title: Sex-dependent changes in metabolism and behavior, as well as reduced anxiety after eliminating ventromedial hypothalamus excitatory output.
abstract: OBJECTIVE
  The ventromedial hypothalamic nucleus (VMH) regulates energy homeostasis as well as social and emotional behaviors. Nearly all VMH neurons, including those in the sexually dimorphic ventrolateral VMH (VMHvl) subregion, release the excitatory neurotransmitter glutamate and use the vesicular glutamate transporter 2 (Vglut2). Here, we asked how glutamatergic signaling contributes to the collective metabolic and behavioral responses attributed to the VMH and VMHvl.
  
  
  METHODS
  Using Sf1-Cre and a Vglut2 floxed allele, Vglut2 was knocked-out in SF-1 VMH neurons (Vglut2 (Sf1-Cre) ). Metabolic and neurobehavioral assays were carried out initially on Vglut2 (fl/fl) and Vglut2 (Sf1-Cre) mice in a mixed, and then in the C57BL/6 genetic background, which is prone to hyperglycemia and diet induced obesity (DIO).
  
  
  RESULTS
  Several phenotypes observed in Vglut2 (Sf1-Cre) mice were largely unexpected based on prior studies that have perturbed VMH development or VMH glutamate signaling. In our hands, Vglut2 (Sf1-Cre) mice failed to exhibit the anticipated increase in body weight after high fat diet (HFD) or the impaired glucose homeostasis after fasting. Instead, there was a significant sex-dependent attenuation of DIO in Vglut2 (Sf1-Cre) females. Vglut2 (Sf1-Cre) males also display a sex-specific loss of conditioned-fear responses and aggression accompanied by more novelty-associated locomotion. Finally, unlike the higher anxiety noted in Sf1 (Nestin-Cre) mice that lack a fully formed VMH, both male and female Vglut2 (Sf1-Cre) mice were less anxious.
  
  
  CONCLUSIONS
  Loss of VMH glutamatergic signaling sharply decreased DIO in females, attenuated aggression and learned fear in males, and was anxiolytic in males and females. Collectively, our findings demonstrate that while glutamatergic output from the VMH appears largely dispensable for counter regulatory responses to hypoglycemia, it drives sex-dependent differences in metabolism and social behaviors and is essential for adaptive responses to anxiety-provoking stimuli in both sexes.
authors.affiliation: Department of Cellular and Molecular Pharmacology, Mission Bay Campus, University of California, San Francisco 94143, United States.
authors.forename: Clement C
authors.initials: CC
authors.lastname: Cheung
authors.affiliation: Department of Cellular and Molecular Pharmacology, Mission Bay Campus, University of California, San Francisco 94143, United States.
authors.forename: William C
authors.initials: WC
authors.lastname: Krause
authors.affiliation: Department of Physiology and Neurology, Mission Bay Campus, University of California, San Francisco 94143, United States.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Edwards
authors.affiliation: Department of Anatomy, Mission Bay Campus, University of California, San Francisco 94143, United States.
authors.forename: Cindy F
authors.initials: CF
authors.lastname: Yang
authors.affiliation: Department of Anatomy, Mission Bay Campus, University of California, San Francisco 94143, United States.
authors.forename: Nirao M
authors.initials: NM
authors.lastname: Shah
authors.affiliation: Department of Physiology and Neurology, Mission Bay Campus, University of California, San Francisco 94143, United States.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Hnasko
authors.affiliation: Department of Cellular and Molecular Pharmacology, Mission Bay Campus, University of California, San Francisco 94143, United States.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Ingraham
keywords: Anxiety; Excitatory output; Male aggression; Sex-dependent obesity; VGlut2; VMH