DOI

10.17077/etd.kjtqmy8x

Document Type

Dissertation

Date of Degree

Spring 2016

Access Restrictions

.

Degree Name

PhD (Doctor of Philosophy)

Degree In

Neuroscience

First Advisor

Wu, Chun-Fang

First Committee Member

Kitamoto, Toshihiro

Second Committee Member

Manak, J. Robert

Third Committee Member

Mohapatra, Durga P.

Fourth Committee Member

Narayanan, Nandakumar

Fifth Committee Member

Richerson, George B.

Abstract

Proper control of movements is critical for an animal’s survival, and requires the robust function of a number of genetic, molecular, neuronal and biomechanical processes. This dissertation describes a body of inter-related studies utilizing a diverse collection of Drosophila mutants to probe the roles individual genes play in shaping motor pattern generation. A particular emphasis is placed on describing the consequences of genetic perturbations of voltage-gated sodium, calcium and potassium ion channels (NaV, CaV, and KV respectively) on the function of neuronal circuits that drive motor behavior.

Here, I describe the development of several quantitative protocols to study alterations in of walking (IowaFLI Tracker) and flight motor program activity and behavior in Drosophila mutants. These approaches were utilized to analyze the highly-stereotypic aberrant motor program associated with electroconvulsive stimulation (ECS)-induced seizure discharge activity in each hyperexcitable mutant. Several quantitative and mechanistic similarities between flight motor program activity and ECS-evoked discharges were identified, and the distinct aberrant ECS-evoked activity disclosed an electrophysiological signature of each mutation.

Ion channel mutants display a diverse spectrum of neuronal excitability phenotypes that was highlighted in a novel hyperexcitable mutant, Shaker wings down (Swd), characterized by ether-induced leg shaking reminiscent of certain KV channel mutants (e.g. Shaker, KV1) is presented. Detailed analyses revealed disrupted walking and flight, correlated with neuronal hyperexcitability and aberrant action potential generation. Surprisingly, the Swd mutation site was mapped to a single amino acid in the voltage sensor region in paralytic (para, encoding the only NaV gene in Drosophila). Genetic analysis of intra-genic heteroallelic interactions amongst Swd and other identified para alleles further revealed a number of complex mechanisms underlying a wide phenotypic spectrum of altered neuronal excitability and motor pattern generation.

The effects of perturbed ion channel function on motor program generation are compared with progressive alterations associated normal aging as well as neurodegeneration. A number of age-resilient and age-vulnerable circuits were identified along with circuit-function biomarkers of aging. Throughout this study, an integrative framework utilizing non-linear dimensional reduction approaches unraveled a broader perspective to visualize and quantify similarities and distinctions between discharge phenotypes across a large collection of Drosophila mutants.

Public Abstract

Individual neurons that make up the nervous system must act as an ensemble to generate appropriate patterns of electrical activity that control locomotion. Using novel high-throughput behavioral and electrophysiological methods to study walking, flight and evoked seizure behavior in the fruit fly Drosophila melanogaster, this dissertation explores the genetic, developmental and environmental influences on the generation of neuronal activity that underlies normal and abnormal locomotion.

Keywords

Epilepsy, Flight, Ion Channel, Motor Coordination, Neurodegeneration, Seizure

Pages

xvii, 297 pages

Bibliography

Includes bibliographical references (pages 257-297).

Comments

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Copyright

Copyright © 2016 Atulya Srisudarshan Ram Iyengar

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