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Biological Psychology 79 (2008) 23–29

Provisional hypotheses for the molecular genetics of cognitive
development: Imaging genetic pathways in the
anterior cingulate cortex
John Fossella a,*, Jin Fan a,b, Xun Liu a, Kevin Guise a, Karin Brocki a,
Patrick R. Hof b, Raja Kittappa c, Ronald McKay c, Michael Posner d

Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, United States
Department of Neuroscience, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, United States
Laboratory of Molecular Biology, National Institute of Neurological Disorders and Stroke, National Institutes of Health,
Bethesda, MD 20892, United States
Department of Psychology, University of Oregon, Eugene, OR 97403, United States

Received 28 September 2007; accepted 18 December 2007
Available online 28 December 2007

Brain imaging genetic research involves a multitude of methods and spans many traditional levels of analysis. Given the vast permutations
among several million common genetic variants with thousands of brain tissue voxels and a wide array of cognitive tasks that activate specific brain
systems, we are prompted to develop specific hypotheses that synthesize converging evidence and state clear predictions about the anatomical
sources, magnitude and direction (increases vs. decreases) of allele- and task-specific brain activity associations. To begin to develop a framework
for shaping our imaging genetic hypotheses, we focus on previous results and the wider imaging genetic literature. Particular emphasis is placed on
converging evidence that links system-level and biochemical studies with models of synaptic function. In shaping our own imaging genetic
hypotheses on the development of Attention Networks, we review relevant literature on core models of synaptic physiology and development in the
anterior cingulate cortex.
# 2008 Elsevier B.V. All rights reserved.
Keywords: Genetic; Imaging; Brain; Cingulate; Development

1. Introduction
Imaging genetic studies on the human brain involve a
universe of permutations among several million common
genetic variants with thousands of voxels in both white and gray
matter and a wide array of cognitive tasks that activate specific
brain systems. In order to avoid statistical limitations and
expenditures inherent to unconstrained exploratory imaginggenetic analyses, we have adopted a hypothesis-driven
investigative approach where predictions are synthesized from
evidence obtained from structural and functional studies in
humans, mice, and cell-based systems. We are focused on the
developmental biology of Attention Networks and, most
recently, on the role of the anterior cingulate cortex (ACC).

* Corresponding author.
E-mail address: (J. Fossella).
0301-0511/$ – see front matter # 2008 Elsevier B.V. All rights reserved.

Activity in this well-studied brain region has been implicated in
cognitive monitoring of control (Botvinick et al., 2004),
conflict resolution (Botvinick et al., 2001), effortful control and
self-regulation (Posner and Rothbart, 2007). Extensive projections from the ACC subgenual area 25 to the amygdala,
parabrachial nucleus and periaqueductal grey are thought to
underlie the role of this region in emotion (Vogt, 2005),
somatosensory pain (Sikes and Vogt, 1992), social exclusion
pain (Eisenberger et al., 2003) and placebo modulation of pain
(Derbyshire et al., 2004; Raz et al., 2005). In each of these
complex cognitive processes, the ACC participates in linking
sensory inputs with top down rules or expectations in order to
generate motor responses that guide behavior. Lesions to this
area can have wide ranging effects from transient reduction of
performance in specific tasks (Janer and Pardo, 1991) to an
inability to make decisions in the real world (Eslinger and
Damasio, 1985); whereas cingulotomies reduce the unpleasantness of pain (Zhuo, 2005) and stimulation of specific

