Cholinergic neurons in the dorsomedial hypothalamus regulate food intake

Mar 9, 2017Molecular metabolism

Cholinergic neurons in the brain's energy control center influence eating behavior

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Abstract

Mice lacking the gene in the dorsomedial hypothalamus (DMH) show reduced body weight compared to control.

Activation of DMH cholinergic neurons promotes food intake.
Optogenetic stimulation of DMH cholinergic neurons supports this increase in food consumption.
DMH cholinergic neurons connect to pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus.
Acetylcholine enhances GABAergic transmission to ARC POMC neurons, which is inhibited by a muscarinic receptor antagonist.
Direct activation of cholinergic fibers in the ARC stimulates food intake, and this effect is blocked by the muscarinic receptor antagonist.
ACh released from DMH cholinergic neurons is linked to the regulation of food intake and body weight.

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OBJECTIVE: Central cholinergic neural circuits play a role in the regulation of feeding behavior. The dorsomedial hypothalamus (DMH) is considered the appetite-stimulating center and contains cholinergic neurons. Here, we study the role of DMH cholinergic neurons in the control of food intake.

METHODS: To selectively stimulate DMH cholinergic neurons, we expressed stimulatory designer receptors exclusively activated by designer drugs (DREADDs) and channelrhodopsins in DMH cholinergic neurons by injection of adeno-associated virus (AAV) vectors into the DMH of choline acetyltransferase (ChAT)-IRES-Cre mice. We also generated transgenic mice expressing channelrhodopsins in cholinergic neurons with the Cre-LoxP technique. To delete thegene exclusively in the DMH, we injected an AAV carrying a Cre recombinase transgene into the DMH of floxed ChAT mice. Food intake was measured with and without selective stimulation of DMH cholinergic neurons. Chat

RESULTS: Mice lacking thegene in the DMH show reduced body weight as compared to control. Chemogenetic activation of DMH cholinergic neurons promotes food intake. This orexigenic effect is further supported by experiments of optogenetic stimulation of DMH cholinergic neurons. DMH cholinergic neurons innervate pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus (ARC). Treatment with acetylcholine (ACh) enhances GABAergic inhibitory transmission to ARC POMC neurons that is blocked by the muscarinic receptor antagonist. Direct activation of cholinergic fibers in the ARC readily stimulates food intake that is also abolished by the muscarinic receptor antagonist. Chat

CONCLUSION: ACh released from DMH cholinergic neurons regulates food intake and body weight. This effect is mediated in part through regulation of ARC POMC neurons. Activation of muscarinic receptors on GABAergic axon terminals enhances inhibitory tone to ARC POMC neurons. Hence, this novel DMH → ARCpathway plays an important role in the control of food intake and body weight. ACh POMC

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Cholinergic neurons in the dorsomedial hypothalamus regulate food intake

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