Internal States Influence the Representation and Modulation of Food Intake by Subthalamic Neurons


Deep brain stimulation of the subthalamic nucleus (STN) is an effective therapy for motor deficits in Parkinson’s disease (PD), but commonly causes weight gain in late-phase PD patients probably by increasing feeding motivation. It is unclear how STN neurons represent and modulate feeding behavior in different internal states. In the present study, we found that feeding caused a robust activation of STN neurons in mice (GCaMP6 signal increased by 48.4% ± 7.2%, n = 9, P = 0.0003), and the extent varied with the size, valence, and palatability of food, but not with the repetition of feeding. Interestingly, energy deprivation increased the spontaneous firing rate (8.5 ± 1.5 Hz, n = 17, versus 4.7 ± 0.7 Hz, n = 18, P = 0.03) and the depolarization-induced spikes in STN neurons, as well as enhanced the STN responses to feeding. Optogenetic experiments revealed that stimulation and inhibition of STN neurons respectively reduced (by 11% ± 6%, n = 6, P = 0.02) and enhanced (by 36% ± 15%, n = 7, P = 0.03) food intake only in the dark phase. In conclusion, our results support the hypothesis that STN neurons are activated by feeding behavior, depending on energy homeostatic status and the palatability of food, and modulation of these neurons is sufficient to regulate food intake.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8


  1. 1.

    Faggiani E, Benazzouz A. Deep brain stimulation of the subthalamic nucleus in Parkinson’s disease: From history to the interaction with the monoaminergic systems. Prog Neurobiol 2017, 151: 139–156.

    CAS  PubMed  Google Scholar 

  2. 2.

    Hamani C, Florence G, Heinsen H, Plantinga BR, Temel Y, Uludag K, et al. Subthalamic nucleus deep brain stimulation: Basic concepts and novel perspectives. eNeuro 2017, 4: ENEURO.0140–17.2017.

  3. 3.

    Chen X, Zhang C, Li Y, Huang P, Lv Q, Yu W, et al. Functional connectivity-based modelling simulates subject-specific network spreading effects of focal brain stimulation. Neurosci Bull 2018, 34: 921–938.

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Bannier S, Montaurier C, Derost PP, Ulla M, Lemaire JJ, Boirie Y, et al. Overweight after deep brain stimulation of the subthalamic nucleus in Parkinson disease: long term follow-up. J Neurol Neurosurg Psychiatry 2009, 80: 484–488.

    CAS  PubMed  Google Scholar 

  5. 5.

    Foubert-Samier A, Maurice S, Hivert S, Guelh D, Rigalleau V, Burbaud P, et al. A long-term follow-up of weight changes in subthalamic nucleus stimulated Parkinson’s disease patients. Rev Neurol (Paris) 2012, 168: 173–176.

    CAS  Google Scholar 

  6. 6.

    Montaurier C, Morio B, Bannier S, Derost P, Arnaud P, Brandolini-Bunlon M, et al. Mechanisms of body weight gain in patients with Parkinson’s disease after subthalamic stimulation. Brain 2007, 130: 1808–1818.

    CAS  PubMed  Google Scholar 

  7. 7.

    Kistner A, Lhommee E, Krack P. Mechanisms of body weight fluctuations in Parkinson’s disease. Front Neurology 2014, 5: 84.

  8. 8.

    Witjas T, Baunez C, Henry JM, Delfini M, Regis J, Cherif AA, et al. Addiction in Parkinson’s disease: Impact of subthalamic nucleus deep brain stimulation. Mov Disord 2005, 20: 1052–1055.

    PubMed  Google Scholar 

  9. 9.

    Balestrino R, Baroncini D, Fichera M, Donofrio CA, Franzin A, Mortini P, et al. Weight gain after subthalamic nucleus deep brain stimulation in Parkinson’s disease is influenced by dyskinesias’ reduction and electrodes’ position. Neurol Sci 2017, 38: 2123–2129.

    PubMed  Google Scholar 

  10. 10.

    Millan SH, Hacker ML, Turchan M, Molinari AL, Currie AD, Charles D. Subthalamic nucleus deep brain stimulation in early stage Parkinson’s disease is not associated with increased body mass index. Parkinsons Dis 2017, 2017: 7163801.

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Markaki E, Ellul J, Kefalopoulou Z, Trachani E, Theodoropoulou A, Kyriazopoulou V, et al. The role of ghrelin, neuropeptide Y and leptin peptides in weight gain after deep brain stimulation for Parkinson’s disease. Stereotact Funct Neurosurg 2012, 90: 104–112.

    PubMed  Google Scholar 

  12. 12.

    Novakova L, Ruzicka E, Jech R, Serranova T, Dusek P, Urgosik D. Increase in body weight is a non-motor side effect of deep brain stimulation of the subthalamic nucleus in Parkinson’s disease. Neuro Endocrinol Lett 2007, 28: 21–25.

    PubMed  Google Scholar 

  13. 13.

