Participation of the a7nAChR receptor in the mechanisms involved in the modulation of hypothalamic and hippocampal neurogenesis and neurodifferentiation in the offspring of obese mothers.

• Grant number: 25/17125-8
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: September 01, 2025
• End date: December 31, 2028
• Field of knowledge: Health Sciences - Nutrition - Malnutrition and Physiological Development
• Principal Investigator: Adriana Souza Torsoni
• Grantee: Paloma Brasilio Villalta
• Host Institution: Faculdade de Ciências Aplicadas (FCA). Universidade Estadual de Campinas (UNICAMP). Limeira , SP, Brazil
• Associated research grant: 23/11144-5 - Impairment in the expression/function of the alpha7 nicotinic cholinergic receptor: mechanisms and implications for diseases associated with inflammatory processes, AP.TEM

Abstract

The rising prevalence of maternal obesity in nearly all countries parallels a marked increase in the incidence of childhood neurodevelopmental disorders. Large-scale mother-child cohort studies have consistently reported associations between maternal obesity and both physical and mental health disorders in the offspring. Evidence from our research group and others demonstrates that maternal obesity programs neural circuits in the offspring that regulate appetite and satiety, resulting in early-life hyperphagia and excessive weight gain during childhood.It is also evident that maternal obesity programs offspring neurogenesis by altering the signaling of proteins involved in regulating neuronal proliferation and differentiation in the hypothalamus and hippocampus-regions critically involved in the control of behavior and cognition. Dyslipidemia and obesity-associated inflammation are known to contribute to a broad range of neurological disorders, including cognitive impairment, autonomic nervous system imbalance, peripheral polyneuropathy, and neurodegenerative diseases.Notably, the a7 nicotinic acetylcholine receptor (a7nAChR) has been implicated in several neurodegenerative pathologies and behavioral disorders. Adult hippocampal neurons that develop in the absence of a7nAChR exhibit dendritic abnormalities, potentially impairing their capacity to receive inputs from other neurons. Furthermore, pharmacological activation of a7nAChR suppresses neural progenitor cell (NPC) proliferation while promoting neuronal differentiation, underscoring the importance of a7nAChR in the generation of new neurons.Despite these advances, surprisingly little is known about the neural mechanisms through which maternal obesity programs neurobehavioral disorders in the offspring, or the specific role of a7nAChR in these processes. Based on this knowledge gap, we hypothesize that a7nAChR actively contributes to the protection of NPCs by controlling the expression of inflammatory cytokines and maintaining a microenvironment favorable for appropriate NPC proliferation and differentiation, thereby supporting neurogenesis in the hypothalamus and hippocampus. The present study will investigate (1) the impact of maternal obesity on a7nAChR expression in the hypothalamus and hippocampus of the offspring, and on the development of these central nervous system regions; (2) the effect of maternal obesity on the differentiation of neural progenitor cells into astrocytes, and into POMC and NPY neurons in the hypothalamus; and (3) the effect of a7nAChR deletion on the differentiation of neural progenitor cells into neurons and astrocytes.