Interactions between hypothalamic microglia and the orexinergic system in response to neonatal stress and chemosensitivity to CO2.

• Grant number: 25/02015-2
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: March 01, 2025
• End date: February 28, 2029
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Luana Tenório Lopes
• Grantee: Gabriel Fernandes Gonçalves
• Host Institution: Faculdade de Ciências Agrárias e Veterinárias (FCAV). Universidade Estadual Paulista (UNESP). Campus de Jaboticabal. Jaboticabal , SP, Brazil
• Associated research grant: 23/07205-9 - Stress and neuroinflammation: implications on anxiety behaviour and breathing control, AP.JP

Abstract

It is well established in the literature that exposure to different forms of stress in the neonatal phase impairs the development and disrupts the functioning of the hypothalamic-pituitary-adrenal and sympathetic-adrenal-medullary systems. Additionally, a scientific consensus is emerging showing that the origins of many diseases manifested in adulthood are largely a result of developmental disturbances that occur during the first years of life. We have recently demonstrated that orexinergic neurons present in the dorsomedial hypothalamus of females (and not males) previously subjected to neonatal separation stress are hyperactivated in adult animals exposed to hypercapnia (increased inspired CO2 concentration). This sex-specific prevalence and increased chemosensitivity to CO2 is a feature observed in some psychiatric disorders, including anxiety. Interestingly, researchers in the field, are beginning to show that exposure to various types of stress causes dysfunction in microglia, the innate immune cells present in the central nervous system. Although some studies show that the magnitude of the inflammatory response is exacerbated in anxiety, little is known about the mechanisms that cause neuroimmune dysregulation. Thus, further investigations are needed to discover how neuroimmune and neuroendocrine mechanisms influence anxiety's pathophysiology. Here, focusing on the hypothalamus nuclei, we will use a multifaceted pre-clinical approach to characterize the link between stress and neuro-inflammation and how this interaction impacts behaviour and breathing in the context of anxiety. To address our goal, we will perform respiratory measurements, behavioural tests, EEG/EMG, immunohistochemistry, electron microscopy, RT-PCR, ELISA, neuroimaging/PET scan studies and electrophysiology (patch-clamp). In addition, we will investigate whether chemogenetic and therapeutic interventions (use of psychedelics) can alter respiratory, metabolic, inflammatory and behavioural responses induced by early exposure to stress.