    Ruzicka E, Novakova L, Jech R, Urgosik D, Ruzicka F, Haluzik M. Decrease in blood cortisol corresponds to weight gain following deep brain stimulation of the subthalamic nucleus in Parkinson’s disease. Stereotact Funct Neurosurg 2012, 90: 410–411.

    PubMed  Google Scholar 

  14. 14.

    Ruzicka F, Jech R, Novakova L, Urgosik D, Bezdicek O, Vymazal J, et al. Chronic stress-like syndrome as a consequence of medial site subthalamic stimulation in Parkinson’s disease. Psychoneuroendocrinology 2015, 52: 302–310.

    PubMed  Google Scholar 

  15. 15.

    Ruzicka F, Jech R, Novakova L, Urgosik D, Vymazal J, Ruzicka E. Weight gain is associated with medial contact site of subthalamic stimulation in Parkinson’s disease. PLoS One 2012, 7: e38020.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Novakova L, Haluzik M, Jech R, Urgosik D, Ruzicka F, Ruzicka E. Hormonal regulators of food intake and weight gain in Parkinson’s disease after subthalamic nucleus stimulation. Neuro Endocrinol Lett 2011, 32: 437–441.

    CAS  PubMed  Google Scholar 

  17. 17.

    Seifried C, Boehncke S, Heinzmann J, Baudrexel S, Weise L, Gasser T, et al. Diurnal variation of hypothalamic function and chronic subthalamic nucleus stimulation in Parkinson’s disease. Neuroendocrinology 2013, 97: 283–290.

    CAS  PubMed  Google Scholar 

  18. 18.

    Gradinaru V, Mogri M, Thompson KR, Henderson JM, Deisseroth K. Optical deconstruction of parkinsonian neural circuitry. Science 2009, 324: 354–359.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Barutca S, Turgut M, Meydan N, Ozsunar Y. Subthalamic nucleus tumor causing hyperphagia–case report. Neurol Med Chir (Tokyo) 2003, 43: 457–460.

    Google Scholar 

  20. 20.

    Etemadifar M, Abtahi SH, Abtahi SM, Mirdamadi M, Sajjadi S, Golabbakhsh A, et al. Hemiballismus, hyperphagia, and behavioral changes following subthalamic infarct. Case Rep Med 2012, 2012: 768580.

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Baunez C, Amalric M, Robbins TW. Enhanced food-related motivation after bilateral lesions of the subthalamic nucleus. J Neurosci 2002, 22: 562–568.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Baunez C, Dias C, Cador M, Amalric M. The subthalamic nucleus exerts opposite control on cocaine and ‘natural’ rewards. Nat Neurosci 2005, 8: 484–489.

    CAS  PubMed  Google Scholar 

  23. 23.

    Kenny PJ. Reward mechanisms in obesity: new insights and future directions. Neuron 2011, 69: 664–679.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Bojanowska E, Ciosek J. Can we selectively reduce appetite for energy-dense foods? An overview of pharmacological strategies for modification of food preference behavior. Curr Neuropharmacol 2016, 14: 118–142.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Fang PH, Yu M, Ma YP, Li J, Sui YM, Shi MY. Central nervous system regulation of food intake and energy expenditure: role of galanin-mediated feeding behavior. Neurosci Bull 2011, 27: 407–412.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Schwartz GJ, Zeltser LM. Functional organization of neuronal and humoral signals regulating feeding behavior. Annu Rev Nutr 2013, 33: 1–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Sternson SM, Eiselt AK. Three pillars for the neural control of appetite. Annu Rev Physiol 2017, 79: 401–423.

    CAS  PubMed  Google Scholar 

  28. 28.

    Berridge KC. Food reward: Brain substrates of wanting and liking. Neurosci Biobehav Rev 1996, 20: 1–25.

    CAS  PubMed  Google Scholar 

  29. 29.

    Darbaky Y, Baunez C, Arecchi P, Legallet E, Apicella P. Reward-related neuronal activity in the subthalamic nucleus of the monkey. Neuroreport 2005, 16: 1241–1244.

    PubMed  Google Scholar 

  30. 30.

    Breysse E, Pelloux Y, Baunez C. The good and bad differentially encoded within the subthalamic nucleus in rats. eNeuro 2015, 2: ENEURO.0014-0015.2015.

  31. 31.

    Rossi PJ, Gunduz A, Okun MS. The subthalamic nucleus, limbic function, and impulse control. Neuropsychol Rev 2015, 25: 398–410.

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Cho JR, Treweek JB, Robinson JE, Xiao C, Bremner LR, Greenbaum A, et al. Dorsal raphe dopamine neurons modulate arousal and promote wakefulness by salient stimuli. Neuron 2017, 94: 1205–1219.e8.

    CAS  PubMed  Google Scholar 

  33. 33.

