2012 |
Miller, Julie Elizabeth |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Synaptotagmin 4: Role in Vocal Motor Function and Parkinson's Disease. @ University of California Los Angeles
DESCRIPTION (provided by applicant): Communication deficits accompany a wide array of developmental disorders and adult-acquired neurological diseases. The neurobehavioral genetic bases for these deficits are poorly understood, rendering treatment challenging yet motivating experimental investigation. Songbirds are advantageous models for uncovering the neural basis for human vocal communication given their structural and functional similarities to humans and the ability to conduct molecular, physiological, and behavioral manipulations not feasible in humans. This proposal focuses on dopaminergic (DA) regulation of a key candidate molecule, Synaptotagmin 4 (Syt4), in basal ganglia circuitry dedicated to learned vocalizations using the songbird model. In both songbird and human basal ganglia, DA regulates pathways important for behavior; when dopamine is lost as occurs in Parkinson's Disease (PD), vocal and non-vocal motor symptoms arise. The molecular pathways that mediate the vocal changes, currently unknown, must be determined in order to remediate this facet of the disease. Recent converging evidence highlights the importance of Syt4 in these pathways. Our studies on Syt4 gene expression show that its levels within the song-dedicated sub-region of the songbird basal ganglia are tightly linked to singing. Bioinformatic studies from the lab predict that Syt4 interacs with other genes in a DA pathway supporting learned vocal behavior. Additional findings implicate Syt4 in human cognitive specializations that distinguish our species from other primates. I thus hypothesize that dopaminergic regulation of Syt4 is functionally specific to vocal pathways, and that loss of DA converts Syt4 regulation from being driven by patterned activity associated with vocalizing to generalized non-specific activity. To test this, I will first determie whether Syt4 is regulated by natural fluctuations in DA that occur during vocal behavior under different social contexts and in a Parkinsonian-like state. Follow up experiments will then test whether loss of DA, such as occurs in PD, switches Syt 4 regulation to that found in non-vocal areas. Results from these aims will provide insight into molecular mechanisms operating in the basal ganglia to support vocal behavior in songbirds and potentially, humans, with the promise of new therapeutic targets to treat vocal disorders. PUBLIC HEALTH RELEVANCE: Communication deficits are a debilitating component in a wide range of developmental disorders (e.g. Autism Spectrum) and adult-acquired neurological diseases (e.g. Parkinson's) with additional negative effects on mental health. The neural and genetic bases for speech deficits are not well-understood. My proposal uses an advantageous animal model for speech, the vocal-learning songbird, to test whether a gene that is linked to birdsong, Synaptotagmin 4, is important in brain pathways for normal vocalization and whether it becomes misregulated in a Parkinsonian-like state.
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2021 |
Miller, Julie Elizabeth |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Alpha-Synuclein Driven Cellular Changes and Vocal Dysfunction in Parkinson's Disease
SUMMARY Diagnosis of Parkinson?s Disease (PD) is made late, delaying treatment and limiting the ability to halt disease progression. Treatments that target the prodromal phase of PD, prior to the appearance of the cardinal motor signs (tremor, rigidity, etc) and the degeneration of dopamine-producing neurons, do not exist because we lack reliable biomarkers of early disease. Based on accumulating evidence, vocal dysfunction is present during the prodromal phase of PD and offers a convenient entry point to identify early neuropathological changes as potential treatment targets. Data from our laboratory and others has shown that the overexpression of a known human-PD causing gene, alpha-synuclein (?-syn, SNCA) in the rodent and finch brain, leads to early vocal abnormalities consistent with human disease. As a synaptic protein, ?-syn is critically involved in cell functions including facilitating neurotransmitter release. Its cellular toxicity in PD has been targeted in human clinical trials but late in the disease, when the neuropathology is already widespread. In fact, little is known about how the physiological role of ?-syn shifts to a pathophysiological one early on in PD. This R21 proposal addresses these shortcomings by investigating early stage abnormalities in vocal motor output that can occur years before traditional motor symptoms. We propose to develop an integrated, early stage platform for the evaluation of the ?-syn-mediated changes in neuronal and synaptic activity that drive abnormal vocal output. To do so, we use the zebra finch model system because it has specialized song-dedicated brain nuclei that can be experimentally targeted; cell-specific changes in activity are then directly related to the vocal output. Area X is a song-dedicated nucleus within the finch basal ganglia. Within Area X, striatal Medium Spiny Neurons (MSNs) and Globus Pallidus-like (PAL) projection neurons show singing-related firing activity that is directly related to variations in song structure. When ?-syn is virally overexpressed in Area X, we detect PD-like changes in song including reduced pitch, amplitude, and abnormal timing. In Aim 1, we test the hypothesis that these song changes result from reduced MSN activity and increased PAL activity in freely behaving birds implanted with extracellular electrode arrays. Aim 2 tests the hypothesis that ?-syn overexpression in Area X results in a time-dependent suppression of glutamatergic currents in MSNs and enhanced GABAergic currents in PAL neurons in living brain slices. Our powerful integrative approach uses in vivo and ex vivo measurements of neural activity to evaluate how ?-syn driven changes in specific neuronal sub-types correlates to the behavioral output. The characterization of neuropathophysiological mechanisms underlying early stage PD-like vocal deficits will offer new disease-modifying treatment targets.
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