Activity-dependent astrocyte glucose dynamics regulate hippocampal neurogenesis

Abstract Newly generated neurons in adult hippocampal neurogenesis face a critical survival phase immediately after birth, heavily reliant on glucose-derived energy. However, the competitive and activity-dependent acquisition and utilization of this fuel remains poorly understood. This study utilizes advanced tools to decipher how hippocampal neural activity governs astrocyte glucose metabolism and lactate production, ultimately dictating the fate of young newborn neurons. Three specific aims guide our investigation. Aim 1 pinpoints specific hippocampal interneurons that regulate astrocyte glucose uptake and metabolism, forging a crucial link between neuronal circuit activity and activity-dependent astrocyte glucose dynamics. Aim 2 unravels the mechanisms behind lactate's role in newborn neuron survival, determining whether it directly fuels them or activates critical signaling pathways. Aim 3, inspired by observations of impaired neurogenesis and glucose metabolism in Alzheimer's disease, investigates whether astrocytes hold the key to this decline. Their lactate dynamics and associated key metabolic enzymes for lactate and glucose will be analyzed for defects. Glucose uptake will be genetically manipulated to definitively establish its role. By uncovering the interplay between neuronal activity, astrocyte metabolism, and lactate, this project aims to examine the underlying mechanisms of activity-induced adult neurogenesis in health and disease. It paves the way for novel neuroimaging techniques and offers new insights for therapeutic development in neurodegenerative disorders.