AbstractClinical and preclinical studies report that chronic stress induces behavioral deficits as well as volumetric changes and synaptic alterations in corticolimbic brain regions including the anterior cingulate cortex (ACC), amygdala (AMY), nucleus accumbens (NAc) and hippocampus (HPC). In this study, we aimed to investigate the structural changes associated with chronic restraint stress (CRS) exposure and determine the relation between these volumetric changes with behavioral and synaptic alterations. Mice exposed to 2 and 5 weeks of CRS exhibited a significant increase in behavioral emotionality. Macrostructural changes assessed via MRI identified a negative CRS effect on total brain volume, proportional to behavioral emotionality. Region-specific changes within corticolimbic brain structures identified that only the ACC showed significant decrease in volume following CRS exposure (p<0.05). Reduced ACC correlated with increased behavioral emotionality (r=−0.50; p=0.002). Although not significantly altered by CRS, AMY and NAc (but not the HPC) volumes were negatively correlated with behavioral emotionality. Structural covariance network analysis revealed progressive decreased ACC degree following CRS exposure. Finally, reduced ACC volume correlated with decreased PSD95 (but not VGLUT1) puncta density (r=0.35, p<0.05), which also correlated with increased behavioral emotionality (r=−0.36, p<0.05), together suggesting that altered synaptic strength is an underlying substrate of the volumetric and behavioral effects of CRS Our results demonstrate that chronic stress effects on ACC volume and synaptic density are linked to the expression of depressive-like deficits. Our findings highlight key structural and morphological alterations in the ACC relevant to stress-related illness including mood and anxiety disorders.HighlightsChronic restraint stress induces decreases in anterior cingulate volume at 2 and 5 weeks following stress exposureVolume of the anterior cingulate cortex, amygdala and nucleus accumbens negatively correlate with behavioral emotionalityChronic stress induces a progressive decrease in strength and degree in structural covariance network connectivity of the anterior cingulate cortexPuncta density in the anterior cingulate cortex of post-synaptic marker PSD95 negatively correlates with behavioral emotionality and positively correlates with anterior cingulate cortex volume.
Reduced anterior cingulate cortex volume induced by chronic stress correlates with increased behavioral emotionality and decreased synaptic puncta density