Developmental imaging genetics: Linking dopamine function to adolescent behavior

In the paper

“adolescence is often a time when various mental illnesses emerge such as mood disorders, drug abuse disorders, eating disorders, and psychoses (Pine 2002; Chambers, Taylor et al. 2003; Sisk and Zehr 2005; Paus, Keshavan et al. 2008)”

What the sources say

• Not checked yetcites Pine 2002 source
• Not checked yetcites Chambers, Taylor et al. 2003 source
• Not checked yetcites Sisk and Zehr 2005 source

In the paper

“adolescents are capable of mature decision-making (Paus 2005), abstract thinking, and often engage rational behavior (Steinberg, Cauffman et al. 2009).”

What the sources say

• Not checked yetcites Paus 2005 source
• Not checked yetcites Steinberg, Cauffman et al. 2009 source

In the paper

“Across species and cultures, there are characteristic behaviors during adolescence including peaks in sensation/novelty seeking coupled with diminished levels of harm avoidance, leading to an increase in risky behaviors (Laviola, Macri et al. 2003).”

What the sources say

• Not checked yetcites Laviola, Macri et al. 2003

In the paper

“functional connectivity studies suggest that the integration and coordination between brain regions, including subcortical to cortical connections, become more refined and efficient over adolescence, leading to reduced task-irrelevant connections, strengthening of connections supporting goal-directed actions, and elimination of redundant connections (Durston, Davidson et al. 2006; Liston, Watts et”

What the sources say

• Not checked yetcites Durston, Davidson et al. 2006 source
• Not checked yetcites Liston, Watts et al. 2006 source
• Not checked yetcites Fair, Cohen et al. 2009 source

In the paper

“Evidence suggests that adolescents tend to both process incentives differently than adults (for reviews see: Geier and Luna (2009; Ernst, Daniele et al. 2011)), leading to suboptimal and often risky decision-making.”

What the sources say

• Not checked yetcites Geier and Luna 2009 source
• Not checked yetcites Ernst, Daniele et al. 2011 source

In the paper

“neurobiological models of adolescent development suggest that an over active adolescent incentive system, driven by the striatum, with a still maturing cognitive system, driven by the PFC, may create a functional imbalance in optimal behavioral regulation (i.e. suppressing a potentially rewarding, but inappropriate behavior) thereby enhancing risk taking behavior in adolescence ((Nelson, Leibenlu”

What the sources say

• Not checked yetcites Nelson, Leibenluft et al. 2005 source
• Not checked yetcites Ernst, Pine et al. 2006 source
• Not checked yetcites Casey, Getz et al. 2008 source

In the paper

“This approach, known as ‘imaging genetics’, is grounded in the idea that brain function and structure can serve as intermediate phenotypes between genes and behavior, given the relative proximity of brain function to the genotype (Hariri and Weinberger 2003).”

What the sources say

• Not checked yetcites Hariri and Weinberger 2003

In the paper

“The human striatum is recognized as a core node for incentive processing and resulting behaviors, specifically in the ability to synthesize changing environmental cues and appropriately update behaviors through integration with the prefrontal cortex (PFC) by way of overlapping but functionally segregated pathways (Alexander, DeLong et al. 1986; Postuma and Dagher 2006; Di Martino, Scheres et al. 2”

What the sources say

• Not checked yetcites Alexander, DeLong et al. 1986 source
• Not checked yetcites Postuma and Dagher 2006
• Not checked yetcites Di Martino, Scheres et al. 2008 source

In the paper

“functional neuroimaging studies of incentive processing demonstrate differential striatal and PFC activation in adolescence relative to adulthood (Bjork, Knutson et al. 2004; Ernst, Nelson et al. 2005; Galvan, Hare et al. 2006; Bjork, Smith et al. 2010; van Leijenhorst, Moor et al. 2010; Padmanabhan 2011), with the majority of studies reporting an increase in striatal activation, coupled with”

What the sources say

• Not checked yetcites Bjork, Knutson et al. 2004 source
• Not checked yetcites Ernst, Nelson et al. 2005 source
• Not checked yetcites Galvan, Hare et al. 2006 source

In the paper

“Slow changes in tonic levels of DA may be a preparatory mechanism for an organism to respond to environmental cues associated with reward (Schultz 1998).”

