0306 Corticotropin-Releasing Hormone Receptor 1 Gene Polymorphism Modulates Cognitive Flexibility Following Acute Stress and Total Sleep Deprivation

Introduction Dynamic decision processes requiring flexible updating of information are impaired by stress and sleep loss, both of which activate the hypothalamic-pituitary-adrenal (HPA) stress response. Corticotropin-releasing hormone (CRH) initiates the HPA pathway. The CRH receptor (CRHR1) gene contains a single nucleotide polymorphism that modulates this response. We investigated whether cognitive flexibility is affected by CRHR1 polymorphism following a night of acute stress and total sleep deprivation (TSD). Methods N=46 healthy, young adults (21.8±3.4y; 21 females) participated in an in-laboratory 31h sleep deprivation study. Beginning at 19:30 until 07:30, the Maastricht Acute Stress Test (MAST) was administered every 4h. The MAST alternates a cold pressor task with an oral subtraction task five times in a single bout. At 29h wakefulness, subjects performed a novel go/no-go reversal learning task. Stimulus-response rules were presented at the beginning of the task, and subjects were asked to either respond or withhold a response to the presented stimuli while receiving accuracy feedback. Halfway through the task, the stimulus-response rules were reversed. Performance was assessed by discriminability index (d’), hit rate (HR), and false alarm rate (FAR). Saliva samples were collected immediately prior, immediately after, and 30min after each MAST and assayed for cortisol. One saliva sample from each subject was assayed for CRHR1 genotype. Results CRHR1 genotypes were in Hardy-Weinberg equilibrium (χ 2=2.97, p=0.08). Mixed effects ANOVA with fixed effects of CRHR1 genotype, pre/post-reversal, and their interaction found a significant CRHR1 by reversal interaction for d’ (F2,319=3.88, p=0.022) and HR (F2,319=3.16, p=0.044) following a night of stress and TSD. No such interaction was found at well-rested baseline (d’: F2,319=2.51, p=0.083; HR: F2,319=1.55, p=0.213). Subjects homozygous for the T allele had higher mean post-MAST cortisol levels (0.40±0.06 µg/dL) with better pre-reversal performance, but worse post-reversal performance compared to heterozygous and homozygous G allele carriers. Conclusion CRHR1 genotype modulates dynamic decision making following a night of acute stress and TSD. A higher cortisol stress response (T/T genotype) is beneficial to maintaining task relevant information (stability), but significantly impairs the ability to update task-relevant information following a change in situational demands (flexibility). Support CDMRP grant W81XWH-17-C-0088