Apmpoa neurons coordinate nutrition and sexual behavior

The National Institute of Child Health and Human Development awarded the University of South Florida $114,237 on June 5, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865) to conduct research dissecting estrogen receptor alpha (ERA) functions in anteroventral and periventricular medial preoptic area neurons co-expressing the long-form leptin receptor. The research examines how ERA signaling as a nuclear receptor and mRNA-binding protein—distinct from membrane signaling—regulates sexual behavior in response to nutritional status in mice, with the goal of identifying neurobiological mechanisms for potential therapeutic interventions in sexual dysfunction. The award also investigates whether leptin receptor signaling in ERA-expressing neurons is required for normal male sexual behavior under varying nutritional conditions. The period of performance runs from June 5, 2026, through May 31, 2028, with place of performance in Tampa, Florida.

Abstract

Nutrition plays a bidirectional regulation of sexual behavior, but the mechanism is unclear. Estrogen and leptin signal nutritional statuses to modulate energy balance and sexual behavior. I found that estrogen receptor α (ERΑ) and the long-form leptin receptor (lepr) CO-localized in several brain regions, including the anteroventral and periventricular portions of the medial preoptic area (apmpoa), the periaqueductal gray (PAG) and the arcuate nucleus of the hypothalamus (ARH). Mice with deletions of ERΑ specifically in lepr+ neurons (erαδlepr mice) demonstrated profoundly impaired sexual behavior of both sexes. I further found that ERΑ in lepr+ neurons was required for rescuing male sexual dysfunction related to overnutrition or undernutrition, whereas no such rescue effects were seen in female mice. ERΑ functions as a nuclear receptor to regulate gene transcription, as a membrane protein to initiate rapid signaling, and as an mrna-binding protein to regulate translation. Interestingly, my findings showed that the indispensable roles of ERΑ in apmpoalepr+ neurons in regulating sexual behavior likely involved ERΑ functions as a nuclear receptor and/or an mrna-binding protein but do not require membrane ERΑ signaling. The current proposal aims to 1) dissect ERΑ functions as a nuclear receptor and/or mrna-binding protein in apmpoalepr+ neurons in sexual behavior, and 2) determine whether lepr in apmpoaerα+ neurons is required for normal male sexual behavior under different nutritional statuses. These studies will identify the neurobiological mechanism by which apmpoa ERΑ and leptin signaling interact to coordinate nutrition and sexual behavior, which may provide a framework for developing novel therapeutic interventions for sexual dysfunction. The proposed experiments take advantage of my research skills in mouse reproduction and sexual behavior (acquired during my graduate studies) and my strength in nutrition, neural circuitry, and mouse intersectional genetics, optogenetics, fiber photometry (available in my postdoctoral mentor's group). My long-term goal is to become an independent investigator in the neural control of reproduction and sexual behavior. The K99-funded mentored period will allow me to hone my technical skills, and advance grantsmanship, laboratory management, mentoring and teaching skills, etc. I will start looking for faculty positions at the assistant professor level towards the end of the first year of the K99 stage to ensure a smooth transition to the R00 phase. This will undoubtedly help me move toward my career goal of becoming an independent research scientist at an academic institution.