What the sources say

• Not checked yetcites Schultz 1998 source

In the paper

“These two mechanisms of DA signaling have been found to lead to distinct behaviors (Floresco, West et al. 2003) and are regulated by reuptake and degradation enzymes.”

What the sources say

• Not checked yetcites Floresco, West et al. 2003

In the paper

“Fast phasic events occur in response to reward-related events, which may serve as important teaching signals for error detection and modulate behavioral changes in response to the environment (Schultz 1998).”

What the sources say

• Not checked yetcites Schultz 1998 source

In the paper

“Animal and post-mortem human literature suggests an overexpression of receptors for serotonin, dopamine, adenergic, and endocannabinoids (Lidow and Rakic 1992), a peak in the density of interneurons (Anderson, Classey et al. 1995; Lewis 1997; Erickson and Lewis 2002), and an increase in levels of GABA (Hedner, Iversen et al. 1984).”

What the sources say

• Not checked yetcites Lidow and Rakic 1992 source
• Not checked yetcites Anderson, Classey et al. 1995
• Not checked yetcites Lewis 1997 source

In the paper

“DA neurons in the midbrain project to medium spiny neurons in the NAcc as well as pyramidal neurons in the PFC, thereby modulating the firing rates of these neurons and establishing a strong reciprocal relationship between striatum and PFC (Grace, Floresco et al. 2007).”

What the sources say

• Not checked yetcites Grace, Floresco et al. 2007 source

In the paper

“DA levels are modulated by two dissociable processes of DA discharge that interact, (1) a constant background tonicity regulated by baseline firing of DA neurons and glutamatergic afferents from cortical to striatal regions, and (2) a burst firing high-amplitude phasic release (Grace, Floresco et al. 2007).”

What the sources say

• Not checked yetcites Grace, Floresco et al. 2007 source

In the paper

“increased myelination in cortical to subcortical axons, changes in axon caliber, pruning of synapses and receptors, cell shrinkage, and glial changes (Yakovlev and Lecours 1967; Rakic, Bourgeois et al. 1986; Benes, Turtle et al. 1994; Andersen 2003) refine the developing brain and strengthen and consolidate highly used connections, while weakening or eliminating redundant or weakly used”

What the sources say

• Not checked yetcites Yakovlev and Lecours 1967
• Not checked yetcites Rakic, Bourgeois et al. 1986 source
• Not checked yetcites Benes, Turtle et al. 1994

In the paper

“Research on DA transporters has been inconsistent in the midbrain suggesting no consistent developmental change (Moll, Mehnert et al. 2000), increases over adolescence (Galineau, Kodas et al. 2004), and peaks in late childhood (Coulter, Happe et al. 1996).”

What the sources say

• Not checked yetcites Moll, Mehnert et al. 2000 source
• Not checked yetcites Galineau, Kodas et al. 2004
• Not checked yetcites Coulter, Happe et al. 1996

In the paper

“A peak in activity of midbrain DA neurons has been documented in the rat model (McCutcheon, White et al. 2009), suggesting an overall increase in DA levels.”

What the sources say

• Not checked yetcites McCutcheon, White et al. 2009

In the paper

“These systems also interact as tonic DA activity regulates phasic signaling in an inhibitory fashion and phasic DA has been shown to enhance tonic activity (Niv, Daw et al. 2007).”

What the sources say

• Not checked yetcites Niv, Daw et al. 2007 source

In the paper

“Other studies have noted a peak in tonic DA concentrations in late adolescence with a subsequent decline in adulthood ((Badanich, Adler et al. 2006; Philpot, Wecker et al. 2009).”

What the sources say

• Not checked yetcites Badanich, Adler et al. 2006 source
• Not checked yetcites Philpot, Wecker et al. 2009

In the paper

“Dopaminergic innervation to the PFC peaks in adolescence (Rosenberg and Lewis 1995; Benes, Taylor et al. 2000), with the largest increase being in cortical layer III, a region that that is highly implicated in cognitive processing (Lewis and Gonzalez-Burgos 2000).”

