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Maternal Obesity Programs Offspring Hypothalamic and Hippocampal Neurogenesis: The role of alpha7 nicotinic acetylcholine receptor (a7nAChR) in the differentiation of Neural Progenitor Cells (NPCs)

Abstract

Neural progenitor cells (NPCs) can differentiate into neurons, astrocytes, and oligodendrocytes. Differentiation and proliferation are regulated by various cell communication factors (e.g., Notch/Hes1) and neuroregulatory transcription factors (bHLH, including Mash1 and Ngn3). We have recently shown that TNF± and reactive oxygen species can also modulate these factors, suggesting that the inflammatory environment can disrupt the fine control of differentiation/proliferation.Additionally, maternal obesity modifies the expression of proteins related to maintenance, differentiation, and neuronal proliferation (increased Notch1 and Hes1 and reduced Mash1 and Ngn2/3), making NPC proliferation challenging. These cellular processes begin during the gestational period (between days E9-E14) and continue for a few weeks after birth, and they can be affected by obesity during pregnancy and/or lactation, inhibiting the formation of POMC and AGRP neuronal projections.Since 2012, we have been investigating how maternal consumption of a high-fat diet during the perinatal period affects metabolism and appetite control in offspring. Results from our group show that maternal obesity reduces the expression of the ±7nAChR receptor in the offspring's liver and adipose tissue, and a high-fat diet reduces its expression in the hypothalamus, liver, spleen, and medullary cells.Preliminary results show that the hypothalamus of offspring from obese mothers has reduced expression of the ±7nAChR receptor on the day of birth (PN0) but recovers by PN28. However, the damage may have occurred during critical periods of central nervous system development, even in the intrauterine phase.In in vitro studies, we have shown that the deletion of the ±7nAChR receptor in hypothalamic-origin neuronal cells makes the cells more sensitive to inflammatory processes induced by microglial activation and reduces cell proliferation. The ±7nAChR receptor has been associated with various neurodegenerative pathologies and behavioral disorders, including in humans. The literature is quite clear regarding the importance of this receptor in controlling inflammation. Therefore, we believe that the loss of the ±7nAChR receptor at such an early stage, i.e., during gestational development, may impair energy/glycemic homeostasis (hypothalamus) and cognitive development, learning, and memory (hippocampus).Adult hippocampal neurons, which developed in the absence of the ±7nAChR receptor, exhibit dendritic abnormalities, which may result in the loss of the ability to receive stimuli from other neurons. Furthermore, pharmacological activation of the ±7nAChR receptor inhibits NPC proliferation and stimulates differentiation through a mechanism involving the FGFR1 pathway, indicating the importance of the ±7nAChR receptor in the process.Interestingly, our studies show that the offspring of obese mothers have altered Notch and HES-5 protein signaling pathways in the hypothalamus and hippocampus, along with an increase in the number of NPY neurons in the adult hypothalamus. As described above, Notch signaling and proteins like HES-5 play a crucial role in regulating neurogenesis, ensuring that the process occurs in a coordinated manner and maintaining the neural progenitor cell reserve for the continuous development of the nervous system.Collaboration with the University of California group (UCLA) will allow for the standardization of the technique of obtaining and culturing mouse NPCs in our laboratory in Brazil. This collaboration will intensify through participation in events, short-duration courses, and the exchange of students and researchers. Developing this technique in the laboratory in Brazil will enable us to investigate neurogenesis under different culture conditions, evaluate the mechanisms related to impaired neurogenesis, and understand how the ±7nAChR receptor participates in NPC proliferation/differentiation. (AU)

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