Brain-Wide Connectivity and Topographic Organization of Leptin Receptor Neurons in the Dorsomedial Hypothalamus.

OBJECTIVE

The dorsomedial hypothalamus (DMH) integrates metabolism and autonomic homeostasis, but whether subnuclear functional topography exists remains unclear. This study compared whole-brain input-output connectomes of leptin receptor (LepRb) neurons in dorsal DMH (DMD) versus DMH to test for connection-biased segregation.

METHODS

Rabies monosynaptic retrograde tracing and Cre-dependent AAV anterograde tracing in LepRb-Cre mice mapped and quantified input-output projections of DMDLepRb and DMHLepRb neurons.

RESULTS

Both DMDLepRb and DMHLepRb neurons received inputs from 58 upstream nuclei and projected to 43 downstream targets across the telencephalon, diencephalon, midbrain, pons, and medulla, forming extensive overlapping networks with similar global architectures. Nevertheless, they showed significant connection weight biases: DMDLepRb preferentially integrated arousal, defensive, and emotional signals and projected to stress/defense-related nuclei, whereas DMHLepRb preferentially integrated viscerosensory and reward-aversion signals and projected to metabolic/circadian nuclei.

CONCLUSION

DMDLepRb and DMHLepRb neurons share highly homologous whole-brain input-output architecture but exhibit local connection-weight biases, revealing conserved architecture with local specialization and providing a circuit basis for functional heterogeneity.