Validating a novel ADHD model for medication development

Majdak, Petra

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Description

Title

Validating a novel ADHD model for medication development

Author(s)

Majdak, Petra

Issue Date

2016-08-08

Director of Research (if dissertation) or Advisor (if thesis)

Rhodes, Justin S.

Doctoral Committee Chair(s)

• Rhodes, Justin S.
• Chung, Hee Jung
• Ceman, Stephanie
• Uddin, Eva M

Department of Study

Neuroscience Program

Discipline

Neuroscience

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Attention-deficit/hyperactivity disorder (ADHD)
• Selective breeding

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder which manifests as deficits in impulse control, excessive activity in home or school settings, and an inability to focus attention on relevant stimuli. While millions of individuals with ADHD lack this ability to effectively modulate behaviors and optimize societal, academic, or occupational performance, surprisingly little is known regarding its genetic etiology and few improvements in therapeutics have been accomplished over the past decades. This lack of progress is partly attributable to the dearth of genetic models of ADHD enabling unbiased exploration of the genetic architecture of hyperactive-impulsive behavior. The goal of my dissertation is to fill this critical need for a genetic model which may be used to meaningfully advance the field of ADHD research. Toward that end, I systemically evaluated the face, construct, and predictive validity of a genetically variable line mice selectively bred for increased home cage activity in order to determine whether it may faithfully recapitulate facets of ADHD symptomatology. In Chapter 1, the rodent models of ADHD currently used are reviewed in terms of their validity, advantages and limitations, and the extent to which these models have informed or obfuscated our understanding of ADHD. Chapter 2 summarizes promising results from our initial foray into assessing the predictive validity of the line; Generation 11 High-Active mice demonstrate home cage hyperactivity which is paradoxically ameliorated by chronic low-dose amphetamine. Furthermore in this chapter I establish a statistical procedure for estimating whether line differences are due to selection for hyperactivity versus genetic drift; results suggest the genetic underpinnings of home cage hyperactivity are unique and likely differ from those mediating other forms of increased physical activity. Chapter 3 vastly expounds on the face validity of the line by confirming the hyperactivity and motor impulsivity of the High-Active line in two different versions of the operant Go/No-go task and within adolescent males and adult females. Interestingly, the High-Active line shows little evidence of inattention as assessed by spontaneous alternation in the Y-maze, suggesting High-Active validity may be circumscribed to the Hyperactive-Impulsive subtype of ADHD. Furthermore the predictive validity of the line is reaffirmed in this chapter as the same low-dose amphetamine which reduces hyperactivity also paradoxically ameliorates motor impulsivity. Analysis of regional neural activation of High-Active versus Control mice at baseline and in response to low-dose amphetamine indicates dysregulated prefrontal cortex and cerebellum may partly modulate High-Active impulsive behavior. Chapter 4 addresses a fundamental question regarding the construct validity of the High-Active line. In this large-scale cross-fostering experiment I demonstrate that the significant deficits in the maternal competence of High-Active dams do not influence the hyperactivity of High-Active offspring; raw genetics mediate this transgenerational phenotype whose expression cannot be influenced even by the most stressful of perinatal environments. I further infer evidence of extreme dopaminergic dysregulation in the High-Active line, as only a genetic ablation of the dopamine transporter has produced dams which even somewhat approach the severity of High-Active deficits in maternal care. In Chapter 5 I propose high-yield uses of this now-validated model of ADHD, including strategies for uncovering relevant genetic etiological factors, identifying novel compounds to advance therapeutic approaches, and elucidating endophenotypes which may aid in the diagnosis of ADHD. Ultimately the efforts of this dissertation have culminated in a validated genetic model of Hyperactive-Impulsive ADHD which is poised to serve as a platform for significantly advancing our understanding of this ubiquitous, heritable behavioral disorder.

Graduation Semester

2016-12

Type of Resource

text

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Copyright and License Information

Copyright 2016 Petra Majdak

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