University of Calgary PRISM: University of Calgary's Digital Repository Graduate Studies The Vault: Electronic Theses and Dissertations 2014-01-30 Functional Neocortical Movement Encoding in the Rat Brown, Andrew Brown, A. (2014). Functional Neocortical Movement Encoding in the Rat (Unpublished doctoral thesis). University of Calgary, Calgary, AB. doi:10.11575/PRISM/26247 http://hdl.handle.net/11023/1355 doctoral thesis University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. Downloaded from PRISM: https://prism.ucalgary.ca UNIVERSITY OF CALGARY Functional Neocortical Movement Encoding in the Rat by Andrew R. Brown A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF NEUROSCIENCE CALGARY, ALBERTA JANUARY, 2014 © Andrew R. Brown 2014 Abstract The motor cortex has long been known to play a central role in the generation and control of volitional movement, yet its intrinsic functional organization is not fully understood. Two alternate views on the functional organization of motor cortex have been proposed. Short- duration (>50 ms) intracortical stimulation (SD-ICMS) reveals a somatotopic representation of body musculature, whereas long-duration (~500 ms) ICMS (LD-ICMS) reveals a topographic representation of coordinated movement endpoint postures. The functional organization of motor cortex in the rat was probed using combined approaches of in vivo microstimulation, behavioural analysis of forelimb motor performance, and acute cortical cooling deactivation. The first study, using a rodent model of Parkinson’s disease and therapeutic deep brain stimulation of the subthalamic nucleus, determined that acute changes (<60 s) in cortical output function and motor performance are reflected in reversible alterations in movement thresholds and representation sizes. A second study characterized forelimb movement representations under SD-ICMS revealing a dual-representation (digit, wrist, elbow, shoulder) within rostral (RFA) and caudal (CFA) forelimb motor areas. LD-ICMS elicited forelimb reach-to-grasp behaviour (elevate, advance, grasp, retract) with a functional segregation between RFA (grasp) and CFA (elevate, advance, retract) representations. Behaviourally distinct functional roles between these two areas was confirmed through behavioural assessment during selective cortical cooling deactivation. A final study demonstrated increased movement representation overlap assessed with LD-ICMS following repeated kindled-seizures that was not attributed to changes in intracortical inhibition. Current experimentation provides the first causal evidence for movement-based rather than muscle-based functional organization of motor cortex and functional neocortical movement encoding in the rat. ii Acknowledgements I wish to thank Dr. G. Campbell Teskey for invaluable guidance and support throughout my graduate program. Thanks to Dr. Bin Hu for spurring the development of Chapter 2. Thanks to Dr. Richard Dyck for use of the sliding microtome and imaging equipment. Thanks to Dr. Michael Antle for providing the TH+ primary antibody, DAB reaction reagents, and visualization equipment in addition to technical support for the immunohistochemical analyses. Many thanks to Dr. Stephen Lomber for technical support and assistance in adapting cooling deactivation techniques for present use. Thanks to Gerard Coughlin for assistance with kindling and experimentation in Chapter 4. Thanks to Bonita Gunning for assistance and technical support. Appreciation to AI-HS, NSERC, Department of Neuroscience and University of Calgary for funding support. iii Table of Contents Abstract ............................................................................................................................... ii Acknowledgements ............................................................................................................ iii Table of Contents ............................................................................................................... iv List of Tables .................................................................................................................... vii List of Figures and Illustrations ....................................................................................... viii List of Abbreviations ...........................................................................................................x CHAPTER ONE: INTRODUCTION ..................................................................................1 1.1 Motor cortex organization as a somatotopic representation of body musculature ....4 1.2 Short-duration intracortical microstimulation reveals somatic muscle encoding in motor cortex .............................................................................................................7 1.3 Long-duration intracortical microstimulation reveals movement encoding in motor cortex........................................................................................................................8 1.4 Sensorimotor neocortex and corticospinal projections in the rat .............................14 1.5 Lesion techniques to investigate neural function .....................................................22 1.6 Behavioural assessment of forelimb motor ability ..................................................25 1.7 Motor map plasticity and behaviour ........................................................................30 1.8 Thesis objectives and hypothesis .............................................................................32 CHAPTER TWO: ..............................................................................................................35 HIGH FREQUENCY STIMULATION OF THE SUBTHALAMIC NUCLEUS ACUTELY RESCUES MOTOR DEFICITS AND NEOCORTICAL MOVEMENT REPRESENTATIONS FOLLOWING 6-HYDROXYDOPAMINE ADMINISTRATION IN RATS ...............................................................................35 2.1 Abstract ....................................................................................................................36 2.2 Introduction ..............................................................................................................37 2.3 Materials and Methods .............................................................................................38 2.3.1 Rats ..................................................................................................................38 2.3.2 Experimental procedures .................................................................................39 2.3.3 Behavioural testing ..........................................................................................39 2.3.3.1 Cylinder Test ..........................................................................................39 2.3.3.2 Open field ..............................................................................................40 2.3.4 Lesion and chronic electrode implantation procedures ...................................41 2.3.5 Deep brain stimulation ....................................................................................42 2.3.6 Intracortical microstimulation .........................................................................42 2.3.7 Lesion assessment and verification of DBS electrode placement ...................45 2.3.8 Statistical analyses ...........................................................................................47 2.4 Results ......................................................................................................................47 2.4.1 Lesion quantification .......................................................................................47 2.4.2 DBS electrode placement and stimulation intensity ........................................48 2.4.3 STN DBS improves behavioural impairments in 6-OHDA lesion rats ...........48 2.4.3.1 Forelimb Placements ..............................................................................55 2.4.3.2 Line crossings ........................................................................................55 2.4.3.3 Rears ......................................................................................................55 iv 2.4.4 6-OHDA lesion decreases forelimb map area and increases movement thresholds ..........................................................................................................................56 2.4.5 STN DBS acutely increases forelimb map area and reduces movement thresholds following 6-OHDA lesion................................................................................61 2.5 Discussion ................................................................................................................65 CHAPTER THREE: ..........................................................................................................69 FUNCTIONALLY SEGREGATED MOVEMENT ENCODING IN RAT NEOCORTICAL FORELIMB MOTOR AREAS .................................................................................69 3.1 Abstract ....................................................................................................................70 3.2 Introduction ..............................................................................................................71