Afferent Connections Of Hcrt Neurons

The afferent innervation of Hcrt neurons is less well understood. Colocalization of Hcrt with receptors for the neurotransmitters GABA92 and NPY34 suggests that Hcrt neurons are innervated by GABAergic and NPYergic neurons. GABAergic innervation may arise locally from GABAergic neurons that are abundant in the hypothalamus.93 NPY, agouti-related peptide (AgRP), and alpha-MSH are neurotransmitters found in the arcuate nucleus of the hypothalamus, an important regulator of food intake and body weight.94 Hcrt and MCH neurons receive innervation from NPY-, AgRP-, and alpha-MSH-immunoreactive fibers,18,19 suggesting that Hcrt participates in some level of feeding regulation. Leptin, a hormone synthesized by adipose tissue, is thought to regulate body weight through leptin receptors in the arcuate nucleus.95 (N.E. for a detailed description of intrahypothalamic afferents to hcrt neurons see Chapters 6 and 7). The presence of leptin receptors in Hcrt neurons suggests a role for Hcrt in feeding and body weight regulation.23,96 In addition, regulation of feeding-related motivation from the nucleus accumbens is suggested by studies showing that pharmacological blockade of GABAergic accumbens neurons promotes Hcrt neuron activation, as indicated by c-Fos expression.97

Circadian modulation of the Hcrt neurons is suggested by the presence of a small number of direct projections from the SCN seen in the rat with anterograde tracing, as well as apposition with arginine-vasopressin (A VP)- and vasoactive intestinal peptide (VIP)-immunoreactive fibers, whose cell bodies are found in the SCN in the human brain.29 Furthermore, Hcrt neurons receive innervation from the DMH, a region that receives dense SCN input that is GABAergic and glutamatergic.98

Indirect evidence for cholinergic and monoaminergic innervation of Hcrt neurons is suggested by in vitro slice electrophysiological experiments that demonstrate excitatory effects of acetylcholine and inhibitory effects of noradrenaline and serotonin on Hcrt neurons.32,99 Evidence for noradrenergic innervation is supported by the presence of dopamine beta-hydroxylase-immunoreactive axons in putative contact with Hcrt neurons.70 Evidence for serotonergic innervation is supported by 5-HT1A receptor-like immunoreactivity localization in Hcrt neurons and 5-HT transporter immunoreactive nerve endings found in close apposition to Hcrt neurons.100

Preliminary results of retrograde tracing experiments show putative afferents from limbic forebrain regions including the infralimbic cortex, nucleus accumbens, lateral septum, bed nucleus of the stria terminalis, preoptic area, amygdala, ventromedial hypothalamic nucleus, DMH, LHA, tuberomammillary nucleus, DR, substantia nigra, periaqueductal gray, parabrachial nucleus, and nucleus raphe magnus.101 Further studies are necessary to confirm afferents that specifically innervate the Hcrt neurons.

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