What the sources say

• Not checked yetcites Rosenberg and Lewis 1995 source
• Not checked yetcites Benes, Taylor et al. 2000
• Not checked yetcites Lewis and Gonzalez-Burgos 2000

In the paper

“In the striatum, peaks in both D1 and D2 receptors occur in childhood and begin to decline in adolescence, evident in both animal and human work (Seeman, Bzowej et al. 1987; Lidow and Rakic 1992; Montague, Lawler et al. 1999; Andersen, Thompson et al. 2002).”

What the sources say

• Not checked yetcites Seeman, Bzowej et al. 1987 source
• Not checked yetcites Lidow and Rakic 1992 source
• Not checked yetcites Montague, Lawler et al. 1999

In the paper

“non-human primate research suggests that the density of D1 and D2 receptors in PFC increase at different rates, with D1 receptor density demonstrating earlier peaks than D2, which peaks in late-adolescence/early adulthood (Tseng and O'Donnell 2007).”

What the sources say

• Not checked yetcites Tseng and O'Donnell 2007

In the paper

“abnormalities in DA signaling are implicated in the pathophysiology of neuropsychiatric disorders that often emerge in adolescence (e.g. schizophrenia, drug abuse).”

In the paper

“Adolescents also show decreased aversive response to substances of abuse (i.e. milder withdrawal responses, reduced psychomotor effects) (Spear 2002; Doremus, Brunell et al. 2003; Levin, Rezvani et al. 2003) and increased sensitivity to DA receptor antagonists (Spear, Shalaby et al. 1980; Spear and Brake 1983; Teicher, Barber et al. 1993).”

What the sources say

• Not checked yetcites Spear 2002
• Not checked yetcites Doremus, Brunell et al. 2003
• Not checked yetcites Levin, Rezvani et al. 2003 source

In the paper

“DA signaling in adolescence may also influence and be influenced by differences in rates of maturation of subcortical systems relative to cortical, and an functional imbalance in the adolescent brain that is driven by striatal signaling with immaturities in PFC-driven regulation (Chambers, Taylor et al. 2003; Ernst, Pine et al. 2006).”

What the sources say

• Not checked yetcites Chambers, Taylor et al. 2003 source
• Not checked yetcites Ernst, Pine et al. 2006 source

In the paper

“The adult literature suggests that increasing DA signaling through administration of DA or DA agonists increases novelty-seeking and exploration behaviors, whereas reducing DA signaling with antagonists halts such behaviors (Pijnenburg, Honig et al. 1976; Fouriezos, Hansson et al. 1978; Le Moal and Simon 1991).”

What the sources say

• Not checked yetcites Pijnenburg, Honig et al. 1976
• Not checked yetcites Fouriezos, Hansson et al. 1978
• Not checked yetcites Le Moal and Simon 1991

In the paper

“Other research has suggested that in the striatum, DA transporter levels increase into late childhood and remain stable through adolescence (Coulter, Happe et al. 1996; Tarazi, Tomasini et al. 1998; Galineau, Kodas et al. 2004).”

What the sources say

• Not checked yetcites Coulter, Happe et al. 1996
• Not checked yetcites Tarazi, Tomasini et al. 1998
• Not checked yetcites Galineau, Kodas et al. 2004

In the paper

“It is posited that the DA system is at a “functional ceiling” in adolescence relative to childhood or adulthood (Chambers, Taylor et al. 2003), due to peaks in midbrain DA cell firing, overall tonic levels, innervation, as well as increased receptor densities.”

What the sources say

• Not checked yetcites Chambers, Taylor et al. 2003 source

In the paper

“Adding to this complexity, maturational changes in DA function have not been mapped directly onto behaviors in adolescence suggesting that a comprehensive examination of the interaction of various aspects of the DA system (e.g. receptors, clearance, innervation) and their direct effects on behavior is warranted (Spear 2011; Luciana, Wahlstrom et al. 2012).”

What the sources say

• Not checked yetcites Spear 2011 source
• Not checked yetcites Luciana, Wahlstrom et al. 2012

In the paper

“These early findings point to a hypothesized model of adolescent DA function whereby overall heightened DA signaling leads to heightened motivation, or approach-like behaviors-due to increased activation of the direct pathway and inhibition of the indirect pathway.”

In the paper

“For example, the elevation of tonic DA during adolescence may impact regulation of the phasic response in response to salient or rewarding information (for review see (Luciana, Wahlstrom et al. 2012)), but this has not been empirically tested.”

