A Model System for Studying the Role of Dopamine in the Prefrontal Cortex during Early Development in Humans: Early and Continuously Treated Phenylketonuria

Abstract

After a brief overview of the anatomy of dorsolateral prefrontal cortex (DL-PFC) and of its anatomical connections with other brain regions, findings are summarized that DL-PFC subserves working memory and inhibitory control abilities even during infancy. Evidence suggests that one change in the prefrontal neural circuit helping to make possible some of the cognitive advances seen in infants between 6 and 12 months of age might be changes in the dopaminergic innervation of prefrontal cortex. The period of 3–6 years is then examined as a period when there is particularly marked improvement in the working memory and inhibitory control abilities thought to depend upon DL-PFC. Perhaps that improvement is made possible, in part, by maturational changes in DL-PFC, perhaps even in its dopamine projection, although that remains to be demonstrated. (To propose that changes in the dopamine innervation of prefrontal cortex play a role in making possible some cognitive advances is not to negate the role of experience nor the role of other maturational changes in the prefrontal neural system.)

As an initial way to begin looking at the role of dopamine in prefrontal cortex function in human beings during infancy and early childhood, we studied a group of children who, there was reason to believe, have reduced levels of dopamine in prefrontal cortex but otherwise normal brains. These are children treated early and continuously for phenylketonuria (PKU), whose phenylalanine levels are 3–5 times normal and whose tyrosine (Tyr) levels are below normal. The rationale for studying these children and the results obtained in those studies are summarized, as are the results from our work with an animal model of early, and continuously, treated PKU. Evidence on dissociations among tasks that require DL-PFC but are differentially sensitive to the dopamine content of DL-PFC is discussed. The evidence shows that not all cognitive tasks dependent on DL-PFC are dependent on dopamine in DL-PFC. It is my hope that this review will offer some insight into cognitive development, into the role of prefrontal cortex in cognitive development, and into the role of dopamine in prefrontal cortex function.