Alcohol-induced damage to the fimbria/fornix reduces hippocampal-prefrontal cortex connection during early abstinence.

INTRODUCTION: Alcohol dependence is characterized by a gradual reduction in cognitive control and inflexibility to contingency changes. The neuroadaptations underlying this aberrant behavior are poorly understood. Using an animal model of alcohol use disorders (AUD) and complementing diffusion-weighted (dw)-MRI with quantitative immunohistochemistry and electrophysiological recordings, we provide causal evidence that chronic intermittent alcohol exposure affects the microstructural integrity of the fimbria/fornix, decreasing myelin basic protein content, and reducing the effective communication from the hippocampus (HC) to the prefrontal cortex (PFC). Using a simple quantitative neural network model, we show how disturbed HC-PFC communication may impede the extinction of maladaptive memories, decreasing flexibility. Finally, combining dw-MRI and psychometric data in AUD patients, we discovered an association between the magnitude of microstructural alteration in the fimbria/fornix and the reduction in cognitive flexibility. Overall, these findings highlight the vulnerability of the fimbria/fornix microstructure in AUD and its potential contribution to alcohol pathophysiology. Fimbria vulnerability to alcohol underlies hippocampal-prefrontal cortex dysfunction and correlates with cognitive impairment.

Mapping microglia and astrocyte activation in vivo using diffusion MRI.

While glia are increasingly implicated in the pathophysiology of psychiatric and neurodegenerative disorders, available methods for imaging these cells in vivo involve either invasive procedures or positron emission tomography radiotracers, which afford low resolution and specificity. Here, we present a noninvasive diffusion-weighted magnetic resonance imaging (MRI) method to image changes in glia morphology. Using rat models of neuroinflammation, degeneration, and demyelination, we demonstrate that diffusion-weighted MRI carries a fingerprint of microglia and astrocyte activation and that specific signatures from each population can be quantified noninvasively. The method is sensitive to changes in glia morphology and proliferation, providing a quantitative account of neuroinflammation, regardless of the existence of a concomitant neuronal loss or demyelinating injury. We prove the translational value of the approach showing significant associations between MRI and histological microglia markers in humans. This framework holds the potential to transform basic and clinical research by clarifying the role of inflammation in health and disease.