TY - JOUR
T1 - Energy state alters regulation of proopiomelanocortin neurons by glutamatergic ventromedial hypothalamus neurons
T2 - Pre- And postsynaptic mechanisms
AU - Rau, Andrew R.
AU - Hentges, Shane T.
N1 - Publisher Copyright:
© 2021 American Physiological Society. All rights reserved.
PY - 2021/3
Y1 - 2021/3
N2 - To maintain metabolic homeostasis, motivated behaviors are driven by neuronal circuits that process information encoding the animal's energy state. Such circuits likely include ventromedial hypothalamus (VMH) glutamatergic neurons that project throughout the brain to drive food intake and energy expenditure. Targets of VMH glutamatergic neurons include proopiomelanocortin (POMC) neurons in the arcuate nucleus that, when activated, inhibit food intake. Although an energy-state-sensitive, glutamate circuit between the VMH and POMC neurons has been previously indicated, the significance and details of this circuit have not been fully elucidated. Thus, the goal of the present work was to add to the understanding of this circuit. Using a knockout strategy, the data show that the VMH glutamate → POMC neuron circuit is important for the inhibition of food intake. Conditional deletion of the vesicular glutamate transporter (VGLUT2) in the VMH results in increased bodyweight and increased food intake following a fast in both male and female mice. Additionally, the targeted blunting of glutamate release from the VMH resulted in an ~32% reduction in excitatory inputs to POMC cells, suggesting that this circuit may respond to changes in energy state to affect POMC activity. Indeed, we found that glutamate release is increased at VMH-to-POMC synapses during feeding and POMC AMPA receptors switch from a calcium-permeable state to a calcium-impermeable state during fasting. Collectively, these data indicate that there is an energy-balance-sensitive VMH-to-POMC circuit conveying excitatory neuromodulation onto POMC cells at both pre- and postsynaptic levels, which may contribute to maintaining appropriate food intake and body mass. NEW & NOTEWORTHY Despite decades of research, the neurocircuitry underlying metabolic homeostasis remains incompletely understood. Specifically, the roles of amino acid transmitters, particularly glutamate, have received less attention than hormonal signals. Here, we characterize an energy-state-sensitive glutamate circuit from the ventromedial hypothalamus to anorexigenic proopiomelanocortin (POMC) neurons that responds to changes in energy state at both sides of the synapse, providing novel information about how variations in metabolic state affect excitatory drive onto POMC cells.
AB - To maintain metabolic homeostasis, motivated behaviors are driven by neuronal circuits that process information encoding the animal's energy state. Such circuits likely include ventromedial hypothalamus (VMH) glutamatergic neurons that project throughout the brain to drive food intake and energy expenditure. Targets of VMH glutamatergic neurons include proopiomelanocortin (POMC) neurons in the arcuate nucleus that, when activated, inhibit food intake. Although an energy-state-sensitive, glutamate circuit between the VMH and POMC neurons has been previously indicated, the significance and details of this circuit have not been fully elucidated. Thus, the goal of the present work was to add to the understanding of this circuit. Using a knockout strategy, the data show that the VMH glutamate → POMC neuron circuit is important for the inhibition of food intake. Conditional deletion of the vesicular glutamate transporter (VGLUT2) in the VMH results in increased bodyweight and increased food intake following a fast in both male and female mice. Additionally, the targeted blunting of glutamate release from the VMH resulted in an ~32% reduction in excitatory inputs to POMC cells, suggesting that this circuit may respond to changes in energy state to affect POMC activity. Indeed, we found that glutamate release is increased at VMH-to-POMC synapses during feeding and POMC AMPA receptors switch from a calcium-permeable state to a calcium-impermeable state during fasting. Collectively, these data indicate that there is an energy-balance-sensitive VMH-to-POMC circuit conveying excitatory neuromodulation onto POMC cells at both pre- and postsynaptic levels, which may contribute to maintaining appropriate food intake and body mass. NEW & NOTEWORTHY Despite decades of research, the neurocircuitry underlying metabolic homeostasis remains incompletely understood. Specifically, the roles of amino acid transmitters, particularly glutamate, have received less attention than hormonal signals. Here, we characterize an energy-state-sensitive glutamate circuit from the ventromedial hypothalamus to anorexigenic proopiomelanocortin (POMC) neurons that responds to changes in energy state at both sides of the synapse, providing novel information about how variations in metabolic state affect excitatory drive onto POMC cells.
KW - Electrophysiology
KW - Energy balance
KW - Glutamate
KW - Optogenetics
KW - Transgenic mice
UR - http://www.scopus.com/inward/record.url?scp=85102601949&partnerID=8YFLogxK
U2 - 10.1152/JN.00359.2020
DO - 10.1152/JN.00359.2020
M3 - Article
C2 - 33441043
AN - SCOPUS:85102601949
SN - 0022-3077
VL - 125
SP - 720
EP - 730
JO - Journal of Neurophysiology
JF - Journal of Neurophysiology
IS - 3
ER -