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J. David Jentsch, PhD, Associate Professor

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Title: J. David Jentsch, PhD, Associate Professor


1
Impulsivity Causes and Consequences
  • J. David Jentsch, PhD, Associate Professor
  • Departments of Psychology and
  • Psychiatry Biobehavioral Sciences
  • University of California, Los Angeles

2
Cognitive Control
  • Learning and memory reflect the acquisition
    and persistence of experience-dependence
    modifications in behavior however, these
    mechanisms are often not sufficient to permit
    adaptive, flexible behavior
  • Cognitive control is rubric that describes
    another set of processes that contribute the
    ability to voluntarily modulate behavior, either
    in the service of future plans, changing
    conditional rules or complex and variable
    contextual influences

3
Cognitive Control
  • Requires multiple domains of cognitive function,
    including
  • Working memory (ability to maintain internal
    representations of distant goals)
  • Ability to update the contents of our internal
    representations as contingencies shift
  • Contributes to our ability to execute planned
    behavior
  • Inhibitory control of pre-potent responding

4
Implications of Poor Cognitive Control
  • Inability to delay gratification, integrate
    complex outcomes in decision making, stop
    reward-directed behavior (addiction)
  • Generally, the impulsive aspects of substance
    abuse can be thought of as a loss of the ability
    to maintain internal representations of future
    goals and to inhibit immediately gratifying
    behavior

5
Questions
  • What are the determinants of individual variation
    in cognitive control and impulsivity?
  • What neuropharmacological targets emerge as
    important mechanisms for the modulation of
    cognitive control?

6
Pathways to Deconstructing a Complex Phenotype
  • Recent studies from Lynn Fairbanks (UCLA) have
    identified impulsive approach and aggression as a
    heritable trait in non-human primates
  • Heritability supports search for genetic
    mechanisms that may be common to those driving
    the phenotype in humans

7
Trait Impulsivity
  • Rapid, unplanned, inflexible approach to novelty
    (social or non-social) or to rewards exploratory
    (image right) or aggressive (highly risky) in
    nature
  • Orthogonal to anxious aspects of temperament,
    leading to at least 4 categories of phenotypic
    responses to challenge

8
Impulsivity A Stable Indicator of Temperament
Males (n70)
Females (n56)
r0.83
r0.89
Impulsivity
Data represent two challenge tests separated by
16 months Fairbanks et al. (2004) Biol.
Psychiatry, 55 642-7
9
Genetic Determinants?
  • 48-basepair, exon 3 variable number tandem repeat
    polymorphism in the DRD4 (dopamine D4 receptor)
    gene
  • In humans, 4 and 7 repeats are the most common
    alleles
  • 7-repeat allele associated with greater risk for
    ADHD and higher impulsivity/novelty-seeking
  • Vervets carry 5 or 6 repeats, with the 5-repeat
    version being associated with greater impulsivity
  • This polymorphism accounts for 13 of the
    variance in impulsive responding in the
    impulsivity tests (Bailey et al. 2007
    Psychiatric Genetics, 17 23-7)

10
Is Impulsivity an Indicator of Poor Cognitive
Control in Monkeys?
11
Experimental Design
  • Adolescent (4 year old) male vervet monkeys,
    living in social groups
  • Drawn into the study according to the following
    criteria
  • Common DRD4 allele (DRD4.6)/low impulsivity
  • Common DRD4 allele (DRD4.6)/high impulsivity
  • Rare DRD4.5 allele

12
Spatial Delayed Response
  • Maintenance of information in working memory
  • Relies upon DLPFC (amongst other circuits)

Curtis and DEsposito (2004) Cog. Affec. Behav.
Neurosci., 4 528-39
13
Spatial Delayed Response Performance
James et al. (2007) J. Neurosci., 27(52)14358-64.
14
DRD4 and Working Memory
  • These studies that DRD4 genotype modulates
    working memory in the hypothesized direction
    (rare allele associates with high impulsivity and
    poor working memory)
  • This genotype contributes in a non-unique fashion
    as compared with the as-of-yet unknown genotypes
    also driving this super-phenotype that spans the
    temperamental and cognitive domains

