National Institute on Alcohol Abuse and Alcoholism 5U01AA029969-05

5/11 Microglial MyD88 in Mouse Models of Excessive Alcohol Intake

This NIH grant funds research at Duke University to study how microglial MyD88 influences parvalbumin interneurons and perineuronal nets in mouse models, aiming to understand mechanisms underlying excessive alcohol intake and alcohol use disorder.

Description

Repeated alcohol exposure can be a potent neuroinflammatory stimulus. Alcohol activates microglia within the brain via toll-like-receptors (TLRs); this activation leads to production of inflammatory mediators which contribute to dependence and abuse. Fast spiking parvalbumin positive (PV+) GABAergic interneurons (PVIs) are critical for normal brain function. PVIs are often surrounded by specialized extracellular matrix molecules called perineuronal nets (PNNs) which protect and buffer them from inflammation and oxidative stress. Increased PNNs are implicated in alcohol use disorder (AUD), possibly due to a “locking in” of neuroplasticity mechanisms underlying habitual behavior such as drug seeking despite adverse consequences. Preliminary data show that mice with microglial-specific ablation of MyD88 exhibit decreased proinflammatory responses but increased PVIs and PNN interactions in the frontal cortex, correlating with increased alcohol intake. The project aims to investigate the role of microglial MyD88 in regulating PVIs and PNNs and their impact on excessive drinking behavior.

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