Aversive emotion rapidly activates orexin neurons and increases heart rate in freely moving mice

Abstract

The perifornical area of the hypothalamus has been known as the center for the defense response, or fight-or-flight response, which is characterized by a concomitant rise in arterial blood pressure, heart rate, and respiratory frequency. It is well established that orexin neurons, which are located in this region, play a critical role in this response. In this study, we further examined this role by recording orexin neuronal activity and heart rate in freely moving mice using an original dual-channel fiber photometry system in vivo. Analysis of orexin neuron activity in relation to autonomic responses to aversive stimuli revealed a rapid increase in neuronal activity just prior to changes in heart rate. In addition, we examined whether orexin neurons would be activated by a conditioned neutral sound that was previously associated with aversive stimulus. We show that the memory of the aversive stimulus activated orexin neurons and increased heart rate. Our data suggest that orexin neurons are a key component linking aversive emotions to autonomic defense response. Our data also suggest that targeting orexin neurons may enable treatment of psychiatric disorders associated with chronic stress and traumatic memories.

Activity of putative orexin neurons during cataplexy

“…Thus, the fluorescence sources in models 1 and 2 were similar. More importantly, these values were similar to those obtained in orexin-preserved mice (ORX +/+ ; ORX-tTA mice injected with AAV-GCaMP6 and AAV-mCherry) in our previous study [ 11 ] (∆GCaMP ca. 40%, ∆mCherry ca.…”

“…The resulting mouse lines showed close resemblance to each other from histological (location in the lateral and dorsal hypothalamic area) and physiological (response to intruder stress) points of view, indicating reasonable validity of the models. Most importantly, the changes in fluorescence of GCaMP6 and mCherry were similar to those obtained in orexin-preserved mice (ORX +/+ ; ORX-tTA mice injected with AAV-GCaMP6 and AAV-mCherry) in our previous study [ 11 ] (∆GCaMP approximately 40%, ∆mCherry approximately 0%), indicating that intruder stress activated both intact orexin neurons and putative orexin neurons in a similar manner.…”

“…Changes in heart rate in the current study (ca. 70 bpm) were relatively smaller than in those reported in a previous study [ 11 ] (ca. 150 bpm).…”

“…In addition to the awake-stabilizing role of orexin, orexin neuronal activity is closely linked to sympathetic autonomic outflow [ 10 , 11 ]. Therefore, changes in the heart rate during cataplexy may be a good indicator of the activity of orexin neurons.…”

“…We recently succeeded in assessing real-time orexin neuronal activity along with electrocardiograms in freely behaving mice using a fiber photometry system [ 11 ]. Using this system, we reported that aversive stimulus-evoked activation of orexin neurons preceded a heart rate increase.…”