Pilot: Astrocyte p38 as a Nexus Between Central and Peripheral Metabolism and Brain Function

Astrocyte p38 as a nexus between central and peripheral metabolism and brain function ABSTRACT Astrocytes are critical regulators of the overall brain metabolic and inflammatory environment, directly modulating neuronal function and output of the central nervous system. We have recently been exploring the role of one core cellular pathway in controlling astrocyte function: p38 alpha mitogen activated protein kinase (p38). In the course of our studies, we have found that early genetic abrogation of astrocyte p38 restricts hippocampal neuroinflammation and enhances synaptic strength when the mice are aged. These effects further corresponded with an enhancement of non-synaptic mitochondrial uncoupling. Surprisingly, we also found that loss of astrocyte p38 can reduce baseline body weight, increase hypothalamic levels of N-acetylaspartate, and increase anxiety- type behavior. Together, these data indicate that astrocyte p38 plays a much wider role in regulating central and peripheral metabolism than anticipated. The current proposal therefore aims to delineate these effects by testing the central hypothesis that astrocyte p38 inhibition enhances mitochondrial uncoupling, altering gliotransmission and synaptic energy metabolism to enhance synaptic activity in circuits that control systemic metabolism. We will combine operant-conditioning based assessment of reward demand before and after loss of astrocyte p38, with terminal assays of synaptic and non-synaptic mitochondrial function, and central and peripheral metabolomics. A better understanding of this biology will inform follow-up studies in the context of various neurological diseases and insults