PB, Nobile CW, Lopez-Santiago LF, Ferrario CR. Eating “Junk-Food” Produces Rapid and Long-Lasting Increases in NAc CP-AMPA Receptors: Implications for Enhanced Cue-Induced Motivation and Food Addiction. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2016/07/08 ed. 2016 Dec;41(13):2977–2986.

      5. Oginsky MF, Ferrario CR. Eating “junk food” has opposite effects on intrinsic excitability of nucleus accumbens core neurons in obesity-susceptible versus -resistant rats. Journal of neurophysiology. 2019/08/01 ed. 2019 Sep 1;122(3):1264–1273.

        • Brown R.M.
        • Kupchik Y.M.
        • Spencer S.
        • Garcia-Keller C.
        • Spanswick D.C.
        • Lawrence A.J.
        • et al.
        Addiction-like Synaptic Impairments in Diet-Induced Obesity.
        Biol Psychiatry. 2017 01; 81: 797-806
        • Gerfen C.R.
        • Engber T.M.
        • Mahan L.C.
        • Susel Z.
        • Chase T.N.
        • Monsma F.J.
        • et al.
        D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons.
        Science. 1990 Dec 7; 250: 1429-1432
        • Kupchik Y.M.
        • Brown R.M.
        • Heinsbroek J.A.
        • Lobo M.K.
        • Schwartz D.J.
        • Kalivas P.W.
        Coding the direct/indirect pathways by D1 and D2 receptors is not valid for accumbens projections.
        Nat Neurosci. 2015 Sep; 18: 1230-1232
        • Kravitz A.V.
        • Tye L.D.
        • Kreitzer A.C.
        Distinct roles for direct and indirect pathway striatal neurons in reinforcement.
        Nat Neurosci. 2012 Jun; 15: 816-818
        • Yttri E.A.
        • Dudman J.T.
        Opponent and bidirectional control of movement velocity in the basal ganglia.
        Nature. 2016 19; 533: 402-406
        • Cui G.
        • Jun S.B.
        • Jin X.
        • Pham M.D.
        • Vogel S.S.
        • Lovinger D.M.
        • et al.
        Concurrent activation of striatal direct and indirect pathways during action initiation.
        Nature. 2013 Feb 14; 494: 238-242
        • Bariselli S.
        • Fobbs W.C.
        • Creed M.C.
        • Kravitz A.V.
        A competitive model for striatal action selection.
        Brain Res. 2019 Jun 15; 1713: 70-79
        • Friend D.M.
        • Devarakonda K.
        • O’Neal T.J.
        • Skirzewski M.
        • Papazoglou I.
        • Kaplan A.R.
        • et al.
        Basal Ganglia Dysfunction Contributes to Physical Inactivity in Obesity.
        Cell Metab. 2017 07; 25: 312-321
      6. Licholai JA, Nguyen KP, Fobbs WC, Schuster CJ, Ali MA, Kravitz AV. Why Do Mice Overeat HFDs? How HFD Alters the Regulation of Daily Caloric Intake in Mice. Obesity (Silver Spring, Md). 2018/05/01 ed. 2018 Jun;26(6):1026–1033.

        • Yang Y.
        • Smith D.L.
        • Keating K.D.
        • Allison D.B.
        • Nagy T.R.
        Variations in body weight, food intake and body composition after long-term HFD feeding in C57BL/6J mice.
        Obesity (Silver Spring). 2014 Oct; 22: 2147-2155
        • Blaisdell A.P.
        • Lau Y.L.M.
        • Telminova E.
        • Lim H.C.
        • Fan B.
        • Fast C.D.
        • et al.
        Food quality and motivation: A refined low-fat diet induces obesity and impairs performance on a PR schedule of instrumental lever pressing in rats.
        Physiology & Behavior. 2014 Apr 10; 128: 220-225
      7. Sharma S, Fernandes MF, Fulton S. Adaptations in brain reward circuitry underlie palatable food cravings and anxiety induced by HFD withdrawal. International journal of obesity (2005). 2012/12/12 ed. 2013 Sep;37(9):1183–1191.

      8. Naef L, Seabrook L, Baimel C, Judge AK, Kenney T, Ellis M, et al. Disinhibition of the orbitofrontal cortex biases goal-directed behaviour in obesity. bioRxiv. 2020 Apr 3;2020.04.02.022681.

