Altered postnatal chromatin development in the nucleus accumbens primes enduring stress sensitivity

Area of Science:

• Neuroscience
• Epigenetics
• Psychiatry

Background:

• Early-life stress (ELS) increases lifetime risk for psychiatric disorders by sensitizing individuals to future stressors.
• The nucleus accumbens (NAc), a key brain region, shows enduring epigenetic changes after ELS, including H3K4me1 enrichment.
• H3K4me1 is linked to open chromatin and primed genomic enhancers, suggesting a role in stress sensitization.

Purpose of the Study:

• To investigate if H3K4me1 enrichment in the NAc is sufficient to prime cellular and behavioral responses to adult stress.
• To explore the role of the histone methyltransferase Setd7 in mediating these epigenetic and behavioral changes.

Main Methods:

• Viral-mediated overexpression of Setd7 in the juvenile NAc of mice.
• Analysis of chromatin accessibility and gene expression.
• Electrophysiological recordings of medium spiny neurons in the NAc.
• Behavioral assessments of stress sensitivity.

Main Results:

• Juvenile Setd7 overexpression induced persistent chromatin changes, opening regulatory elements and altering gene expression.
• Epigenetic alterations specifically affected D2-type medium spiny neurons, mimicking changes seen in stressed mice.
• Juvenile, but not adult, Setd7 overexpression enhanced behavioral sensitivity to subsequent stress.

Conclusions:

• Altered postnatal chromatin development in the NAc via H3K4me1 enrichment is sufficient to prime long-lasting stress sensitivity.
• This study provides neurobiological evidence that epigenetic maturation in the juvenile brain encodes enduring stress vulnerability.