Identifying the role of microglia in synaptic plasticity and activity of PVHSim2 neurons upon a high-fat diet

• Grant number: 25/08401-1
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: September 01, 2025
• End date: August 31, 2026
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Pedro Manoel Mendes de Moraes Vieira
• Grantee: Henrique Cesar Calderon Ferraiuolo
• Supervisor: Bradford Lowell
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: Harvard University, Boston, United States
• Associated to the scholarship: 21/10419-5 - The immunometabolic role of mitochondrial dynamics in microglial cells in Obesity models, BP.DD

Abstract

The complex neural and molecular mechanisms regulating hunger, focusing particularly on AgRP neurons and their interactions with hypothalamic circuits and microglia remains to be fully explored. Hunger is a biological signal that arises when energy stores are low, triggering responses from hormones like ghrelin and leptin and promoting feeding behavior to maintain energy homeostasis.AgRP neurons, located in the arcuate nucleus (ARC) of the hypothalamus, are key regulators of appetite. When activated by energy deficits, they promote hunger by inhibiting satiety-inducing POMC neurons and antagonizing MC4R signaling. Dysregulation of these neurons is implicated in obesity, particularly through mechanisms like leptin resistance, which disrupts normal hunger-satiety signaling.Recent discoveries have highlighted the role of a specific subpopulation of PVH (paraventricular nucleus of the hypothalamus) neurons-those expressing Sim2, Trh, and Adcyap1 (PVHSim2) -in driving ARCAgRP neuron activation. These neurons provide excitatory input to AgRP neurons, particularly during early fasting, helping initiate food-seeking behavior before critical energy deficits occur.Additionally, ARCAgRP neurons are modulated by circadian rhythms and possibly learned behaviors. Circadian input is transmitted via the DMH (dorsomedial hypothalamus), while PVHSim2 neurons appear to integrate cognitive and contextual information from the prefrontal cortex and hippocampus. This suggests a dual regulatory system-metabolic/circadian and learned/anticipatory.A major focus of the project is the synaptic plasticity in the PVH-ARCAgRP pathway. Fasting increases the strength of excitatory PVH inputs to ARCAgRP neurons, a plastic process involving NMDA receptors and synaptic organizers like BDNF and Cbln2. PVHSim2 neurons express these plasticity mediators, and microglia likely assist in this process through synapse pruning, remodeling, and cytokine signaling (e.g., IL-10, BDNF).Microglia are central to the development and maintenance of synaptic circuits. In response to high-fat diets or obesity, microglia become activated and release pro-inflammatory molecules (e.g., IL-1¿, TNF-¿), impairing hypothalamic function and contributing to leptin resistance and weight gain. They also produce C1q, tagging synapses for pruning, and interact modulates synapse through BDNF and IL-10, suggesting a link between inflammation, plasticity, and energy regulation.In sum, the PVHSim2-ARCAgRP circuit is a key integrative hub for hunger regulation, modulated by metabolic signals, circadian rhythms, and learned behaviors. Microglia may play a pivotal role in maintaining the plasticity of this circuit. Disruption in any part of this system, particularly through microglia-mediated inflammation, may drive the onset and progression of obesity. For that reason, this project seeks to further elucidate the role of microglial cells in driving synaptic plasticity and modulating neuronal activity during a high fat diet and obesity onset. (AU)