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

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.

BDNF val66met genotype and schizotypal personality traits interact to influence probabilistic association learning.

The brain derived neurotrophic factor (BDNF) val66met polymorphism rs6265 influences learning and may represent a risk factor for schizophrenia. Healthy people with high schizotypal personality traits display cognitive deficits that are similar to but not as severe as those observed in schizophrenia and they can be studied without confounds of antipsychotics or chronic illness. How genetic variation in BDNF may impact learning in individuals falling along the schizophrenia spectrum is unknown. We predicted that schizotypal personality traits would influence learning and that schizotypal personality-based differences in learning would vary depending on the BDNF val66met genotype. Eighty-nine healthy adults completed the Schizotypal Personality Questionnaire (SPQ) and a probabilistic association learning test. Blood samples were genotyped for the BDNF val66met polymorphism. An ANOVA was performed with BDNF genotype (val homozygotes and met-carriers) and SPQ score (high/low) as grouping variables and probabilistic association learning as the dependent variable. Participants with low SPQ scores (fewer schizotypal personality traits) showed significantly better learning than those with high SPQ scores. BDNF met-carriers displaying few schizotypal personality traits performed best, whereas BDNF met-carriers displaying high schizotypal personality traits performed worst. Thus, the BDNF val66met polymorphism appears to influence probabilistic association learning differently depending on the extent of schizotypal personality traits displayed.