Prenatal alcohol exposure and the retrosplenial cortex: Structural and functional mechanisms across species

The retrosplenial cortex (RSC) is a structurally and functionally complex hub with broad connectivity, integrating sensory inputs, cognitive states, and memory to guide behavior. It supports perspective transformation, predictive modeling, and memory retrieval, making it critical for navigation, executive function, and higher cognition. Animal studies show that the RSC is vulnerable to developmental alcohol exposure. Early work revealed widespread apoptotic neurodegeneration, in cortical layers II to V, followed by evidence of vascular injury, selective interneuron loss, and persistent alterations in inhibitory synaptic transmission. These cellular changes are associated with circuit-level dysfunction, including disrupted thalamic input, impaired hippocampal and prefrontal connectivity, and sex-dependent alterations in functional organization. Behaviorally, such disruptions could contribute to the long-lasting deficits in memory, cognitive flexibility, and sleep regulation, paralleling impairments seen in fetal alcohol spectrum disorders (FASDs). Human neuroimaging studies align with these findings, revealing structural and developmental abnormalities in the posterior cingulate cortex and other regions adjacent to or interconnected with the RSC. Reported alterations include reduced gray and white matter volumes, atypical developmental trajectories, and paradoxical volume increases suggestive of compensatory processes. Functional imaging demonstrates altered activation and inefficient recruitment of neural networks during memory and executive function tasks. Diffusion tensor imaging reveals disrupted white matter integrity, altered cingulum microstructure, and subtle changes in hub connectivity. Together, animal and human evidence position the RSC as a key locus of alcohol-related neurotoxicity. Importantly, pharmacological, nutritional, and behavioral interventions show potential to mitigate RSC pathology and improve outcomes, making this region a promising target for intervention in FASDs.