Figure 2. Molecular and electrophysiological interactions of hypocretins with histamine neurons. (A) Co-expression of histidine-decarboxylase (HDC) and hypocretin receptors (OR1 and OR2; single cell RT-PCR). (B) Hypocretin-1/Orexin-A (300 nM) induced increases in spontaneous firing and (C) tetrodotoxin-insensitive depolarization in TMN neurons (intracellular sharp electrode recordings). (D) Dose dependent postsynaptic depolarization by Orexin-A/B. (E-G) Block of hypocretin-induced depolarization by inhibition of sodium-calcium-exchangers (NCX). Modified from Eriksson et al.14
Thus, hypocretin/dynorphin containing neurons excite TMN neurons directly via Hcrt2 receptors and through presynaptic disinhibition gated by dynorphin. Unfortunately, the mechanisms controlling co-expression and -release of dynorphins in hypocretin neurons are unknown. However, it may be transcriptional mechanisms, intrinsic to hypocretin neurons and imprinted by metabolic3,89,90 and circadian state cues8,91,92 and aminergic influences that gate sleep-wake transitions6,13 and basic body functions. 35,36,93
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