Alzheimer’s Disease (AD) is the most prevalent form of dementia and is the sixth leading cause of death in the elderly. Evidence suggests that forms of stress, including prenatal maternal stress (PMS), could exacerbate AD development. To better understand the mechanism linking PMS and AD, we investigated behavior and specific epigenetic markers of the 3xTg-AD mouse model compared to aged-controls in offspring of stressed mothers and non-stressed mothers.

Social isolation in early childhood can have life-long effects on social behaviors and development. Cerebellar crus I has additionally been linked to social behaviors through forebrain pathways. In this study, we hypothesized that social isolation of mice from postnatal day 21 (P21) until p35 would result in impaired social behaviors. Additionally, we hypothesized that gq DREADD injections into crus I, to increase levels of cerebellar stimulation, at the start of the isolation period would counteract the effects of isolation, leading to mice who displayed normal social behaviors. Social behavior at P35 was tested using the 3-Chamber Task, a well-established model, and SLEAP deep-learning software was used to obtain quantifiable data. We found no difference in social behaviors between socially raised and isolated mice. However, gq DREADD mice displayed greater levels of social interaction and exploration than either socially raised mice or isolated mice. This research carries implications for possible therapeutic interventions for groups prone to social isolation, such as those with developmental disabilities, minority groups, the elderly, and prison populations.

Stress and stress-related disorders increase the risk of Alzheimer’s Disease (AD) later in life. Some evidence suggests that prenatal maternal stress (PMS) can exacerbate AD. However, the effects of PMS on AD have not been as well studied. Epigenetic changes have been shown to contribute to AD and this is a possible mechanism by which PMS could accelerate AD. Thus, the present study aimed to investigate the effects of PMS on histone modifications, which change gene expression through alterations made to chromatin structure and thereby DNA accessibility. We utilized female 3xTG-AD mice and performed spatial and learning memory assessments between 5 and 6 months of age. Tissue was analyzed for AD pathology and epigenetic markers at 6 months of age were assessed PMS was shown to influence histone modifications H3K4me3 and H3K27me3 in a manner known to promote the expression of genes associated with neurodegeneration. Further, PMS impaired spatial memory, and, interestingly, the data resembled the pattern of H3K4me3 expression across groups, suggesting that this epigenetic modification could modulate the learning and memory effects of PMS. While the presence of hallmark AD pathologies were not accelerated by PMS, PMS did increase early tau phosphorylation events. Thus, this evidence suggests that PMS impairs spatial memory through epigenetic modifications and may potentially exacerbate AD later in life.