Biology subjects

Rashford, R. L.

Publications and source records attributed to Rashford, R. L..

2 recordsLinked to original sources

bioRxiv2024

Early-life stress alters postnatal chromatin development in the nucleus accumbens

Early-life stress (ELS) sensitizes individuals to subsequent stressors to increase lifetime risk for psychiatric disorders. Within the nucleus accumbens (NAc) -- a key limbic and reward-associated brain region -- ELS sensitizes both cellular and transcriptional response to later stress, which are programmed by enduring epigenetic changes. Among the histone modifications persistently enriched by ELS in NAc is H3K4me1, which is associated with open chromatin and epigenetic priming of genomic enhancers. Here, we sought to determine whether H3K4me1 enrichment in NAc was sufficient to prime cellular and behavioral responses to adult stress. Viral-mediated overexpression of the histone H3 monomethyltransferase Setd7 in juvenile NAc induced lifelong chromatin changes and predominately opened chromatin at long-range cis-regulatory elements predicted to enhance immediate early-genes and transcriptional regulators of mesolimbic development and synaptic activity. These epigenetic changes altered physiological properties of D2-type medium spiny neurons in NAc to resemble neurons of stressed mice, without significantly altering D1-type neurons. Finally, juvenile -- but not adult -- Setd7 overexpression and H3K4me1 enrichment in NAc enhanced behavioral sensitivity to future stress. Together, these data indicate that altered postnatal chromatin development in NAc by H3K4me1 enrichment is sufficient to prime lifelong transcriptional, physiological, and behavioral stress sensitivity.

neuroscience↗

bioRxiv2022

Reactivation of early-life stress-sensitive neuronal ensembles contributes to lifelong stress hypersensitivity

Early-life stress (ELS) is one of the strongest lifetime risk factors for depression, anxiety, suicide, and other psychiatric disorders, particularly after facing additional stressful events later in life. Human and animal studies demonstrate that ELS sensitizes individuals to subsequent stress. However, the neurobiological basis of such stress sensitization remains largely unexplored. We hypothesized that ELS-induced stress sensitization would be detectable at the level of neuronal ensembles, such that cells activated by ELS would be more reactive to adult stress. To test this, we leveraged transgenic mice to genetically tag, track, and manipulate experience-activated neurons. We found that in both male and female mice, ELS-activated neurons within the nucleus accumbens (NAc), and to a lesser-extent the medial prefrontal cortex, were preferentially reactivated by adult stress. To test whether reactivation of ELS-activated ensembles in the NAc contributes to stress hypersensitivity, we expressed hM4Dis receptor in control or ELS-activated neurons of pups and chemogenetically inhibited their activity during experience of adult stress. Inhibition of ELS-activated NAc neurons, but not control-tagged neurons, ameliorated social avoidance behavior following chronic social defeat stress in males. These data provide evidence that ELS-induced stress hypersensitivity is encoded at the level of corticolimbic neuronal ensembles.

neuroscience↗