Pre‐Stress Trait Anxiety Levels Shape Hippocampal Responses to Acute Stress in High Anxiety Male Mice

Stress is a major risk factor for neuropsychiatric disorders. However, how stress influences highly anxious populations and how pre-stress anxiety-related behavior variability mediates stress-elicited molecular responses remain elusive. Here, we investigated the effects of acute stress on the hippocampus in high anxiety-related behavior (HAB) male mice and explored how pre-stress high anxiety-related behavior shapes hippocampal and peripheral molecular signatures following acute stress. We first exposed HAB male mice to acute restraint stress (ARS) and investigated ARS effects on hippocampal proteome. We extensively characterized the pre-stress behavior of HAB mice, ranked them in high and low anxiety HAB subpopulations according to their pre-stress anxiety-related profiles and assessed whether divergent high anxiety-related behavior levels influence molecular stress responses. We found that ARS exerts imperceptible hippocampal proteome effects in HAB mice. However, when we compared high versus low anxiety HAB subpopulations following ARS, we observed profound stress-induced molecular changes in low anxiety ARS versus low anxiety control HAB mice, but not in high anxiety ARS versus high anxiety control HAB mice, predominantly impacting mitochondrial translation. When further exploring pre-stress anxiety variability effects in the presence and absence of stress, we observed that high versus low anxiety HAB subpopulations display divergent molecular profiles only after ARS, but not in its absence, leading to changes in RNA metabolism along with altered mitochondrial dynamics players. Taken together, our data showcase that individual behavioral variability largely shapes molecular stress responses in HAB male populations through modulating mitochondrial pathways.