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

Abstract

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. Summary Fimbria vulnerability to alcohol underlies hippocampal-prefrontal cortex dysfunction and correlates with cognitive impairment.

Multi‐level prediction of substance use: Interaction of white matter integrity, resting‐state connectivity and inhibitory control measured repeatedly in every‐day life

“…58 Notably, it has been demonstrated that chronic substance use such as alcohol exposure affects white matter microstructural integrity, leading through disturbed functional connectivity to decreased cognitive flexibility in rats. 59 A possible explanation for the involvement of our highlighted white matter regions in sustaining inhibition abilities in SUD populations could reside in its links to functional connectivity, as previously suggested in patients with hypertension. Our most striking result was the relation between white matter integrity and the momentary expression of inhibition abilities, sustaining its impact on subsequent use.…”

“…Indeed, white matter integrity has been observed to constrain resting‐state network organization, strength 57 and even adaptation 58 . Notably, it has been demonstrated that chronic substance use such as alcohol exposure affects white matter microstructural integrity, leading through disturbed functional connectivity to decreased cognitive flexibility in rats 59 . A possible explanation for the involvement of our highlighted white matter regions in sustaining inhibition abilities in SUD populations could reside in its links to functional connectivity, as previously suggested in patients with hypertension 60 …”

A Systematic Review and Meta-analysis on the Transcriptomic Signatures in Alcohol Use Disorder

“…Previous research has repeatedly shown that especially inflammation - related genes are up-regulated in alcohol dependence 46–48 . And furthermore, that neuroinflammatory processes indeed promote AUD development and progression 49, 50 . Consequently, the role of anti-inflammatory approaches is suggested to be particularly promising as for AUD treatment 51 .…”