UNIVERSITY OF MINNESOTA This is to certify that I have examined this copy of a doctoral Dissertation by Neil Chadwick Schmitzer-Torbert and have found that it is complete and satisfactory in all respects, and that any and all revisions required by the final examining committee have been made. A. David Redish ———————————————————————– Name of Faculty Adviser ———————————————————————– Signature of Faculty Adviser ———————————————————————– Date GRADUATE SCHOOL THE INVOLVEMENT OF THE RODENT STRIATUM IN NAVIGATION A DISSERTATION SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL OF THE UNIVERSITY OF MINNESOTA BY Neil Chadwick Schmitzer-Torbert IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY A. David Redish, Adviser December 2004 c Copyright by Neil Chadwick Schmitzer-Torbert 2005 Acknowledgements The experiments that I have done over the past four years in the Redish lab would not have been pos- sible without help from many people. In the lab, I have had the benefit of working with many great technicians, including Mallika Arudi, Deborah Bang, Dan Bernal, Chris Boldt, Giuseppe Cortese, Sarah Jutila, Monica Kumar, Susan Nwoke, Liz Ortiz, Kelsey Seeland, Saumya Rao, and Tim Singe- wald, who all assisted with the experiments described in this thesis. I have also been fortunate to work with a number of graduate students in the lab, including Pratibha Aia, Jadin Jackson, Adam Johnson, Beth Masimore, Saumya Rao, and Jon Waataja (during his lab rotation). I am particularly indebted to Deborah Bang and Sarah Jutila for technical work on the histology, and Maureen Reidl of the Elde lab for her assistance in this area. Kelsey Seeland, Chris Boldt and Giuseppe Cortese have each given heroic efforts over the years to assemble the hyperdrives used for chronic record- ings. Mallika Arudi and Giuseppe Cortese have assisted in most of the surgeries, and I have had no shortage of willing volunteers to lend a hand during hyperdrive implantations. Chris Boldt was also kind enough to run some of my experiments while I was out of town, for which I am very thankful. Jadin Jackson, Adam Johnson and Beth Masimore deserve special thanks for helpful discussions about experiments and in the development of interesting analyses. They have also been good friends, which is, I think, more valuable. During my graduate career, I have been fortunate to receive funding from several sources, in- cluding an NSF Graduate Research Fellowship, over a year of support from NSF-IGERT Training Grant #9870633 and a year of funding by a University of Minnesota Graduate Fellowship. i Abstract The basal ganglia are a collection of nuclei which have important roles in motor control and cogni- tive processing, and are the target of several human neurodegenerative disorders. The experiments described here examine the normal functioning of the basal ganglia by examining neural activity in the striatum (also termed caudoputamen, the major input structure of the basal ganglia). The thesis begins with a review of literature related to our current understanding of striatal function, with a spe- cial emphasis on the anatomy of the basal ganglia and striatum, the behavioral correlates of striatal neurons, and the function of the striatum in learning and memory. Experiments are then presented which address current issues in striatal function, including the identification of projection neurons and interneurons in extracellular recordings from awake, behaving rats, the behavioral correlates of striatal neurons in navigation tasks, and the representation of task parameters by ensembles of striatal neurons. On the basis of extracellularly recorded spike trains, neurons in the rodent striatum could be differentiated into phasic and tonic subtypes, which are believed to correspond respectively to pro- jection neurons and interneurons of the striatum. Tonic neurons could be further differentiated into 3 subtypes on the basis of firing properties and extracellular action potential parameters, and may each correspond to distinct striatal neural types. Phasic neurons which were responsive during navigation tasks were active either during navigation or during reward-receipt. Tonic neuron subtypes were also behaviorally modulated: two subtypes showed spatial oscillations as rats were running in a sequen- tial navigation task, while the third subtype was only modulated following the presentation of a cue which signaled food delivery. Ensembles of striatal neurons provided high-quality representations of task parameters such as spatial location and reward-delivery. However, a strong representation of space was only obtained in a sequential navigation task, and not in a navigation task in which spatial location was ambiguously associated with reward-delivery. Also, in the sequential navigation the striatal spatial representation developed with a time-course the preceded the development of a stable route through the environment, suggesting that the striatum may participate in developing a stable stimulus-response strategy in navigation. iii Contents Acknowledgements i Abstract iii 1 Introduction and overview of the thesis 1 2 The Basal Ganglia 5 2.1 Organization of the basal ganglia ............................ 