A spatial and projection-based transcriptomic atlas of paraventricular hypothalamic cell types.

Area of Science:

• Neuroscience
• Molecular Biology
• Genomics

Background:

• The paraventricular hypothalamus (PVH) is crucial for regulating appetite, social behavior, autonomic functions, and hormone secretion.
• Understanding specific PVH neuron populations and their molecular markers is essential for deciphering homeostatic control.
• A comprehensive catalog of PVH cell types and their projections is currently lacking.

Purpose of the Study:

• To create a high-resolution spatial and circuit-based gene expression atlas of the paraventricular hypothalamus (PVH).
• To identify and characterize novel PVH neuron subtypes and their molecular profiles.
• To map the projections of PVH neuron populations to specific brain regions like the parabrachial nucleus (PB) and spinal cord.

Main Methods:

• Single-cell/nucleus RNA sequencing was employed to catalog PVH neuron subtypes.
• Multiplexed error-robust fluorescence in situ hybridization (MERFISH) was used for spatial mapping of these neurons.
• Projection-based profiling identified specific neuronal connections.

Main Results:

• The study resolved 26 Sim1+ and 29 GABAergic neuron populations within the PVH and surrounding areas.
• Distinct transcriptional programs were identified between neuroendocrine and centrally-projecting PVH neurons.
• PB-projecting PVH neurons expressing bombesin-like receptor 3 (Brs3) were found to regulate food intake, with their activation reducing appetite and silencing leading to obesity.

Conclusions:

• The developed atlas provides a valuable resource with detailed spatial and circuit-based gene expression profiles of the PVH.
• This research identifies specific PVH neuron populations involved in regulating satiety and sympathetic nervous system activity.
• The findings offer new molecular targets for understanding and potentially treating disorders related to appetite and metabolism.