An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger.
Hunger is a hard-wired motivational state essential for survival. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) at the base of the hypothalamus are crucial to the control of hunger. They are activated by caloric deficiency and, when naturally or artificially stimulated, they potently induce intense hunger and subsequent food intake. Consistent with their obligatory role in regulating appetite, genetic ablation or chemogenetic inhibition of AgRP neurons decreases feeding. Excitatory input to AgRP neurons is important in caloric-deficiency-induced activation, and is notable for its remarkable degree of caloric-state-dependent synaptic plasticity. Despite the important role of excitatory input, its source(s) has been unknown. Here, through the use of Cre-recombinase-enabled, cell-specific neuron mapping techniques in mice, we have discovered strong excitatory drive that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing thyrotropin-releasing hormone (TRH) and pituitary adenylate cyclase-activating polypeptide (PACAP, also known as ADCYAP1). Chemogenetic stimulation of these afferent neurons in sated mice markedly activates AgRP neurons and induces intense feeding. Conversely, acute inhibition in mice with caloric-deficiency-induced hunger decreases feeding. Discovery of these afferent neurons capable of triggering hunger advances understanding of how this intense motivational state is regulated.
1] Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA (M.J.K.); National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA (M.J.K.); Cardiovascular and Metabolic Diseases, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, USA (B.P.S.); Division of Pediatric Endocrinology, Departments of Pediatrics, University of Michigan, Ann Arbor, Michigan 48105, USA (D.P.O.); Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, Massachusetts 02139, USA (L.V.). [3].
Michael J
MJ
Krashes
1] Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA (M.J.K.); National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA (M.J.K.); Cardiovascular and Metabolic Diseases, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, USA (B.P.S.); Division of Pediatric Endocrinology, Departments of Pediatrics, University of Michigan, Ann Arbor, Michigan 48105, USA (D.P.O.); Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, Massachusetts 02139, USA (L.V.). [3].
Bhavik P
BP
Shah
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Joseph C
JC
Madara
1] Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA (M.J.K.); National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA (M.J.K.); Cardiovascular and Metabolic Diseases, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, USA (B.P.S.); Division of Pediatric Endocrinology, Departments of Pediatrics, University of Michigan, Ann Arbor, Michigan 48105, USA (D.P.O.); Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, Massachusetts 02139, USA (L.V.).
David P
DP
Olson
1] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA.
David E
DE
Strochlic
1] Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Center for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK.
Alastair S
AS
Garfield
1] Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA (M.J.K.); National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA (M.J.K.); Cardiovascular and Metabolic Diseases, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, USA (B.P.S.); Division of Pediatric Endocrinology, Departments of Pediatrics, University of Michigan, Ann Arbor, Michigan 48105, USA (D.P.O.); Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, Massachusetts 02139, USA (L.V.).
Linh
L
Vong
Division of Pediatric Endocrinology, Departments of Pediatrics, University of Michigan, Ann Arbor, Michigan 48105, USA.
Hongjuan
H
Pei
Center for Brain Science, Department of Molecular and Cellular Biology, Harvard University, 16 Divinity Avenue, Cambridge, Massachusetts 02138, USA.
Mitsuko
M
Watabe-Uchida
1] Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Center for Brain Science, Department of Molecular and Cellular Biology, Harvard University, 16 Divinity Avenue, Cambridge, Massachusetts 02138, USA.
Naoshige
N
Uchida
1] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA.
Stephen D
SD
Liberles
1] Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA.
Bradford B
BB
Lowell
D054369:Agouti-Related Protein / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D001066:Appetite / Q000187:drug effects / Q000502:physiology; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000378:metabolism; D001931:Brain Mapping; D058948:Cell Tracking; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D000229:Dependovirus / Q000235:genetics; D004435:Eating / Q000187:drug effects / Q000502:physiology; D005260:Female; D005508:Food Deprivation; D006815:Hunger / Q000187:drug effects / Q000502:physiology*; D019426:Integrases / Q000378:metabolism; D008297:Male; D051379:Mice; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000502:physiology*; D010446:Peptide Fragments / Q000172:deficiency / Q000378:metabolism; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism; D011820:Rabies virus / Q000235:genetics; D012528:Satiety Response / Q000502:physiology; D013973:Thyrotropin-Releasing Hormone / Q000378:metabolism
D054369:Agouti-Related Protein; D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D013973:Thyrotropin-Releasing Hormone; C045073:Cre recombinase; D019426:Integrases; D003024:Clozapine; C079149:clozapine N-oxide