However, we excluded the data from three animals (two model 1 and one model 2) because of failure in adeno-associated virus (AAV) injection or optic fiber implantation was noted on histological examination. 1A1: ORX −/− ORX-tTA mice injected with AAV-GCaMP6 and AAV-mCherry) and four model 2 mice (Fig. Therefore, in this study, we measured putative orexin neuronal activity in two orexin-knockout mice models during cataplexy given that both activation and inhibition can be predicted from available circumstantial evidence. As an extension of the system, we hypothesized that it would be possible to assess putative orexin neuronal activity in orexin-knockout mice during cataplexy. Using this system, we reported that aversive stimulus-evoked activation of orexin neurons preceded a heart rate increase. We recently succeeded in assessing real-time orexin neuronal activity along with electrocardiograms in freely behaving mice using a fiber photometry system. In this context, a decrease in heart rate during cataplexy has been reported in narcolepsy patients and narcolepsy dogs, indicating the inhibition of orexin neuronal activity during cataplexy, which is in contrast to the abovementioned counterbalance activation hypothesis. Therefore, changes in the heart rate during cataplexy may be a good indicator of the activity of orexin neurons. ![]() In addition to the awake-stabilizing role of orexin, orexin neuronal activity is closely linked to sympathetic autonomic outflow. Although these observations fit the above hypothesis well, excitation of orexinergic neurons during cataplexy episodes in a time resolution of seconds has never been observed. A microdialysis study showed orexin spillover with positive emotions in the amygdala of human patients with resistant epilepsy (but not narcolepsy). Lesion or inactivation of the amygdala in orexin-deficient mice reduced cataplexy, indicating a cataplexy-inducing role for amygdala neurons. Furthermore, activation of orexin neurons results in the inhibition of the amygdala via the activation of serotonin neurons in the dorsal raphe, which receive orexinergic innervation. An increase in orexin levels in the amygdala reduces cataplexy, indicating a cataplexy-inhibiting role for orexin neurons. The current hypothesis holds that it involves simultaneous excitation of cataplexy-inhibiting orexin neurons and cataplexy-inducing amygdala neurons. It is unclear why the absence of orexin neuronal transmission results in cataplexy. Cataplexy is a major symptom of narcolepsy, which is caused by abnormal loss of orexin (hypocretin)-producing neurons in humans, orexin-deficiency in mice, and orexin receptor mutation in dogs. This study will serve as a basis for better treatment of cataplexy in narcolepsy patients.Ĭataplexy is an emotionally triggered loss of muscle strength and postural collapse threatening daily life of narcolepsy patients. 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. We propose that the activity of orexin neurons during cataplexy is moderately inhibited by an unknown mechanism. 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. ![]() 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. TetO-GCaMP6 was then introduced into mice via an adeno-associated virus injection or natural crossing. We first prepared orexin-knockout mice crossed with transgenic mice carrying a tetracycline-controlled transactivator transgene under the control of the orexin promoter. We created two animal models of orexin-knockout mice with a GCaMP6 fluorescent indicator expressed in putative orexin neurons. To test this hypothesis, we measured the activity of putative orexin neurons in orexin-knockout mice during cataplexy episodes using fiber photometry. The current hypothesis predicts simultaneous excitation of cataplexy-inhibiting orexin neurons and cataplexy-inducing amygdala neurons. It is unclear why orexin-deficient animals, but not wild-type mice, show cataplexy.
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