        • Figlewicz D.P.
        • Jay J.L.
        • Acheson M.A.
        • Magrisso I.J.
        • West C.H.
        • Zavosh A.
        • et al.
        Moderate high fat diet increases sucrose self-administration in young rats.
        Appetite. 2013 Feb; 61: 19-29
      9. Inbar D, Gendelis S, Mesner S, Menahem S, Kupchik YM. Chronic calorie‐dense diet drives differences in motivated food-seeking between obesity‐prone and resistant mice. Addiction Biology [Internet]. 2020 May [cited 2021 Nov 27];25(3). Available from:

        • Hodos W.
        PR as a measure of reward strength.
        Science. 1961 Sep 29; 134: 943-944
        • Bickel W.K.
        • Freitas-Lemos R.
        • Tomlinson D.C.
        • Craft W.H.
        • Keith D.R.
        • Athamneh L.N.
        • et al.
        Temporal discounting as a candidate behavioral marker of obesity.
        Neurosci Biobehav Rev. 2021 Oct; 129: 307-329
        • Zhang L.
        • Rashad I.
        Obesity and time preference: the health consequences of discounting the future.
        J Biosoc Sci. 2008 Jan; 40: 97-113
        • Matikainen-Ankney B.A.
        • Earnest T.
        • Ali M.
        • Casey E.
        • Wang J.G.
        • Sutton A.K.
        • et al.
        An open-source device for measuring food intake and operant behavior in rodent home-cages.
        Elife. 2021 Mar 29; 10e66173
      10. Aberman JE, Salamone JD. Nucleus accumbens dopamine depletions make rats more sensitive to high ratio requirements but do not impair primary food reinforcement. Neuroscience. 1999/07/17 ed. 1999;92(2):545–552.

      11. Salamone JD, Correa M, Yang JH, Rotolo R, Presby R. Dopamine, Effort-Based Choice, and Behavioral Economics: Basic and Translational Research. Front Behav Neurosci [Internet]. 2018 [cited 2020 Aug 25];12. Available from:

      12. du Hoffmann J, Nicola SM. Dopamine invigorates reward seeking by promoting cue-evoked excitation in the nucleus accumbens. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2014/10/24 ed. 2014 Oct 22;34(43):14349–14364.

        • Bryce C.A.
        • Floresco S.B.
        Alterations in effort-related decision-making induced by stimulation of dopamine D1, D2, D3, and corticotropin-releasing factor receptors in nucleus accumbens subregions.
        Psychopharmacology (Berl). 2019 Sep; 236: 2699-2712
      13. Ko D, Wanat MJ. Phasic Dopamine Transmission Reflects Initiation Vigor and Exerted Effort in an Action- and Region-Specific Manner. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2016/02/19 ed. 2016 Feb 17;36(7):2202–2211.

