Individual differences in trait affect, personality, and temperament are critical in shaping complex human behaviors, successfully navigating social interactions, and overcoming challenges from our ever-changing environments. Such individual differences may also serve as important predictors of vulnerability to neuropsychiatric disorders, including depression, anxiety, and addiction, especially upon exposure to environmental adversity. Accordingly, identifying the biological mechanisms that give rise to individual trait differences affords a unique opportunity to develop a deeper understanding of complex human behaviors, disease liability, and treatment. Having established multiple modal neural processes supporting specific aspects of complex behavioral processes, human neuroimaging studies, especially those employing BOLD fMRI, have now begun to reveal the neural substrates of interindividual variability in these and related constructs. Moreover, recent studies have established that BOLD fMRI measures represent temporally stable and reliable indices of brain function. Thus, much like their behavioral counterparts, patterns of brain activation represent enduring, trait-like phenomena, which in and of themselves may serve as important markers of individual differences as well as disease liability and pathophysiology.
As neuroimaging studies continue to illustrate the predictive links between regional brain activation and trait-like behaviors (e.g., increased amygdala reactivity predicts trait anxiety), an important next step is to identify systematically the underlying mechanisms driving variability in brain circuit function. In this regard, recent neuroimaging studies employing pharmacological challenge paradigms, principally targeting monoamine neurotransmission, have revealed that even subtle alterations in dopaminergic, noradrenergic, and serotonergic signaling can have profound impacts on the functional response of brain circuitries supporting affect, personality, and temperament. Similarly, multimodal neuroimaging approaches have provided evidence for directionally specific links between key components of monoaminergic signaling cascades, assessed with radiotracer PET, and brain function, assessed with BOLD fMRI. Collectively, pharmacological fMRI and multimodal PET/fMRI are revealing how variability in behaviorally relevant brain activation emerges as a function of underlying variability in key brain signaling pathways (e.g., increased serotonin signaling predicting increased amygdala reactivity). The next logical step is to identify the sources of interindividual variability in these key neurochemical signaling mechanisms.
In the modern era of human molecular genetics, this step is firmly planted in the direction of identifying common variation in the genes that influence the functioning or availability of components in these pathways. Because DNA sequence variation across individuals represents the ultimate wellspring of variability in emergent molecular, neurobiological, and related behavioral processes, understanding the links among genes, brain, and behavior is important for establishing a mechanistic foundation for individual differences in behavior and related psychiatric disease. Moreover, such genetic polymorphisms can be readily identified from DNA collected via cells from individual blood or even saliva samples using relatively well-tolerated, inexpensive, and standardized laboratory protocols. Once collected and isolated, an individual's DNA can be amplified repeatedly, providing an almost endless reservoir of material for genotyping of additional candidate polymorphisms as they are identified. When a precise cascade of related neurobiological and behavioral effects are clearly established, common polymorphisms can serve as incredibly powerful predictive markers of such emergent properties that are more readily accessible (e.g., samples can be collected in doctors' offices), applicable (e.g., even newborns can be genotyped), and economical (e.g., costing only tens of dollars per sample in comparison to the hundreds and even thousands of dollars required for fMRI and PET) than their technological counterparts in neuroimaging and neuropharmacology. Of course, arriving at this ultimate reduction requires intensive and expansive efforts wherein all these technologies as well as epidemiological and clinical studies are first brought to bear on explicating the detailed biological mechanisms mediating individual differences in trait behaviors and related risk for neuropsychiatric disease. More importantly, the limitations of such genetic reductionism, especially the probabilistic nature of the biological impact of candidate functional polymorphisms whose likely effects are dynamically moderated by other genetic variants as well as environmental and epigenetic factors, should always be considered in evaluating and characterizing the potential real-world value of genetic markers. Unlike their Mendelian counterparts, most common genetic polymorphisms in studies of individual differences in behaviorally relevant brain function will not have absolute effects on their related emergent biological pathways.
