Attention-deficit/hyperactivity disorder (ADHD) is one of the most common childhood neuropsychiatric disorders. Based on neuroimaging studies, the striatum is reported to be abnormal in size, but it is still not clear how they change during developmental stages. Spontaneously hypertensive rats (SHRs) are the commonly used animal model for ADHD. We investigated volume differences of the striatum at various ages before puberty in SHRs versus a control strain, Wistar–Kyoto rats (WKYs). Volumes of the bilateral striatum were measured using micrographs of Nissl-stained serial sections in both strains of rats at the ages of 4, 5, 6, 7, 8, 9, and 10 weeks (n = 4, each strain at each age). The results demonstrated that the age of a significant striatal volume difference between SHRs and WKYs was 5 weeks; however, there was no significant difference for the corresponding total brain volume at each matched age. It suggested that the timing for striatal abnormalities in ADHD occurs during an early stage of childhood.
Attention-deficit/hyperactivity disorder (ADHD) is one of the most common childhood neurobehavioral disorders. It affects 8–12% of children, predominantly boys (Biederman and Faraone, 2005). The neurobiology of ADHD remains unknown. Numerous volumetric imaging studies have emphasized the important role of basal ganglia in the pathophysiology of ADHD (Hynd et al., 1993, Castellanos et al., 1994, Castellanos et al., 1996, Castellanos et al., 2002, Filipek et al., 1997, Mataro et al., 1997 and Pineda et al., 2002). There are several nuclei comprising the basal ganglia; the globus pallidus internal segment and substantia nigra pars reticulata are the two output nuclei, while the main input nucleus is the striatum (the caudate and putamen collectively) (Uttera and Basso, 2008). The basal ganglia receive input from the neocortex via the striatum and send processed information to the prefrontal cortex, which is involved in motor planning, learning, and execution (Haber, 2003). Lou et al. (1984) noted decreased metabolism in the striatal region, particularly the caudate nuclei region, in patients with attention-deficit disorder. A monozygotic twin study showed significantly smaller-sized caudate nuclei in patients with ADHD compared to the other unaffected twin (Castellanos et al., 2003). An imaging study in girls with ADHD (with an age range of 5.3–16.0 years) found that the pallidum and caudate volumes were significantly correlated with symptom severity and cognitive performance (Castellanos et al., 2001). Castellanos et al. (2002) proposed that volumetric differences in the caudate nucleus may be transient and possibly related to an improvement in hyperactivity/impulsivity with increasing age in ADHD children.
Imaging studies, like those previously mentioned, enable the tracing of gross anatomical changes in brain regions of ADHD children; however, it is still difficult to explore microscopic changes in humans while avoiding interference from possible treatment effects, especially when studying age-dependent volume abnormalities of the brain. Animal models provide a good opportunity to detect microscopic developmental changes in the brain due to the availability of brain tissues and the shorter life cycle of animals. They also provide relatively simpler experimental conditions, including homogeneous subjects, and a lack of previous drug treatment, family interactions, and other social factors encountered in human ADHD patients. A validated animal model of ADHD is the spontaneously hypertensive rat (SHR) strain, which was derived from Wistar–Kyoto (WKY) rats. The SHR strain manifests almost all of the behavioral characteristics of ADHD, including sustained attention deficits, impulsivity, and hyperactivity that occur in novel situations (Sagvolden, 2000).
SHRs further exhibit brain pathologies similar to ADHD. For example, the striatum may be an important brain region for the pathology of ADHD in SHRs. There is a strong possibility that the dopamine transporter gene is overexpressed in the striatum of ADHD subjects (Russell et al., 2005), consistent with the finding that the dopamine transporter is increased in the prehypertensive SHR striatum (Russell, 2003), and extracellular dopamine levels are lower in the caudate nucleus (Linthorst et al., 1991 and De Jong et al., 1995). Some volumetric comparisons of brain regions between SHRs and WKY rats were done. SHR brain volumes, specifically the prefrontal cortex, occipital cortex, and hippocampus, are smaller than those of WKY rats (Tajima et al., 1993, Sabbatini et al., 1999 and Sabbatini et al., 2000), whereas the volume of the neostriatum was unchanged (Sabbatini et al., 1999). MRI also revealed significantly increased ventricular volume in SHRs compared to WKY rats at 3 months of age (Bendel and Eilam, 1992). However, the above volumetric studies were conducted on adult rats. Hypertension would be a confounding factor in the SHR model of ADHD, since hypertension develops at 10–12 weeks of age (considered an adult) in SHRs, but hyperactivity is observed at 3–4 weeks of age before rats enter puberty (Russell et al., 2005).
The aim of this study was to trace age-series changes in striatal volume in the SHR model of ADHD. While hypertension was not present in young hyperactive SHRs, we compared volume differences of the striatum between male SHRs and WKY rats aged 4–10 weeks, which covers the growth stages from weaning to puberty. Findings from this study can advance our understanding of the timing of volume changes in the striatum with ADHD.
2. Methods