What the sources say

• Not checked yetcites Luciana, Wahlstrom et al. 2012

In the paper

“Increases in both D1 and D2 receptors, as seen in adolescence thus may have an overall excitatory effect on the brain, which could result in an increase in behaviors that are DA dependent (such as reward and novelty seeking).”

In the paper

“For example, increasing DA levels in individuals who have high baseline DA levels impairs cognitive performance, (perhaps pushing them over the peak of the inverted U curve) whereas improvements are noted in individuals with lower baseline levels (pushing them closer to the apex of the curve) (Mattay, Goldberg et al. 2003; Apud, Mattay et al. 2007; Cools, Frank et al. 2009).”

What the sources say

• Not checked yetcites Mattay, Goldberg et al. 2003
• Not checked yetcites Apud, Mattay et al. 2007 source
• Not checked yetcites Cools, Frank et al. 2009

In the paper

“D1 receptors stimulation allows for maintenance of information online and stabilization of functional states, and D2 receptor binding is involved in flexible updating of information and allowing for the transition between functional states (Seamans, Durstewitz et al. 2001; Durstewitz and Seamans 2002; Seamans and Yang 2004).”

What the sources say

• Not checked yetcites Seamans, Durstewitz et al. 2001
• Not checked yetcites Durstewitz and Seamans 2002
• Not checked yetcites Seamans and Yang 2004 source

In the paper

“Indeed, the study of the influence of genetic polymorphisms on brain function or “imaging genetics” has already provided considerable insight on the influence of genetically driven variability on brain physiology (e.g. (Hariri and Weinberger 2003; Brown and Hariri 2006; Drabant, Hariri et al. 2006; Hariri and Lewis 2006)).”

What the sources say

• Not checked yetcites Hariri and Weinberger 2003
• Not checked yetcites Brown and Hariri 2006
• Not checked yetcites Drabant, Hariri et al. 2006

In the paper

“Following this model, it is possible that baseline inter-individual differences in adolescence would be unique relative to differences in adulthood due to maturation in the DA system.”

In the paper

“Despite an overall peak in DA signaling and general maturational processes that occur in adolescence, there is considerable individual variability both in DA signaling, as well as DA-influenced behaviors, likely due to a combination of genetic and environmental factors (Depue and Collins 1999; Frank and Hutchison 2009).”

What the sources say

• Not checked yetcites Depue and Collins 1999 source
• Not checked yetcites Frank and Hutchison 2009

In the paper

“AG heterozygotes, who have increased D1 receptors, showed increased recruitment of DLPFC relative to AA homozygotes, who engaged a more widely distributed set of brain regions.”

What the sources say

• Not checked yetcites Tura, Turner et al. 2008

In the paper

“The D2 receptor, which is expressed more abundantly in striatum relative to PFC, exerts a strong influence on frontostriatal connectivity through both inhibition of excitatory and disinhib tion of inhibitory pathways (Cepeda and Levine 1998; Goto and Grace 2005).”

What the sources say

• Not checked yetcites Cepeda and Levine 1998
• Not checked yetcites Goto and Grace 2005

In the paper

“These findings are in line with other work suggesting that increased prefrontal DA tone results in improved cognitive performance and more efficient prefrontal signaling (e.g. (Egan, Goldberg et al. 2001; Mattay, Goldberg et al. 2003)).”

What the sources say

• Not checked yetcites Egan, Goldberg et al. 2001
• Not checked yetcites Mattay, Goldberg et al. 2003

In the paper

“Simultaneously, D1 receptor activation on local GABAergic (inhibitory) interneurons serves to inhibit irrelevant glutamatergic inputs (Durstewitz, Seamans et al. 2000).”

What the sources say

• Not checked yetcites Durstewitz, Seamans et al. 2000

In the paper

“In adolescence, when there is a higher density of D2 receptors, the relationship between brain activation and D2 receptor availability might parallel previous findings using pharmacological interventions that target D2 receptors (Kirsch, Reuter et al. 2006; van der Schaaf, van Schouwenburg et al. 2012), suggesting an age by genotype interaction that is yet to be empirically tested.”

