Role of Basal Ganglia Output on Thalamo-Cortical Activity and Licking Behavior in Mice Restricted; Files Only

Morrissette, Arthur (Fall 2018)

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The planning and execution of voluntary movement involves multiple brain areas including the cortex, thalamus, and basal ganglia. How these areas interact to control movement remains unknown. The basal ganglia are thought to contribute to motor control by providing tonic inhibitory output to the thalamus in order to suppress unwanted movements and facilitate desired ones. To test this prediction, we used rapid optogenetic activation and inactivation of the GABAergic output of the basal ganglia to the motor thalamus in mice that were trained in a sensory cued left/right licking task. We found that 1s of unilateral optogenetic inhibition of GABAergic output from the substantia nigra reticulata (SNr) biased decision making towards the contralateral lick spout even during ipsilaterally cued trials. In contrast, 1s of optogenetic excitation of SNr terminals in motor thalamus resulted in a bias towards the ipsilateral direction. Output from the SNr continues to the motor thalamus which then projects widely across sensorimotor cortex. Thus, in order to examine cortical activity across cortex with high spatiotemporal resolution, we utilized mice expressing the fluorescent voltage indicator in excitatory cortical neurons. While previous studies have shown that the pupil provides important insights in neural processing as a proxy for arousal, it is unknown how arousal signals as measured by pupil diameter are represented by changes in cortical activity. We found that pupil diameter is tightly coupled to global changes in cortical voltage. This coupling is dependent on both frequency and location, with lower frequency signals and medial areas of the sensory-motor cortex most strongly coupled with arousal especially during periods of orofacial movements. Finally, we measured voltage activity across cortex in behaving mice to determine the voltage changes across cortex while mice prepared, withheld, and initiated licking movements. We found that membrane voltage in the contralateral motor cortex before the onset of the response period predicts the reaction time on a trial-to-trial basis such that increased voltage activity preceding the first lick is elevated on faster reaction time trials. Together, these experiments provide new insight in to the mechanisms by which the basal ganglia-thalamocortical circuits contribute to voluntary motor behavior. 

Table of Contents

Chapter 1: General Introduction. 1

1.1 The Basal Ganglia. 2

1.1.1 Basal Ganglia Anatomy. 2

1.1.2 Basal Ganglia Control of Movement. 5

1.1.3 Basal Ganglia Disorders and Movement. 9

1.2 Cognitive Control of Movement. 10

1.2.1 Thalamic Control of Movement. 11

1.2.2 Cortical Motor Systems. 16

1.2.3 Control of Voluntary Licking Behavior. 23

1.3 Thesis Organization. 26

Chapter 2: Unilateral optogenetic inhibition and excitation of basal ganglia output show opposing effects on directional lick choices and movement initiation in mice. 27

2.1 Abstract. 27

2.2 Significance Statement. 29

2.3 Introduction. 30

2.4 Methods. 32

2.5 Results. 41

2.6 Discussion. 59

Chapter 3: Wide-Field Imaging of Spatiotemporal Cortical Voltage Activity Underlying Arousal During Spontaneous Behavior. 66

3.1 Abstract. 66

3.2 Introduction. 67

3.3 Methods. 69

3.4 Results. 77

3.5 Discussion. 92

Chapter 4: Cortical Voltage Dynamics Underlying Movement Preparation and Initiation in Awake, Behaving Mice. 96

4.1 Introduction. 96

4.2 Methods. 100

4.3 Results. 105

4.4 Discussion. 116

Chapter 5: General Discussion. 119

5.1 Establishment of Cortical Voltage Imaging Techniques in Awake, Behaving Mice. 120

5.2 Cortical Voltage Dynamics in During Awake, Spontaneous Behavior. 122

5.3 Cortical Voltage Imaging of Movement Preparation and Initiation. 123

5.4 Future Directions. 124

References. 127

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