Nutritional state-dependent ghrelin activation of vasopressin neurons via retrograde trans-neuronal-glial stimulation of excitatory GABA circuits.
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.
Department of Cell and Molecular Biology and Neuroscience Program, Tulane University, New Orleans, Louisiana 70118.
Juhee
J
Haam
Katalin C
KC
Halmos
Shi
S
Di
Jeffrey G
JG
Tasker
D000255:Adenosine Triphosphate / Q000378:metabolism; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D054439:Ghrelin / Q000494:pharmacology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology*; D051381:Rats; D017208:Rats, Wistar; D055366:Synaptic Potentials / Q000187:drug effects / Q000235:genetics; D013779:Tetrodotoxin / Q000494:pharmacology; D014667:Vasopressins / Q000235:genetics / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000779:Anesthetics, Local; D004791:Enzyme Inhibitors; D054439:Ghrelin; D018377:Neurotransmitter Agents; C485184:enhanced green fluorescent protein; D014667:Vasopressins; D049452:Green Fluorescent Proteins; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D000255:Adenosine Triphosphate; D002118:Calcium
ATP; astrocyte; ghrelin; hypothalamus; paraventricular nucleus; vasopressin