What the sources say

• Not checked yetcites Kirsch, Reuter et al. 2006
• Not checked yetcites van der Schaaf, van Schouwenburg et al. 2012

In the paper

“D2 receptors have two distinct isoforms, the short isoform (D2-S) acts mainly as a presynaptic autoreceptor, inhibiting DA release, whereas the long isoform (D2-L) primarily functions to inhibit the post synaptic cell (Centonze, Grande et al. 2003).”

What the sources say

• Not checked yetcites Centonze, Grande et al. 2003

In the paper

“Decreased D2 autoreceptor function increases DA release and individuals with decreased D2-S demonstrate increased novelty-seeking and reward reactivity (Zald, Cowan et al. 2008; Pecina, Mickey et al. 2012).”

What the sources say

• Not checked yetcites Zald, Cowan et al. 2008
• Not checked yetcites Pecina, Mickey et al. 2012

In the paper

“It is thus possible that inter-individual differences are expressed differentially as a function of relative DA across development based on genotype (e.g. the val allele may confer a relative advantage for cognitive function earlier in development, when DA levels are higher than in adulthood).”

In the paper

“Furthermore, increasing DA levels interacts with the COMT val158met SNP consistent with the putative inverted U model with met individuals demonstrating diminished cortical efficiency during tasks of cognitive control and val individuals demonstrating improvements (Mattay, Goldberg et al. 2003; Apud, Mattay et al. 2007).”

What the sources say

• Not checked yetcites Mattay, Goldberg et al. 2003
• Not checked yetcites Apud, Mattay et al. 2007 source

In the paper

“This is adolescents carrying the met allele may surpass optimal thresholds, which could result in less efficient cortical function, relative to val (Wahlstrom, Collins et al. 2010; Wahlstrom, White et al. 2010).”

What the sources say

• Not checked yetcites Wahlstrom, Collins et al. 2010
• Not checked yetcites Wahlstrom, White et al. 2010

In the paper

“The DA transporter (DAT) is mainly expressed in the striatum and is responsible for DA reuptake, clearing DA from the extracellular space after release (Jaber, Bloch et al. 1998).”

What the sources say

• Not checked yetcites Jaber, Bloch et al. 1998

In the paper

“The DAT binding site density for the most common repeat alleles (9-repeat and 10-repeat) is significantly less for the 9-repeat allele than the 10-repeat allele, linking the 9-repeat allele with reduced DAT expression and greater striatal synaptic DA (Fuke, Suo et al. 2001; Mill, Asherson et al. 2002; VanNess, Owens et al. 2005), although some studies have suggested the opposite (Mill, Asherson et”

What the sources say

• Not checked yetcites Fuke, Suo et al. 2001
• Not checked yetcites Mill, Asherson et al. 2002 source
• Not checked yetcites VanNess, Owens et al. 2005

In the paper

“However, no studies to date have examined the influence of these polymorphisms across development.”

In the paper

“The COMT val allele is associated with high enzymatic activity and consequently low synaptic dopamine levels, whereas the COMT met allele results in approximately one third less enzyme activity and consequently high synaptic dopamine (Chen, Lipska et al. 2004).”

What the sources say

• Not checked yetcites Chen, Lipska et al. 2004 source

In the paper

“During a visuo-spatial working memory task in individuals between the ages of 6 and 20,Dumontheil et al. (2011), demonstrated that activation in frontal and parietal regions increased across development in individuals homozygous for the val allele, but not met carriers, suggesting delayed development of cognitive function in individuals with the val allele.”

What the sources say

• Not checked yetcites Dumontheil et al. (2011) source

In the paper

“Following the inverted U model, increased D1 and D2 receptor availability may result in increased competition between the direct and indirect pathways which may be more exacerbated in adolescents with higher receptor availability at baseline, leading to a generally more disorganized processing system.”

In the paper

“Based on this evidence, it is posited that adolescents, who have increased DA levels relative to adults, may follow a similar pattern as a function of COMT genotype as the pharmacological studies in adults.”

In the paper

“A SNP in the DRD4 gene (rs6277, −521 SNP) results in a 40% reduction in RNA transcription for the T-allele relative to the C-allele (Okuyama, Ishiguro et al. 1999), although another study found no differences (Kereszturi, Kiraly et al. 2006).”

What the sources say

• Not checked yetcites Okuyama, Ishiguro et al. 1999
• Not checked yetcites Kereszturi, Kiraly et al. 2006

In the paper

“Lower DAT expression reduces synaptic DA clearance thereby increasing DA levels (Cagniard, Balsam et al. 2006; Cagniard, Beeler et al. 2006).”