2005b).. recent imaging genetic studies on the serotonin transporter that examine the BOLD response in brain regions that share synaptic connectivity are readily supported by converging evidence obtained from studies at the systems level. on the other (Heinz et al. When such deficits are shown to co-segregate with disorders and also shown to be heritable. Although many complex disorders have a strong genetic component.. Finally. Pezawas et al.. 1998. Healthy relatives of patients with schizophrenia show 11. Subsequent imaging-genetic experiments on the maoa and drd4 genes revealed significant genotype-dependent differences in the blood oxygen level dependent (BOLD) response. or alternate strategy. 1. Rapid presentation of visual stimuli. deficits in the structure and function of the ACC are well reported for many disorders. could be linked together. is predicted to enhance activity-dependent synaptic processes (Egan et al. a task that has been shown to activate specific anatomical networks involved in orienting to sensory events. Fan and Posner. constituted a natural midpoint or ‘conceptual bridge’ where evidence-based links between brain structure/function.. divided attention and attentional set shifting typically show high heritabilities in twin studies (Cannon et al. such as the prefrontal cortex. a separate group replicated the maoa finding (Meyer-Lindenberg et al. that are rich in dopaminergic innervation and where expression of the dopamine transporter is reduced (Sesack et al. appears well situated for genetic analysis. 1981. we recognize that traditional behavioralgenetic studies often generate mixed results that can be difficult to replicate (Kendler.2. which. on the other side. 2007).5% (Goghari et al.. in particular. 2001). validity and heritability of the ANT as an endophenotype for genetic studies.. suggest that a variant allele of a specific candidate gene is correlated with an increase (or decrease) in volume or BOLD response for a particular brain region. 2002). perhaps. This prediction extends to task-related activity in regions. 2004). maintaining an alert state and resolving conflict between stimuli and responses (Corbetta and Shulman. imaging-genetic studies on the development of the ACC are. 1998)...24 J. We also found executive attention deficits in schizophrenia (Wang et al. Test–retest studies on the ANT show the executive network is the most reliable (0. 2000..89) (Fan et al. Similarly. Despite a few robust and highly replicated findings in the imaging genetics literature. For one. and biochemical pathway level. In the case of COMT. 2000). Subsequent behavioral genetic investigations on a mixed population of 200 healthy adults showed modest genetic associations for common variants in genes including monoamine oxidase a (MAOA) and the dopamine d4 receptor (DRD4) (Fossella et al. in a rat model. The seminal work of Pezawas and colleagues (Pezawas et al. In beginning to understand the biological basis for normal complex cognitive processes and abnormal processes related to neuropsychiatric illness we have undertaken a genetic approach. Mesulam. an attractive endophenotype. 2003).1.4% less right cingulate gray matter volume. Fossella et al. Pardo et al. 2006). Variation in tasks that activate regions of the ACC. a hypothesis based on the function of specific genes at the level of the synapse. Imaging-genetic studies of attention link genotype to cingulate activation Our efforts to understand how biochemical factors might relate to normal attention and abnormal behavior. which has an indirect relationship to synaptic activity. 2005a). and genetic variation. on one side. Using a whisker stimulation paradigm.. / Biological Psychology 79 (2008) 23–29 cingulate subregions can relieve symptoms associated with negative mood and anxiety (Ressler and Mayberg. the BOLD-response. on one side. 2005). Thus. have relied on the Attention Network Task (ANT).77) component. For example. 2006).. A small-scale twin study (n = 50 pairs) found that executive attention network efficiency has a heritability of (h2 = 0. when subjects were performing the executive attention component of the task (Fan et al. 1. 8% reduction in surface area and bilateral reductions in thickness of up to 2. Also. Similar visual stimulation in humans induces a relative increase in BOLD activity in the primary visual areas (Clapp et al. 2003)... 2004). for gaining access to details of the genetic risk of complex mental illness. 2005. such as spatial working memory. twin studies reveal that genetic factors contribute about 60% of the variance in ERPs (event-related potentials) that arise from activity in the ACC such as the N2 and P3 amplitudes (Anokhin et al. during a particular contrast of task conditions.. remains poorly understood in terms of biochemical pathways. located in the ACC. naturally. The cingulate region. then the term ‘endophenotype’ can be used to indicate that the genetic basis for variation in such traits will likely inform the genetic risk for a more complex disorder.. Tests of this central hypothesis support this core synaptic model and find an inverted U-shaped response of BOLD versus genotype that is consistent with the dose–response effects of neuromodulators on synaptic function (Mattay et al. 2005). 2006). 2001). central hypotheses of studies on the Val108Met variant in the catecholO-methyl transferase (COMT) gene predict that the less active Methionine protein isoform leads to slightly higher levels of extrasynaptic dopamine. it is important to mention that there are still many gaps in the existing converging evidence and known limitations to the hypothesis shaping framework we are describing here.. 2007).. then.. Lu and . Bridging levels of analysis: from genes to BOLD response A standard hypothesis for an imaging-genetic experiment would. can give rise to a form of long-term potentiation that lasts up to 2 h (Clapp et al. We initially explored the reliability. a brief review of our own imaging genetic research on the development of normal attention shows that variation in several genes involved in dopaminergic regulation correlates with individual differences in brain activity in the ACC. Interestingly. we found individual differences in ACC activity that were associated with variation in a genetic marker linked to the dopamine d2 receptor (DRD2) (Fossella et al. In a follow-up study. 2005) has identified allele-specific grey matter volume associations and functional activations in this brain region with polymorphic expression states of the serotonin transporter (5HTT). Later.

