Exploring the Hyperdirect Pathway's impact on Movement Preparation and Execution in Healthy and Parkinsonian Mice Restricted; Files Only

Abstract

The cortico-subthalamic-Substantia Nigra Pars Reticulata (SNr) hyperdirect pathway is known to play a crucial role in inhibiting various regions of the cortex and thalamus involved in motor programs, thereby suppressing ongoing motor plans. However, the specific regions and functions of the cortico-subthalamic nucleus (STN) projection remain incompletely understood. Targeting the STN through interventions like Deep Brain Stimulation (DBS) has shown therapeutic benefits for Parkinson’s Disease patients, yet the underlying mechanism remains unclear. This study aims to investigate the role of the STN in the hyperdirect pathway and its behavioral impact on the planning and execution of forearm reaching behavior in mice.

This study was conducted on one wildtype and one transgenic MitoPark mice (a Parkinson’s Disease mouse model). Bilateral optogenetic stimulation was applied to excitatory and inhibitory layer 5 cortical neurons in the primary motor cortex (M1) and secondary motor cortex (M2) projecting to the STN when the mice performed a directional forelimb reaching task. Results indicate that 300ms of 20 Hz-optogenetic excitation at M1 prior to movement onset significantly prolonged the reaching time in the MitoPark mouse aged 19 to 28 weeks. Additionally, 2000ms of 20 Hz-optogenetic excitation at both M1 and M2, spanning from 500ms before movement onset to its execution, significantly extended reaching time in wildtype mice. Furthermore, such optogenetic excitation at M1 decreased the success rate of reaching in the MitoPark mouse which exhibited notably impaired motor function during weeks 29 to 33. These findings suggest that 20 Hz excitation of the motor cortex can negatively impact movement by increasing reaction time in both wildtype and MitoPark mice, and potentially explain the increased task failure rates as parkinsonian symptoms worsen in the MitoPark mouse. 

Table of Contents

Background and rationale for the research project ......................................................................... 1

Aims................................................................................................................................................ 4

Materials and method...................................................................................................................... 4 Bilateral retrograde rAA V-somBiPOLES Injection ................................................................... 4 Circular Cranial Window and Headpost Implantation................................................................ 5 Water Restriction......................................................................................................................... 5 Behavioral Training of Directional Forearm Reaching Behavioral Task ................................... 5 Optogenetic Stimulation and Behavioral Data Collection .......................................................... 9 Behavioral Data Analysis.......................................................................................................... 11

Hypotheses and rationales............................................................................................................. 12

Results........................................................................................................................................... 14 Behavioral Data Collection ....................................................................................................... 14 Histology ................................................................................................................................... 15

................ 19 a) .................................................... 19 .... 30

...................................................................................................................... 41 Discussion ..................................................................................................................................... 45 Future Directions .......................................................................................................................... 50 

About this Honors Thesis

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School	Emory College
Department	Neuroscience and Behavioral Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Neuroscience
Keyword	motor control Motor System Behavioral Biology mice Basal Ganglia Parkinson's Disease movement MitoPark Optogenetics Hyperdirect Pathway'
Committee Chair / Thesis Advisor	Dieter Jaeger, Emory University
Committee Members	Adriana Galvan, Emory University Chris Rodgers, Emory University

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