Abstract
Prenatal alcohol exposure (PAE) has been shown to impair learning, memory and executive functioning in children. Perseveration, or the failure to respond adaptively to changing contingencies, is a hallmark on neurobehavioral assessment tasks for human fetal alcohol spectrum disorder (FASD). Adaptive responding is predominantly a product of the medial prefrontal cortex (mPFC) and is regulated by corticosteroids. In our mouse model of PAE we recently reported deficits in hippocampal formation-dependent learning and memory and a dysregulation of hippocampal formation glucocorticoid receptor (GR) subcellular distribution. Here, we examined the effect of PAE on frontal cortical-dependent behavior, as well as mPFC GR subcellular distribution and the levels of regulators of intracellular GR transport. PAE mice displayed significantly reduced response flexibility in a Y-maze reversal learning task. While the levels of total nuclear GR were reduced in PAE mPFC, levels of GR phosphorylated at serines 203, 211 and 226 were not significantly changed. Cytosolic, but not nuclear, MR levels were elevated in the PAE mPFC. The levels of critical GR trafficking proteins, FKBP51, Hsp90, cyclophilin 40, dynamitin and dynein intermediate chain, were altered in PAE mice, in favor of the exclusion of GR from the nucleus, indicating dysregulation of GR trafficking. Our findings suggest that there may be a link between a deficit in GR nuclear localization and frontal cortical learning deficits in prenatal alcohol-exposed mice.
Highlights
Optimal levels of glucocorticoid-dependent signaling are necessary for learning and attention
The Y-maze reversal learning task was analyzed separately for the two phases, initial acquisition phase and the reversal phase (Figure 1). Performance of both groups of mice improved with repeated trial sessions [F (1,20) = 37.5, p,.0001] and there was an overall difference between the Prenatal alcohol exposure (PAE) and saccharin 0.066% (w/v) alone (SAC) in Y-maze reversal learning [F(1,20) = 18.8, p,.0001]
We have reported that PAE increased nuclear localization of the glucocorticoid receptor (GR) in the adolescent male mouse hippocampal formation [14]
Summary
Optimal levels of glucocorticoid-dependent signaling are necessary for learning and attention. Dysregulation within glucocorticoid signaling pathways alters habitual responding [1] and can affect decision making. In a series of studies, Gourley and colleagues [2] demonstrated that glucocorticoid receptor (GR) signaling in the medial prefrontal cortex (mPFC) is necessary for adaptive responding and flexible decision making strategies, under stressful conditions. Glucocorticoids, acting via the GR, exert a wide array of actions both in the periphery and in the brain, including regulation of neural pathways connecting the mPFC with the hippocampus and the amygdala [3]. Trafficking of the GR between these cellular compartments is controlled by multiple proteins, including FK506-binding proteins (FKBP51; FKBP5) and (FKBP52, FKBP4), heat shock protein 90 (Hsp90), cyclophilin 40, dynein and dynamitin [7]
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