Delay discounting, genetic sensitivity, and leukocyte telomere length.

In a graying world, there is an increasing interest in correlates of aging, especially those found in early life. Leukocyte telomere length (LTL) is an emerging marker of aging at the cellular level, but little is known regarding its link with poor decision making that often entails being overly impatient. Here we investigate the relationship between LTL and the degree of impatience, which is measured in the laboratory using an incentivized delay discounting task. In a sample of 1,158 Han Chinese undergraduates, we observe that steeper delay discounting, indexing higher degree of impatience, is negatively associated with LTL. The relationship is robust after controlling for health-related variables, as well as risk attitude-another important determinant of decision making. LTL in females is more sensitive to impatience than in males. We then asked if genes possibly modulate the effect of impatient behavior on LTL. The oxytocin receptor gene (OXTR) polymorphism rs53576, which has figured prominently in investigations of social cognition and psychological resources, and the estrogen receptor ß gene (ESR2) polymorphism rs2978381, one of two gonadal sex hormone genes, significantly mitigate the negative effect of impatience on cellular aging in females. The current results contribute to understanding the relationship between preferences in decision making, particularly impatience, and cellular aging, for the first time to our knowledge. Notably, oxytocin and estrogen receptor polymorphisms temper accelerated cellular aging in young females who tend to make impatient choices.

Genetic variation in CD38 and breastfeeding experience interact to impact infants' attention to social eye cues.

Attending to emotional information conveyed by the eyes is an important social skill in humans. The current study examined this skill in early development by measuring attention to eyes while viewing emotional faces in 7-mo-old infants. In particular, we investigated individual differences in infant attention to eyes in the context of genetic variation (CD38 rs3796863 polymorphism) and experiential variation (exclusive breastfeeding duration) related to the oxytocin system. Our results revealed that, whereas infants at this age show a robust fear bias (increased attention to fearful eyes), their attention to angry and happy eyes varies as a function of exclusive breastfeeding experience and genetic variation in CD38. Specifically, extended exclusive breastfeeding duration selectively enhanced looking preference to happy eyes and decreased looking to angry eyes. Importantly, however, this interaction was impacted by CD38 variation, such that only the looking preferences of infants homozygous for the C allele of rs3796863 were affected by breastfeeding experience. This genotype has been associated with reduced release of oxytocin and higher rates of autism. In contrast, infants with the CA/AA genotype showed similar looking preferences regardless of breastfeeding exposure. Thus, differences in the sensitivity to emotional eyes may be linked to an interaction between the endogenous (CD38) and exogenous (breastfeeding) availability of oxytocin. These findings underline the importance of maternal care and the oxytocin system in contributing to the early development of responding to social eye cues.

Association between the dopamine D4 receptor gene exon III variable number of tandem repeats and political attitudes in female Han Chinese.

Twin and family studies suggest that political attitudes are partially determined by an individual's genotype. The dopamine D4 receptor gene (DRD4) exon III repeat region that has been extensively studied in connection with human behaviour, is a plausible candidate to contribute to individual differences in political attitudes. A first United States study provisionally identified this gene with political attitude along a liberal-conservative axis albeit contingent upon number of friends. In a large sample of 1771 Han Chinese university students in Singapore, we observed a significant main effect of association between the DRD4 exon III variable number of tandem repeats and political attitude. Subjects with two copies of the 4-repeat allele (4R/4R) were significantly more conservative. Our results provided evidence for a role of the DRD4 gene variants in contributing to individual differences in political attitude particularly in females and more generally suggested that associations between individual genes, and neurochemical pathways, contributing to traits relevant to the social sciences can be provisionally identified.

Common oxytocin receptor gene (OXTR) polymorphism and social support interact to reduce stress in humans.

The neuropeptide oxytocin has played an essential role in the regulation of social behavior and attachment throughout mammalian evolution. Because recent studies in humans have shown that oxytocin administration reduces stress responses and increases prosocial behavior, we investigated whether a common single nucleotide polymorphism (rs53576) in the oxytocin receptor gene (OXTR) might interact with stress-protective effects of social support. Salivary cortisol samples and subjective stress ratings were obtained from 194 healthy male participants before, during, and after a standardized psychosocial laboratory stress procedure. Participants were randomly assigned either to prepare alone or to receive social support from their female partner or close female friend while preparing for the stressful task. Differential stress responses between the genotype groups were observed depending on the presence or absence of social support. Only individuals with one or two copies of the G allele of rs53576 showed lower cortisol responses to stress after social support, compared with individuals with the same genotype receiving no social support. These results indicate that genetic variation of the oxytocin system modulates the effectiveness of positive social interaction as a protective buffer against a stressful experience.

All-trans retinoic acid upregulates reduced CD38 transcription in lymphoblastoid cell lines from Autism spectrum disorder.