        • Christoffel D.J.
        • Walsh J.J.
        • Heifets B.D.
        • Hoerbelt P.
        • Neuner S.
        • Sun G.
        • et al.
        Input-specific modulation of murine nucleus accumbens differentially regulates hedonic feeding.
        Nat Commun. 2021 Apr 9; 12: 2135
        • Nicola S.M.
        • Deadwyler S.A.
        Firing Rate of Nucleus Accumbens Neurons Is Dopamine-Dependent and Reflects the Timing of Cocaine-Seeking Behavior in Rats on a PR Schedule of Reinforcement.
        J Neurosci. 2000 Jul 15; 20: 5526-5537
        • Peoples L.L.
        • West M.O.
        Phasic Firing of Single Neurons in the Rat Nucleus Accumbens Correlated with the Timing of Intravenous Cocaine Self-Administration.
        J Neurosci. 1996 May 15; 16: 3459-3473
        • Nicola S.M.
        • Yun I.A.
        • Wakabayashi K.T.
        • Fields H.L.
        Cue-Evoked Firing of Nucleus Accumbens Neurons Encodes Motivational Significance During a Discriminative Stimulus Task.
        Journal of Neurophysiology. 2004 Apr; 91: 1840-1865
        • Beatty J.A.
        • Song S.C.
        • Wilson C.J.
        Cell-type-specific resonances shape the responses of striatal neurons to synaptic input.
        J Neurophysiol. 2015 Feb 1; 113: 688-700
        • Fobbs W.C.
        • Bariselli S.
        • Licholai J.A.
        • Miyazaki N.L.
        • Matikainen-Ankney B.A.
        • Creed M.C.
        • et al.
        Continuous Representations of Speed by Striatal Medium Spiny Neurons.
        J Neurosci. 2020 19; 40: 1679-1688
        • Hikida T.
        • Kimura K.
        • Wada N.
        • Funabiki K.
        • Nakanishi S.
        Distinct roles of synaptic transmission in direct and indirect striatal pathways to reward and aversive behavior.
        Neuron. 2010 Jun 24; 66: 896-907
        • Roberts-Wolfe D.
        • Bobadilla A.C.
        • Heinsbroek J.A.
        • Neuhofer D.
        • Kalivas P.W.
        Drug Refraining and Seeking Potentiate Synapses on Distinct Populations of Accumbens Medium Spiny Neurons.
        J Neurosci. 2018 Aug 8; 38: 7100-7107
        • Lobo M.K.
        • Nestler E.J.
        The striatal balancing act in drug addiction: distinct roles of direct and indirect pathway medium spiny neurons.
        Front Neuroanat. 2011; 5: 41
        • Terrier J.
        • Lüscher C.
        • Pascoli V.
        Cell-Type Specific Insertion of GluA2-Lacking AMPARs with Cocaine Exposure Leading to Sensitization, Cue-Induced Seeking, and Incubation of Craving.
        Neuropsychopharmacology. 2016 Jun; 41: 1779-1789
        • Oginsky M.F.
        • Maust J.D.
        • Corthell J.T.
        • Ferrario C.R.
        Enhanced cocaine-induced locomotor sensitization and intrinsic excitability of NAc medium spiny neurons in adult but not in adolescent rats susceptible to diet-induced obesity.
        Psychopharmacology. 2016 Mar 1; 233: 773-784
        • Grimm J.W.
        • Harkness J.H.
        • Ratliff C.
        • Barnes J.
        • North K.
        • Collins S.
        Effects of systemic or nucleus accumbens-directed dopamine D1 receptor antagonism on sucrose seeking in rats.
        Psychopharmacology. 2011 Jul 1; 216: 219-233
        • Grippo R.M.
        • Tang Q.
        • Zhang Q.
        • Chadwick S.R.
        • Gao Y.
        • Altherr E.B.
        • et al.
        Dopamine Signaling in the Suprachiasmatic Nucleus Enables Weight Gain Associated with Hedonic Feeding.
        Current Biology. 2020 Jan; 30 (e8): 196-208
        • O’Connor E.C.
        • Kremer Y.
        • Lefort S.
        • Harada M.
        • Pascoli V.
        • Rohner C.
        • et al.
        Accumbal D1R Neurons Projecting to Lateral Hypothalamus Authorize Feeding.
        Neuron. 2015 Nov 4; 88: 553-564
        • Bond C.W.
        • Trinko R.
        • Foscue E.
        • Furman K.
        • Groman S.M.
        • Taylor J.R.
        • et al.
        Medial Nucleus Accumbens Projections to the Ventral Tegmental Area Control Food Consumption.
        J Neurosci. 2020 Jun 10; 40: 4727-4738
        • Baldo B.A.
        • Kelley A.E.
        Discrete neurochemical coding of distinguishable motivational processes: insights from nucleus accumbens control of feeding.
        Psychopharmacology (Berl). 2007 Apr; 191: 439-459
        • Vachez Y.M.
        • Tooley J.R.
        • Abiraman K.
        • Matikainen-Ankney B.
        • Casey E.
        • Earnest T.
        • et al.
        Ventral arkypallidal neurons inhibit accumbal firing to promote reward consumption.
        Nature Neuroscience. 2021 Mar; 24: 379-390
        • Kelley A.E.
        • Baldo B.A.
        • Pratt W.E.
        • Will M.J.
        Corticostriatal-hypothalamic circuitry and food motivation: integration of energy, action and reward.
        Physiol Behav. 2005 Dec 15; 86: 773-795
        • Kelley A.E.
        • Swanson C.J.
        Feeding induced by blockade of AMPA and kainate receptors within the ventral striatum: a microinfusion mapping study.
        Behav Brain Res. 1997 Dec; 89: 107-113
        • Maldonado-Irizarry C.S.
        • Swanson C.J.
        • Kelley A.E.
        Glutamate receptors in the nucleus accumbens shell control feeding behavior via the lateral hypothalamus.
        J Neurosci. 1995 Oct; 15: 6779-6788
        • Basso A.M.
        • Kelley A.E.
        Feeding induced by GABA(A) receptor stimulation within the nucleus accumbens shell: regional mapping and characterization of macronutrient and taste preference.
        Behav Neurosci. 1999 Apr; 113: 324-336
        • Urstadt K.R.
        • Kally P.
        • Zaidi S.F.
        • Stanley B.G.
        Ipsilateral feeding-specific circuits between the nucleus accumbens shell and the lateral hypothalamus: regulation by glutamate and GABA receptor subtypes.
        Neuropharmacology. 2013 Apr; 67: 176-182
        • Floresco S.B.
        • McLaughlin R.J.
        • Haluk D.M.
        Opposing roles for the nucleus accumbens core and shell in cue-induced reinstatement of food-seeking behavior.
        Neuroscience. 2008 Jun 26; 154: 877-884
        • Kelley A.E.
        Functional specificity of ventral striatal compartments in appetitive behaviors.
        Ann N Y Acad Sci. 1999 Jun 29; 877: 71-90
        • Cone J.J.
        • Chartoff E.H.
        • Potter D.N.
        • Ebner S.R.
        • Roitman M.F.
        Prolonged High Fat Diet Reduces Dopamine Reuptake without Altering DAT Gene Expression.
        PLOS ONE. 2013 Mar 13; 8e58251
        • Adams W.K.
        • Sussman J.L.
        • Kaur S.
        • D’souza A.M.
        • Kieffer T.J.
        • Winstanley C.A.
        Long-term, calorie-restricted intake of a HFD in rats reduces impulse control and ventral striatal D2 receptor signalling - two markers of addiction vulnerability.
        Eur J Neurosci. 2015 Dec; 42: 3095-3104
        • Hryhorczuk C.
        • Florea M.
        • Rodaros D.
        • Poirier I.
        • Daneault C.
        • Des Rosiers C.
        • et al.
        Dampened Mesolimbic Dopamine Function and Signaling by Saturated but not Monounsaturated Dietary Lipids.
        Neuropsychopharmacology. 2016 Feb; 41: 811-821
      14. Darling RA, Dingess PM, Schlidt KC, Smith EM, Brown TE. Incubation of food craving is independent of macronutrient composition. Scientific reports. 2016/08/04 ed. 2016 Aug 3;6:30900.

