Sex-specific spatial memory deficits associated with region-specific neuroinflammatory changes in the dorsal hippocampus of rats exposed to neonatal repeated maternal separation.

The hippocampus is an essential brain structure for memory and emotional regulation and is particularly vulnerable to early life stress, which disrupts its development and increases the risk of neuropsychiatric disorders. Using the neonatal maternal separation model of early life stress, we explored sex-specific behavioral and molecular alterations, focusing on hippocampal function, neuroinflammation, and associated signaling pathways. Our results show that neonatal maternal separation induces mechanical and thermal hypersensitivity, as well as anxiety-like behaviors in both male and female rats, but spatial memory deficits were observed exclusively in males. These male-specific cognitive impairments are associated with a pro-inflammatory response in the dorsal CA1 subregion of the hippocampus. Molecular analyses also showed sex- and region-specific changes in oxytocinergic signaling and chloride cotransporters, suggesting plastic mechanisms affecting local neuronal inhibition. These findings highlight the pronounced sex differences in hippocampal vulnerability to early adversity, with males displaying an intense neuroinflammatory signature in dorsal CA1 associated with spatial memory deficits. This work highlights that the cognitive component of pain needs to be studied more systematically to better understand sex differences that are not necessarily easy to observe in the sensory and emotional components.