Cognitive impact of genetic variation of the serotonin transporter in primates is associated with differences in brain morphology rather than serotonin neurotransmission

Abstract

A powerful convergence of genetics, neuroimaging and epidemiological research has identified the biological pathways mediating individual differences in complex behavioral processes and the related risk for disease. Orthologous genetic variation in non-human primates (NHPs) represents a unique opportunity to characterize the detailed molecular and cellular mechanisms that bias behaviorally and clinically relevant brain function. We report that a rhesus macaque orthologue of a common polymorphism of the serotonin transporter gene (rh5-HTTLPR) has strikingly similar effects on behavior and brain morphology to those in humans. Specifically, the rh5-HTTLPR (S)hort allele broadly affects cognitive choice behavior and brain morphology without observably affecting the 5-hydroxytryptamine (5-HT) transporter or 5-HT(1A) concentrations in vivo. Collectively, our findings indicate that 5-HTTLPR-associated behavioral effects reflect genotype-dependent biases in cortical development rather than static differences in serotonergic signaling mechanisms. Moreover, these data highlight the vast potential of NHP models in advancing our understanding of human genetic variation affecting behavior and neuropsychiatric disease liability.

Figure-1

S allele carriers make better probabilistic reward choices than LL subjects. (A) Both LS and LL subjects decrease the choice of the probabilistic reward when the reward probability is reduced during the task. The symbols below the graph refer to stimulus associated with the highest expected value at each probability level as described in further detail in the Supplement. (B) However, LS subjects make more advantageous choices (i.e. select the stimulus with the highest expected value) than LL subjects over the range of reward probabilities. *p=0.044 (C) The response time to choose between stimuli on a trial following reward omission is only increased in LS subjects. (main effect of reward outcome on previous trial LS p=0.005;LL p=0.125).

Figure-2

S allele carriers exhibit better performance across multiple cognitive tasks. (A) S allele carriers are more tolerant of delay to obtain a larger reward than LL subjects. Despite the reduced reward magnitude of the immediate reward, LL subjects choose immediate reward more frequently than LS subjects, thereby further reducing its magnitude (genotype × delay interaction p=0.057). At 5 sec delay, S allele carriers choose the larger, delayed reward more often than LL subjects. *p=0.002 (B) S allele carriers more quickly adapt their choices to a new reward contingency on a non-serial reversal learning task. LS and LL subjects performed similarly during stimulus discrimination learning, but following reversal of the reward contingency LS subjects more rapidly switched to the new stimulus associated with the larger reward (performance based on 15 reversals; main effect of genotype p=0.034, trial by genotype interaction p=0.003. *post-hoc comparison between genotypes p<0.05. (Inset) Both groups learn at a similar following the start of a new set of stimuli). (C) S allele carriers exhibit better performance than LL subjects on a delayed match to sample task. The accuracy of LS and LL subjects declined with increasing delay, but the decline in performance of LL subjects was more severe (genotype × delay interaction p=0.046;* post-hoc comparison between genotypes p=0.025)

Figure-3

PET imaging did not reveal genotype-associated differences. (A) PET Imaging with [¹¹C] DASB demonstrated similar levels of 5-HT transporter binding potential in both LS and LL subjects (multivariate regression for all regions p=0.695) (B) PET Imaging using [¹¹C] WAY100635 revealed no difference in 5-HT_1A binding potential between LS and LL subjects (multivariate regression for all regions p=0.116). AC: anterior cingulate, VS: ventral striatum, AMY: amygdala, HIPP: hippocampus, DR: dorsal raphe

Figure-4

Multiple clusters of decreased gray matter volume in S allele carriers in frontal, temporal, and parietal cortices using a whole brain analysis. (A-E) Coronal views of clusters encompassing (A) Brodmann areas 8, 9, 10, 11, and 24;(B) areas 10, 13, 24, and 45;(C) amygdala, inferotemporal cortex area TE, and temporal pole;(D) area TE;(E) area 5. (F-H) Sagittal views of clusters in (F) left Brodmann area 45, temporal pole, and area TE;(G) areas 8,9, and 24;(H) areas 10, 13, and 32. (I) axial view highlighting that the clusters of reduced gray matter volume in S allele carriers are concentrated in the ventral frontal corical regions (Brodmann areas 10, 11, 13, and 45). (J) Based on post-mortem observations in humans, an ROI analysis was performed for the pulvinar nucleus of the thalamus, which revealed larger grey matter volume in S allele carriers.The values in the left bottom corners indicate the distance (in mm) from a reference location in the brainstem (negative values in sagital sections refer to the left side of the brain).