Deficits in social behavior in mice lacking the CD38 gene have been attributed to impaired secretion of oxytocin. In humans, similar deficits in social behavior are associated with autistic spectrum disorder (ASD), for which genetic variants of CD38 have been pinpointed as provisional risk factors. We sought to explore, in an in vitro model, the feasibility of the theory that restoring the level of CD38 in ASD patients could be of potential clinical benefit. CD38 transcription is highly sensitive to several cytokines and vitamins. One of these, all-trans retinoic acid (ATRA), a known inducer of CD38, was added during cell culture and tested on a large sample of N = 120 lymphoblastoid cell (LBC) lines from ASD patients and their parents. Analysis of CD38 mRNA levels shows that ATRA has an upmodulatory potential on LBC derived from ASD patients as well as from their parents. The next crucial issue addressed in our study was the relationship between levels of CD38 expression and psychological parameters. The results obtained indicate a positive correlation between CD38 expression levels and patient scores on the Vineland Adaptive Behavior Scale. In addition, analysis of the role of genetic polymorphisms in the dynamics of the molecule revealed that the genotype of a single-nucleotide polymorphism (rs6449182; C>G variation) in the CpG island of intron 1, harboring the retinoic-acid response element, exerts differential roles in CD38 expression in ASD and in parental LBC. In conclusion, our results provide an empirical basis for the development of a pharmacological ASD treatment strategy based on retinoids.

Single-component near-infrared optogenetic systems for gene transcription regulation.

Near-infrared (NIR) optogenetic systems for transcription regulation are in high demand because NIR light exhibits low phototoxicity, low scattering, and allows combining with probes of visible range. However, available NIR optogenetic systems consist of several protein components of large size and multidomain structure. Here, we engineer single-component NIR systems consisting of evolved photosensory core module of Idiomarina sp. bacterial phytochrome, named iLight, which are smaller and packable in adeno-associated virus. We characterize iLight in vitro and in gene transcription repression in bacterial and gene transcription activation in mammalian cells. Bacterial iLight system shows 115-fold repression of protein production. Comparing to multi-component NIR systems, mammalian iLight system exhibits higher activation of 65-fold in cells and faster 6-fold activation in deep tissues of mice. Neurons transduced with viral-encoded iLight system exhibit 50-fold induction of fluorescent reporter. NIR light-induced neuronal expression of green-light-activatable CheRiff channelrhodopsin causes 20-fold increase of photocurrent and demonstrates efficient spectral multiplexing.

Genetic variation in the oxytocin system and its link to social motivation in human infants.

Frontal brain asymmetry has been linked to motivational processes in infants and adults, with left lateralization reflecting motivation to approach and right lateralization reflecting motivation to withdraw. We examined the hypothesis that variability in infants' social motivation may be linked to genetic variation in the oxytocin system. Eleven-month-old infants' brain responses and looking preferences to smiling and frowning individuals were assessed in conjunction with a polymorphism in CD38 (rs3796863) linked to autism spectrum disorder (ASD) and reduced oxytocin. Frontal brain asymmetry and looking preferences differed as a function of CD38 genotype. While non-risk A-allele carriers displayed left lateralization to smiling faces (approach) and a heightened looking preference for the individual who smiled, infants with the CC (ASD risk) genotype displayed withdrawal from smiling faces and a preference for the individual who frowned. Findings demonstrate that the oxytocin system is linked to brain and behavioral markers of social motivation in infancy.

A near-infrared genetically encoded calcium indicator for in vivo imaging.

While calcium imaging has become a mainstay of modern neuroscience, the spectral properties of current fluorescent calcium indicators limit deep-tissue imaging as well as simultaneous use with other probes. Using two monomeric near-infrared (NIR) fluorescent proteins (FPs), we engineered an NIR Förster resonance energy transfer (FRET)-based genetically encoded calcium indicator (iGECI). iGECI exhibits high levels of brightness and photostability and an increase up to 600% in the fluorescence response to calcium. In dissociated neurons, iGECI detects spontaneous neuronal activity and electrically and optogenetically induced firing. We validated the performance of iGECI up to a depth of almost 400 µm in acute brain slices using one-photon light-sheet imaging. Applying hybrid photoacoustic and fluorescence microscopy, we simultaneously monitored neuronal and hemodynamic activities in the mouse brain through an intact skull, with resolutions of ~3 µm (lateral) and ~25-50 µm (axial). Using two-photon imaging, we detected evoked and spontaneous neuronal activity in the mouse visual cortex, with fluorescence changes of up to 25%. iGECI allows biosensors and optogenetic actuators to be multiplexed without spectral crosstalk.

Screening and Cellular Characterization of Genetically Encoded Voltage Indicators Based on Near-Infrared Fluorescent Proteins.

