Orexin A Preferentially Excites Glucose-Sensitive Neurons in the Lateral Hypothalamus of the Rat In Vitro

Abstract

Falls in blood glucose induce hunger and initiate feeding. The lateral hypothalamic area (LHA) contains glucose-sensitive neurons (GSNs) and orexin neurons, both of which are stimulated by falling blood glucose and are implicated in hypoglycemia-induced feeding. We combined intracellular electrophysiological recording with fluorescein labeling of GSNs to determine their neuroanatomic and functional relationships with orexin neurons. Orexin A (1 mol/l) caused a 500% increase (P < 0.01) in spontaneous firing rate and rapid and lasting depolarization that was tetrodotoxin-resistant and thus a direct postsynaptic effect. Orexin A altered the intrinsic neuronal properties of GSNs, consistent with increased excitability. Confocal microscopy showed that GSNs were intimately related to orexin neurons: orexin-immunoreactive axons were frequently entwined around GSN dendrites, establishing close and putatively synaptic contacts. Orexin-cell axons also passed in close proximity to glucose-responsive neurons, which are inhibited by low glucose, but orexin A caused smaller depolarization than on GSNs and only a 200% increase in spontaneous firing rate (P < 0.05 vs. GSN). We conclude that GSNs are specific target neurons for orexin A and suggest that they may mediate, at least in part, the acute appetite-stimulating effect of orexin A. Orexin neurons may regulate GSNs so as to control the onset and termination of hypoglycemiainduced feeding. Diabetes 50:2431-2437, 2001 R educed availability of glucose, the brain's main metabolic fuel, causes intense hunger (1). The lateral hypothalamic area (LHA) is crucial to the hyperphagia induced by hypoglycemia and glucoprivation, as this feeding response is abolished by LHA lesions (1). The LHA neuronal systems that drive glucoprivic feeding are unknown, but promising candidates include the glucose-sensing neurons and orexin (hypocretin) neurons that are prominent in this region.Glucose-sensing neurons, which alter their firing behavior in response to changes in ambient glucose concentration, are found in the hypothalamus and in several other central nervous system regions (2). Glucose-sensitive neurons (GSNs) are inhibited by rising glucose concentrations but excited when glucose falls, whereas glucose-responsive neurons (GRNs) are stimulated as glucose rises and are inhibited by hypoglycemia (3,4). GSNs are particularly abundant in the LHA, where they account for 30 -40% of all neurons (3,5). These cells are stimulated directly by low glucose in vitro (3,6) but are also regulated indirectly in vivo, being inhibited by rising glucose levels in the hindbrain and viscera and by gastric distension (1,7). These indirect signals are presumed to be relayed to the LHA from the nucleus of the solitary tract (NTS) in the medulla, which contains glucose-sensing neurons and also receives vagal afferents from visceral glucose sensors and gastric stretch receptors (7). In view of these properties, lateral hypothalamic GSNs are assumed to participate in triggering and controlling glucoprivic feeding...

Hypocretinergic Control of Spinal Cord Motoneurons

“…The preceding results are in agreement with those obtained from in vitro studies that have reported that Hcrt produces neuronal depolarization (Horvath et al, 1999;Bayer et al, 2001;Eggermann et al, 2001;Eriksson et al, 2001;Liu et al, 2001Liu et al, , 2002Brown et al, 2002;Soffin et al, 2002) and changes in membrane conductance (Eriksson et al 2001;Burlet et al 2002). However, in neurons of the locus coeruleus, the application of Hcrt promotes depolarization accompanied by a decrease or no change in membrane conductance (Hagan et al, 1999;Ivanov and Aston-Jones, 2000).…”

Excitation of Ventral Tegmental Area Dopaminergic and Nondopaminergic Neurons by Orexins/Hypocretins

“…A subpopulation of orexin neurons possess leptin receptors (Willie et al, 2001), and leptin administration is known to modulate the rewarding effect of lateral hypothalamic stimulation (Fulton et al, 2000). Furthermore, orexin neurons are sensitive to metabolic state, receiving input from glucose-sensitive neurons (Liu et al, 2001). One model of the role of the orexin modulation of VTA neurons could be as follows: lack of adequate metabolic substrate would lead to increased activity in orexin neurons, excitation of dopaminergic and GABAergic neurons in the VTA, leading to increased arousal, locomotor activity, and a search for food.…”

Cholinergic Modulation of Appetite-Related Synapses in Mouse Lateral Hypothalamic Slice

“…If the GABAergic input to PF LH neurons participates in appetite-related neural circuitry, then, based on previous literature, we expect certain profiles of glucose response characteristics of the synaptic transmission in PF LH (Liu et al, 2001;Song et al, 2001;Wang et al, 2004). In these experiments, the external concentration of glucose was lowered from 10 to 1 mM.…”