Review
What the rodent prefrontal cortex can teach us about attention-deficit/hyperactivity disorder: the critical role of early developmental events on prefrontal function

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Abstract

The present review surveys a broad range of findings on the functions of the rodent prefrontal cortex (PFC) in the context of the known pathophysiology of attention-deficit/hyperactivity disorder (ADHD). An overview of clinical findings concludes that dysfunction of the right PFC plays a critical role in ADHD and that a number of early developmental factors conspire to increase the risk of the disorder. Rodent studies are described which go far in explaining how the core processes which are deficient in ADHD are mediated by the PFC and that the mesocortical dopamine (DA) system plays a central role in modulating these functions. These studies also demonstrate a surprising degree of cerebral lateralization of prefrontal function in the rat. Importantly, the PFC is highly vulnerable to a wide variety of early developmental insults, which parallel the known risk factors for ADHD. It is suggested that the regulation of physiological and behavioral arousal is a fundamental role of the PFC, upon which many “higher” prefrontal functions are dependent or at least influenced. These right hemispheric arousal systems, of which the mesocortical DA system is a component, are greatly affected by early adverse events, both peri- and postnatally. Abnormal development, particularly of the right PFC and its DAergic afferents, is suggested to contribute directly to the core deficits of ADHD through dysregulation of the right frontostriatal system.

Introduction

The neurodevelopmental disorder known as attention-deficit/hyperactivity disorder (ADHD), is the most prominent childhood psychiatric condition and its features or core deficits frequently persist well into adulthood. It is increasingly appreciated that functional deficits in frontostriatal circuitry contribute substantially to the pathophysiology of ADHD and that the right prefrontal cortex (PFC) is especially important in this regard. While genetics play a very important role in this condition, intrauterine, perinatal and postnatal factors have all been significantly linked with the development of ADHD.

Studies in the rodent have revealed that the PFC is intimately involved in mediating numerous neural functions of central relevance to ADHD, not only behavioral inhibition, attentional processes, and working memory, but also less appreciated aspects of this condition such as arousal level, physiological stress responsiveness, and emotional self-regulation. Not surprisingly, the maturation of these prefrontal circuits is significantly affected by a wide variety of early developmental events, both adverse and advantageous. The present review examines many of these animal findings and describes the important modulatory role of mesocortical dopamine (DA) on PFC function, as well as the extent to which this system may be particularly vulnerable to early developmental insults. Many of these findings also highlight the important role of cerebral laterality in mediating the above processes, even at the level of the rodent.

The first section of the paper thus provides a brief overview of the pathophysiology of ADHD with particular reference to PFC dysfunction and the proposed nature of altered DA function in this condition. The following sections review the rodent literature in terms of how the PFC modulates the various processes deemed central to ADHD symptomology. The final sections discuss first the evidence that early adverse events contribute to the development of ADHD, and secondly, that in rodents numerous early manipulations modeled upon these types of events lead to long-lasting impairments in prefrontal function. It is proposed that early adverse events impact negatively on the maturation of prefrontal circuits particularly in the right hemisphere, and that deficits in mesocortical DA function in this region contribute significantly to ADHD symptomology.

Section snippets

Prefrontal involvement in ADHD pathophysiology and the possible role of DA

Numerous reviews have elucidated the behavioral and cognitive characteristics of ADHD in great detail, as well as describing the known neuropathological correlates of this condition [9], [10], [35], [38], [161], [171]. The present paper focuses on the pivotal role that the PFC appears to play in mediating the spectrum of ADHD symptomology.

Heilman et al. [77] proposed that the pathophysiology of ADHD derives from right-sided frontal-striatal dysfunction in combination with an impairment of the

Rodent studies of PFC function of relevance to ADHD

Others have proposed rodent models of ADHD symptomology. For example, the spontaneously hypertensive rat (SHR) model has been extensively studied and tested as an animal model for ADHD [147]. This genetic model has paralleled the symptoms of ADHD in humans since they display hyperactivity, impulsivity, poor stability of performance and poor sustained attention when tested with other strains of rats, such as the Wistar–Kyoto (WKY) control rats. Interestingly, SHR rats exhibit reduced

Early adverse events and ADHD

As acknowledged earlier, there is a strong genetic component in the occurrence of ADHD, which may well involve the aberrant development of DAergic frontostriatal circuitry. In addition however, a number of independent risk factors have been identified for subsequent ADHD diagnosis, which may affect the development of these same systems. In general, complications associated with pregnancy, delivery or infancy have been linked with increased risk of ADHD diagnosis [88], [111], [140], [162], [184]

Effects of early developmental manipulations on rodent PFC function

The developing prefrontal cortex is extremely sensitive to a wide variety of perturbations. For example, prenatal stress leads to enhanced anxiety in the offspring, and lateralized changes in PFC DA function [63]. Such treatments also produce lasting changes in both DA and glutamate receptor expression in medial PFC [12]. Similarly, cocaine exposure in utero results in offspring with dramatically increased levels of Fos protein expression selectively in the ventral and medial prefrontal regions

Summary: towards a better understanding prefrontal dysfunction in ADHD

ADHD undoubtedly involves the abnormal development and functioning of entire networks of structures, not only prefrontal, but certainly striatal and even cerebellar (see [37], [38]). What is presently proposed, is that right prefrontal cortex may play the most critical role in the expression of ADHD, by virtue of its direct role in mediating the core deficits of this condition, and by its regulation of striatal and other subcortical functions. The right PFC also appears to be particularly

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