A gene-brain-cognition pathway: prefrontal activity mediates the effect of COMT on cognitive control and IQ.

A core thesis of cognitive neurogenetic research is that genetic effects on cognitive ability are mediated by specific neural functions, however, demonstrating neural mediation has proved elusive. Pairwise relationships between genetic variation and brain function have yielded heterogeneous findings to date. This heterogeneity indicates that a multiple mediator modeling approach may be useful to account for complex relationships involving function at multiple brain regions. This is relevant not only for characterizing healthy cognition but for modeling the complex neural pathways by which disease-related genetic effects are transmitted to disordered cognitive phenotypes in psychiatric illness. Here, in 160 genotyped functional magnetic resonance imaging participants, we used a multiple mediator model to test a gene-brain-cognition pathway by which activity in 4 prefrontal brain regions mediates the effects of catechol-O-methyltransferase (COMT) gene on cognitive control and IQ. Results provide evidence for gene-brain-cognition mediation and help delineate a pathway by which gene expression contributes to intelligence.

Neurogenetics and pharmacology of learning, motivation, and cognition.

Many of the individual differences in cognition, motivation, and learning-and the disruption of these processes in neurological conditions-are influenced by genetic factors. We provide an integrative synthesis across human and animal studies, focusing on a recent spate of evidence implicating a role for genes controlling dopaminergic function in frontostriatal circuitry, including COMT, DARPP-32, DAT1, DRD2, and DRD4. These genetic effects are interpreted within theoretical frameworks developed in the context of the broader cognitive and computational neuroscience literature, constrained by data from pharmacological, neuroimaging, electrophysiological, and patient studies. In this framework, genes modulate the efficacy of particular neural computations, and effects of genetic variation are revealed by assays designed to be maximally sensitive to these computations. We discuss the merits and caveats of this approach and outline a number of novel candidate genes of interest for future study.

Genetics as a tool for the dissociation of mental operations over the course of development.

In recent years it has become possible to differentiate separable aspects of attention and to characterize the anatomical structure and dynamic states of their underlying networks. When individual differences in the structure and dynamics of these networks are used as dependent measures in associations with individual genetic variation, it becomes possible to assign cellular and molecular changes that occur over the course of normal development to specific aspects of network structure and function. In this way, a more granular understanding of the physiology of neural networks can be obtained. Here we review a translational research strategy focused on how genetic variation contributes to the normal development of attentional function. We seek to use genetic information to help construct a multinode, multinetwork model that can explain, in part, individual differences in the development of attention over the course of development.

Dopamine transporter genotype conveys familial risk of attention-deficit/hyperactivity disorder through striatal activation.

OBJECTIVE: The dopamine transporter (DAT1) gene has been implicated in attention-deficit/hyperactivity disorder (ADHD), although the mechanism by which it exerts its effects remains unknown. The polymorphism associated with ADHD has been shown to affect expression of the transporter in vitro and in vivo. Dopamine transporters are predominantly expressed in the striatum, but also in the cerebellar vermis. Stimulant medication is often effective in ADHD and is believed to exert its effects by blocking dopamine transporters in the striatum. We set out to investigate the effect of the DAT1 genotype in ADHD in a small, preliminary study. We hypothesized that the DAT1 genotype would affect brain activation patterns in a manner similar to that of stimulant medication, with the lesser expressing allele mirroring its effects. METHOD: We investigated DAT1 gene effects on brain activation patterns in an all-male sample of sibling pairs discordant for ADHD (n = 20) and controls (n = 9). All of the subjects participated in a functional magnetic resonance imaging session using a go/no-go paradigm and provided a DNA sample for analysis. RESULTS: DAT1 genotype affected activation in the striatum and cerebellar vermis. The genotype interacted with familial risk of ADHD in the striatum but not the vermis. CONCLUSIONS: These preliminary results suggest that the DAT1 gene effects in the striatum are involved in translating the genetic risk of ADHD into a neurobiological substrate. As such, this study represents a first step in elucidating the neurobiological mechanisms underlying genetic influences in ADHD. Furthermore, these results may contribute to long-term possibilities for the development of new treatments: If the DAT1 genotype has differential effects on striatal activation, then it may be useful as a surrogate endpoint in individualized treatments targeting genotype/functional magnetic resonance imaging activation profiles.

