Orexin-A directly depolarizes dorsomedial hypothalamic neurons, including those innervating the rostral ventrolateral medulla

The dorsomedial hypothalamus (DMH) receives dense orexinergic innervation. Intra-DMH application of orexins increases arterial pressure and heart rate in rats. We studied the effects of orexin-A on DMH neurons, including those innervating the medullary cardiovascular center, the rostral ventrolatera...

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Published in:European journal of pharmacology 2021-05, Vol.899, p.174033-174033, Article 174033
Main Authors: Li, Tzu-Ling, Lee, Yen-Hsien, Wu, Feng-Hsu, Hwang, Ling-Ling
Format: Article
Language:English
Subjects:
Animals
Autonomic neuroscience
Brain stem
Cardiovascular function
Dorsomedial Hypothalamic Nucleus - cytology
Dorsomedial Hypothalamic Nucleus - drug effects
Dorsomedial Hypothalamic Nucleus - metabolism
Female
Hypocretin
Hypothalamus
In Vitro Techniques
Male
Medulla Oblongata - cytology
Medulla Oblongata - drug effects
Medulla Oblongata - metabolism
Membrane Potentials
Neural Pathways - drug effects
Neural Pathways - metabolism
Neuroanatomical Tract-Tracing Techniques
Neurons - drug effects
Neurons - metabolism
Orexin
Orexins - pharmacology
Potassium - metabolism
Rats
Rats, Sprague-Dawley
Sodium-Calcium Exchanger - metabolism
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Summary:The dorsomedial hypothalamus (DMH) receives dense orexinergic innervation. Intra-DMH application of orexins increases arterial pressure and heart rate in rats. We studied the effects of orexin-A on DMH neurons, including those innervating the medullary cardiovascular center, the rostral ventrolateral medulla (RVLM), by using whole-cell recordings in brain slices. In the presence of tetrodotoxin, orexin-A (30–1000 nM) depolarized 56% of DMH neurons (EC50 82.4 ± 4.4 nM). Under voltage-clamp recording, orexin-A (300 nM) induced three types of responses characterized by different current-voltage relationships, namely unchanged, increased, and decreased slope conductance in 68%, 14%, and 18% of orexin-A-responsive neurons, respectively. The reversal potential of the decreased-conductance response was near the equilibrium potential of K+ and became more positive in a high-K+ solution, suggesting that K+ conductance blockade is the underlying mechanism. In a low-Na+ solution, unchanged-, increased-, and decreased-conductance responses were observed in 56%, 11%, and 33% of orexin-A-responsive neurons, respectively, implying that a non-selective cation current (NSCC) underlies orexin-A-induced responses in a small population of DMH neurons. KBR-7943 (70 μM), an inhibitor of Na+-Ca2+ exchanger (NCX), suppressed orexin-A-induced depolarization in 7 of 10 neurons. In the presence of KBR-7943, the majority of orexin-A-responsive neurons exhibited decreased-conductance responses. These findings suggest that NCX activation may underlie orexin-A-induced depolarization in the majority of orexin-responsive DMH neurons. Of 19 RVLM-projecting DMH neurons identified by retrograde labeling, 17 (90%) were orexin-A responsive. In conclusion, orexin-A directly excited over half of DMH neurons, including those innervating the RVLM, through decreasing K+ conductance, activating NCX, and/or increasing NSCC.
ISSN:0014-2999
1879-0712
DOI:10.1016/j.ejphar.2021.174033