Serotonin Transporter Genotype Modulates Social Reward and Punishment in Rhesus Macaques

Platt ML (2009) Serotonin Transporter Genotype Modulates Social Reward and Punishment in Rhesus Macaques. PLoS ONE 4(1): e4156. doi:10.1371/journal.pone.0004156 Serotonin Transporter Genotype Modulates Social Reward and Punishment in Rhesus Macaques Karli K. Watson 0 Jason H. Ghodasra 0 Michael L. Platt 0 Laurie Santos, Yale University, United States of America 0 1 Department of Neurobiology, Duke University, LSRC Room , Durham , North Carolina, United States of America, 2 Feinberg School of Medicine, Northwestern University , Chicago, Illinois , United States of America Background: Serotonin signaling influences social behavior in both human and nonhuman primates. In humans, variation upstream of the promoter region of the serotonin transporter gene (5-HTTLPR) has recently been shown to influence both behavioral measures of social anxiety and amygdala response to social threats. Here we show that length polymorphisms in 5-HTTLPR predict social reward and punishment in rhesus macaques, a species in which 5-HTTLPR variation is analogous to that of humans. Methodology/Principal Findings: In contrast to monkeys with two copies of the long allele (L/L), monkeys with one copy of the short allele of this gene (S/L) spent less time gazing at face than non-face images, less time looking in the eye region of faces, and had larger pupil diameters when gazing at photos of a high versus low status male macaques. Moreover, in a novel primed gambling task, presentation of photos of high status male macaques promoted risk-aversion in S/L monkeys but promoted risk-seeking in L/L monkeys. Finally, as measured by a ''pay-per-view'' task, S/L monkeys required juice payment to view photos of high status males, whereas L/L monkeys sacrificed fluid to see the same photos. Conclusions/Significance: These data indicate that genetic variation in serotonin function contributes to social reward and punishment in rhesus macaques, and thus shapes social behavior in humans and rhesus macaques alike. - Funding: We gratefully acknowledge financial support from the Cure Autism Now Foundation (KKW), National Institutes of Health (R01 5R01-EY-013496-07 to MLP and Training Grant in Fundamental and Translational Neuroscience to KKW), and Howard Hughes Medical Institute (JHG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. The synaptic serotonin transporter plays a crucial role in regulating emotion in both human and non-human primates. Expression levels of the serotonin transporter gene depend on the serotonin transporter linked polymorphic region (5-HTTLPR), a sequence of tandem repeats upstream of the promoter that is polymorphic in humans and simian primates [1]. Humans and rhesus macaques have short (S) and long (L) allelic variants of 5HTTLPR, and in both species the presence of the S allele interacts with early environment to produce long term effects on behavior, personality, and measures of central nervous system function [2 5]. Presence of the S allele in captive rhesus macaques predisposes them towards increased alcohol consumption [6], exacerbated neuroendocrine responses to stress [3], and greater rates of affective responding [4]. Similarly, human S carriers who experience childhood abuse or trauma are at elevated risk of alcoholism and depression [2]. Moreover, functional imaging studies indicate that human S carriers exhibit enhanced amygdala response to social threats such as angry faces [7,8]. Based on these observations, we predicted that allelic variation in 5-HTTPLR would influence individual reactivity to social reward and punishment in rhesus macaques, as it appears to do in humans. We tested this hypothesis in three complimentary experiments: First, we measured eye gaze patterns and pupil diameter in male rhesus macaques when they were given the opportunity to look at images of other rhesus macaques; second, we measured the effects of seeing social images on subsequent gambling for juice rewards; and third, we measured the amount of juice male rhesus macaques sacrificed or demanded for the opportunity to see these images. These experiments provide three implicit measures of the influence of social stimuli on neural systems mediating reward and punishment [911]. 5-HTTLPR genotype modulates gaze pattern and pupil diameter in rhesus macaques when viewing social images Eight adult male rhesus macaques (four L/L and four S/L) were presented with a series of images depicting faces (see Figure 1A) or scrambled faces of familiar macaque monkeys (see Figure 1B for task sequence). Eye position and pupil diameter were monitored using an infrared camera based eye tracking system. S/L monkeys spent less total time looking at face images relative to scrambled face images (27.967.7% for face images, 40.5611.0% for scrambled), whereas L/L monkeys looked equally at both image Figure 1. Tasks used to assess the influence of 5-HTTLPR genotype on social reward and punishment. (A) Stimuli consisted of images of familiar conspecifics. Image pools used in the pay-per-view and primed risk taking task were identical, and consisted of four categories: gray square, faces of familiar low status individuals, faces of familiar high status individuals, and perinea of familiar females. Each of the three latter image pools consisted of 60 different images of either three (face pools) or four (perinea pool) different individuals. Images used for the free viewing task consisted of high and low status faces similar, but not identical, to those used in the other two tasks; and scrambled faces. Trial structures and reward schedules for (B) the free viewing task, (C) primed risk taking task, and (D) pay-per-view task. Stimuli for the free viewing task were randomly interleaved. The risk taking and pay-per-view tasks utilized a blocked trial structure so that reward contingencies were apparent to the animal after sampling each option. doi:10.1371/journal.pone.0004156.g001 categories (39.8612.9 face versus 38.1616.9 scrambled; Repeated measures ANOVA, F = 22.81, df = 1, p,0.01; post-hoc Fishers Least Significant Difference (LSD) test, df = 4.6, p = 0.017; Figure 2A). Moreover, when presented with faces, S/L monkeys spent less total time looking in the eye region than L/L monkeys did (11.964.6% for S/L versus 16.9611.9% for L/L; Repeated measures ANOVA, MS = 0.45, SS = 0.45, F = 15.24, df = 1, p = 0.017; LSD t-test; Figure 2B ). Animals with the two genotypes modulated by the social status of the displayed face, with a greater mean pupil diameter induced by the presentation of high-status faces (* indicates p = 0.05). In contrast, no significant difference in the pupil diameters of L/L animals was observed to correlate with image category. doi:10.1371/journal.pone.0004156.g002 did not spend significantly different amounts of time observing the mouth regio (...truncated)