The effects of BDNF production by Kiss1 neurons in adult hypothalamic neurogenesis

• Grant number: 24/03519-1
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: June 04, 2024
• End date: September 28, 2024
• Field of knowledge: Biological Sciences - Physiology - General Physiology
• Principal Investigator: Licio Augusto Velloso
• Grantee: Ariane Maria Zanesco
• Supervisor: Carol Fuzeti Elias
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: University of Michigan, United States
• Associated to the scholarship: 21/07288-6 - Characterization of the molecular mechanisms that regulate adult neurogenesis in the hypothalamus in response to reproductive stimulus, BP.DR

Abstract

The hypothalamus is a key region in the central nervous system that controls different functions such as energy balance, thermogenesis, and reproduction, which are essential to species' adaptation and survival. Adult neurogenesis in the hypothalamus has been known to renew subpopulations of neurons that play central roles in controlling energy homeostasis. Additionally, preliminary studies have been suggesting that stimuli with reproductive hormones also induce neurogenesis in the hypothalamus, potentially generating neurons that play an important role in preserving reproductive capacity. Recent studies indicate that BDNF is an important mediator in the process of hypothalamic neurogenesis in response to regulatory signals of energy homeostasis. Using published data from a single-cell RNA sequencing analysis, obtained from the arcuate nucleus of the hypothalamus (ARC) and median eminence to evaluate hypothalamic neurons that express BDNF, we have identified the subpopulation Kiss1. Kiss1 neurons are important for reproductive function and integrate the neuronal control of energy balance. Based on these data, we have hypothesized that the BDNF synthesis in these neurons is essential to generating a neurogenesis-inducing signal that aims to renew neurons with a reproduction regulatory function. Using an immunofluorescence assay, we have confirmed that BDNF is produced by Kiss1 neurons, and BDNF receptors are expressed in Kiss1 neurons and the other cells nearby. Using a cre/lox approach, we have identified that the BDNF ablation in Kiss1 neurons leads to a premature vaginal opening, a weight decreases in the uterus and ovary, and compromises the ovulatory cycle by increasing the time spent in the diestrus phase in female mice. On the other hand, no changes were observed in the sexual development of male littermates. Regarding food intake and body weight, no changes were observed in both sexes throughout the period analyzed. These findings suggest a new important mechanism regulated by BDNF produced by Kiss1 neurons in the hypothalamus which affects sexual maturation in a sex-dependent manner. Future experiments will be performed to assess whether the lack or overexpression of BDNF in Kiss1 neurons would affect hypothalamic neurogenesis.