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Browsing by Subject "Cerebellum"

Now showing 1 - 8 of 8
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    Computational studies of cerebellar cortical circuitry
    (2013-05) Popa, Laurentiu Silviu
    This thesis includes two directions of research regarding the function and physiology of the cerebellum. One direction was concentrated on the cerebellum involvement in motor control during a visually guided tracking task performed by non-human primates. The second effort aimed to characterize the effects of the P/Q-type Ca2+ channelopathy on the physiology of the cerebellar cortex in tottering mice and to explore the mechanisms that transform homeostatic deficits due to genetic mutations into transient phenotype such as episodic dystonia. Understanding the cerebellum function is an ongoing challenge. The cerebellum has been implicated in error processing required for on-line motor control and motor learning. The dominant view is that the error related signals are encoded by the Purkinje cell complex spike discharge. The results presented in this thesis show that the Purkinje cell simple spike activity robustly signals a rich representation of task specific performance errors, independently from the kinematic signals. The results also show that a large majority of the Purkinje cells encode behavioral parameters dually by a pair of signals, one predictive and one feedback related. The predictive signals could provide the neural substrate for the feedback-independent compensatory movements that maintain motor behavior accuracy. The dual representation is also consistent with the signals needed to generate the prediction sensory error used to update an internal model. These results provide new insights into the cerebellum function and have interesting implications for the forward internal model hypothesis. The tottering mouse is an autosomal recessive disorder involving a mutation in the gene encoding the P/Q-type Ca2+ channels and is one of the animal models for the episodic ataxia type 2. The most remarkable aspect of the tottering mouse phenotype are the transient attacks of dystonia triggered by stress, ethanol or caffeine. The neural processes underlying the transient phenotype are unknown. The results presented in this thesis, based on the flavoprotein autofluorescenece imaging, show that the tottering mouse dysfunction is associated with the presence of transient synchronous low frequency oscillations in the cerebellar cortex. For a large majority of cerebellar cortical neurons the optical oscillations reflect the oscillations present in their spontaneous activity. The oscillations appear to be intrinsic to the cerebellar cortex and in the awake animals increased oscillatory cerebellar activation becomes highly coherent with the EMG activity during episodic dystonia. Low frequency oscillations of the cerebellum represent a novel abnormality in the tottering mouse and could provide insights into the mechanism underlying the transient phenotype of the episodic ataxia type 2.
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    Defining a Neuroprotective Pathway for the Treatment of Ataxias
    (2016-08) Leathley, Emily
    Spinocerebellar Ataxias (SCAs) are a group of genetic diseases characterized by progressive ataxia caused by neurodegeneration of specific cell types, namely Purkinje Cells (PCs) of the cerebellum. Mouse models of SCA Type 1 (SCA1) can be used to study the molecular mechanisms underlying PC degeneration and death. One SCA1 mouse model, ATXN1[30Q]D776, has an initial ataxia but no progressive degeneration or PC death. RNA-seq experiments identified the up-regulation in the cerebellum of the peptide hormone Cholecystokinin (Cck) in these mice. Knocking out Cck or the Cck1 receptor (Cck1R) in ATXN1[30Q]D776 mice confers a progressive disease where PC death occurs by thirty-six weeks of age. Weighted Gene Co-expression Network Analysis (WGCNA) performed on cerebellar RNA-seq data from ATXN1[30Q]D776;Cck-/- mice identified a disease progression-related gene set named the Pink Module that is influenced by Cck. A Cck1R agonist, A71623, was administered via osmotic minipump to ATXN1[30Q]D776;Cck-/- mice and AXTN1[82Q] mice, which are a more faithful representation of human SCA1 PC degeneration. In both mouse models, A71623 protected against progressive ataxia and PC degeneration. These results suggest that manipulation of the Cck-Cck1R pathway may be a therapeutic target for treatment of diseases involving PC degeneration.
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    Does cerebellar cortex function as a forward internal model for motor control?
    (2013-06) Hewitt, Angela L.
