Identification of BDNF production in Kiss1 neurons and its effects in sexual maturation in male and female mice

RESUMO

INTRODUÇÃO: Distinct hypothalamic neuronal populations regulate energy balance and sexual behavior; essential mechanisms to guarantee species evolution success. Kiss1 neurons are involved in both of them, by controlling LH pulses and GnRH releasing, and by integrating peripheral hormonal signals with POMC and AGRP neurons. High-fat feeding can cause damage to these neuronal signaling triggering an inflammatory process that leads to neural death. This hypothalamic dysfunction leads to an imbalance of energy metabolism resulting in obesity and impairment of the endocrine network essential for reproductive success. A single-cell RNA sequencing analysis of data obtained from the arcuate nucleus of the hypothalamus (ARC) and median eminence reveals that Kiss1 neurons express BDNF. This neuronal factor is an important mediator of adult hypothalamic neurogenesis and is modulated by various central and peripheral signals. Recent data have been suggesting that reproductive stimuli are able to modulate neurogenesis in the hypothalamus in order to preserve reproductive capacity.

OBJETIVOS: Based on that, this study aimed to confirm whether BDNF and its receptors, TrkB and p75NTR, are expressed by Kiss1 neurons, and evaluate the effects of BDNF knockout specifically in this neuronal group on energy balance and sexual maturation in both male and female mice.

MÉTODOS: All experiments were approved by the Animal Use Ethics Committee of UNICAMP (CEUA: 5591-1/2020). By using Kiss1-hrGFP reporter mice, we confirmed by immunofluorescence, that BDNF and its receptors overlap with Kiss1 neurons. To selectively knockout BDNF in Kiss1 neurons we employed a Cre-loxP approach. These mutant mice were employed to assess whether BDNF depletion in Kiss1 neurons affects sexual maturation.

RESULTADOS: For that, we daily evaluated female and male littermates during their sexual development period. We identified that female mice tend to show a delay in their sexual maturation, characterized by a compromised ovulatory cycle and a reduced ovary weight compared with controls. 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.

CONCLUSÃO: Our data reveal a new important mechanism regulated by BDNF in the hypothalamus which affects sexual maturation in a sex-dependent manner. Future experiments will be employed to assess whether the lack of BDNF in Kiss1 neurons would affect hypothalamic neurogenesis.

BIBLIOGRAFIA: Artegiani B et al. (2017). A single-cell RNA sequencing study reveals cellular and molecular dynamics of the hippocampal neurogenic niche. Cell Rep. 21:3271-3284. Campbell JN, Macosko EZ, Fenselau H, Pers TH, Lyubetskaya A, Tenen D, … Tsai LT (2017). A molecular census of arcuate hypothalamus and median eminence cell types. Nature Neuroscience. 20(3):484–496. Engel DF, Bobbo VCD, Solon CS, Nogueira GA, Moura-Assis A, Mendes NF, Zanesco AM, Papangelis A, Ulven T, Velloso LA. Activation of GPR40 induces hypothalamic neurogenesis through p38- and BDNF-dependent mechanisms. Sci Rep. 2020 Jul 6;10(1):11047

PALAVRA-CHAVE: Hypothamalus, Adult Neurogenesis, BDNF and Sexual Maturation