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bioRxiv · 10.64898/2026.10.09.758035

Sustained Activation of a Defensive Behavior-Related Circuit Elicits a distinct Homeostatic Sleep Response

Yang, C.·Lombardi, V.·Uygun, D. S.·Brown, R. E.·McKenna, J. T.·Basheer, R.
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Abstract

Animals and humans often forgo sleep in response to other physiological needs. Prolonged wakefulness leads to a compensatory homeostatic sleep response involving enhanced amounts of sleep and electroencephalographic delta (0.5-4 Hz) power, yet how the type of preceding wakefulness and brain activity affects this response is poorly understood. Here we compared the pattern of brain activity and the homeostatic sleep response following sustained wakefulness induced by either gentle handling (GH), a widely used form of sleep deprivation in rodents; or optogenetic stimulation of neurons involved in avoidance/defensive responses, basal forebrain (BF) vesicular glutamatergic transporter type 2 (vGluT2) neurons. Local infusion of ionotropic glutamate receptor antagonists partially attenuated the wake-inducing effect of vGluT2-stimulation, but not that of GH, suggesting mediation by other non-glutamatergic BF subtypes. These antagonists also tended to produce more NREM sleep and a shorter NREM latency in the recovery period following vGluT2-stimulation. Both manipulations increased high theta (7-9 Hz) during wakefulness, an effect partially blocked by local infusion of the glutamate antagonist cocktail. Enhanced NREM sleep time and NREM delta power in the recovery period were more pronounced following GH than following vGluT2 stimulation. Whole-brain cFos immunohistochemistry revealed stronger neuronal activity in brain regions involved in stress and avoidance/defensive behaviors with vGluT2 stimulation, compared to GH. Our results demonstrate that activation of a brain system involved in defensive behavior (BF vGluT2) elicits a distinct and diminished homeostatic sleep response compared to GH, potentially an evolutionary sleep adaptation which would maintain vigilance in the face of an ongoing threat.

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Yang, C., Lombardi, V., Uygun, D. S., Brown, R. E., McKenna, J. T., Basheer, R.. 2026-10-12. Sustained Activation of a Defensive Behavior-Related Circuit Elicits a distinct Homeostatic Sleep Response. https://doi.org/10.64898/2026.10.09.758035

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