15
What about other genes?
  • Pedigree-wide assessment for working memory (and
    other cognitive control-related processes) for
    whole-genome linkage analyses

16
What about other aspects of cognitive control?
  • Executive control over behavior (reversal
    learning)

17
Reversal Learning and Cognitive Control
  • Subjects (rodents, monkeys or humans) learn a
    discrimination based upon positive and negative
    feedback, alone
  • Once learned, the contingencies change, and
    behavior must be flexibly altered in order to
    obtain desired outcomes
  • Reversal, as compared with acquisition,
    selectively measures the ability to change or
    inhibit a conditioned response

18
(No Transcript)
19
Reversal Learning and the Orbitofrontal Cortex
Dias et al. (1996) Nature, 380 69-72
20
Impulsivity and Discrimination Learning and
Reversal
Subjects were n12 juvenile (2 ½ year old
subjects)
21
Impulsivity
  • In young subjects (juveniles and adolescents),
    impulsive temperament is a strong predictor of
    working memory maintenance and flexible
    responding, two key aspects of cognitive control
  • The impulsive youngster exhibits a spectrum of
    cognitive control impairments that depend upon
    variation in AD/HD risk genes

22
Genomic/neurochemical determinants?
23
Catecholamine Mechanisms
  • Role for the DRD4 gene in modulating impulsivity
    and cognitive control suggests that catecholamine
    mechanisms, generally, remain important targets
    for neuropharmacological interventions
  • We know D1-like receptors play a critical role in
    working memory
  • What about other dimensions of cognitive control,
    such as the ability to update behavior in
    response to reinforcement shifts (reversal
    learning?)

24
D1/D5 Mechanisms Do Not Modulate Reversal
Learning Performance
SCH 23390 D1-like antagonist Dose 0.03 mg/kg
Lee et al. (2007) Neuropsychopharmacol.,
32(10)2125-34
25
D2/D3 Mechanisms Selectively Modulate Reversal
Learning Performance
Raclopride D2-like antagonist Dose 0.03 mg/kg
Lee et al. (2007) Neuropsychopharmacol.,
32(10)2125-34
26
Dopaminergic Mechanisms
  • Differently from working memory (maintenance of
    central representations), reversal learning
    (flexible responding) depends more on D2-like
    than D1-like receptors
  • We propose that D1- and D2-like receptors
    dissociably contribute to the maintenance vs.
    updating of central representations and behavior
  • New emphasis on D2-like mechanisms in cortex for
    cognitive control is needed

27
Cortical D2 Receptors and Cognitive Control
  • Ideal strategies include mechanisms that
    selectively increase, in an activity-dependent
    manner, extra-cellular levels of dopamine, which
    then can act on D1-like and D2-like receptors to
    facilitate working memory and executive control
    over behavior
  • Inhibition of the noradrenaline transporter??

28
Atomoxetine Improves Reversal Learning in Monkeys

29
Conclusions
  • Progress on the genetics of individual variation
    in cognitive control in experimental animals
  • Including the identification of subjects that
    naturally exhibit a range of psychiatric
    disorder-related symptoms and endophenotypes
  • Pharmacological studies reveal a critical role
    for dopamine D2-like and alpha-adrenergic
    mechanisms in flexible responding

30
Collaborators and Students
  • Lynn Fairbanks (primatology)
  • Nelson Freimer (genetics)
  • Eydie London (molecular imaging)
  • Emanuele Seu (post-doc), Alex James (graduate
    student), Stephanie Groman (graduate student)

31
Acknowledgements
  • National Institute on Drug Abuse
  • P20-DA22539 (Methamphetamine Abuse, Inhibitory
    Control Treatment Implications)
  • National Institute of Mental Health
  • P50-MH77248 (CIDAR Translational Research to
    Enhance Cognitive Control)
  • RL1-MH83270 (Translational Models for Memory and
    Cognitive Control)
  • Tennenbaum Center for the Biology of Creativity
    at UCLA
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