Activity of putative orexin neurons during cataplexy

Abstract

It is unclear why orexin-deficient animals, but not wild-type mice, show cataplexy. The current hypothesis predicts simultaneous excitation of cataplexy-inhibiting orexin neurons and cataplexy-inducing amygdala neurons. To test this hypothesis, we measured the activity of putative orexin neurons in orexin-knockout mice during cataplexy episodes using fiber photometry. We created two animal models of orexin-knockout mice with a GCaMP6 fluorescent indicator expressed in putative orexin neurons. We first prepared orexin-knockout mice crossed with transgenic mice carrying a tetracycline-controlled transactivator transgene under the control of the orexin promoter. TetO-GCaMP6 was then introduced into mice via an adeno-associated virus injection or natural crossing. The resulting two models showed restricted expression of GCaMP6 in the hypothalamus, where orexin neurons should be located, and showed excitation to an intruder stress that was similar to that observed in orexin-intact mice in our previous study. The activity of these putative orexin neurons increased immediately before the onset of cataplexy-like behavior but decreased (approximately − 20% of the baseline) during the cataplexy-like episode. We propose that the activity of orexin neurons during cataplexy is moderately inhibited by an unknown mechanism. The absence of cataplexy in wild-type mice may be explained by basal or residual activity-induced orexin release, and emotional stimulus-induced counter activation of orexin neurons may not be necessary. This study will serve as a basis for better treatment of cataplexy in narcolepsy patients.

Deficiency of orexin signaling during sleep is involved in abnormal REM sleep architecture in narcolepsy

“…Several neural circuitry models of narcolepsy have proposed that orexin neurons receive excitatory inputs and should be activated to prevent the triggering of cataplexy ( 20 – 24 , 38 ). The activity of orexin neurons during “cataplexy-like attacks” has been described by video recording ( 39 ). However, based on the consensus of the International Working Group on Rodent Models of Narcolepsy ( 40 ), EEG and EMG recordings in addition to video are necessary to define cataplexy; otherwise, the term “abrupt behavioral arrest” is more appropriate when only video is used.…”

Peripheral vs. Core Body Temperature as Hypocretin/Orexin Neurons Degenerate: Exercise Mitigates Increased Heat Loss

“…These observations suggest a role for Hcrt/Ox neurons but not the Hcrt/Ox neuropeptides in BAT thermogenesis and highlights the importance of an intact Hcrt/Ox system in normal thermoregulation, but also underscores the importance of other molecules coexpressed in Hcrt/Ox-containing neurons in thermogenesis. The activity of putative Hcrt/Ox neurons lacking the Hcrt/Ox peptides increased immediately before the onset of cataplexy attack but decrease during attacks [69]. Local administration of a glutamate receptor antagonist to the dorsomedial hypothalamus inhibits BAT activation by PGE 2 , suggesting glutamate may be the critical modulator of sympathetic BAT stimulation by neurons in this region including Hcrt/Ox-containing neurons [70].…”

Recent advances in neuropeptide-related omics and gene editing: Spotlight on NPY and somatostatin and their roles in growth and food intake of fish

“…And Y1R knockout mice have been reported to explore the role of Y1R in the regulation of bone and energy homeostasis ( 97 ). Ablating orexin in mice have been reported in the fields of sleep regulation, social fear, cataplexy and lipid metabolism ( 112 , 113 , 115 , 118 ). Orexin receptor-deficient mice have been used to support the unique role of orexin receptors 1 and 2 in long-term energy metabolism ( 173 ).…”