The brain evolved to control behavior, and locomotion is among the behaviors most critical to animal survival. The neural mechanisms of skilled locomotion have been studied for decades, yet recently developed technologies offer the opportunity to shine new light on this long studied behavior. I leveraged these technologies to develop a system for studying the behavioral strategies and neural mechanisms of skilled locomotion in mice. In Chapter 2, I use detailed 3D kinematic tracking and behavioral modelling to describe a rapid sensorimotor decision that determines the kinematic strategies used by mice to step over obstacles. Despite the whisker dependency of this behavior, performance is minimally affected by manipulations of whisker sensory cortex, whereas motor cortex manipulations impair but did not prevent obstacle clearance. Neither cortical manipulation substantially impacts the sensorimotor decision. In Chapter 3, we turn to the cerebellum. The cerebellum is thought to contribute to the coordination of movement, as evinced by the locomotor deficits that are a hallmark of cerebellar ataxia. However, much cerebellar research has focused on simple behaviors involving single body parts. Furthermore, the recent discovery of reward signals in the cerebellar cortex has drawn attention to its potential non-motor functions, but whether such signals exist in the output of the cerebellum is unknown. We conducted an electrophysiological survey of the deep cerebellar nuclei to characterize the signals communicated by the cerebellum to downstream structures. Preliminary analyses from this ongoing work suggest that cerebellar output is dominated by orofacial and locomotor signals, whereas reward related modulations are largely accounted for by the behavioral correlates of reward delivery. Collectively, these results demonstrate that quantitative whole body analyses of ethologically inspired behaviors can enhance our understanding of the neural control of sensorimotor behaviors.

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The cerebellum was investigated in different mouse models for neurodegenerative diseases Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA). Cerebellar pathology was detected in SMA mouse models.

High precision is critical for normal neural circuit function, but that precision is not innate. The location, strength, and number of inputs in a neural circuit are modified in early postnatal development in a process called refinement. The refinement of long-range excitatory projections is well-known, but less is known about the refinement of long-range inhibitory projections. What we do know about inhibitory projection refinement comes from the glycinergic medial nucleus to the trapezoid body to lateral superior olive (MNTB-LSO) projection of the auditory brainstem. During early postnatal life, the MNTB-LSO projection undergoes morphological and physiological refinement. Notably, the MNTB-LSO projection transiently expresses vesicular glutamate transporter 3 (VGLUT3) and synaptotagmin 1 (Syt1), transiently releases glutamate, and undergoes glutamate-dependent refinement. However, it remains uncertain whether glutamate release is specific to the auditory brainstem or could be a more general phenomenon of inhibitory projections. To shed light on this question, I investigated another inhibitory projection of the hindbrain, the GABAergic Purkinje projection of the cerebellum. The Purkinje projection shares key characteristics with the MNTB-LSO projection, including its inhibitory nature, location in the hindbrain, obvious topographic organization, heterogeneity of the target cells, and expression of VGLUT3 transcript and protein. In this thesis, I sought to determine: 1) whether the expression profile of VGLUT3 and Syt1 in the Purkinje projection matches that of the MNTB-LSO projection, and whether the Purkinje projection also releases glutamate, 2) whether the expression profile of synaptic vesicle protein 2 (SV2) isoforms, SV2B and SV2C, matches the expression profile of other synaptic vesicle proteins in the Purkinje and MNTB-LSO projection, and 3) whether the Purkinje projection undergoes postnatal morphological refinement like the MNTB-LSO projection. I found that like the MNTB-LSO projection, the Purkinje projection transiently expresses VGLUT3 and Syt1, releases glutamate in early postnatal life, and may undergo morphological refinement. / Dissertation / Doctor of Philosophy (PhD) / Everything you do, whether it be playing your favorite sport or begrudgingly reading this thesis, requires neural circuits, which are the basic functional unit of the nervous system. How neurons are wired together is crucial for their role in executing a task. But how these neurons fine-tune their connections – in a process called refinement, by getting the right connections to the right location, of the right strength, and of the right number – is an open-ended question in neuroscience. Refinement is more well-studied in excitatory projection neurons, but we know very little about how refinement occurs in inhibitory projection neurons. I compare some of the unusual characteristics of what we do know about inhibitory refinement in the auditory brainstem to another famous projection of the hindbrain, the Purkinje projection. Understanding more about the refinement of inhibitory projections gives key insights into how neural circuits function and how they facilitate complex behaviours.