    Motor control theorists have postulated that to produce rapid, finely tuned movements, a component of the control circuitry must bypass long sensory feedback delays by providing an estimate of the consequences resulting from a motor command. This control element, termed a forward internal model, receives an efferent copy of the motor command and information about the current state in order to predict the future state (i.e. kinematic variables like position, velocity) of the limb. Previous psychophysical, imaging, and patient case studies suggest that the cerebellum is a possible location for implementation of an internal model. However, very few electrophysiological studies have investigated whether the firing discharge from cerebellar neurons is consistent with the output of a forward internal model. To specifically evaluate the simple spike firing from Purkinje cells in lobules IV-VI, we trained rhesus macaques to perform different hand movement tasks using a 2 joint robotic manipulandum. Two electrophysiology experiments tested several aspects of a forward internal model. First, we hypothesize that Purkinje cell simple spike firing predicts future hand kinematics, even when the task is highly unpredictable. Second, the encoding is invariant, so that the model output can generalize to other tasks. A third hypothesis is that the simple spike discharge will show evidence of learning when animals adapt to a predictable mechanical perturbation, as expected from a forward internal model. Experimental results found many theoretical components of a forward internal model present in the Purkinje cell simple spike discharge. Simple spikes encode both feedforward and feedback representations of movement kinematics, with position and velocity signals explaining the most firing variability. These representations supply the predictive kinematic signals used downstream and the feedback information potentially used locally to construct predictions, calculate errors, and update the model. Many Purkinje cells exhibit dual encoding for a single kinematic parameter, so that these separate feedforward and feedback mechanisms may take place within individual cells. For most cells, model coefficients generated from random tracking data accurately estimate simple spike firing in either circular tracking or center-out reach. Adaptation to a predictable perturbation initiates steady, progressive changes in the parameter sensitivity (βs) of both the feedforward and feedback signals. The timing sensitivity (τ) also demonstrates significant shifts, with time encoding in the simple spikes often changing sign during adaptation (e.g. feedback to feedforward). Population analyses suggest that large changes in parameter sensitivity first occur in the feedback signals, then transfer to the feedforward representations. This may reflect use of the simple spike feedback to update model predictions. These results conclude that kinematic encoding from the cerebellar cortex uses a forward internal model that can generalize between tasks, but is also highly plastic and adaptable.
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    Encoding and control of motor prediction and feedback in the cerebellar cortex
    (2017-08) Streng, Martha
    Extensive research implicates the cerebellum as a forward internal model that predicts the sensory consequences of motor commands and compares them to their actual feedback, generating prediction errors that guide motor learning. However, lacking is a characterization of how information relevant to motor control and sensory prediction error is processed by cerebellar neurons. Of major interest is the contribution of Purkinje cells, the primary output neurons of the cerebellar cortex, and their two activity modalities: simple and complex spike discharges. The dominant hypothesis is that complex spikes serve as the sole error signal in the cerebellar cortex. However, no current hypotheses fully explain or are completely consistent with the spectrum of previous experimental observations. To address these major issues, Purkinje cell activity was recorded during a pseudo-random manual tracking task requiring the continuous monitoring and correction for errors. The first hypothesis tested by this thesis was whether climbing fiber discharge controls the information present in the simple spike firing. During tracking, complex spikes trigger robust and rapid changes in the simple spike modulation with limb kinematics and performance errors. Moreover, control of performance error information by climbing fiber discharge is followed by improved tracking performance, suggesting that it is highly important for optimizing behavior. A second hypothesis tested was whether climbing fiber discharge is evoked by errors in movement. Instead, complex spikes are modulated predictively with behavior. Additionally, complex spikes are not evoked as a result of a specific ‘event’ as has been previously suggested. Together, this suggests a novel function of complex spikes, in which climbing fibers continuously optimize the information in the simple spike firing in advance of changes in behavior. A third hypothesis tested is whether the simple spike discharge is responsible for encoding the sensory prediction errors crucial for online motor control. To address this, two novel manipulations of visual feedback during pseudo-random tracking were implemented to assess whether disrupting sensory information pertinent to motor error prediction and feedback modulates simple spike activity. During these manipulations, the simple spike modulation with behavior is consistent with the predictive and feedback components of sensory prediction error. Together, this thesis addresses a major outstanding question in the field of cerebellar physiology and develops a novel hypothesis about the interaction between the two activity modalities of Purkinje cells.