5 2.1.1 Anatomy . ................................... 5 2.1.2 Striatal neuron types . ............................ 7 2.2 Behavioral correlates of striatal neurons . ..................... 17 2.2.1 Tonic versus phasic neurons . ..................... 19 2.2.2 Phasically active neurons (PANs) . ..................... 20 2.2.3 Tonically active neurons (TANs) . ..................... 25 2.2.4 Changes in striatal activity . ..................... 26 2.3 Striatal function . ................................... 27 2.3.1 Learning and memory . ............................ 27 2.3.2 Sequence learning . ............................ 31 2.3.3 Reinforcement Learning and Basal Ganglia Function . .......... 32 3 Methods 37 3.1 Animals . ................................... 37 3.2 Tasks .......................................... 37 3.3 Surgery . ................................... 39 3.4 Recording . ................................... 40 3.5 Histology . ................................... 41 3.6 Neural Data Analysis . ............................ 41 3.7 Behavioral measures. ............................ 42 4 Classification of striatal neurons 47 4.1 Results .......................................... 48 4.1.1 Data sets . ................................... 48 4.1.2 Phasic/Tonic separation ............................ 48 4.1.3 Multiple subtypes of tonic neurons . ..................... 49 4.1.4 Cell classification is stable between behavioral conditions .......... 51 4.1.5 Spike timing relationships between cell types ................. 52 4.1.6 Relationship of cell type classification to extracellular waveforms . 53 v 4.2 Discussion . ................................... 56 4.2.1 Cell type correspondence ............................ 57 5 The Multiple T Task 59 5.1 Introduction . ................................... 59 5.2 Results .......................................... 59 5.2.1 Behavior . ................................... 59 5.2.2 Neurophysiology . ............................ 61 5.2.3 Phasic-firing neurons . ............................ 62 5.2.4 Tonic-firing neurons . ............................ 69 5.2.5 Striatal representation of task parameters . ................. 73 5.2.6 Neural learning correlates . ..................... 75 5.3 Discussion . ................................... 77 5.3.1 Phasic firing neurons . ............................ 78 5.3.2 Tonic firing neurons . ............................ 80 5.3.3 Striatal representation . ............................ 80 6 The Take 5 task 81 6.1 Introduction . ................................... 81 6.2 Results .......................................... 81 6.2.1 Behavior . ................................... 81 6.2.2 Neurophysiology . ............................ 82 6.2.3 Phasic-firing neurons . ............................ 83 6.2.4 Tonic-firing neurons . ............................ 83 6.2.5 Striatal representation of task parameters . ................. 85 6.3 Discussion . ................................... 86 7 Conclusions 95 Glossary 101 Chapter 1 Introduction and overview of the thesis The basal ganglia constitute a large volume of subcortical tissue and include several distinct nuclei. Over the past two centuries, the basal ganglia have been the subject of a significant number of investigations, but today our understanding of basal ganglia function remains murky. In 1664, based on observations of paralysis in patients with basal ganglia degeneration, Thomas Willis proposed that the corpus striatum (including the caudate nucleus, putamen and globus pallidus) represented the origin of motor behavior (Finger, 1994). Although Willis’ theory was not accepted without dispute, the corpus striatum was widely believed to be the origin of the motor tract controlling the movement of skeletal muscles until the discovery of the motor cortex in 1870. Experimental approaches in animals and clinical observations in humans led to the development by 1940 of a view of basal ganglia function in which the corpus striatum was seen to exert inhibitory control over the production of movements (Finger, 1994), a view which persists today in current models of basal ganglia anatomy and function. In addition to motor function, the basal ganglia have been implicated in cognitive abilities. In particular, the striatum (also termed the caudoputamen, the major input structure to the