Whole-Brain Connectome Identifies PMv^LepRb Neurons as a Hypothalamic Hub Linking Metabolic State to Instinctive...

Metabolic state strongly shapes social and reproductive behaviors, yet the neural circuits that convert internal energy signals into behavioral responses remain poorly defined. The ventral premammillary nucleus (PMv) of the hypothalamus has been implicated in this process, particularly through leptin receptor-expressing (LepRb) neurons, but its brain-wide circuit organization is still unclear. Here, we used Cre-dependent retrograde (RV) and anterograde (HSV) viral tracing techniques in LepRb-Cre mice to construct a comprehensive, single-cell-resolution input-output map of PMv^LepRb neurons. 3D reconstruction showed that these neurons receive dense convergent inputs, mainly from hypothalamic and forebrain regions involved in energy balance, motivation, and limbic processing. In contrast, their outputs extend not only back to several input regions but also prominently to midbrain and pontine autonomic centers, including the periaqueductal gray (PAG) and parabrachial nucleus (PB). Quantitative analysis revealed that forebrain regions were more likely to participate in reciprocal connectivity, whereas brainstem regions were dominated by outgoing projections. This organization suggests that PMv^LepRb neurons are positioned to integrate metabolic and motivational signals and relay them to downstream systems controlling instinctive behavioral and autonomic responses. These findings provide a structural basis for understanding how energy state can influence decisions related to social competition and reproduction.