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    Exploration and Evaluation of Core Circadian Rhythm Components in Relation to Autism Spectrum Disorders
    (2022-08) Lorsung, Ethan
    Autism spectrum disorders (ASDs) are a spectrum of neurodevelopmental disorders characterized by impaired social interaction and communication, as well as stereotyped and repetitive behaviors. ASDs affect nearly 2% of the United States child population and the worldwide prevalence has dramatically increased in recent years. The etiology is not clear but ASD is thought to be caused by a combination of intrinsic and extrinsic factors. Circadian rhythms are the ∼24 h rhythms driven by the endogenous biological clock, and they are found in a variety of physiological processes. Growing evidence from basic and clinical studies suggest that the dysfunction of the circadian timing system may be associated with ASD and its pathogenesis. Here I review the findings that link circadian dysfunctions to ASD in both experimental and clinical studies, then I report novel research furthering the relationship between the core circadian gene Bmal1 and ASD. I first introduce the organization of the circadian system and ASD. Next, I review physiological indicators of circadian rhythms that are found disrupted in ASD individuals, including sleep–wake cycles, melatonin, cortisol, and serotonin. I then review evidence in epidemiology, human genetics, and biochemistry that indicates underlying associations between circadian regulation and the pathogenesis of ASD. Finally, I design and report findings of my original basic research, including pervasive abnormalities in the developing mouse cerebellum and social deficits as a result of deletion of the core circadian component Bmal1. In conclusion, I propose that understanding the functional importance of the circadian clock in normal and aberrant neurodevelopmental processes may provide a novel perspective to tackle ASD, and clinical treatments for ASD individuals should comprise an integrative approach considering the dynamics of daily rhythms in physical, mental, and social processes.
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    Normal and diseased circuitry in the cerebellar and cerebral cortex
    (2014-09) Cramer, Samuel William
    The cerebellum is a major motor control structure with a highly ordered circuity. The parallel fibers (PFs) are a dominant element of the cerebellar circuitry. Parallel fibers are the bifurcated axons of the granule cells (GCs) that project across the surface of the cerebellar cortex and synapse on the major output neuron, the Purkinje cell (PC). However, the role of PFs in the cerebellum has long been controversial and a matter of intense debate. Early studies inspired the "beam" hypothesis whereby GC activation results in PF driven, post-synaptic excitation of beams of PCs. However, the "radial" hypothesis postulates that the ascending limb of the GC axon provides the dominant input to PCs and generates patch-like PC responses. To address the beam versus patch controversy and PF function in the cerebellar cortex, this thesis used optical imaging and single PCs recordings in the mouse cerebellar cortex, both in normal mice and in a murine model of a P/Q-type Ca2+ channelopathy. The results provide the first demonstration of beam-like activation of PCs in the cerebellar cortex to peripheral input in normal mice. Furthermore, the pattern of PC responses depends on extracellular glutamate and its local regulation by excitatory amino acid transporters. The findings account for the contradictions of previous studies, clarifying why the responses in some regions of the cerebellar cortex are patch-like and other beam-like.Altered GC-PF-PC synaptic transmission is hypothesized to produce cerebellar motor dysfunction. This thesis tests this hypothesis in the tottering (tg/tg) mouse that has mutation in the gene that codes for the α1A pore-forming subunit of the P/Q-type voltage gated Ca2+ channel and is a model for human episodic ataxia type 2 (EA2). This channel is highly expressed on both GCs and PCs. Further, both EA2 patients and tg/tg mice have cerebellar ataxia. The thesis shows that the GC-PF-PC synaptic transmission is reduced in the tg/tg mouse and a main pharmacological therapy for EA2, 4-aminopyridine, rescues the deficits. The results strongly implicate decreased GC-PF-PC function in the baseline ataxia. Both EA2 patients and tg/tg mice have non-episodic neurologic dysfunction, such as the cerebellar ataxia, but also episodic dysfunction. The episodic abnormalities involve the cerebral cortex, including epilepsy, migraine headaches and cognitive dysfunction. The final component of the thesis examined whether episodic abnormalities are present in the cerebral cortex of the tg/tg mouse. Optical imaging and single cell recording results demonstrate highly abnormal excitability changes throughout the cerebral cortex of tg/tg mice consisting of transient low frequency oscillations (LFOs) very high power. The LFOs are mediated, at least in part, by neuronal activity. Unexpectedly, the LFOs are driven by reducing excitatory inputs to the cerebral cortex. Furthermore, the high power LFOs are decreased markedly by acetazolamide and 4-aminopyridine, the primary treatments for EA2, demonstrating disease relevance. The LFOs in the tg/tg mouse represent an abnormal state involving decreased excitatory synaptic transmission and may underlie non-cerebellar symptoms that characterize P/Q-type Ca2+ channelopathies.
