ABSTRACT
BACKGROUND: Melanin-concentrating hormone (MCH)-expressing neurons have been implicated in regulation of energy homeostasis and reward, yet the role of their electrical activity in short-term appetite and reward modulation has not been fully understood. OBJECTIVES: We investigated short-term behavioral and physiological effects of MCH neuron activity manipulations. METHODS: We used optogenetic and chemogenetic approaches in Pmch-cre transgenic mice to acutely stimulate/inhibit MCH neuronal activity while probing feeding, locomotor activity, anxiety-like behaviors, glucose homeostasis, and reward. RESULTS: MCH neuron activity is neither required nor sufficient for short-term appetite unless stimulation is temporally paired with consumption. MCH neuronal activation does not affect short-term locomotor activity, but inhibition improves glucose tolerance and is mildly anxiolytic. Finally, using two different operant tasks, we showed that activation of MCH neurons alone is sufficient to induce reward. CONCLUSIONS: Our results confirm diverse behavioral/physiological functions of MCH neurons and suggest a direct role in reward function.
Subject(s)
Appetite/physiology , Behavior, Animal/physiology , Blood Glucose/metabolism , Feeding Behavior/physiology , Hypothalamic Hormones/metabolism , Locomotion/physiology , Melanins/metabolism , Neurons/physiology , Pituitary Hormones/metabolism , Reward , Animals , Female , Homeostasis/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neurons/metabolism , OptogeneticsABSTRACT
Glucose is the essential energy source for the brain, whose deficit, triggered by energy deprivation or therapeutic agents, can be fatal. Increased appetite is the key behavioral defense against hypoglycemia; however, the central pathways involved are not well understood. Here, we describe a glucoprivic feeding pathway by tyrosine hydroxylase (TH)-expressing neurons from nucleus of solitary tract (NTS), which project densely to the hypothalamus and elicit feeding through bidirectional adrenergic modulation of agouti-related peptide (AgRP)- and proopiomelanocortin (POMC)-expressing neurons. Acute chemogenetic inhibition of arcuate nucleus (ARC)-projecting NTSTH neurons or their target, AgRP neurons, impaired glucoprivic feeding induced by 2-Deoxy-D-glucose (2DG) injection. Neuroanatomical tracing results suggested that ARC-projecting orexigenic NTSTH neurons are largely distinct from neighboring catecholamine neurons projecting to parabrachial nucleus (PBN) that promotes satiety. Collectively, we describe a circuit organization in which an ascending pathway from brainstem stimulates appetite through key hunger neurons in the hypothalamus in response to hypoglycemia.
