@article {WirzENEURO.0359-17.2017, author = {Lisa Wirz and Martin Reuter and Jan Wacker and Andrea Felten and Lars Schwabe}, title = {A Haplotype Associated with Enhanced Mineralocorticoid Receptor Expression Facilitates the Stress-Induced Shift from {\textquoteleft}Cognitive{\textquoteright} to {\textquoteleft}Habit{\textquoteright} Learning}, elocation-id = {ENEURO.0359-17.2017}, year = {2017}, doi = {10.1523/ENEURO.0359-17.2017}, publisher = {Society for Neuroscience}, abstract = {Stress induces a shift from hippocampus-dependent {\textquoteleft}cognitive{\textquoteright} toward dorsal striatum-dependent {\textquoteleft}habit{\textquoteright} 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 EEG (experiment I) or 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 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, 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 {\textquoteleft}cognitive{\textquoteright} 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 crosstalk, allowing the dorsal striatum to guide behavior under stress.Significance Statement Stressful events may trigger a shift from hippocampus-dependent, {\textquoteleft}cognitive{\textquoteright} toward dorsal striatum-dependent, {\textquoteleft}habitual{\textquoteright} control of learning. While being generally adaptive for performance under stress, this shift may contribute to stress-related psychopathology. However, there are substantial individual differences in the stress-induced bias toward habit learning, the source of which is not fully understood. In line with pharmacological studies pointing to a critical role of the mineralocorticoid receptor (MR) in the stress-induced learning bias, we report here that a MR haplotype associated with enhanced MR expression facilitates habit learning under stress. Using electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), we show that this genetic modulation is most likely mediated by altered hippocampus activity and amygdala-hippocampus crosstalk.}, URL = {https://www.eneuro.org/content/early/2017/11/13/ENEURO.0359-17.2017}, eprint = {https://www.eneuro.org/content/early/2017/11/13/ENEURO.0359-17.2017.full.pdf}, journal = {eNeuro} }