The Role of Supraoptic Nucleus Astrocytes in Modulating Osmoregulatory Responses from Organum Vasculosum of the Lamina Terminalis

• Grant number: 24/22511-1
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: June 01, 2025
• End date: May 31, 2026
• Field of knowledge: Biological Sciences - Biophysics - Cellular Biophysics
• Principal Investigator: Melina Pires da Silva
• Grantee: Karoline Martins dos Santos
• Supervisor: Charles W Bourque
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Institution abroad: McGill University, Canada
• Associated to the scholarship: 23/01652-3 - PARTICIPATION OF ASTROCYTES AS ACTIVE ELEMENTS IN OSMOTRANSDUCTION OF THE SUPRAOPTIC NUCLEUS OF MICE, BP.PD

Abstract

Extracellular osmolality plays a crucial role in maintaining cellular volume and proper cellular function. Osmotic changes can cause significant damage, including disruptions to cell membrane integrity and intracellular transport. To keep osmolality within normal levels (295-300 mOsm/Kg.H2O), the body relies on homeostatic mechanisms where specialized sensors, known as osmoreceptors, detect osmotic variations. In the central nervous system (CNS), osmoreceptors are located in circumventricular organs (CVOs), regions lacking a blood-brain barrier that allow real-time monitoring of osmotic fluctuations. Among the CVOs, the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) play fundamental roles by communicating with the supraoptic nucleus (SON) and the paraventricular nucleus (PVN), hypothalamic regions crucial for homeostatic regulation.Under hyperosmolar conditions, the OVLT activates magnocellular neurons in the SON and PVN, promoting the synthesis and release of vasopressin (VP) and oxytocin (OT). These neurohormones regulate osmolality by controlling water and salt excretion/reabsorption in the kidneys, restoring hydroelectrolytic balance. Additionally, magnocellular neurons in the SON also act as osmoreceptors, detecting osmotic fluctuations and modulating VP and OT production. While neuronal mechanisms for osmotic detection are well-studied, recent research suggests that cells such as astrocytes may also participate in osmoregulation.For a long time, neurons were believed to be solely responsible for brain function, while glial cells, including astrocytes, were thought to play only structural roles. However, experimental evidence shows that astrocytes are functional elements integrated into synapses, regulating synaptic transmission and responding to neuronal activity. They help maintain the synaptic microenvironment by reabsorbing potassium ions and neurotransmitters like glutamate, preventing hyperexcitability and desensitization of postsynaptic receptors. Furthermore, astrocytes release gliotransmitters that modulate postsynaptic neuronal activity.Evidence also indicates that astrocytes have sensory functions, such as detecting oxygen levels and changes in extracellular osmotic pressure. Based on this, we hypothesize that SON astrocytes could act as "bridges" between synaptic signals from primary osmoreceptors (OVLT) and magnocellular neurons in the SON. However, it remains unclear whether astrocytes mediate these responses and whether they are essential for triggering specific cellular behaviors associated with osmoregulation.This project aims to investigate the interaction between astrocytes and magnocellular neurons in the SON under physiological conditions, maintaining intact communication with OVLT. The primary objective is to determine whether SON astrocytes influence the activity of these neurons and, if so, to elucidate the underlying mechanisms of this interaction. To achieve this, we will employ a combination of advanced techniques, including calcium imaging to record astrocytic activity in angled brain slices during OVLT stimulation. Additionally, we will assess the impact of specific astrocytic inhibition on magnocellular neurons in the SON and explore the mechanisms involved in astroglial and neuronal activation, with a focus on neurotransmitters released by astrocytes during OVLT-driven activation.