2002a. via transcriptional activation. .3.. Also...) are sensitive to different aspects of cellular and neural network physiology. 2007a). First. begin to specify the association of a genetic variant with a certain physiological process. Fossella et al.. Following amputation of a central digit of the hindpaw. we seek to shape our hypotheses within the context of a particular task where the role of the ACC is well characterized. the use of multiple imaging modalities has been suggested as a means to learn more about the physiological basis for fMRI-BOLD changes. in mice lacking either the GluR5 or GluR6 subunit. A core synaptic model for imaging genetic studies of the ACC With these limitations and the existing literature in mind. for example. however. structure vs. Intracellular recordings showed rapid MK-801 (an NMDA antagonist) sensitive depolarization in response to injury followed by a prolonged state of depolarization (Wu et al. Activation of CREB was not observed in CaMKIV knockout mice using theta-burst stimulation (Wei et al.. Zhuo and colleagues have developed paradigms involving peripheral hindlimb injury.. For example. 2001). and atrophy of apical and basal dendritic arborizations in pyramidal neurons (Araya et al.. diffusion.. fMRI in conjunction with EEG and deep electrodes has been successful at linking synaptic physiology with neurovascular coupling processes (Logothetis. Zhuo. 2007). functional vs. Thus. In our recent work using the ANT. mice lacking AC1 and/or AC8 show reduction of persistent pain which can be reversed via injection of AC activators such as forskolin (Wei et al. but not GluR2 subunits of AMPA receptors modulate an early induction phase while both NR2A and NR2B subunits are necessary for the maintenance of LTP (Toyoda et al. the synaptic changes associated with long-lasting potentiation and depressions are well studied at these levels of analysis. 2001). 2005). NR2B as well as AC1 and AC8 were implicated in this in vivo form of plasticity using gene targeted mouse models (Wei et al.. 2002a).. kainate EPSP’s were reduced in single knockout and absent entirely in double 5/6 targeted animals (Wu et al. 2006. on presynaptic and postsynaptic enhancement mechanisms as well as structural changes at the synaptic cleft. we can. 2005c).. the M5 muscarinic acetylcholine receptor (M5R)..J. Not surprisingly. reduced blood flow. 2005. 2005a). we seek to construct hypotheses around synaptic processes as a point of convergence between systemslevel and biochemical-level pathways. Among other processes. we have started to formulate provisional imaging-genetic hypotheses for understanding how genetic factors might modulate attentional efficiency via the ACC. Looking more closely at the biochemical level. egr1 and creb which. Our provisional hypotheses are rooted largely on the extensive findings of Zhuo and colleagues who have characterized a form 25 of long-term potentiation (LTP) in the mouse and rat cingulate cortex (Zhao et al. these forms of potentiation are dependent.. will better inform future hypotheses. Characterization of plasticity using various gene-targeted mouse models reveals specific roles for NMDA receptors. gives rise to abnormal. Second. Mice that overexpress the NR2B subunit. 2007). In particular. Pharmacological manipulations reveal that GluR1. several different forms of stimulation such as spike-EPSP-pairing and theta-burst stimulation are used to mimic endogenous activity of ACC neurons and are able to induce a form of potentiation that can last from 40 to 120 min (Wei et al. to the extent that these different imaging modalities (EEG vs. 2001) and these behavioral responses were reversed by administration of selective NR2B antagonists (Wu et al. To explore plasticity in the ACC without the use of artificial stimulation. 2005).and low gamma-band activity after the target onset. and a decrease of all frequency bands before response followed by an increase after the response (Fan et al. 2006).and non-MRI-based imaging modalities (such as EEG) permits us to examine the validity and robustness of individual imaging genetic findings across imaging modalities. Again. etc. 2002a. Also. Lastly. This extended period of depolarization was accompanied by a well-known set of immediate early genes such as c-fos. 2006). For example. 2007).. it is clear that there are many overlapping signal transduction cascades that couple neural activity with vasodilation and vasoconstriction (Raichle and Mintun. / Biological Psychology 79 (2008) 23–29 colleagues (Lu et al. Similarly. Indeed.. 2006). the effective connectivity among regions within the ACC shows that interactions between the anterior rostral cingulate zone (RCZa) and the caudal cingulate zone (CCZ) of the ACC is modulated by the context of conflict (Fan et al. demonstrate increased sensitivity to peripheral injury (Wei and Zhuo. 2002b). with caution. it has been observed that LTP in the ACC is absent in mice lacking the FMRP synaptic protein (Zhao et al. As noted earlier. more genetic study directed to the BOLD response per se. Presynaptic mechanisms are supported by increased input–output curves and decreased paired pulse facilitation in ACC slice recordings from animals suffering from chronic pain (Zhao et al. Wei et al. to different extents. voxel size 156 mm  156 mm  2000 mm) in layers IV–VI of the rat whisker barrel cortex was tightly correlated with changes in cerebral blood volume (CBV) and neuronal activity as measured by cfos expression.. Our utilization of several MRI. may help sustain periods of potentiation lasting for several days. 2005) and the transcription factor EGR1 (Ko et al.. 2004) found that the hemodynamic response as measured by high resolution fMRI (3T. 2005b). Wei et al. high-density scalp electrical recordings during the executive attention component of the ANT reveal an early (<400 ms) increase in gamma-band activity. Gene deletion of adenylate cyclase subunits AC8 and AC1 reduced forskolin-induced plasticity and abolished LTP in the ACC using both theta-burst and EPSP-paring (Liauw et al. adenylyl cyclase subunits (AC1 and AC8). 2007b). 1. the core model suggests that LTP in the ACC occurs after peripheral injury and may mediate persistent pain. when inactivated. rapid and long-lasting enhancements of sensory responses are observed to peripheral stimulation (Wei and Zhuo.. a later (>400 ms) decrease in beta. In their experimental system. and calcium calmodulin dependent kinase type-IV (CaMKIV) in longlasting plasticity in the ACC. 2003). longlasting vasoconstriction of cerebral arteries..