      15. Dingess PM, Darling RA, Derman RC, Wulff SS, Hunter ML, Ferrario CR, et al. Structural and Functional Plasticity within the Nucleus Accumbens and Prefrontal Cortex Associated with Time-Dependent Increases in Food Cue-Seeking Behavior. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2017/03/16 ed. 2017 Nov;42(12):2354–2364.

        • Matikainen-Ankney B.
        • Ali M.A.
        • Miyazaki N.L.
        • Fry S.A.
        • Licholai J.A.
        • Kravitz A.V.
        Weight loss after obesity is associated with increased food motivation and faster weight re- gain.
        Obesity (Silver Spring). 2020;
        • Astrup A.
        • Greenway F.L.
        • Ling W.
        • Pedicone L.
        • Lachowicz J.
        • Strader C.D.
        • et al.
        Randomized controlled trials of the D1/D5 antagonist ecopipam for weight loss in obese subjects.
        Obesity (Silver Spring). 2007 Jul; 15: 1717-1731
        • Chen R.
        • Blosser T.R.
        • Djekidel M.N.
        • Hao J.
        • Bhattacherjee A.
        • Chen W.
        • et al.
        Decoding molecular and cellular heterogeneity of mouse nucleus accumbens.
        Nat Neurosci. 2021 Dec; 24: 1757-1771
        • Ackroff K.
        • Sclafani A.
        Maltodextrin and sucrose preferences in sweet-sensitive (C57BL/6J) and subsensitive (129P3/J) mice revisited.
        Physiol Behav. 2016 Oct 15; 165: 286-290
        • Pothion S.
        • Bizot J.C.
        • Trovero F.
        • Belzung C.
        Strain differences in sucrose preference and in the consequences of unpredictable chronic mild stress.
        Behavioural Brain Research. 2004 Nov 5; 155: 135-146
        • Robinson M.J.
        • Burghardt P.R.
        • Patterson C.M.
        • Nobile C.W.
        • Akil H.
        • Watson S.J.
        • et al.
        Individual Differences in Cue-Induced Motivation and Striatal Systems in Rats Susceptible to Diet-Induced Obesity.
        Neuropsychopharmacol. 2015 Aug; 40: 2113-2123
        • Sclafani A.
        • Clyne A.E.
        Hedonic response of rats to polysaccharide and sugar solutions.
        Neuroscience & Biobehavioral Reviews. 1987 Jun 1; 11: 173-180
      16. Richardson NR, Roberts DC. PR schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. Journal of neuroscience methods. 1996/05/01 ed. 1996 May;66(1):1–11.

        • London T.D.
        • Licholai J.A.
        • Szczot I.
        • Ali M.A.
        • LeBlanc K.H.
        • Fobbs W.C.
        • et al.
        Coordinated Ramping of Dorsal Striatal Pathways preceding Food Approach and Consumption.
        J Neurosci. 2018 Apr 4; 38: 3547-3558