DAT1-Genotype and Menstrual Cycle, but Not Hormonal Contraception, Modulate Reinforcement Learning: Preliminary Evidence

Abstract

Hormone by genotype interactions have been widely ignored by cognitive neuroscience. Yet, the dependence of cognitive performance on both baseline dopamine (DA) and current 17ß-estradiol (E2) level argues for their combined effect also in the context of reinforcement learning. Here, we assessed how the interaction between the natural rise of E2 in the late follicular phase (FP) and the 40 base-pair variable number tandem repeat polymorphism of the dopamine transporter (DAT1) affects reinforcement learning capacity. 30 women with a regular menstrual cycle performed a probabilistic feedback learning task twice during the early and late FP. In addition, 39 women, who took hormonal contraceptives (HC) to suppress natural ovulation, were tested during the “pill break” and the intake phase of HC. The present data show that DAT1-genotype may interact with transient hormonal state, but only in women with a natural menstrual cycle. We found that carriers of the 9-repeat allele (9RP) experienced a significant decrease in the ability to avoid punishment from early to late FP. Neither homozygote subjects of the 10RP allele, nor subjects from the HC group showed a change in behavior between phases. These data are consistent with neurobiological studies that found that rising E2 may reverse DA transporter function and could enhance DA efflux, which would in turn reduce punishment sensitivity particularly in subjects with a higher transporter density to begin with. Taken together, the present results, although based on a small sample, add to the growing understanding of the complex interplay between different physiological modulators of dopaminergic transmission. They may not only point out the necessity to control for hormonal state in behavioral genetic research, but may offer new starting points for studies in clinical settings.

Influence of ovarian hormones on value-based decision-making systems: Contribution to sexual dimorphisms in mental disorders

“…The findings of Reimers et al (2014) are consistent with the positive effect of estradiol in behavioral control discussed in Section 2.3.3. However, Jakob et al (2018) results indicate estradiol-related disturbances in the coding of the negative RPE signal during avoidance learning particularly in women whose striatal dopamine levels are already low. A similar effect was discussed with high estradiol dose in rodent models, making it likely that by facilitating the dopaminergic neurotransmission in the limbic areas increased estradiol interferes with a suppression of the tonic dopamine signal required for coding a negative RPE.…”

“…Better behavioral performance in the task during the follicular phase was associated with increased activation in the inferior frontal junction and rostral cingulate. As shown by preliminary results in Jakob et al (2018), learning of active avoidance was increasingly disturbed from early to late follicular phase in women who supposedly have lower dopaminergic neurotransmission in the striatum as indicated by the presence of 9-repeat allele in their DAT1-genotype, but their reward sensitivity remained unchanged.…”

“…A similar effect was discussed with high estradiol dose in rodent models, making it likely that by facilitating the dopaminergic neurotransmission in the limbic areas increased estradiol interferes with a suppression of the tonic dopamine signal required for coding a negative RPE. An inverted U-shape relationship between estradiol and behavioral control could be suggested (Jakob et al, 2018). Finally, increase in hedonic experience with higher estradiol might be related to positive effects of estradiol on the dopaminergic positive RPE signal and thus promote reinforcement learning.…”

The Straw That Broke the Camel’s Back: Natural Variations in 17β-Estradiol and COMT-Val158Met Genotype Interact in the Modulation of Model-Free and Model-Based Control

“…In line with the dopamine-agonistic properties of estradiol, previous studies with humans showed that estradiol influenced model-free learning, also in interaction with the dopaminergic baseline capacity of the striatum that followed an inverted U-shape relationship (Diekhof, 2015;Jakob et al, 2018; see also Diekhof, 2018). In one study reward sensitivity was compromised when estradiol level reached its peak in the late follicular phase of the menstrual cycle.…”

Avoidance Learning Across the Menstrual Cycle: A Conceptual Replication

“…Yet, it is still possible that the subjects from the two cycle phases differed in an aspect that was not matched here. For example, genetic variability in dopaminergic baseline capacity could represent a significant source of inter-subject variance (28), which was not controlled here. Since the results from the meta-analysis conformed to the present observation, and further replicated an already published within-subject finding, we think that it is very unlikely that an unknown inter-subject aspect determined the group-difference in avoidance learning.…”