Browsing by Subject "Purkinje cell"

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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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    PKA phosphorylation of ATAXIN1 in Purkinje cells modulates early onset of ataxia
    (2017-01) Perez Ortiz, Judit
    Spinocerebellar ataxia type 1 (SCA1) is a fatal adult-onset, autosomal dominant ataxia characterized in part by dysfunction and degeneration of Purkinje cells of the cerebellum. The fundamental basis of pathology is an aberration in the regulation of RNA splicing and gene transcription. SCA1 is caused by an unstable CAG trinucleotide repeat mutation in the ATXN1 gene that codes for a toxic ATXN1 protein with an abnormal polyglutamine repeat. Decreasing mutant ATXN1 can reverse disease phenotypes in SCA1 mouse models. Phosphorylation of ATXN1 at Serine 776 (S776) is critical for disease and this modification influences ATXN1 protein levels and protein-protein interactions, which can exacerbate toxicity. Previous in vitro studies implicated PKA, cAMP protein kinase, in phosphorylation of ATXN1 at S776. The hypothesis being tested is that PKA-mediated ATXN1-S776 phosphorylation stabilizes ATXN1 and drives pathogenic pathways involved in disease. SCA1 mouse models expressing wild type human ATXN1[30Q] or mutant human ATXN1[82Q] were crossed to a PKA mutant mice that exhibit attenuated PKA activity. I found that PKA hypofunction leads to a decrease of phospho-S776-ATXN1 and total ATXN1 expressed in cerebellar Purkinje neurons. Mouse Atxn1 protein expressed in other cerebellar cell types was unchanged, pointing to cell specificity. In order to evaluate the disease relevance of these effects, I tested SCA1 disease metrics in the affected model, including motor behavior, histopathology and gene expression changes. Motor performance was improved to wild type levels early in disease, but progressive Purkinje cell atrophy was not averted. These results hinted at a dissociation between mechanisms causing ataxia versus Purkinje cell degeneration. Indeed, RNA sequencing studies revealed transcriptional changes linked to motor dysfunction that are distinct from those associated with progressive pathology. This work suggests ATXN1 is phosphorylated by PKA in Purkinje neurons early in disease and drives pathways that underlie early onset ataxia that are independent of pathways promoting progressive neurodegeneration.