The Subthalamic Neurons are Activated by Both Orexin-A and Orexin-B.

Abstract

The subthalamic nucleus is an important nucleus in the indirect pathway of the basal ganglia circuit and therefore is involved in motor control under both normal and pathological conditions. Morphological studies reveal that the subthalamic nucleus receives relatively dense orexinergic projections originating from the hypothalamus. Both orexin-1 (OX1) and orexin-2 (OX2) receptors are expressed in the subthalamic nucleus. To explore the functions of orexinergic system in the subthalamic nucleus, extracellular electrophysiological recordings and behavioral tests were performed in the present study. Exogenous application of orexin-A significantly increased the spontaneous firing rate from 5.70 ± 0.66 Hz to 9.87 ± 1.18 Hz in 64.00% subthalamic neurons recorded. OX1 receptors are involved in orexin-A-induced excitation. Application of orexin-B increased the firing rate from 7.47 ± 0.92 Hz to 11.85 ± 1.39 Hz in 80.95% subthalamic neurons recorded, entirely through OX2 receptors. Both OX1 and OX2 receptor antagonists decreased the firing rate in 43.75% and 62.50% subthalamic neurons recorded respectively, suggesting the involvement of endogenous orexinergic system in the control of spontaneous firing activity. Further elevated body swing test revealed that microinjection of orexins and the receptor antagonists into the subthalamic nucleus induced contralateral-biased swing and ipsilateral-biased swing, respectively. Taken together, the present study suggests that orexins play important roles in the subthalamic nucleus which may provide further evidence for the involvement of subthalamic orexinergic tone in Parkinson's disease.

SIGNIFICANCE:

Previous morphological studies indicate that the subthalamic nucleus receives orexinergic innervation and expresses both OX1 and OX2 receptors. Using in vivo multibarrel electrophysiological recordings, the present study revealed that exogenous application of orexin-A and orexin-B increased the spontaneous firing rate of the subthalamic neurons through OX1 and OX2 receptors. Endogenous orexinergic system was involved in the control of spontaneous firing of the subthalamic neurons. Further behavioral test revealed that intrasubthalamic application of orexins and the receptor antagonists induced biased swing behavior. The present study may provide further evidence for the involvement of subthalamic orexinergic tone in Parkinson's disease.

• Authors: Qing Sheng, Yan Xue, Ying Wang, An-Qi Chen, Cui Liu, Yun-Hai Liu, Hong-Yan Chu, Lei Chen
• Journal: Neuroscience (Neuroscience) Vol. 369 Pg. 97-108 (01 15 2018) ISSN: 1873-7544 [Electronic] United States
• PMID: 29138106 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Chemical References

• 1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea
• 1-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-((4-pyridinylmethyl)amino)-1-butanone
• Benzoxazoles
• Isoquinolines
• Naphthyridines
• Neurotransmitter Agents
• Orexin Receptors
• Orexins
• Pyridines
• Urea

Topics

• Action Potentials (drug effects, physiology)
• Animals
• Benzoxazoles (pharmacology)
• Isoquinolines (pharmacology)
• Male
• Motor Activity (drug effects, physiology)
• Naphthyridines
• Neurons (drug effects, metabolism)
• Neurotransmitter Agents (pharmacology)
• Orexin Receptors (metabolism)
• Orexins (metabolism, pharmacology)
• Pyridines (pharmacology)
• Rats, Wistar
• Subthalamic Nucleus (drug effects, metabolism)
• Urea (analogs & derivatives, pharmacology)