A Genetically Defined Circuit for Arousal from Sleep during Hypercapnia.

Area of Science:

• Neuroscience
• Sleep Medicine
• Respiratory Physiology

Background:

• The neural mechanisms driving arousal during sleep apnea remain unclear.
• Glutamatergic neurons in the external lateral parabrachial nucleus (PBel) are implicated in arousal responses to hypoxia and hypercapnia.
• Calcitonin gene-related peptide (CGRP) is expressed in a subset of PBel neurons responding to CO2.

Purpose of the Study:

• To investigate the role of PBel^CGRP neurons in mediating arousal from hypercapnia.
• To identify the specific neural circuit involving PBel^CGRP neurons in arousal.
• To explore PBel^CGRP neurons as a potential therapeutic target for sleep apnea.

Main Methods:

• Utilized chemogenetics and optogenetics to selectively activate or inhibit PBel^CGRP neurons in vivo.
• Assessed arousal responses to various stimuli including elevated CO2, hypoxia, acoustic tone, and shaking.
• Mapped the downstream neural network influenced by PBel^CGRP neuron activity.

Main Results:

• Selective activation of PBel^CGRP neurons induced wakefulness.
• Inhibition of PBel^CGRP neurons abolished arousal to elevated CO2 but not to other stimuli.
• Optogenetic inhibition of PBel^CGRP terminals revealed a forebrain network essential for hypercapnic arousal.

Conclusions:

• PBel^CGRP neurons serve as a critical molecularly defined switch for arousal from hypercapnia.
• These findings identify a novel cellular target within the brainstem for managing sleep fragmentation in obstructive sleep apnea.
• Targeting the PBel^CGRP circuit may mitigate associated cardiovascular and cognitive deficits.