Title: J. David Jentsch, PhD, Associate Professor
1Impulsivity Causes and Consequences
- J. David Jentsch, PhD, Associate Professor
- Departments of Psychology and
- Psychiatry Biobehavioral Sciences
- University of California, Los Angeles
2Cognitive 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
3Cognitive 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
4Implications 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
5Questions
- 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?
6Pathways 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
7Trait 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
8Impulsivity 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
9Genetic 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)
10Is Impulsivity an Indicator of Poor Cognitive
Control in Monkeys?
11Experimental 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
12Spatial 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
13Spatial Delayed Response Performance
James et al. (2007) J. Neurosci., 27(52)14358-64.
14DRD4 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
15What about other genes?
- Pedigree-wide assessment for working memory (and
other cognitive control-related processes) for
whole-genome linkage analyses
16What about other aspects of cognitive control?
- Executive control over behavior (reversal
learning)
17Reversal 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)
19Reversal Learning and the Orbitofrontal Cortex
Dias et al. (1996) Nature, 380 69-72
20Impulsivity and Discrimination Learning and
Reversal
Subjects were n12 juvenile (2 ½ year old
subjects)
21Impulsivity
- 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
22Genomic/neurochemical determinants?
23Catecholamine 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?)
24D1/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
25D2/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
26Dopaminergic 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
27Cortical 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??
28Atomoxetine Improves Reversal Learning in Monkeys
29Conclusions
- 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
30Collaborators and Students
- Lynn Fairbanks (primatology)
- Nelson Freimer (genetics)
- Eydie London (molecular imaging)
- Emanuele Seu (post-doc), Alex James (graduate
student), Stephanie Groman (graduate student)
31Acknowledgements
- 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