Corbett, C. | Search bioRxiv

bioRxiv2026

Oligodendrocyte stress response as a driver of vascular dementia

Vascular dementia (VaD) is a prevalent and devastating neurocognitive disorder characterized by profound white matter damage, yet the precise cellular mechanisms linking cerebrovascular stress to demyelination remain poorly understood. Here, we characterize the impact of a chronic cardiometabolic stress regimen combining a high-fat diet and hypertension (HF/HBP) on central nervous system structure and function. Adult HF/HBP mice exhibit progressive oligodendroglial cell loss and myelin thinning, followed by cognitive impairments, anxiety-like behavior, and memory deficits that recapitulate clinical features of VaD. Mechanistically, we identify the integrated stress response (ISR) as a central driver of this pathology; pharmacological inhibition of the ISR restores myelination, while cell-specific genetic deletion of the ISR-activating kinase PERK from oligodendrocytes fully protects mice from HF/HBP-induced pathological and behavioral defects. Furthermore, we provide translational evidence that the ISR is activated in oligodendrocytes in human cases of cerebrovascular disease. Together, these findings reveal a critical, cell-autonomous role for oligodendroglial ISR activation during cerebrovascular stress and position this pathway as a viable therapeutic target to mitigate VaD pathogenesis.

neuroscience↗

bioRxiv2020

Pubertal androgens reduce the effects of social stress on anxiety-related behaviors in California mice

Anxiety disorders are more common in women than men, and this difference arises during puberty. Increased secretion of gonadal hormones during puberty influences brain structure and function, but the extent to which hormones modulate anxiety-related brain circuits is unclear. The slow developing California mouse (Peromyscus californicus) is an ideal species for studying the effects of hormones on brain function during adolescence. In adults social defeat stress reduces social approach and increases vigilance in females but not males. Here we show this sex difference is absent in juvenile mice, and that prepubertal castration sensitizes adult males to social defeat. Since adult castration has no effect on stress sensitivity, our data show that gonadal hormones act during puberty to program behavioral responses to stress later in life. In adults, calcium imaging in the medioventral bed nucleus of the stria terminalis shows that threatening social contexts increase calcium transients. Furthermore, prepubertal castration generalizes these responses to less threatening social contexts. Prepubertal treatment with the non-aromatizable androgen dihydrotestosterone acts in males and females to reduce sensitivity to social defeat in adults. Together, these data indicate activation of androgen receptors during puberty are critical for programing behavioral responses to stress in adulthood, highlighting a possible mechanism contributing to sex differences in anxiety. Significance StatementPuberty is a key period when sex differences in anxiety emerges. Gonadal hormone release increases during this time but it is largely unknown how they impact brain circuits and behavior. We show that androgens play a key role in programming behavioral responses to social defeat stress. The bed nucleus of the stria terminalis responds to social threats and these responses are more generalized in males without gonadal hormone exposure during puberty. Our findings highlight the importance of pubertal androgens in determining adult behavioral responses to social stress.

developmental biology↗