|BOLD fMRI||blood oxygen level-dependent functional magnetic resonance imaging|
|PET||positron emission tomography|
|Multimodal PET/fMRI||multimodal neuroimaging data are collected in the same subjects to map the links between the density of a specific component of a molecular signaling pathway, assayed with radiotracer PET, and task-related brain function, assayed with BOLD fMRI|
Through the careful integration of these complementary approaches and technologies, investigators have already made significant progress in describing the contributions of multiple common genetic polymorphisms to individual differences in complex behavioral phenotypes and disease liability—in particular, by identifying effects of functional genetic variation on the neural processes that mediate behavioral responses to environmental challenge (Caspi & Moffitt 2006
, Hariri & Holmes 2006
). This article reviews how the integration of psychology, neuroimaging, neuropharmacology, and molecular genetics can work toward the ultimate goal of understanding the detailed mechanisms mediating individual differences in human behavior and, in turn, establishing predictive markers of disease vulnerability. The vast potential of such an integrated approach is highlighted by reviewing recent studies whose collective results demonstrate that common sequence variations in human genes that bias key components of molecular signaling cascades results in altered brain circuit function that mediates individual differences in complex behavioral traits such as temperamental anxiety and impulsivity (). With their increased utilization and continued expansion, each level of analysis in this integrative strategy—brain circuit function, neural signaling cascades, and molecular genetics—also has the potential to uniquely illuminate clinically relevant information that can be used to devise individually tailored treatment regimes and establish predictive disease markers. In lieu of further describing a general framework, three specific examples, detailed below and summarized in , are used to illustrate the effectiveness of this integrated strategy to parse biological mechanisms mediating individual differences in complex behaviors. In each, subjects were retrospectively genotyped for the candidate functional polymorphisms of interest from stored samples of DNA, and this information was used to group subjects on the basis of their individual genotypes. The behavioral assessments in all three examples were conducted as a component of a larger parent protocol that preceded measurement of task-related regional brain function with BOLD fMRI by an average interval of 29 weeks. The fact that robust brain-behavior correlations were observed despite the separation in time is consistent with the suggestion that both metrics (i.e., brain function and behavior) are remarkably stable, possibly indicative of trait-related variation. Such a link further underscores the likelihood that interindividual variability in brain-behavior associations is influenced by genetic polymorphisms affecting functioning of signaling pathways modulating underlying neural circuitries.
Figure 1 Integration of complementary technologies can be used to reveal the neurobiology of individual differences in complex behavioral traits. (a) Individual differences in personality and temperament are critical to shaping complex human behaviors and may (more ...)
Summary of studies reviewed in this article that link individual differences in complex behavioral traits with underlying variability in brain circuit function, molecular signaling pathways and functional genetic polymorphisms1
|Functional Polymorphism||a gene sequence variant present at >1% in a population that affects the regulation of the gene and/or the functioning of its protein product|
Multiple mechanisms involving de novo biosynthesis, vesicular release, active reuptake, metabolic degradation, and a myriad of both pre- and postsynaptic receptors contribute to the regulation of neurotransmission and its subsequent modulation of brain function. In general, component processes that affect the magnitude of signaling (e.g., biosynthesis, reuptake, autoregulation, degradation) rather than localized effects on target neurons (e.g., postsynaptic receptors) represent key bottlenecks in neurotransmitter regulation of neural circuit function. To illustrate the powerful capacity of functional genetic polymorphisms to model emergent variability in signaling pathways, each of the three exemplars below focuses on a different critical node in regulating the magnitude of neurotransmission: autoregulatory negative feedback, active synaptic reuptake, and enzymatic degradation. In the first example, individual differences in trait anxiety are mapped onto threat-related amygdala reactivity. Variability in amygdala reactivity is, in turn, mapped to serotonin signaling. Finally, variability in serotonin signaling is mapped to a common functional polymorphism impacting the capacity for negative feedback inhibition of serotonergic neurons in the midbrain. In the second example, similar links are described among variability in impulsivity, reward-related ventral striatum reactivity, dopamine signaling, and a polymorphism impacting synaptic clearance of striatal dopamine. In the third and last example, a common polymorphism affecting the enzymatic degradation of endocannabinoids is linked to divergent effects on threat-related amygdala and reward-related ventral striatum reactivity.