A Dopaminergic Gene Cluster in the Prefrontal Cortex Predicts Performance Indicative of General Intelligence in Genetically Heterogeneous Mice

Abstract

BackgroundGenetically heterogeneous mice express a trait that is qualitatively and psychometrically analogous to general intelligence in humans, and as in humans, this trait co-varies with the processing efficacy of working memory (including its dependence on selective attention). Dopamine signaling in the prefrontal cortex (PFC) has been established to play a critical role in animals' performance in both working memory and selective attention tasks. Owing to this role of the PFC in the regulation of working memory, here we compared PFC gene expression profiles of 60 genetically diverse CD-1 mice that exhibited a wide range of general learning abilities (i.e., aggregate performance across five diverse learning tasks).Methodology/Principal FindingsAnimals' general cognitive abilities were first determined based on their aggregate performance across a battery of five diverse learning tasks. With a procedure designed to minimize false positive identifications, analysis of gene expression microarrays (comprised of ≈25,000 genes) identified a small number (<20) of genes that were differentially expressed across animals that exhibited fast and slow aggregate learning abilities. Of these genes, one functional cluster was identified, and this cluster (Darpp-32, Drd1a, and Rgs9) is an established modulator of dopamine signaling. Subsequent quantitative PCR found that expression of these dopaminegic genes plus one vascular gene (Nudt6) were significantly correlated with individual animal's general cognitive performance.Conclusions/SignificanceThese results indicate that D1-mediated dopamine signaling in the PFC, possibly through its modulation of working memory, is predictive of general cognitive abilities. Furthermore, these results provide the first direct evidence of specific molecular pathways that might potentially regulate general intelligence.

Longitudinal attentional engagement rescues mice from age-related cognitive declines and cognitive inflexibility

“…It is worth noting that subregions of the prefrontal cortex (PFC) may play a critical role in the mediation of general cognitive performance through their regulation of attentional control and/ or working memory capacity (Sawaguchi and Goldman-Rakic 1991;Durstewitz et al 2000;Thurley et al 2008;Kolata et al 2010; for review, see Matzel and Kolata 2010). In fact, Kolata et al (2010) have reported that the expression levels of a cluster of dopamine D1-related genes in the prefrontal cortex predict animals' general cognitive performances. It is tempting to speculate that working training might impact this same dopaminergic cluster (or its functional constituents), and thus might modulate cognitive abilities in a manner similar to that with which it modulates innate cognitive abilities.…”

Integrating Neurotransmission in Striatal Medium Spiny Neurons

“…Thus, DARPP-32 is a switch that can act as a feed-forward amplifier of PKA effects when phosphorylated on Thr-34 and dephosphorylated on Thr-75, or, in dramatic contrast, as a PKA inhibitor when phosphorylated on Thr-75 by Cdk5. Perhaps, this critical role in DA signaling and exquisite regulation accounts for the apparent correlation of DARPP-32 with cognitive abilities in humans (Meyer-Lindenberg et al 2007) and mice (Kolata et al 2010). …”

Individual differences: Case studies of rodent and primate intelligence.

“…We also know from our own work that smart and dull animals are genetically different (Kolata et al, 2010). But what can be said about the actual degree to which general cognitive ability is heritable?…”