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Leptin receptor neurons in the dorsomedial hypothalamus input to the circadian feeding network.

ABSTRACT: Salient cues, such as the rising sun or availability of food, entrain biological clocks for behavioral adaptation. The mechanisms underlying entrainment to food availability remain elusive. Using single-nucleus RNA sequencing during scheduled feeding, we identified a dorsomedial hypothalamus leptin receptor-expressing (DMH^LepR) neuron population that up-regulates circadian entrainment genes and exhibits calcium activity before an anticipated meal. Exogenous leptin, silencing, or chemogenetic stimulation of DMH^LepR neurons disrupts the development of molecular and behavioral food entrainment. Repetitive DMH^LepR neuron activation leads to the partitioning of a secondary bout of circadian locomotor activity that is in phase with the stimulation and dependent on an intact suprachiasmatic nucleus (SCN). Last, we found a DMH^LepR neuron subpopulation that projects to the SCN with the capacity to influence the phase of the circadian clock. This direct DMH^LepR-SCN connection is well situated to integrate the metabolic and circadian systems, facilitating mealtime anticipation.

SUBMITTER: Tang Q

PROVIDER: S-EPMC10456850 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Leptin receptor neurons in the dorsomedial hypothalamus input to the circadian feeding network.

Tang Qijun Q Godschall Elizabeth E Brennan Charles D CD Zhang Qi Q Abraham-Fan Ruei-Jen RJ Williams Sydney P SP Güngül Taha Buğra TB Onoharigho Roberta R Buyukaksakal Aleyna A Salinas Ricardo R Sajonia Isabelle R IR Olivieri Joey J JJ Calhan O Yipkin OY Deppmann Christopher D CD Campbell John N JN Podyma Brandon B Güler Ali D AD

Science advances 20230825 34

Salient cues, such as the rising sun or availability of food, entrain biological clocks for behavioral adaptation. The mechanisms underlying entrainment to food availability remain elusive. Using single-nucleus RNA sequencing during scheduled feeding, we identified a dorsomedial hypothalamus leptin receptor-expressing (DMH<sup>LepR</sup>) neuron population that up-regulates circadian entrainment genes and exhibits calcium activity before an anticipated meal. Exogenous leptin, silencing, or chemo ...[more]

PMID: 37624889

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Project description:ObjectiveCentral 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.MethodsTo 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 the Chat gene 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.ResultsMice lacking the Chat gene 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.ConclusionACh 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 DMHACh → ARCPOMC pathway plays an important role in the control of food intake and body weight.

Dataset Information

Leptin receptor neurons in the dorsomedial hypothalamus input to the circadian feeding network.

Publications

Leptin receptor neurons in the dorsomedial hypothalamus input to the circadian feeding network.

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