    Xiao C, Cho JR, Zhou C, Treweek JB, Chan K, McKinney SL, et al. Cholinergic mesopontine signals govern locomotion and reward through dissociable midbrain pathways. Neuron 2016, 90: 333–347.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Xiao C, Miwa JM, Henderson BJ, Wang Y, Deshpande P, McKinney SL, et al. Nicotinic receptor subtype-selective circuit patterns in the subthalamic nucleus. J Neurosci 2015, 35: 3734–3746.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Zhou C, Gu W, Wu H, Yan X, Deshpande P, Xiao C, et al. Bidirectional dopamine modulation of excitatory and inhibitory synaptic inputs to subthalamic neuron subsets containing alpha4beta2 or alpha7 nAChRs. Neuropharmacology 2019, 148: 220–228.

    CAS  PubMed  Google Scholar 

  36. 36.

    Zhong W, Li Y, Feng Q, Luo M. Learning and stress shape the reward response patterns of serotonin neurons. J Neurosci 2017, 37: 8863–8875.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Sun C, Tang K, Wu J, Xu H, Zhang W, Cao T, et al. Leptin modulates olfactory discrimination and neural activity in the olfactory bulb. Acta Physiol (Oxf) 2019, 227: e13319.

    Google Scholar 

  38. 38.

    Wang D, Liu P, Mao X, Zhou Z, Cao T, Xu J, et al. Task-demand-dependent neural representation of odor information in the olfactory bulb and posterior piriform cortex. J Neurosci 2019, 39: 10002–10018.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Wang D, Wang X, Liu P, Jing S, Du H, Zhang L, et al. Serotonergic afferents from the dorsal raphe decrease the excitability of pyramidal neurons in the anterior piriform cortex. Proc Natl Acad Sci U S A 2020, 117: 3239–3247.

  40. 40.

    Noldus LP, Spink AJ, Tegelenbosch RA. EthoVision: a versatile video tracking system for automation of behavioral experiments. Behav Res Methods Instrum Comput 2001, 33: 398–414.

    CAS  PubMed  Google Scholar 

  41. 41.

    Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods 2012, 9: 671–675.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Benarroch EE. Subthalamic nucleus and its connections: Anatomic substrate for the network effects of deep brain stimulation. Neurology 2008, 70: 1991–1995.

    PubMed  Google Scholar 

  43. 43.

    Wang Y, Wang Y, Liu J, Wang X. Electroacupuncture alleviates motor symptoms and up-regulates vesicular glutamatergic transporter 1 expression in the subthalamic nucleus in a unilateral 6-hydroxydopamine-lesioned hemi-Parkinsonian rat model. Neurosci Bull 2018, 34: 476–484.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Espinosa-Carrasco J, Burokas A, Fructuoso M, Erb I, Martin-Garcia E, Gutierrez-Martos M, et al. Time-course and dynamics of obesity-related behavioral changes induced by energy-dense foods in mice. Addict Biol 2018, 23: 531–543.

    PubMed  Google Scholar 

  45. 45.

    Espinosa-Parrilla JF, Baunez C, Apicella P. Modulation of neuronal activity by reward identity in the monkey subthalamic nucleus. Eur J Neurosci 2015, 42: 1705–1717.

    PubMed  Google Scholar 

  46. 46.

    Pautrat A, Rolland M, Barthelemy M, Baunez C, Sinniger V, Piallat B, et al. Revealing a novel nociceptive network that links the subthalamic nucleus to pain processing. Elife 2018, 7: e36607.

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Ryan PJ. The Neurocircuitry of fluid satiation. Physiol Rep 2018, 6: e13744.

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Matsumoto H, Tian J, Uchida N, Watabe-Uchida M. Midbrain dopamine neurons signal aversion in a reward-context-dependent manner. Elife 2016, 5: e17328.

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Cohen JY, Haesler S, Vong L, Lowell BB, Uchida N. Neuron-type-specific signals for reward and punishment in the ventral tegmental area. Nature 2012, 482: 85–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Serranova T, Jech R, Dusek P, Sieger T, Ruzicka F, Urgosik D, et al. Subthalamic nucleus stimulation affects incentive salience attribution in Parkinson’s disease. Mov Disord 2011, 26: 2260–2266.

    PubMed  Google Scholar 

Download references


This work was supported by the National Natural Science Foundation of China (81701100, 81870891, and 81971038), the Fund for Jiangsu Province Specially-Appointed Professor (2016 and 2018), the Natural Science Foundation of Jiangsu Province, China (BK20171160), the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (17KJA320007 and 18KJA320009), the Jiangsu Province Fund for Dominant Discipline (Anesthesiology), and Academic Startup Packages from Xuzhou Medical University, China (D2017009 and D2017010).

Author information



Corresponding authors

Correspondence to Chunyi Zhou or Cheng Xiao.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wu, H., Yan, X., Tang, D. et al. Internal States Influence the Representation and Modulation of Food Intake by Subthalamic Neurons. Neurosci. Bull. (2020).

Download citation


  • Subthalamic nucleus
  • Food intake
  • Fiber photometry
  • Optogenetics