Neuromodulation and Synaptic Plasticity in the Dorsomedial Hypothalamus.

摘要

The dorsomedial nucleus of the hypothalamus (DMH) is a key player in the maintenance of a number of vital homeostatic functions including the regulation of food intake. Despite this important role, surprisingly little is known about synaptic processing and plasticity of synapses in this nucleus. The main objective of this thesis was to investigate how inhibitory GABAergic synapses in the DMH are modulated in response to satiety and stress signals. Specifically, using an electrophysiological approach, we examined the impact of the satiety peptide, cholecystokinin, and stress triggered by food deprivation on the signaling and plasticity of GABA synapses in the DMH. Whole cell electrophysiological recordings were obtained from DMH neurons using male Sprague-Dawley rats, postnatal day (P) 21-30. The work presented here demonstrates that CCK potentiates GABAergic synaptic inhibition through two novel mechanisms. First, following dendritic release from DMH neurons, CCK acts in an autocrine fashion to inhibit these neurons through a CCK1 receptor-mediated pathway that requires retrograde NO signaling and potentiation of GABA release from the presynaptic terminal. Second, in response to bursts of afferent activity resulting in surges of glutamate release, CCK triggers long term potentiation of GABA synapses mediated by CCK2 and group I metabotropic receptors putatively localized on neighboring astrocytes. Activation of these receptors stimulates release of ATP which subsequently acts at GABA terminals to increase the probability of GABA release. The present findings also demonstrate that the feeding state of an animal shifts the plasticity of GABA synapses from endocannabinoid-mediated long term depression observed in satiated animals to nitric oxide-mediated long term potentiation. This is due to a stress-induced down-regulation of cannabinoid receptors in food-deprived animals. Overall, the work in this thesis has significantly enhanced our understanding of neuromodulation and synaptic plasticity in the DMH.