The functional integration of the anterior cingulate cortex during conflict processing.

Although functional activation of the anterior cingulate cortex (ACC) related to conflict processing has been studied extensively, the functional integration of the subdivisions of the ACC and other brain regions during conditions of conflict is still unclear. In this study, participants performed a task designed to elicit conflict processing by using flanker interference on target response while they were scanned using event-related functional magnetic resonance imaging. The physiological response of several brain regions in terms of an interaction between conflict processing and activity of the anterior rostral cingulate zone (RCZa) of the ACC, and the effective connectivity between this zone and other regions were examined using psychophysiological interaction analysis and dynamic causal modeling, respectively. There was significant integration of the RCZa with the caudal cingulate zone (CCZ) of the ACC and other brain regions such as the lateral prefrontal, primary, and supplementary motor areas above and beyond the main effect of conflict and baseline connectivity. The intrinsic connectivity from the RCZa to the CCZ was modulated by the context of conflict. These findings suggest that conflict processing is associated with the effective contribution of the RCZa to the neuronal activity of CCZ, as well as other cortical regions.

Using genetic data in cognitive neuroscience: from growing pains to genuine insights.

Research that combines genetic and cognitive neuroscience data aims to elucidate the mechanisms that underlie human behaviour and experience by way of 'intermediate phenotypes': variations in brain function. Using neuroimaging and other methods, this approach is poised to make the transition from health-focused investigations to inquiries into cognitive, affective and social functions, including ones that do not readily lend themselves to animal models. The growing pains of this emerging field are evident, yet there are also reasons for a measured optimism.

Genes, brain, and behavior: bridging disciplines.

With excitement surrounding the publication of the human genome, scientists have set out to uncover the functions of specific genes. This special issue on Genes, Brain, and Behavior attempts to present research strategies that connect major avenues of genetic research across disciplines. For example, anatomical information provided by brain imaging can serve as a convenient link between anatomical abnormalities seen in knockout/transgenic mouse models and abnormal patterns of brain activity seen in certain patient populations. Identifying genetic risk factors for disorders with carefully designed cognitive assays is another strategy that has gained increasing attention. These approaches are being combined with behavioral studies of mouse models of gene function. Alone, each of these approaches provides limited information on gene function in complex human behavior, but together, they are forming bridges between animal models and human psychiatric disorders.

A shift from diffuse to focal cortical activity with development.

Recent imaging studies have suggested that developmental changes may parallel aspects of adult learning in cortical activation becoming less diffuse and more focal over time. However, while adult learning studies examine changes within subjects, developmental findings have been based on cross-sectional samples and even comparisons across studies. Here, we used functional MRI in children to test directly for shifts in cortical activity during performance of a cognitive control task, in a combined longitudinal and cross-sectional study. Our longitudinal findings, relative to our cross-sectional ones, show attenuated activation in dorsolateral prefrontal cortical areas, paralleled by increased focal activation in ventral prefrontal regions related to task performance.

Specificity of the effect of a nicotinic receptor polymorphism on individual differences in visuospatial attention.

Cortical neurotransmitter availability is known to exert domain-specific effects on cognitive performance. Hence, normal variation in genes with a role in neurotransmission may also have specific effects on cognition. We tested this hypothesis by examining associations between polymorphisms in genes affecting cholinergic and noradrenergic neurotransmission and individual differences in visuospatial attention. Healthy individuals were administered a cued visual search task which varied the size of precues to the location of a target letter embedded in a 15-letter array. Cues encompassed 1, 3, 9, or 15 letters. Search speed increased linearly with precue size, indicative of a spatial attentional scaling mechanism. The strength of attentional scaling increased progressively with the number of C alleles (0, 1, or 2) of the alpha-4 nicotinic receptor gene C1545T polymorphism (n = 104). No association was found for the dopamine beta hydroxylase gene G444A polymorphism (n = 135). These findings point to the specificity of genetic neuromodulation. Whereas variation in a gene linked to cholinergic transmission systematically modulated the ability to scale the focus of visuospatial attention, variation in a gene governing dopamine availability did not. The results show that normal variation in a gene controlling a nicotinic receptor makes a selective contribution to individual differences in visuospatial attention.