What the sources say

• Not checked yetcites Cagniard, Balsam et al. 2006
• Not checked yetcites Cagniard, Beeler et al. 2006

In the paper

“Developmental studies using the DAT1 polymorphism suggest that typically developing adolescents with the 9-repeat allele demonstrate reduced activation of prefrontal and striatal regions during inhibitory control (Braet, Johnson et al. 2011), and reward prediction (Paloyelis, Mehta et al. 2012).”

What the sources say

• Not checked yetcites Braet, Johnson et al. 2011
• Not checked yetcites Paloyelis, Mehta et al. 2012

In the paper

“For example, prior studies have shown additive effects of the COMT val158met SNP and the DAT1 3’VNTR during the reward anticipation and outcome stages of reward processing in both PFC and striatum, reporting increased activation associated with genotypes that have increased DA availability (Yacubian, Sommer et al. 2007; Dreher, Kohn et al. 2009).”

What the sources say

• Not checked yetcites Yacubian, Sommer et al. 2007 source
• Not checked yetcites Dreher, Kohn et al. 2009

In the paper

“However, it is also important to keep in mind that meta-analyses tend to be biased, as studies with null findings are generally not published.”

In the paper

“For example,Munafo et al. (2008) conducted a meta-analysis of studies that have reported associations between a VNTR polymorphism in the serotonin transporter gene (5-HTTLPR) and amygdala activation and suggested that an imaging genetics study would require a total sample of about 70 participants to achieve .8 power for an alpha power of .05.”

What the sources say

• Not checked yetcites Munafo et al. (2008) source

In the paper

“Evidence points to a protracted development of brain systems including PFC and the striatum throughout childhood and adolescence.”

In the paper

“The majority of imaging genetics research to date has focused on differences between genotypes in adulthood or within discrete age groups, despite growing evidence that brain systems continue to reorganize across the lifespan and that gene effects likely manifest differently at different stages.”

In the paper

“It is likely that sample sizes will have to be increased in order to replicate previous findings and to generate accurate assessments of the effect sizes of different polymorphisms.”

In the paper

“These results suggest that DAT1 genotype may influence the system differentially in adolescence – with the 9-repeat allele resulting in decreased striatal and cortical reactivity-than in adulthood – when the 9-repeat allele has been associated with increased activation.”

In the paper

“It is possible that in adolescence, when excess DA levels are present, individuals carrying the 9-repeat allele have an overabundance of synaptic DA availability, which may have opposite effects on brain function than in adulthood.”

In the paper

“However, exaggerated DA levels in both striatum and PFC in adolescence may result in an increased sensitivity to rewards coupled with poor executive regulation of impulse driven behaviors, thereby increasing vulnerability for risk-taking behaviors.”

In the paper

“The inability to consistently control behavior concurrent with increased sensation seeking persists in adolescence, leading to increases in risk taking behaviors.”

In the paper

“Similarly, others have suggested that sample sizes of over 25 subjects in each group are necessary for general fMRI studies in order to have adequate reliability (Thirion, Pinel et al. 2007).”

What the sources say

• Not checked yetcites Thirion, Pinel et al. 2007 source

In the paper

“Given evidence that various aspects of the DA system are heightened or changed in adolescence and that single gene effects may manifest differently in the adolescent brain, it is also possible that gene interactions differ in the adolescent brain than in the adult brain.”

In the paper

“DA availability and signaling is heightened during the adolescent period and may promote novelty seeking in an adaptive fashion in order to gain skills that support adult survival.”

In the paper

“Gene expression is one of the primary sources of variability, acting through cellular and system-level neural processes to produce complex phenomena that manifest in behavioral function and dysfunction.”

In the paper

“fMRI is one the most common and reliable methods of measuring brain function at decent spatial and temporal resolutions, but given that it is an indirect measure of brain activity, reflecting a paradigm related change in metabolic consumption (Logothetis, Pauls et al. 2001), interpretation of gene effects is limited.”

What the sources say

• Not checked yetcites Logothetis, Pauls et al. 2001 source

In the paper

“Assuming a relatively even distribution of the alleles, this would result in approximately 30–35 participants per group.”