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 MR 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 MR SNPs associated with increased MR expression and transactivational activity (MR-2G/C C [rs2070951], MR-I180V A [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 MR 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 MR 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.