Although the cerebellum has been traditionally thought of as a motor processing brain region, recent evidence suggests that the cerebellum is functionally diverse. The posterior cerebellum in particular has been shown to play a role in social cognitive processes, and recent work has proposed that this region helps fine tune mental models of social cognition to, for example, to ensure accurate selection of actions in a social scenario. Social interactions with strangers are difficult, in part because we are constantly trying to gauge whether the other person likes or dislikes us without much information for our mental models to help us. From a reward processing standpoint, this requires tracking the value (positive or negative) of people’s valence to us and ensuring that our predictions about people’s affect towards us are correct. The aim of this project was to specify how the posterior cerebellum uniquely contributes to social reward processing, and to distinguish this contribution from regions that are canonically part of the reward and social brain regions. Participants, ages 12-36, completed a well-matched social and monetary reward task in the scanner. In the monetary condition, participants were asked to select which of two doors would result in winning money, and in other trials losing money. In the social condition, participants were asked to select which of two faces representing people would like or dislike them. Representational similarity analysis was used to compare the responses of reward and social brain regions to conditions in which participants either won or lost money and were either liked or disliked by others. We found that portions of the posterior cerebellum were sensitive to social reward, and treated positive social rewards more similarly to negative social rewards than the striatum. These results suggest that these regions in the posterior cerebellum has a dissociable contribution to social reward processing compared to other brain regions. / Psychology

The cerebellar granule cell layer has inspired numerous theoretical models of neural representations that support learned behaviors, beginning with the work of David Marr and James Albus. In these models, granule cells form a sparse, combinatorial encoding of diverse sensorimotor inputs. Such sparse representations are optimal for learning to discriminate random stimuli. However, recent observations of dense, low-dimensional activity across granule cells have called into question the role of sparse coding in these neurons. In this thesis, I generalize theories of cerebellar learning to determine the optimal granule cell representation for tasks beyond random stimulus discrimination, including continuous input-output transformations as required for smooth motor control. I show that for such tasks, the optimal granule cell representation is substantially denser than predicted by classic theories. The results provide a general theory of learning in cerebellum-like systems and suggest that optimal cerebellar representations are task-dependent.

Phenylethanolamine N-methyltransferase (Pnmt) is the enzyme in the catecholamine pathway responsible for converting norepinephrine to epinephrine. Pnmt is present in numerous areas; however, the scope of its expression in the mouse brain is not fully understood. A genetic mouse model was generated by the Ebert lab that exhibited the selective destruction of all Pnmt+ cells through the induction of apoptosis by Diphtheria Toxin A. Unexpected phenotypic defects arose that are characterized by metabolic weight deficits and motor ataxia. The distribution of Pnmt+ neurons was examined throughout the hypothalamus and cerebellum to generate an anatomical map of current and historical Pnmt expression using various histochemical methods. Historical Pnmt expression appears more extensive than current expression levels at the adult stage, indicating that certain cells in the mouse brain may have experienced transient Pnmt expression. The presence of Pnmt in these regions suggests that the destruction of these neurons may play a role in the phenotypic defects observed in the ablation mouse model. Gaining a more comprehensive understanding of the potential role of Pnmt in these areas may elucidate new drug targets or novel methods to treat obesity and motor control disorders such as ataxia.

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Motion of an image across the retina degrades visual accuracy, thus eye position must be held stationary. The horizontal eye velocity-to-position neural integrator (PNI), located in the caudal hindbrain of vertebrates, is believed to be responsible since the neuronal firing rate is sustained and proportional to eye position. The physiological mechanism for PNI function has been envisioned to be either (1) network dynamics within or between the bilateral PNI including brainstem/cerebellar pathways or (2) cellular properties of PNI neurons. These hypotheses were investigated by recording PNI neuronal activity in goldfish during experimental paradigms consisting of disconjugacy, commissurectomy and cerebellectomy.In goldfish, the eye position time constant ([tau]) is modifiable by short-term (~1 hr) visual feedback training to either drift away from, or towards, the center of the oculomotor range. Although eye movements are yoked in direction and timing, disconjugate motion during [tau] modification suggested separate PNIs to exist for each eye. Correlation of PNI neural activity with eye position during disconjugacy demonstrated the presence of two discrete neuronal populations exhibiting ipsilateral and conjugate eye sensitivity. During monocular PNI plasticity, [tau] was differentially modified for each eye corroborating coexistence of distinct neuronal populations within PNI.The hypothesized role of reciprocal inhibitory feedback between PNI was tested by commissurectomy. Both sustained PNI activity and [tau] remained with a concurrent nasal shift in eye position and decrease in oculomotor range. [tau] modification also was unaffected, suggesting that PNI function is independent of midline connections.The mammalian cerebellum has been suggested to play a dominant role for both [tau] and [tau] modification. In goldfish, cerebellar inactivation by either aspiration or pharmacology both prevented and abolished [tau] modifications, but did not affect eye position holding. PNI neurons still exhibited eye position related firing and modulation during training.By excluding all network circuitry either intrinsic or extrinsic to PNI, these results favor a cellular mechanism as the major determinate of sustained neural activity and eye position holding. By contrast, while cerebellar pathways are important for sustaining large [tau] (>20s), they are unequivocally essential for [tau] modification.

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