Overnight Fasting Regulates Inhibitory Tone to Cholinergic Neurons of the Dorsomedial Nucleus of the Hypothalamus

Florian Groessl,Young-Hwan Jo,David A Talmage,Jae Hoon Jeong,Lorna W Role,Anna-Leena Sirén

doi:10.1371/journal.pone.0060828

Abstract

The dorsomedial nucleus of the hypothalamus (DMH) contributes to the regulation of overall energy homeostasis by modulating energy intake as well as energy expenditure. Despite the importance of the DMH in the control of energy balance, DMH-specific genetic markers or neuronal subtypes are poorly defined. Here we demonstrate the presence of cholinergic neurons in the DMH using genetically modified mice that express enhanced green florescent protein (eGFP) selectively in choline acetyltransferase (Chat)-neurons. Overnight food deprivation increases the activity of DMH cholinergic neurons, as shown by induction of fos protein and a significant shift in the baseline resting membrane potential. DMH cholinergic neurons receive both glutamatergic and GABAergic synaptic input, but the activation of these neurons by an overnight fast is due entirely to decreased inhibitory tone. The decreased inhibition is associated with decreased frequency and amplitude of GABAergic synaptic currents in the cholinergic DMH neurons, while glutamatergic synaptic transmission is not altered. As neither the frequency nor amplitude of miniature GABAergic or glutamatergic postsynaptic currents is affected by overnight food deprivation, the fasting-induced decrease in inhibitory tone to cholinergic neurons is dependent on superthreshold activity of GABAergic inputs. This study reveals that cholinergic neurons in the DMH readily sense the availability of nutrients and respond to overnight fasting via decreased GABAergic inhibitory tone. As such, altered synaptic as well as neuronal activity of DMH cholinergic neurons may play a critical role in the regulation of overall energy homeostasis.

Highlights

Obesity increases the risk of a number of health conditions including cardiovascular disease, type 2 diabetes, and several cancers [1]
We found that a single, overnight food deprivation increased fos protein in the dorsomedial nucleus of the hypothalamus (DMH) cholinergic neurons, as compared to control
Arcuate neuropeptide Y (NPY) and POMC neurons are innervated by cholinergic axons [18], consistent with the idea that hypothalamic cholinergic neurons regulate the excitability of orexigenic and anorexigenic neurons in the arcuate nucleus, thereby modulating feeding behavior

Summary

Introduction

Obesity increases the risk of a number of health conditions including cardiovascular disease, type 2 diabetes, and several cancers [1]. The dorsomedial nucleus of the hypothalamus (DMH) is a critical structure for the regulation of a wide range of physiological processes, ranging from reproduction, thermogenesis, stress response, food intake, and circadian rhythms ([5,6,7,8] and for reviews see [9,10,11]). Recent studies have demonstrated the existence of various neurotransmitters and signaling proteins that affect and/or are affected with altered food intake in the DMH. These include leptin-responsive GABAergic neurons [8,12], brain-derived neurotrophic factor (BDNF) [13], neuropeptide Y (NPY) [5], endocannabinoids, and nitric oxide (NO) [14]. A recent study further identifies genes that are highly expressed in the DMH using microarray analysis [15], little information is available about molecular markers specific for the DMH, which would facilitate the development of mouse models with DMH-specific genetic manipulations

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Conclusion