2007 |
Zagha, Edward W |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Function and Modulation of Somatic and Dendritic Kv3.3 Channels in Purkinje Cells @ New York University School of Medicine
[unreadable] DESCRIPTION (provided by applicant): How can a point mutation in an ion channel cause motor deficits, mental retardation and massive neurodegeneration? It was recently discovered that mutations in potassium channel Kv3.3 is the cause of human spinocerebellar ataxia SCA13. Affected individuals with mutations in Kv3.3 display cerebellar atrophy and present with severe neuromuscular and cognitive symptoms. This research focuses on the function of Kv3.3 channels in Purkinje cells of the cerebellum, and is a contribution in understanding the pathophysiology of disease in humans with SCA13. Kv3.3 is most strongly expressed in Purkinje cells, with protein localization in somas, axons and dendrites. A highly stereotyped response of Purkinje cells is the complex spike, a massive all-or-none response to climbing fiber activation involving somatic and dendritic electrical activity and large dendritic Ca ++ transients. Due to the expression and electrical properties of Kv3.3 subunits, we hypothesize that they are active in the complex spike and important in the regulation dendritic Ca++ influx. We intend to use pharmacological and genetic approaches to elucidate the specific functions of somatic and dendritic Kv3.3 channels in modulating the electrical properties and Ca++ dynamics of Purkinje cells. Altered Ca++ homeostasis is a probable cause of pathology in humans with Kv3.3 mutations, and these studies are critical in establishing the roles of these channels in regulating Ca++ dynamics. Studies in our laboratory demonstrated the modulation of Kv3.3 subunits by PKC in heterologous expression systems. PKC plays very important roles in Purkinje cell function and plasticity, and it is possible that this modulation of Kv3.3 is an important mechanism in the cellular effects of PKC. Moreover, mutations in PKC gamma are the cause of human spinocerebellar ataxia SCA14. Thus, mutations in either Kv3.3 or PKC gamma produce similar phenotypes, posing the intriguing possibility that modulation of Kv3.3 channels is involved in the expression of disease in humans with mutations in PKC gamma. A second aim of this study is to demonstrate the modulation and Kv3.3 subunits in Purkinje cells and begin to explore the implications of this modulation on Purkinje cell physiology. [unreadable] [unreadable] [unreadable]
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0.958 |
2012 — 2013 |
Zagha, Edward W |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Influence of Motor Cortex On Network Activity and Sensory Processing in S1
DESCRIPTION (provided by applicant): Context dependence is a fundamental property of sensory perception; our perception of the outside world is not passive, but highly dependent upon our internal state (i.e. attention, desire) and ongoing behavior. For instance, if we feel something moving across the surface of our fingertips, it essential to know whether it is the object or our hand that is moving, when interpreting the nature of the object we are touching. Anatomical studies have shown that the movement (motor) and sensory regions of neocortex are highly interconnected, yet we know little about how signals from motor cortex influence sensory processing. We intend to study this sensorimotor integration at the network and cellular levels in the mouse whisker system, which is one of the primary modalities by which mice navigate their surroundings and is analogous to the human tactile sensory system. By using state-of-the-art optogenetics technology we are able to control the activity of neurons in motor cortex and measure cellular and network activity in somatosensory cortex. We have gathered exciting preliminary data that stimulating motor cortex can effectively alter the ongoing network activity in sensory cortex, which may in turn enhance the reliability of sensory responses. In this proposal, in a first set of experiments we intend to establish a mechanistic understanding of how motor cortex inputs influence cellular excitability and sensory responses in somatosensory cortex. These stimulation studies will be conducted in anesthetized mice, where motor and sensory pathways may be stimulated in an otherwise stable and rhythmic network dynamic. A second set of experiments will be conducted in awake mice, in order to determine the importance of the motor cortex inputs in the local regulation of network activity. By stimulating o suppressing activity in motor cortex and recording network activity in multiple sensory regions, we intend to determine whether this input can bi-directionally regulate local changes in network activity in awake mice. This research may potentially contribute to our understanding of the context dependence of sensory processing, and therefore enable a better understanding of sensory perception and motor coordination, be used as a general model for cortico-cortical regulation of sensory processing, and enhance our understanding of cortical deficits following damage to motor cortex as in ALS and stroke. PUBLIC HEALTH RELEVANCE: The ability of attention, motivation and behavior to modify our perception of the external world is a well known phenomenon, and yet the neural pathways involved in this process are poorly understood. Here we propose to study how a part of the brain that controls movement directly influences how the brain processes sensory information. This research has implications for understanding important pathways potentially contributing to movement and perceptual disorders.
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0.928 |
2019 — 2021 |
Zagha, Edward W |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cortical Feedback Modulation of Sensory Processing During Selective Detection @ University of California Riverside
Project Summary/Abstract A hallmark of mental health is the ability to flexibly interact with our surroundings accord to situational context and internal goals. A long-standing theory of cortical physiology is that context-dependent neural processing is mediated by cortical feedback pathways. According to this theory, internal states related to context or goal-direction are encoded in fronto-parietal cortices. These signals propagate throughout cortex along cortical feedback pathways, whereby they set the initial conditions that influence the representation and routing of sensory responses. Mechanistic descriptions of cortical feedback function, however, are limited due to the difficulty of studying specific cortical pathways in behaving subjects. Innovations in this proposal come from combining a well-defined model system, quantitative behavior, and advanced genetic and physiological tools. We study a motor-to-sensory cortical feedback pathway in the mouse whisker system. Our experiments are designed to test hypotheses for how motor cortex feedback informs sensory cortex about processing incoming sensory stimuli. We implement a quantitative sensory detection task, in which mice learn to respond to target stimuli and ignore distractor stimuli. Thus, our proposal will reveal cortical feedback contributions to both target stimulus detection and non-target stimulus (?noise?) suppression. We specifically hypothesize that motor-to-sensory cortical feedback improves task performance by reducing non-target responses through sensory cortex noise suppression. We study these processes at the resolution of behavior, cortical feedback population activity and sensory cortex single unit sensory processing. We use a host of cutting-edge physiological tools including pathway-specific cortical feedback optogenetic suppression, Ca2+ imaging of axons and terminals and multielectrode recordings of identified neuronal cell-types. Together, these studies will provide mechanistic understandings of cortical feedback signaling during goal-directed behavior. Additionally, these studies will generate new hypotheses for how disturbances of cortical feedback may contribute to dysfunctions of context-dependent processing in neuropsychiatric disease.
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0.958 |