Identification of a novel pontine parabrachial-basal forebrain circuit regulating cortical arousal

2024 Focused Projects Grant for Junior Investigators

MUDASIR KHANDAY, PHD
BETH ISRAEL DEACONESS MEDICAL CENTER

Key Project Outcomes

This project investigated how the brain maintains wakefulness, focusing on a small region in the brainstem called the parabrachial nucleus. We studied a specific group of neurons within this region that produce a signaling molecule called PACAP and send connections to other brain areas involved in alertness.

We found that these neurons are highly active when the brain is awake and much less active during sleep. When we temporarily turned off these neurons, animals rapidly fell asleep, demonstrating that this cell group is essential for staying awake.

Importantly, we discovered that these neurons control wakefulness through specific pathways to different parts of the brain. The strongest effect was observed in connections to the basal forebrain, a region known to activate the cortex and support alertness. When this pathway was inhibited, animals showed a marked increase in sleep. A second pathway to the hypothalamus also contributed to maintaining wakefulness but to a lesser extent. In contrast, connections to the amygdala did not significantly affect sleep under normal conditions.

These findings show that wakefulness is controlled by distinct brain circuits rather than a single uniform system. By identifying the key pathways that keep the brain awake, this work provides a foundation for developing new treatments for sleep disorders, disorders of consciousness such as coma, and improving recovery from anesthesia.