The main focus of the SCBG has been examining genetic factors that contribute to neurobiological systems that influence: reward (prior publications relating to OPRM1), impulsivity (1.), vulnerability to stress and anxiety (2) and alcohol response (3), as these systems may also influence alcohol use and addiction vulnerability in modern humans. In certain instances, genetic variants that are functionally similar to those that moderate risk for human psychiatric disorders and addictions are maintained across species, and some of our studies have suggested there to be convergent evolution or allelic variants maintained by selection across species. We have examined such variation in order to model how genotype can moderate risk in certain environmental contexts (see examples discussed - in turn - below). (1). Impulsivity- In many different species, aggression is important for protection and in the defense and/or acquisition of rank, territory or resources. It can also be exhibited in response to fear or pain, or in order to execute control over other individuals. While aggression in many wild animals commonly plays an adaptive role, among humans or even domestic animals, aggressive behavior also correlates with behavioral problems. Although human aggressive behavior may originally have been adaptive, excessive and inappropriate aggression is a feature of many psychiatric disorders, such as borderline personality disorder, antisocial personality disorder, post-traumatic stress disorder, depression, and psychopathy- which are comorbid with alcohol use disorders. Mesolimbic dopamine release contributes to many reward-dependent and reinforcing processes, and mesocortical neurotransmission is important for executive cognitive function. In humans, variation at the Dopamine D4 Receptor gene (DRD4) predicts vulnerability to ADHD-related phenotypes and to the addictions. We find that- when presented with an unfamiliar intruder animal- rhesus macaques carrying a functionally similar variant (rhDRD4) exhibit behaviors consistent with a social impulsivity phenotype. These animals are much more likely to approach an unfamiliar animal and with very little delay. This pattern of behavior suggests not only impulsivity, but that which is social in nature. It is proposed that functional genetic variants within dopamine system genes have the potential for contributing to individual differences in alcohol use, and some human studies indicate that DRD4 genotype is predictive of various drinking patterns. In macaques, we find similar patterns of drinking behaviors, supporting human findings. Consistent with the fact that this allele predicts increased social impulsivity in macaques, alcohol-seeking is observed only when animals are tested in a social/group setting, suggesting a potential pathway through which these patterns of alcohol use may relate to that observed in humans. (2). Stress Vulnerability- The Corticotropin Releasing Factor/Hormone (CRF) system is critical for survival, but overactivity of the system can lead to pathology. Studies in both non-primate and primate species have shown that upregulation of the CRF system can produce anxiety- and/or depression-like behavioral phenotypes and that CRF system upregulation, whether innate or due to environmental factors, can lead to escalated alcohol drinking. We identified a SNP that is present in a region known to confer interspecies differences in CRF expression and in a region in which a 7-nucleotide sequence (containing an AP-1 consensus site) is present only among primate taxa. Besides the fact that the insertion and maintenance of this sequence in primates may be permissive of promoter activation in certain tissues, there are also known interactions between the Glucocorticoid Receptor at a GRE and AP-1; these interactions can be complex and depend on the constitution of AP-1 (with jun-fos heterodimers and jun-jun homodimers sometimes behaving bidirectionally). The -530 SNP also creates a preferred GRE half site several hundred nucleotides away from the core promoter, which could contribute to intraspecific variation in CRF promoter function. We had previously reported there to be two rhCRF variants - carried on alternative haplotypes - that disrupt GREs and alter promoter response to corticosteroid-mediated transcriptional control.. These variants were both demonstrated to moderate alcohol intake, albeit under different conditions and in animals with different life histories. Here, we investigated a more common variant, present on the ancestral haplotype. This SNP is located in a regulatory region important for driving placental CRF expression, and we show using in vitro systems that it also influences regulation of rhCRF promoter activity by the Type II GR agonist, dexamethasone. When we looked at the potential for expected genotype-phenotype correlations, we found that rhCRF -530 predicts individual differences in birth weight, stress reactivity and central CRF activity. It, too, modulates alcohol self-administration. (3). Alcohol Response: Aggressive tendencies can escalate under the influence of some drugs of abuse, including alcohol. Alcohol induces psychopharmacological effects that are proposed to contribute to alcohol-induced aggression through modulation of serotonin, endogenous opioid, dopamine, and GABA systems. Not only are impulse control deficits and reward-sensitivity instrumental in driving excessive alcohol consumption, but intoxication can impair information processing, and this may lead to misinterpretation of social cues and, thus, escalated aggressive responding. Although genetic factors are likely to play a role in alcohol-related violence, genetic studies in this area are somewhat lacking. We performed Whole Exome Sequencing for animals on the phenotypic extremes for aggressive and non-aggressive behavior under conditions of intoxication, identifying a segregating SNP in the pro-BDNF domain (Brain Derived Neurotrophic Hormone, Val46Met). Though based on the literature, BDNF variation would certainly be a candidate for examining early developmental effects, stress response, and ethanol self-administration, we had not previously considered a role for BDNF variation in driving EtOH-facilitated aggression. The type of aggression for which we had previously reported genotype-phenotype correlations with rhOPRM1 was pro-active and physical. In the present study, rhBDNF variation did not predict this type of aggression, but, rather, predicted Distance Decreasing (fear-related) aggression. This was particulary evident among stress-inoculated animals. Results from genetically selected or modified rodents indicate that Bdnf variation contributes to strain or individual differences in aggression. However, a link between alcohol facilitated aggression and BDNF genetic variation has not been identified. Furthermore, though it is likely a system dysregulated with continued or chronic alcohol use, it is difficult to imagine a mechanism through which genetic variation at this locus might predict differences in ethanol-induced aggression in nave animals. The non-synonymous rhBDNF SNP in rhesus is similar in location to the human Val66Met SNP, which influences mature peptide release, cognition and susceptibility to various psychiatric disorders. In hippocampus, a brain region important to environmental assessment, we reported differences in H3K4me3 binding at promoters critical to driving BDNF expression and, here, we show higher levels of BDNF mRNA expression in response to early stress. This could be considered a predictive adaptive response, as it may reflect increased readiness to recruit BDNF in response to early environmental challenge. It could be that stress-induced regulation of BDNF expression is a factor permitting loss-of-function variation to be maintained.
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