Abstract
Central orexinergic system deficiency results in cataplexy, a motor deficit characterized with a sudden loss of muscle tone, highlighting a direct modulatory role of orexin in motor control. However, the neural mechanisms underlying the regulation of orexin on motor function are still largely unknown. The subthalamic nucleus (STN), the only excitatory structure of the basal ganglia, holds a key position in the basal ganglia circuitry and motor control. Previous study has revealed a wide distribution of orexinergic fibers as well as orexin receptors in the basal ganglia including the STN. Therefore, in the present study, by using whole-cell patch clamp recording and immunostaining techniques, the direct effect of orexin on the STN neurons in brain slices, especially the underlying receptor and ionic mechanisms, were investigated. Our results show that orexin-A elicits an excitatory effect on STN neurons in rats. Tetrodotoxin (TTX) does not block the orexin-induced excitation on STN neurons, suggesting a direct postsynaptic action of the neuropeptide. The orexin-A-induced inward current on STN neurons is mediated by the activation of both OX1 and OX2 receptors. Immunofluorescence result shows that OX1 and OX2 receptors are co-expressed and co-localized in STN neurons. Furthermore, Na+-Ca2+ exchangers (NCXs) and inward rectifier K+ channels co-mediate the excitatory effect of orexin-A on STN neurons. These results demonstrate a dual receptor in conjunction with the downstream ionic mechanisms underlying the excitatory action of orexin on STN neurons, suggesting a potential modulation of the central orexinergic system on basal ganglia circuitry as well as its related motor control and motor diseases.
Highlights
Orexin is a neuropeptide first identified in 1998 (de Lecea et al, 1998; Sakurai et al, 1998)
44.6 ± 2.5 pA to 1.2 ± 0.1 pA on subthalamic nucleus (STN) neurons (n = 16, P < 0.001; Figures 3A–C). All these results suggest that OX1 and OX2 receptors co-mediate the excitatory effect induced by orexin-A on STN neurons
We report that orexin, a hypothalamic neuropeptide, directly excites STN neurons via postsynaptic OX1 and OX2 receptors
Summary
Orexin ( known as hypocretin) is a neuropeptide first identified in 1998 (de Lecea et al, 1998; Sakurai et al, 1998). In the central nervous system, orexin receptors produce excitation by postsynaptic depolarization via activation of non-selective cation channels, inhibition of K+ channels and activation of Na+-Ca2+ exchangers (NCXs), as well as presynaptic action through regulation of the release of other neurotransmitters (Kukkonen and Leonard, 2014; Leonard and Kukkonen, 2014). Accumulating studies have revealed that the central orexinergic system plays a key position in many basic physiological functions, including the sleep-wakefulness cycle, feeding, energy homeostasis and reward processes (Sakurai, 2007; Matsuki and Sakurai, 2008; Zhang et al, 2013; Giardino et al, 2018). The phenotype indicates that orexin may be directly involved in the somatic motor control. The knowledge about orexinergic modulation on motor control is still limited
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