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    Optogenetic Investigation into the Role of Cerebellar Interneurons in Social Behavior
    (2021-02) Zhang, Hao
    Appropriate social behavior is vital for survival and developmental success of humans and animals. Impaired social behavior is a common symptom in mental illness. However, the neural basis underlying social behavior is not well understood. The cerebellum is classically recognized to be involved in motor control, but recently there has been an increasing appreciation of its role in cognitive and social functions. Human neuroimaging and postmortem studies have shown that cerebellar abnormalities, particularly in Purkinje neurons, are associated with neuropsychiatric disorders. Research using animal models suggests dysfunction of Purkinje neurons, which conduct the output from the entire cerebellar cortex, can generate abnormal social behavior. Yet, how the cerebellar dysfunction is transformed to global pathogenesis of social deficits remains unknown. In the cerebellar circuitry, the activity of Purkinje neurons is critically regulated by molecular layer interneurons (MLIs). In this study, we applied an optogenetic approach to selectively manipulate the excitability of MLIs using a mouse line with genetically encoded channelrhodopsin. By developing an optical stimulation protocol, we demonstrated that the cerebellum was critical for social recognition, which provides a mechanistic insight for the cerebellum-mediated neuropsychiatric disorders.
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    Partial Tip60 loss slows cerebellar degeneration in a Spinocerebellar Ataxia Type 1 (SCA1) mouse model.
    (2009-07) Gehrking, Kristin Marie
    Spinocerebellar ataxia type 1 (SCA1) is one of nine dominantly inherited neurodegenerative diseases caused by polyglutamine tract expansion. In SCA1, the expanded polyglutamine tract is in the ataxin-1 (ATXN1) protein. Increased polyglutamine tract length results in earlier disease onset and greater disease severity, which is largely due to cerebellar Purkinje cell degeneration. ATXN1 is part of an in vivo complex with the nuclear receptor (retinoid acid receptor-related orphan receptor alpha [ROR-alpha]) and acetyltransferase (tat-interactive protein 60 kD [Tip60]). ATXN1 and Tip60 interact directly; however, the significance of this interaction is unclear. To test the effect of partial Tip60 loss on SCA1 disease progression, I developed a mutant ATXN1[82Q]/+:Tip60+/- mouse model. Partial Tip60 loss increased ROR-alpha, Rora, and ROR-alpha-mediated gene expression and delayed ATXN1[82]-mediated cerebellar degeneration during midstage disease progression. I also compared ATXN1[82Q]/+ phenotypes between different genetic background strains. Finally in vitro data suggested an ATXN1 polyglutamine length effect on Tip60 acetyltransferase activity. In additional to highlighting genetic background modulation in SCA1 disease, these results suggest a specific temporal role for Tip60 during disease progression and a putative role for Tip60 acetylation in SCA1 disease progression.