We developed genetically encoded voltage indicators using a transmembrane voltage-sensing domain and bright near-infrared fluorescent proteins derived from bacterial phytochromes. These new voltage indicators are excited by 640 nm light and emission is measured at 670 nm, allowing imaging in the near-infrared tissue transparency window. The spectral properties of our new indicators permit seamless voltage imaging with simultaneous blue-green light optogenetic actuator activation as well as simultaneous voltage-calcium imaging when paired with green calcium indicators. Iterative optimizations led to a fluorescent probe, here termed nirButterfly, which reliably reports neuronal activities including subthreshold membrane potential depolarization and hyperpolarization as well as spontaneous spiking or electrically- and optogenetically evoked action potentials. This enables largely improved all-optical causal interrogations of physiology.

Association study of three polymorphisms in the dopamine D2 receptor gene and schizophrenia in the Russian population.

Polymorphisms in the dopamine D2 receptor gene (DRD2) have repeatedly been associated with schizophrenia. Recently, the C957T polymorphism (rs6277), which alters mRNA stability and dopamine-induced upregulation of DRD2 expression in cell cultures and DRD2 mRNA translation in vitro, was tested for an association with the disease. Frequency of the C allele, corresponding to a normal wild-type level of expression, was higher in patients compared to controls, and that of the T allele was lower. To replicate and extend previous findings, we conducted an association study of the C957T polymorphism and two additional SNPs (C939T and TaqIA) in 311 patients with a DSM-IV diagnosis of schizophrenia and 364 mentally healthy people from the Russian population as controls. The results of our study confirmed the association between the C957T polymorphism and schizophrenia. Consistent with previous findings, frequency of the C allele and the CC genotype were higher in patients compared to the control group (p=0.002). Meta-analysis of total 5 samples also suggests significant allelic association. The distribution of C939T genotypes in the case sample was significantly different from that of the controls: in the case sample, the TT genotype frequency was higher compared to the combined frequency of CT and CC genotypes (p=0.002). Though no association was found between the TaqIA polymorphism and schizophrenia, a haplotype-wise analysis revealed a lower frequency of the T-C (C957T-TaqIA) haplotype in patients (p=0.02). In conclusion, our findings provide additional evidence for an association between the C957T polymorphism and schizophrenia.

ADP ribosyl-cyclases (CD38/CD157), social skills and friendship.

Why some individuals seek social engagement while others shy away has profound implications for normal and pathological human behavior. Evidence suggests that oxytocin (OT), the paramount human social hormone, and CD38 that governs OT release, contribute to individual differences in social skills from intense social involvement to extreme avoidance that characterize autism. To explore the neurochemical underpinnings of sociality, CD38 expression of peripheral blood leukocytes (PBL) was measured in Han Chinese undergraduates. First, CD38 mRNA levels were correlated with lower Autism Quotient (AQ), indicating enhanced social skills. AQ assesses the extent of autistic-like traits including the propensity and dexterity needed for successful social engagement in the general population. Second, three CD157 eQTL SNPs in the CD38/CD157 gene region were associated with CD38 expression. CD157 is a paralogue of CD38 and is contiguous with it on chromosome 4p15. Third, association was also observed between the CD157 eQTL SNPs, CD38 expression and AQ. In the full model, CD38 expression and CD157 eQTL SNPs altogether account for a substantial 14% of the variance in sociality. Fourth, functionality of CD157 eQTL SNPs was suggested by a significant association with plasma oxytocin immunoreactivity products. Fifth, the ecological validity of these findings was demonstrated with subjects with higher PBL CD38 expression having more friends, especially for males. Furthermore, CD157 sequence variation predicts scores on the Friendship questionnaire. To summarize, this study by uniquely leveraging various measures reveals salient elements contributing to nonkin sociality and friendship, revealing a likely pathway underpinning the transition from normality to psychopathology.

Oxytocin Pathway Genes: Evolutionary Ancient System Impacting on Human Affiliation, Sociality, and Psychopathology.

