Genetic dissection of behavioral flexibility

Reversal learning in mice

Rick E. Laughlin, Tara L. Grant, Robert Williams, J. David Jentsch

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Background Behavioral inflexibility is a feature of schizophrenia, attention-deficit/hyperactivity disorder, and behavior addictions that likely results from heritable deficits in the inhibitory control over behavior. Here, we investigate the genetic basis of individual differences in flexibility, measured using an operant reversal learning task. Methods We quantified discrimination acquisition and subsequent reversal learning in a cohort of 51 BXD strains of mice (25 mice/strain, n = 176) for which we have matched data on sequence, gene expression in key central nervous system regions, and neuroreceptor levels. Results Strain variation in trials to criterion on acquisition and reversal was high, with moderate heritability (∼.3). Acquisition and reversal learning phenotypes did not covary at the strain level, suggesting that these traits are effectively under independent genetic control. Reversal performance did covary with dopamine D2 receptor levels in the ventral midbrain, consistent with a similar observed relationship between impulsivity and D2 receptors in humans. Reversal, but not acquisition, is linked to a locus on mouse chromosome 10 with a peak likelihood ratio statistic at 86.2 megabase (p < .05 genome-wide). Variance in messenger RNA levels of select transcripts expressed in neocortex, hippocampus, and striatum correlated with the reversal learning phenotype, including Syn3, Nt5dc3, and Hcfc2. Conclusions This work demonstrates the clear trait independence between, and genetic control of, discrimination acquisition and reversal and illustrates how globally coherent data sets for a single panel of highly related strains can be interrogated and integrated to uncover genetic sources and molecular and neuropharmacological candidates of complex behavioral traits relevant to human psychopathology.

Original languageEnglish (US)
Pages (from-to)1109-1116
Number of pages8
JournalBiological Psychiatry
Volume69
Issue number11
DOIs
StatePublished - Jun 1 2011

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Reversal Learning
Behavioral Genetics
Dissection
Phenotype
Chromosomes, Human, Pair 10
Behavior Control
Dopamine D2 Receptors
Impulsive Behavior
Neocortex
Sensory Receptor Cells
Attention Deficit Disorder with Hyperactivity
Mesencephalon
Psychopathology
Individuality
Molecular Biology
Hippocampus
Schizophrenia
Central Nervous System
Genome
Gene Expression

All Science Journal Classification (ASJC) codes

  • Biological Psychiatry

Cite this

Genetic dissection of behavioral flexibility : Reversal learning in mice. / Laughlin, Rick E.; Grant, Tara L.; Williams, Robert; Jentsch, J. David.

In: Biological Psychiatry, Vol. 69, No. 11, 01.06.2011, p. 1109-1116.

Research output: Contribution to journalArticle

Laughlin, Rick E. ; Grant, Tara L. ; Williams, Robert ; Jentsch, J. David. / Genetic dissection of behavioral flexibility : Reversal learning in mice. In: Biological Psychiatry. 2011 ; Vol. 69, No. 11. pp. 1109-1116.
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