title: Lateral Hypothalamic Area Glutamatergic Neurons and Their Projections to the Lateral Habenula Regulate Feeding and Reward.
abstract: The overconsumption of calorically dense, highly palatable foods is thought to be a major contributor to the worldwide obesity epidemic; however, the precise neural circuits that directly regulate hedonic feeding remain elusive. Here, we show that lateral hypothalamic area (LHA) glutamatergic neurons, and their projections to the lateral habenula (LHb), negatively regulate the consumption of palatable food. Genetic ablation of LHA glutamatergic neurons increased daily caloric intake and produced weight gain in mice that had access to a high-fat diet, while not altering general locomotor activity. Anterior LHA glutamatergic neurons send a functional glutamatergic projection to the LHb, a brain region involved in processing aversive stimuli and negative reward prediction outcomes. Pathway-specific, optogenetic stimulation of glutamatergic LHA-LHb circuit resulted in detectable glutamate-mediated EPSCs as well as GABA-mediated IPSCs, although the net effect of neurotransmitter release was to increase the firing of most LHb neurons. In vivo optogenetic inhibition of LHA-LHb glutamatergic fibers produced a real-time place preference, whereas optogenetic stimulation of LHA-LHb glutamatergic fibers had the opposite effect. Furthermore, optogenetic inhibition of LHA-LHb glutamatergic fibers acutely increased the consumption of a palatable liquid caloric reward. Collectively, these results demonstrate that LHA glutamatergic neurons are well situated to bidirectionally regulate feeding and potentially other behavioral states via their functional circuit connectivity with the LHb and potentially other brain regions.
  
  
  CONCLUSIONS
  In this study, we show that the genetic ablation of LHA glutamatergic neurons enhances caloric intake. Some of these LHA glutamatergic neurons project to the lateral habenula, a brain area important for generating behavioral avoidance. Optogenetic stimulation of this circuit has net excitatory effects on postsynaptic LHb neurons. This is the first study to characterize the functional connectivity and behavioral relevance of this circuit within the context of feeding and reward-related behavior.
authors.affiliation: Departments of Psychiatry and Cell Biology and Physiology, Curriculum in Neurobiology, and.
authors.forename: Alice M
authors.identifier: http://orcid.org/0000-0002-3458-2139
authors.initials: AM
authors.lastname: Stamatakis
authors.affiliation: Departments of Psychiatry and Cell Biology and Physiology, Master program Neuroscience and Cognition, Brain Center Rudolf Magnus, Department of Transitional Neuroscience, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
authors.forename: Maaike
authors.identifier: http://orcid.org/0000-0002-7361-9467
authors.initials: M
authors.lastname: Van Swieten
authors.affiliation: Departments of Psychiatry and Cell Biology and Physiology, Curriculum in Neurobiology, and.
authors.forename: Marcus L
authors.identifier: http://orcid.org/0000-0002-4829-7187
authors.initials: ML
authors.lastname: Basiri
authors.affiliation: Departments of Psychiatry and Cell Biology and Physiology.
authors.forename: Grace A
authors.initials: GA
authors.lastname: Blair
authors.affiliation: Departments of Psychiatry and Cell Biology and Physiology.
authors.forename: Pranish
authors.initials: P
authors.lastname: Kantak
authors.affiliation: Departments of Psychiatry and Cell Biology and Physiology, Curriculum in Neurobiology, and Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, and gstuber@med.unc.edu.
authors.forename: Garret D
authors.initials: GD
authors.lastname: Stuber
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D003216:Conditioning, Operant; D005106:Exploratory Behavior; D005247:Feeding Behavior / Q000502:physiology*; D005456:Fluorescent Dyes / Q000378:metabolism; D005822:Genetic Vectors / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D019262:Habenula / Q000502:physiology*; D007026:Hypothalamic Area, Lateral / Q000166:cytology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009434:Neural Pathways / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D012201:Reward; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics / Q000378:metabolism; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D005456:Fluorescent Dyes; D008164:Luminescent Proteins; C493477:Slc17a6 protein, mouse; D050599:Vesicular Glutamate Transport Protein 2; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse; C054562:yellow fluorescent protein, Bacteria; D018698:Glutamic Acid; D053148:Caspase 3
keywords: aversion; feeding; habenula; hypothalamus; optogenetics; reward