Oxytocin (OT), a nonapeptide signaling molecule originating from an ancestral peptide, appears in different variants across all vertebrate and several invertebrate species. Throughout animal evolution, neuropeptidergic signaling has been adapted by organisms for regulating response to rapidly changing environments. The family of OT-like molecules affects both peripheral tissues implicated in reproduction, homeostasis, and energy balance, as well as neuromodulation of social behavior, stress regulation, and associative learning in species ranging from nematodes to humans. After describing the OT-signaling pathway, we review research on the three genes most extensively studied in humans: the OT receptor (OXTR), the structural gene for OT (OXT/neurophysin-I), and CD38. Consistent with the notion that sociality should be studied from the perspective of social life at the species level, we address human social functions in relation to OT-pathway genes, including parenting, empathy, and using social relationships to manage stress. We then describe associations between OT-pathway genes with psychopathologies involving social dysfunctions such as autism, depression, or schizophrenia. Human research particularly underscored the involvement of two OXTR single nucleotide polymorphisms (rs53576, rs2254298) with fewer studies focusing on other OXTR (rs7632287, rs1042778, rs2268494, rs2268490), OXT (rs2740210, rs4813627, rs4813625), and CD38 (rs3796863, rs6449197) single nucleotide polymorphisms. Overall, studies provide evidence for the involvement of OT-pathway genes in human social functions but also suggest that factors such as gender, culture, and early environment often confound attempts to replicate first findings. We conclude by discussing epigenetics, conceptual implications within an evolutionary perspective, and future directions, especially the need to refine phenotypes, carefully characterize early environments, and integrate observations of social behavior across ecological contexts.

The association between 2D:4D ratio and cognitive empathy is contingent on a common polymorphism in the oxytocin receptor gene (OXTR rs53576).

Both testosterone and oxytocin influence an individual's accuracy in inferring another's feelings and emotions. Fetal testosterone, and the second-to-forth digit ratio (2D:4D) as its proxy, plays a role in social cognitive development, often by attenuating socio-affective skill. Conversely, oxytocin generally facilitates socio-affiliative and empathic cognition and behavior. A common polymorphism in the oxytocin receptor gene, OXTR rs53576, has been repeatedly linked with psychosocial competence, including empathy, with individuals homozygous for the G allele typically characterized by enhanced socio-cognitive skills compared to A allele carriers. We examined the role of oxytocin and testosterone in collectively contributing to individual differences in cognitive empathy as measured by Baron-Cohen's "Reading the Mind in the Eyes" task (RMET). Findings are based on a large cohort of male and female students (N=1463) of Han Chinese ethnicity. In line with existing literature, women outperformed men in the RMET. Men showed significantly lower 2D:4D ratio compared to women, indicating higher exposure to testosterone during the prenatal period. Interestingly, variation in the OXTR gene was found to interact with 2D:4D to predict men's (but not women's) RMET performance. Among men with GG allelic variation, those with low fetal testosterone performed better on the RMET, compared to men with GG and high fetal testosterone, suggesting greater identification of another's emotional state. Taken together, our data lend unique support to the mutual influence of the oxytocin and testosterone systems in shaping core aspect of human social cognition early in development, further suggesting that this effect is gender-specific.

Dopaminergic polymorphisms associated with time-on-task declines and fatigue in the Psychomotor Vigilance Test.

Prolonged demands on the attention system can cause a decay in performance over time known as the time-on-task effect. The inter-subject differences in the rate of this decline are large, and recent efforts have been made to understand the biological bases of these individual differences. In this study, we investigate the genetic correlates of the time-on-task effect, as well as its accompanying changes in subjective fatigue and mood. N = 332 subjects performed a 20-minute test of sustained attention (the Psychomotor Vigilance Test) and rated their subjective states before and after the test. We observed substantial time-on-task effects on average, and large inter-individual differences in the rate of these declines. The 10-repeat allele of the variable number of tandem repeats marker (VNTR) in the dopamine transporter gene and the Met allele of the catechol-o-methyl transferase (COMT) Val158Met polymorphism were associated with greater vulnerability to time-on-task. Separately, the exon III DRD4 48 bp VNTR of the dopamine receptor gene DRD4 was associated with subjective decreases in energy. No polymorphisms were associated with task-induced changes in mood. We posit that the dopamine transporter and COMT genes exert their effects by increasing dopaminergic tone, which may induce long-term changes in the prefrontal cortex, an important mediator of sustained attention. Thus, these alleles may affect performance particularly when sustained dopamine release is necessary.

U-shaped relation between plasma oxytocin levels and behavior in the trust game.

Trust underpins much of social and economic exchanges across human societies. In experimental economics, the Trust Game has served as the workhorse for the study of trust in a controlled incentivized setting. Recent evidence using intranasal drug administration, aka 'sniffing', suggests that oxytocin (OT) can function as a social hormone facilitating trust and other affiliative behaviors. Here we hypothesized that baseline plasma OT is a biomarker that partially predicts the degree of trust and trustworthiness observed in the trust game. Using a large sample of 1,158 participants, we observed a significant U-shaped relationship between plasma OT with the level of trust, and marginally with the level of trustworthiness, especially among males. Specifically, subjects with more extreme levels of plasma OT were more likely to be trusting as well as trustworthy than those with moderate levels of plasma OT. Our results contribute to a deeper understanding of the biological basis of human trust and underscore the usefulness of peripheral plasma OT measures in characterizing human social behavior.