Nutritional state-dependent ghrelin activation of vasopressin neurons via retrograde trans-neuronal-glial stimulation of excitatory GABA circuits

• Published in: The Journal of neuroscience Vol. 34; no. 18; pp. 6201 - 6213
• Main Authors: Haam, Juhee, Halmos, Katalin C, Di, Shi, Tasker, Jeffrey G
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 30.04.2014
• Subjects: Adenosine Triphosphate - metabolism; Anesthetics, Local - pharmacology; Animals; Calcium - metabolism; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; gamma-Aminobutyric Acid - metabolism; Ghrelin - pharmacology; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; In Vitro Techniques; Male; Nerve Net - drug effects; Nerve Net - physiology; Neuroglia - drug effects; Neuroglia - metabolism; Neurons - drug effects; Neurons - physiology; Neurotransmitter Agents - pharmacology; Paraventricular Hypothalamic Nucleus - cytology; Rats; Rats, Wistar; Synaptic Potentials - drug effects; Synaptic Potentials - genetics; Tetrodotoxin - pharmacology; Vasopressins - genetics; Vasopressins - metabolism; ghrelin; ATP; astrocyte; hypothalamus; vasopressin; paraventricular nucleus
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.3178-13.2014

Behavioral and physiological coupling between energy balance and fluid homeostasis is critical for survival. The orexigenic hormone ghrelin has been shown to stimulate the secretion of the osmoregulatory hormone vasopressin (VP), linking nutritional status to the control of blood osmolality, although the mechanism of this systemic crosstalk is unknown. Here, we show using electrophysiological recordings and calcium imaging in rat brain slices that ghrelin stimulates VP neurons in the hypothalamic paraventricular nucleus (PVN) in a nutritional state-dependent manner by activating an excitatory GABAergic synaptic input via a retrograde neuronal-glial circuit. In slices from fasted rats, ghrelin activation of a postsynaptic ghrelin receptor, the growth hormone secretagogue receptor type 1a (GHS-R1a), in VP neurons caused the dendritic release of VP, which stimulated astrocytes to release the gliotransmitter adenosine triphosphate (ATP). ATP activation of P2X receptors excited presynaptic GABA neurons to increase GABA release, which was excitatory to the VP neurons. This trans-neuronal-glial retrograde circuit activated by ghrelin provides an alternative means of stimulation of VP release and represents a novel mechanism of neuronal control by local neuronal-glial circuits. It also provides a potential cellular mechanism for the physiological integration of energy and fluid homeostasis.