A Haplotype Associated with Enhanced Mineralocorticoid Receptor Expression Facilitates the Stress-Induced Shift from "Cognitive" to "Habit" Learning.

Stress induces a shift from hippocampus-dependent "cognitive" toward dorsal striatum-dependent "habit" memory. However, not all individuals are susceptible to this shift under stress. Based on pharmacological studies indicating a critical role of the mineralocorticoid receptor (MR) in the stress-induced bias toward dorsal striatal learning, we hypothesized that gene variants contribute to these individual differences. In two experiments, healthy participants were genotyped, exposed to a stressor or control manipulation and performed a learning task that can be solved using hippocampal or dorsal striatal systems, while electroencephalography (EEG; Experiment I) or functional magnetic resonance imaging (fMRI; Experiment II) measurements were taken. Stress led to a shift from hippocampal to dorsal striatal learning which was more pronounced in homo- and heterozygous carriers of a six single nucleotide polymorphisms (SNPs)-comprising haplotype containing the alleles of two associated with increased MR expression and transactivational activity (-2G/C [rs2070951], -I180V [rs5522]). This stress-induced shift toward habit memory was paralleled by an increased feedback-related negativity (FRN), which may reflect striatal processing, and increased caudate activation. Carriers of the haplotype showed a reduced P3a, an event-related potential thought to indicate cognitive processing, and reduced hippocampal activity after stress. Moreover, stress resulted in reduced amygdala-hippocampus connectivity and the decrease in amygdala connectivity to the parahippocampal cortex was particularly pronounced in haplotype carriers. Our findings indicate that genetic variants associated with enhanced MR expression facilitate a stress-induced shift from hippocampal toward dorsal striatal learning, most likely via impaired hippocampal processing and reduced amygdala-hippocampus cross talk, allowing the dorsal striatum to guide behavior under stress.