Whole-brain monosynaptic inputs and outputs of Leptin receptor neurons in the ventral premammillary nucleus in mice

Abstract

Leptin is essential for homeostatic control of energy metabolism and neuroendocrine systems. Leptin elicit its function via binding to the long-form leptin receptor (LepR). In the brain, the hypothalamus, in particular the ventral premammillary nucleus (PMv), shows dense LepR expression. The PMv has been implicated in a variety of fundamental functions in appetitive behavior, energy balance and reproduction. Dysfunction of PMv LepR neurons is associated with obesity, hyperphagia and pituitary hormone deficiencies. However, the reciprocal neural connectivity in the whole brain of PMv LepR neurons was incompletely understood. In the present study, we used a cell-type-specific retrograde and anterogradely tracing system based on a modified rabies virus along with a Cre/loxP gene-expression strategy to map the whole-brain afferents and efferents of PMv LepR neurons in mice. We found that PMv LepR neurons primarily received afferents from 43 nuclei and send efferents to 39 nuclei in the whole brain, intensively located in the preoptic area, hypothalamus and midbrain. PMv LepR neurons received direct inputs from several regions associated with energy metabolism, stress and emotional regulation, such as arcuate hypothalamic nucleus, medial preoptic nucleus, medial amygdala, bed nucleus of stria terminals, paraventricular nucleus. PMv LepR neurons were also directly connected with other functional regions engaged in sleep-wake regulation(the ventral pallidum, lateral preoptic area, lateral hypothalamic area, dorsal raphe nucleus, lateral parabrachial nucleus and locus coeruleus). These results revealed a comprehensive whole-brain neural connectivity of PMv LepR neurons and provided with a neuroanatomic foundation to further elucidating the neural circuits underlying disorders caused by the dysfunction of LepR neurons.

Note:
Funding declaration: This work was supported by School Youth Initiation Foundation (Grant 101520250000204 and 2025SKY116); .Moreover, we thank Xiang-shan Yuan from School of Basic Medical Sciences, Fudan University, for his assistance in statistics analysis.

Conflict of Interests: The authors have no relevant financial or non-financial interests to disclose.

Ethical Approval: Animal care and use conformed to guidelines of Committee on the Ethics of Animal Experiments of Fudan University Shanghai Medical College (Permit No. 20190221-028) and Chinese governmental regulations.

Keywords: Leptin, Leptin receptor, Ventral premammillary nucleus, Retrograde tracing, Metabolism