Text

theses

ETD doctoral

Attention/deficit-hyperactivity disorder (ADHD) is a psychiatric illness characterized by symptoms of inattention, impulsivity and hyperactivity. Aside from the cardinal clinical symptoms, patients with ADHD display reward and motivational impairments. A potential mechanism that might underlie these deficits is an impairment in patients’ ability to flexibly adapt their behavior to changing consequences in the context of action control. Brain regions responsible for action control (the corticostriatal pathways) as well as dopamine signaling within these regions show abnormalities in patients with ADHD. Accordingly, we propose that patients with ADHD exhibit an impairment in action control where they rely on the habit system, exhibiting reflexive actions to stimuli, at the expense of the goal-directed system, which supports reflective behavior modulated by action consequences. In this dissertation, we utilize goal-directed behavior as a behavioral phenotype that might disentangle underlying mechanisms in ADHD. Specifically, we challenge current views of ADHD as a disorder of dopamine hypofunction, and instead argue that the action control deficit in ADHD might result from a misbalance between opposing direct and indirect dopaminergic pathways that govern this behavior. Here, we used behavioral, pharmacological and immunohistochemistry techniques to examine goal-directed action control in spontaneously hypertensive rats (SHR), a rat model of ADHD. Further, we used a computer-based cognitive analogue to replicate and translate our behavioral findings in patients with ADHD. In two separate studies, we examined action control in ADHD, and the effects of methylphenidate, a psychostimulant treatment for ADHD, as well as dopamine D1 receptor (D1R) and dopamine D2 receptor (D2R) agonists and antagonists on goal-directed behavior. Finally, we characterized the neural activation patterns in in the brain regions that are specifically involved in goal-directed and habitual behaviors by quantifying the expression of the immediate early gene c-fos. Our results show that SHR rats as well as patients with ADHD exhibit a selective deficit in goal-directed behavior. Methylphenidate restored this deficit in SHR rats and impaired goal-directed behavior in control rats that previously demonstrated intact action control. Further, we found that stimulation of D1R, but not D2R, or inhibition of D2R, but not D1R, restored goal-directed behavior in SHR rats. At the neural level, we found that SHR rats showed dominant activity in the dorsolateral striatum (the habit region), whereas WKY rats showed a dominant activity in the dorsomedial striatum (the goal-directed region). These patterns of activation flipped when rats received methylphenidate. This novel finding indicates that the core behavioral deficit in ADHD might not be a consequence of dopamine hypofunction, but rather due to a dopamine-dependent misbalance in action control. Unraveling these mechanisms in ADHD can broaden our understanding of the neural circuits underlying cognitive symptoms of ADHD. These findings might elucidate novel potential treatment approaches for ADHD to create a balance between symptom relief and remediation of behavioral deficits.

ETD_8411

doi:10.7282/T38S4T1D

Ph.D.

Includes bibliographical references

by Joman Y. Natsheh

The author owns the copyright to this work.