A brainstem to hypothalamic arcuate nucleus GABAergic circuit drives feeding

Area of Science:

• Neuroscience
• Molecular Biology
• Physiology

Background:

• The obesity epidemic necessitates understanding feeding behavior regulation.
• The dorsal vagal complex (DVC) in the brainstem receives digestive input and influences food intake.
• The function of GABAergic neurons (GABA^DVC) in the DVC remains largely undefined.

Purpose of the Study:

• To define the gene expression signature of GABA^DVC cells.
• To investigate the functional role of GABA^DVC neurons in regulating feeding behavior and body weight.
• To elucidate the neural circuitry through which GABA^DVC neurons exert their effects on appetite.

Main Methods:

• Single-nucleus RNA sequencing (Nuc-seq) to identify GABA^DVC cell clusters.
• Optogenetic stimulation to probe the function of GABA^DVC neurons and their projections.
• Electrophysiological recordings to analyze neuronal activity.
• Intersectional genetics to confirm circuit function.

Main Results:

• Nuc-seq identified 19 distinct clusters of GABA^DVC cells.
• Selective activation of GABA^DVC neurons significantly reduced food intake and body weight.
• Optogenetic activation of the GABA^DVC → hypothalamic arcuate nucleus (ARC) pathway suppressed appetite without aversion.
• Electrophysiology confirmed that GABA^DVC → ARC stimulation inhibits hunger-promoting neuropeptide Y (NPY) neurons via GABA release.

Conclusions:

• GABA^DVC neurons represent a novel modulator of feeding behavior and body weight.
• The GABA^DVC → ARC circuit plays a crucial role in curbing food intake.
• These findings provide new insights into the neural mechanisms underlying obesity by identifying a key appetite-regulating circuit.