Early Life Stress Alters Expression of Glucocorticoid Stress Response Genes and Trophic Factor Transcripts in the Rodent Basal Ganglia

Abstract

Early life stress shapes the developing brain and increases risk for psychotic disorders. Yet, it is not fully understood how early life stress impacts brain regions in dopaminergic pathways whose dysfunction can contribute to psychosis. Therefore, we investigated gene expression following early life stress in adult brain regions containing dopamine neuron cell bodies (substantia nigra, ventral tegmental area (VTA)) and terminals (dorsal/ventral striatum). Sprague–Dawley rats (14F, 10M) were separated from their mothers from postnatal days (PND) 2–14 for 3 h/day to induce stress, while control rats (12F, 10M) were separated for 15 min/day over the same period. In adulthood (PND98), brain regions were dissected, RNA was isolated and five glucocorticoid signalling-related and six brain-derived neurotrophic factor (Bdnf) mRNAs were assayed by qPCR in four brain regions. In the VTA, levels of glucocorticoid signalling-related transcripts differed in maternally separated rodents compared to controls, with the Fkbp5 transcript significantly lower and Ptges3 transcript significantly higher in stressed offspring. In the VTA and substantia nigra, maternally separated rodents had significantly higher Bdnf IIA and III mRNA levels than controls. By contrast, in the ventral striatum, maternally separated rodents had significantly lower expression of Bdnf I, IIA, IIC, IV and VI transcripts. Sex differences in Nr3c1, Bag1 and Fkbp5 expression in the VTA and substantia nigra were also detected. Our results suggest that early life stress has long-lasting impacts on brain regions involved in dopamine neurotransmission, changing the trophic environment and potentially altering responsiveness to subsequent stressful events in a sex-specific pattern.