that long-range patterns of synaptic connectivity are under strong genetic control. and upper lip appear. a genetic mediator of post-natal maturation of dopamine neurons (Romeo et al.. These types of changes might cause relatively minor biochemical changes but would be measurable using neuroimaging. nose. The developing ACC is positioned dorsally.. all induce longlasting changes such as hypometabolism. / Biological Psychology 79 (2008) 23–29 Potentiation in response to injury may occur due to a loss of an auto-regulatory form of long-term depression that helps to normally quiet neuronal activity in the ACC. 2003)). In less severe cases. tachykinin. 2003) and ZIC2 hemizygous mice show deficits in sensorimotor gating (Ogura et al. we reported that maternal separation leads to changes in the frontal midline mRNA expression of tgf-alpha.. and could influence human brain function in clinically meaningful ways. A role for genetics in early cognitive development is most well studied in hereditary developmental disorders such as Williams Syndrome (Karmiloff-Smith. and with a complex culture. These various developmental findings should. Cognitive deficits in humans have been reported in association with DHCR7 (Mueller et al. gliosis and programmed cell death in the ACC. Some of the genes reported include secreted frizzled-related protein 2 (SFRP2) natriuretic peptide precursor C (NPPC). Looking deeper into the development of the ACC. bone morphogenetic proteins (BMPs) are expressed at the dorsal apex (apices in cortices) in the embryonic central nervous system. 2004).4.. Kinsman (Kinsman.. corticospinal tract. near-normal brain development and facial deformities that may affect the eyes. whereas constitutive activation of BMP signaling causes dorsalization of the cortex (Panchision et al. Takahashi and colleagues (Takahashi et al. Detailed anatomical studies have been conducted on populations with holoprosencephaly. 1. 2001). since. endothelin converting enzymelike 1 (ECEL1). the dorsal cortex does not properly develop (Hebert et al. 2003) used MRI to describe a series of seven human brains with the less severe semi-lobular form and provide details of general patterns of malformation across different levels of severity. and.. Mutations in sonic hedgehog (SHH) and several downstream factors including 7-dehydrocholesterol reductase (DHCR7). are conjoined across the midline. In addition. such heritable developmental influences may be very important targets for natural selection on survival and reproduction. Provisional hypotheses in a developmental context In seeking to develop testable imaging genetic hypotheses. patched (PTCH). 2007) and Fragile-X mental retardation (Bagni and Greenough. to better assess the role of genes in the development of the ACC.. Drastic midline deficits in animal models and humans have been linked to the hedgehog signaling pathway. Fossella et al. 2003). we focus on genetic pathways that act to establish and shape structures in the frontal midline... Findings of gene  environment interaction are common in the behavioral literature (for review see (Rutter et al. Monuki et al. 1999).. These findings reveal that without proper functioning of the hedgehog genetic pathway. a genetic disorder where the embryonic forebrain does not sufficiently divide into the double lobes of the cerebral hemispheres. The parenting study suggests an underlying rationale for the long-lasting effects of genes that influence the early stages of cognitive development because an organism like the human. 2007). induction of LTD was only partially successful in injured animals and lossof LTD was site-specific (Wei et al. medial lemniscus and cerebellar peduncles in less severe cases of holoprosencephaly. zic family member 2 (ZIC2). Previously.. 2003). 