Reorganization of the brain's epigenetic landscape occurs alongside early adversity in both human and non‐human animals. Whether this reorganization is simply incidental to or is a causal mechanism of the behavioral abnormalities that result from early adversity is important to understand. Using the scarcity‐adversity model of low nesting resources in Long Evans rats, our lab has previously reported specific epigenetic and behavioral trajectories occurring in response to early disruption of the caregiving environment. To further probe that relationship, the current work investigates the ability of the epigenome‐modifying drug sodium butyrate to prevent maltreatment‐induced methylation changes when administered alongside maltreatment. Following exposure to the scarcity‐adversity model, during which drug was administered prior to each caregiving session, methylation of Brain‐derived Neurotrophic Factor (Bdnf) IX DNA was examined in the Prefrontal Cortex (PFC) of male and female pups at postnatal day (PN) 8. As our previous work reports, increased methylation at this exon of Bdnf in the PFC is a stable epigenetic change across the lifespan that occurs in response to early maltreatment, thus giving us a suitable starting point to investigate pharmacological prevention of maltreatment‐induced epigenetic marks. Here we also examined off‐target effects of sodium butyrate by assessing methylation in another region of Bdnf (exon IV) not affected in the infant brain as well as global levels of methylation in the brain region of interest. Results indicate that a 400 mg/kg (but not 300 mg/kg) dose of sodium butyrate is effective in preventing the maltreatment‐induced rise in methylation at Bdnf exon IX in the PFC of male (but not female) infant pups. Administration of sodium butyrate did not affect the methylation status of Bdnf IV or overall levels of global methylation in the PFC, suggesting potential specificity of this drug. These data provide us an avenue forward for investigating whether the relationship between adversity‐induced epigenetic outcomes in our model can be manipulated to improve behavioral outcomes.
Alzheimer′s disease (AD) is the leading cause of dementia worldwide, but there are limited therapeutic options and no current cure. While the involvement of microglia in AD has been highly appreciated, the role of other innate and adaptive immune cells remains largely unknown, partly due to their scarcity and heterogeneity. This study aimed to study non-microglial immune cells in wild type and AD-transgenic mouse brains across different ages. Our results uncovered the presence of a unique CD8+ T cell population that were selectively increased in aging AD mouse brains, here referred to as ″disease-associated T cells (DATs)″. These DATs were found to express an elevated tissue-resident memory and Type I interferon-responsive gene signature. Further analysis of aged AD mouse brains showed that these CD8+ T cells were not present in peripheral or meningeal tissues. Preventing CD8+ T cell development in AD-transgenic mice via genetic deletion of beta-2 microglobulin (B2m) led to a reduction of amyloid-β ; plaque formation in aged mice, and improved memory in AD-transgenic mice as early as four months of age. The integration of transcriptomic and epigenomic profiles at the single-cell level revealed potential transcription factors that reshape the regulomes of CD8+ T cells. These findings highlight a critical role for DATs in the progression of AD and provide a new avenue for treatment.
Behavioral epigenetics posits that both nature and nurture must be considered when determining the etiology of behavior or disease. The epigenome displays a remarkable ability to respond to environmental input in early sensitive periods but also throughout the lifespan. These responses are dependent on environmental context and lead to behavioral outcomes. While early adversity has been shown to perpetuate issues of mental health, there are numerous intervention strategies shown efficacious to ameliorate these effects. This includes diet, exercise, childhood intervention programs, pharmacological therapeutics, and talk therapies. Understanding the underlying mechanisms of the ability of the epigenome to adapt in different contexts is essential to advance our understanding of mechanisms of adversity and pathways to resilience. The present review draws on evidence from both humans and animal models to explore the responsivity of the epigenome to adversity and its malleability to intervention. Behavioral epigenetics research is also discussed in the context of public health practice and policy, as it provides a meaningful source of evidence concerning child development and disease intervention and prevention.
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