Maternal separation suppresses TGF alpha mRNA expression in the prefrontal cortex of male and female neonatal C57BL/6 mice.

Male C57BL/6 mice that undergo maternal separation (MS) early in life demonstrate higher levels of anxiety upon reaching adulthood compared to normally reared offspring. This study reports that neonatal males and females that undergo MS have reduced mRNA levels of transforming growth factor-alpha (TGF alpha) in the prefrontal cortex, an area of the brain implicated in emotionality, compared to normally reared animals. TGF alpha expression was unaffected by MS in the hippocampus. These data indicate that MS leads to a brain region-specific suppression of TGF alpha expression early in development.

Exploring genetic influences on cognition: emerging strategies for target validation and treatment optimization.

Genomic research has produced an abundance of new candidate targets that remain to be validated as potential treatments for neuropsychiatric disorders. Functional neuroimaging, meanwhile, has provided detailed new insights into the neural circuits involved in emotional and cognitive control. At the growing interface between these independent lines of progress, new efforts are underway to unify our understanding of regional brain function with that of genetic and biochemical influences on behavior. Such a unified understanding of the mechanisms involved in cognitive and emotional control may open up new avenues for therapeutic intervention at the pharmacological and behavioral levels. In line with this, a new initiative sponsored by the National Institutes of Mental Health (NIMH) aims to bridge gaps between clinical diagnostics and the molecular processes that influence susceptibility to psychiatric disorders. A major goal of this initiative is to identify the neural and neurochemical substrates of basic cognitive processes that are disrupted in psychiatric disorders and to examine the influence of genetic factors at the cognitive level. This review describes some well-known findings that are at the forefront of this interface. The progress already made indicates that the goals of the new initiative are well founded and achievable.

Synaptogenesis and heritable aspects of executive attention.

In humans, changes in brain structure and function can be measured non-invasively during postnatal development. In animals, advanced optical imaging measures can track the formation of synapses during learning and behavior. With the recent progress in these technologies, it is appropriate to begin to assess how the physiological processes of synapse, circuit, and neural network formation relate to the process of cognitive development. Of particular interest is the development of executive function, which develops more gradually in humans. One approach that has shown promise is molecular genetics. The completion of the human genome project and the human genome diversity project make it straightforward to ask whether variation in a particular gene correlates with variation in behavior, brain structure, brain activity, or all of the above. Strategies that unify the wealth of biochemical knowledge pertaining to synapse formation with the functional measures of brain structure and activity may lead to new insights in developmental cognitive psychology.

Identification of quantitative trait Loci that affect aggressive behavior in mice.

Despite the previous development of single-gene knock-out mice that exhibit alterations in aggressive behavior, very little progress has been made toward identifying the natural gene variants (alleles) that contribute to individual or strain differences in aggression. Whereas most inbred mouse strains show an intermediate level of inter-male aggression in the resident-intruder or dangler behavioral tests, NZB/B1NJ mice are extremely aggressive and A/J mice are extremely unaggressive. We took advantage of the large phenotypic difference between these strains and used an outcross-backcross breeding protocol and a genome-wide scan to identify aggression quantitative trait loci (QTLs) on distal chromosome 10 (Aggr1; p = 6 x 10(-7)) and proximal chromosome X (Aggr2; p = 2.14 x 10(-5)). Candidate genes for Aggr1 and Aggr2, respectively, include the diacylglycerol kinase alpha subunit gene (Dagk1) and the glutamate receptor subunit AMPA3 gene (Gria3). This is the first report of significant aggression QTLs established through a genome-wide scan in any mammal. The mapping of these QTLs is a step toward the definitive identification of mouse alleles that affect aggression and may lead, ultimately, to the discovery of homologous alleles that affect individual differences in aggression within other mammalian species.