Burton, H. | Search bioRxiv

bioRxiv2025

Preventing Microglial Reactivity Protects from Acute and Progressive Neuronal Dysfunction, Motor Impairments and Sedation following Alcohol Abuse

Alcohol abuse is the primary risk factor for alcohol use disorder (AUD), a leading cause of preventable morbidity and mortality, characterized by systemic inflammation, multi-organ damage, and neurological impairments. While direct effects of alcohol on brain function are well-established, the role of microglia in acute and chronic neurological dysfunction in AUD remains unclear. Using longitudinal in vivo imaging in mice during acute and repeated alcohol abuse, we found that microglia exhibit dynamic morphological responses that precede but parallel ethanol-induced sedation. Ethanol also induced microglia-dependent synapse elimination and reduced neuronal activity and density. Genetic disruption of microglial MyD88 reversed these ethanol-associated changes in microglial reactivity, neuronal structure, and function, while protecting against alcohol-induced intoxication and motor impairments. These findings identify microglia as cellular drivers of acute and chronic brain dysfunction following alcohol abuse, and highlight MyD88 as a critical therapeutic target for the detrimental neurological consequences of AUD.

neuroscience↗

bioRxiv2025

Motor impairment and adaptation in a novel non-human primate model of internal capsule infarct

Loss of distal hand and finger control is among the most disabling consequences of stroke. Functional outcomes are typically worse when infarcts involve subcortical white matter tracts, particularly the internal capsule, yet most preclinical stroke models target cortical regions. To address this gap, we developed a non-human primate model of internal capsule infarct using stereotactically guided endothelin-1 injections to disrupt descending fibers from the primary motor cortex hand area. Serial structural and diffusion MRI, along with histology, confirmed subcortical infarcts centered on the targeted white matter region with no apparent cortical involvement. Motor function was assessed pre- and post-infarct using a joystick-based center-out task (proximal forelimb control) and a Kluver board task (distal forelimb control). Animals exhibited variable impairments in proximal function and consistent post-infarct deficits in distal function, including reduced contralesional hand use, longer retrieval time, and increased in-well digit flexions. One animal showed mild post-infarct impairment and the smallest lesion, highlighting that this model reflects inter-individual differences in infarct size and functional outcome as seen in human subcortical stroke. In contrast, the other two animals developed a compensatory wrist-extended posture on the Kluver board task by 4 weeks post-infarct, which stabilized the hand and enabled improved digit flexion. Incorporating this behavioral adaptation into statistical models improved prediction of motor performance. The observed adaptation may have drawn on spared corticospinal output pathways, allowing animals to re-engage pre-existing motor routines to perform the retrieval. While future studies may benefit from ethologically relevant tasks to further elucidate such adaptations, findings from this study recapitulate key features of human subcortical stroke, including persistent distal motor deficits and emergence of adaptive motor strategies. By combining precise lesioning, longitudinal imaging, and detailed behavioral analysis, this model provides a translationally oriented platform for studying white matter stroke mechanisms and evaluating interventions that promote functional recovery.

neuroscience↗