Endocrine stress responsivity and social memory in 3xTg-AD female and male mice: A tale of two experiments

Stress confers risk for the development and progression of Alzheimer's disease (AD). Relative to men, women are disproportionately more likely to be diagnosed with this neurodegenerative disease. We hypothesized that sex differences in endocrine stress responsiveness may be a factor in this statistic. To test this hypothesis, we assessed basal and stress-induced corticosterone, social recognition, and coat state deterioration (surrogate for depression-like behavior) in male and female 3xTg-AD mice. Prior to reported amyloid plaque deposition, 3xTg females (4 months), but not 3xTg males, had heightened corticosterone responses to restraint exposure. Subsequently, only 3xTg females (6 months) displayed deficits in social memory concomitant with prominent β-amyloid (Aβ) immunostaining. These data suggest that elevated corticosterone stress responses may precede cognitive impairments in genetically vulnerable females. 3xTg mice of both sexes exhibited coat state deterioration relative to same-sex controls. Corticolimbic glucocorticoid receptor (GR) dysfunction is associated with glucocorticoid hypersecretion and cognitive impairment. Our findings indicate sex- and brain-region specific effects of genotype on hippocampal and amygdala GR protein expression. Because olfactory deficits may impede social recognition, in Experiment 2, we assessed olfaction and found no differences between genotypes. Notably, in this cohort, heightened corticosterone stress responses in 3xTg females was not accompanied by social memory deficits or coat state deterioration. However, coat state deterioration was consistent in 3xTg males. We report consistent heightened stress-induced corticosterone levels and Aβ pathology in female 3xTg-AD mice. However, the behavioral findings illuminate unknown inconsistencies in certain phenotypes in this AD mouse model.

Keywords: Alzheimer's disease; Coat state; Depression; Glucocorticoid; Glucocorticoid receptor; HPA; Social memory; Social preference recognition.