2001). To begin then. 2005) where abnormalities can be observed in young children.26 J. Such gene–environment interactions also demonstrate that while heritable factors influence behavior. 2000). 2004) reported abnormalities in the corpus callosum. 2007). at the midline. Along these lines. 2001). 2002.. we recognize that genetic programs contribute greatly to the early development of the brain.... amyloid protein expression (Dodart et al.. Kruppel family member gli2 (GLI2) give rise to holoprosencephaly (reviewed (Cohen. Further behavioral and imaging genetic studies on common polymorphisms in these genes may reveal links between basic developmental processes and structure/function variation in the frontal midline. In human children. 1994). 1999) and drug abuse (Ladenheim et al. Developmental manipulations such as anoxia (Mehmet et al. 1999). the presence of SFRP2 protein impaired the anterior turning of commissural axons after midline crossing (Lyuksyutova et al. a normally formed ACC fails to develop. and instead. 2006) compared gene expression profiles for three types of interneurons and 2 types of projection neurons (layers 5 and 6) in the ACC as well as a number of other cortical and subcortical regions.. precursor 1 (TAC1) and neurexophilin 3 (NXPH3). a recent report shows that a VNTR polymorphism in exon III of the drd4 gene shows a strong correlation with cortical thinning in young children but demonstrates a decreasing correlation as children grow (Shaw et al. ECEL1 is a member of the M13 family of zinc-containing endopeptidases . born helpless. where the cerebral hemispheres meet. a behavioral study of 2-year-old children showed that in the presence of a drd4 7-repeat allele in children with relatively poor parenting showed higher levels of impulsivity while those with high quality parenting did not (Sheese et al. resulting in a single-lobed brain structure and lethal skull and facial defects. the developmental outcome of genetic variation can be heavily influenced by environmental context. We propose that subtle hypomorphic or hypermorphic alleles of genes in the hedgehog and BMP pathways could affect the volume of the cingulate cortex as well as the absolute number of neurons contained in the ACC.. 2005). Sugino and colleagues (Sugino et al. reflecting alterations in the patterning and the wiring of the fetal brain. In a mouse model of neuronal migration in the frontal midline. maternal separation (AvishaiEliner et al. genetic influence on differences in behavior and brain activity in adults may well be the result of genetic processes that act quite early during brain and cognitive development (Scerif and Karmiloff-Smith. 2006)). In the absence of BMP signaling. relate in some way to our adult imaginggenetic finding of drd4-dependent individual differences in ACC activation (Fan et al. presumably. Indeed.

Diminished anxietyand depression-related behaviors in mice with selective deletion of the Tac1 gene. The TAC1 gene encodes the neuropeptides substance P and neurokinin A. Molecular Psychiatry 12. which promotes dopaminergic cell survival. 2006.. T. and FGF8 protein forms a rostrocaudal gradient which induces anterior cell-types at the expense of posterior cell-types (Fukuchi-Shimogori and Grove. Benes.and anxiety-related behaviors (Bilkei-Gorzo et al. NXPH3 expression is restricted mostly to layer 6b of the cerebral cortex. M...P. 265–268.. 2004). Bilkei-Gorzo. 2006). Conclusion As noted. Emerging principles of altered neural circuitry in schizophrenia. Zimmer. Missler. T.. T.. Araya. deficits in attention and cognition are present among individuals who carry mutations in the hedgehog pathway and present with minor forms of holoprosencephaly spectrum (Heussler et al. Wess. 620– 629.. Cohen. Neuroscience 6. I. It is important to note that candidate gene testing. Teyler. Kirk.S. D.M.. 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