The effect of chronic stress and chronic alcohol intake on behavior, brain structure, and functional connectivity in a rat model

Pathological chronic stress is stress exceeding the organism’s ability to cope physiologically, which may act as a risk factor in the onset and relapse of alcohol use disorder. Chronic- restraint stress (CRS) and ethanol intake are independently known to induce changes in brain structure and function, however, their combined effects on neurodevelopment over long periods of time remains largely unexplored. We conducted an in vivo longitudinal rat model with three main goals. 1) to determine if chronic stress increases ethanol intake; 2) to determine the effect of chronic- stress and ethanol intake in behavioral measures, brain structure, and function; and 3) to investigate the effect of sex. This observational study included Wistar rats assigned to four groups: 1) ethanol consumption (EtOH+/CRS-), 2) stress exposure (EtOH-/CRS+), 3) both ethanol and stress exposure (EtOH+/CRS+), and 4) control group (EtOH-/CRS-). Our results showed that chronic stress did not affect ethanol intake but led to reduced body weight gain, elevated corticosterone levels, and impaired recognition memory. Structural MRI revealed that both exposures produced additive brain volume changes in regions such as the olfactory bulb, orbitofrontal cortex, caudate-putamen, hippocampus, and cerebellum. Functional connectivity analysis using network-based statistics identified disrupted cortical-subcortical connections. Results found here were sex-dependent in terms of volumetric changes (higher effects on males) and functional connectivity (higher effects on females). Findings suggest sex-dependent mechanisms where both chronic- ethanol intake and stress affect brain plasticity during neurodevelopment. Understanding these region-specific vulnerabilities is crucial for addressing alcohol use disorders and stress-related neuropathology. Graphical abstract

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