CROSS-MODAL CHANGES IN AUDITORY CORTEX BY VISUAL DEPRIVATION
O Patrick
Johns Hopkins Universitycity: Baltimore country: United States (us)
Grant 7R21NS070645-03 from National Institute Of Neurological Disorders And Stroke
Keywords: Affect; AMPA Receptors; Animals; Area; area striata; Auditory; Auditory area; awake; Biological Neural Networks; Blindness; braille; Brain; Clinical; Cochlear Implants; dark rearing; Data; design; Discrimination (Psychology); Environment; Event; extrastriate visual cortex; Financial compensation; Hearing; In Vitro; in vivo; Intervention; Light; Mediating; Modality; multisensory; Mus; neural prosthesis; Neurons; Perception; Pitch Discrimination; Process; Property; Prosthesis; public health relevance; Reading; receptive field; Recovery; relating to nervous system; Reporting; Rodent; Role; Sensory; sensory cortex; sensory mechanism; sensory system; somatosensory; sound; Sound Localization; success; Synapses; Synaptic Transmission; System; Tactile; Testing; therapeutic development; Vision; Visual Cortex; visual deprivation; Visually Impaired Persons; Whole-Cell Recordings; Work
Relevance: Blind individuals display enhance functionality in the remaining senses, such as better sound localization and discrimination. We will examine how loss of vision affects the function of primary auditory cortex, an area of the brain involved in sound processing. Results from our work will benefit the development of therapeutics for recovering vision, as extensive sensory compensation is known to impede the recovery of the lost sense
Project start date: 2010-05-01
Project end date: 2012-04-30
Budget start date: 1-JUL-2011
Budget end date: 30-APR-2012
7R21NS070645-03 (2011): $183749
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to O Patrick
NEURONAL CIRCUITS AND PLASTICITY OF NEONATAL AUDITORY CORTEX
O Patrick
University Of Maryland College Pk Campuscity: College Park country: United States (us)
Grant 5R01DC009607-03 from National Institute On Deafness And Other Communication Disorders
Abstract: The perception of speech and language requires normal functioning of the auditory cortex. Injury to the developing brain can lead to deficits in speech and language perception that originate from altered auditory cortex function. To understand how these deficits develop and to devise novel treatment approaches for early injuries one has to understand the functional development and plasticity of auditory cortex. During early times in development, additional neuronal circuits are present in all areas of the developing cortex that are absent in the adult cortex. These circuits are formed by subplate neurons. Subplate neurons play a key role in the functional maturation of thalamocortical synapses and inhibitory circuits as well as plasticity during the critical period when sensory experience can sculpt cortical circuits. Despite this demonstrated importance of subplate neurons, it is unknown how these neurons are integrated in the developing cortical circuit, how they respond to sound, and how they influence auditory cortical development. It is our central hypothesis that subplate neurons aid in setting up cortical maps, such as the tonotopic map in auditory cortex, by controlling the activity dependent maturation of thalamocortical and inhibitory circuits. Since these maps are important for the processing of sound information, understanding their formation and plasticity is essential to understanding the effects of early injuries. To address these fundamentally important issues we propose a series of in vivo and in vitro experiments in mouse auditory cortex using a combination of electrophysiological and imaging techniques. 1) To determine the functional connectivity of subplate neurons in auditory cortex. 2) To determine the response characteristics of subplate neurons to sound. 3) To determine how subplate neurons guide thalamocortical maturation and how subplate neurons contribute to the columnar architecture of auditory cortex. Collectively, these experiments will provide the fundamental framework of understanding development and plasticity of auditory cortex by elucidating the function of a previously ignored central component of auditory cortex development. PUBLIC HEALTH RELEVANCE Injury to the developing brain leads to deficits in speech and language perception that might originate in altered function of the primary auditory cortex. Such injury in early life damages subplate neurons, which are critical for normal development. The proposed experiments for the first time elucidate the connectivity and functional role of subplate neurons in the developing auditory cortex by physiological and imaging methods and thus they lay the groundwork for better understanding of auditory cortical development. Results should also add to knowledge of normal development in children and to understanding causes of neurodevelopmental disorders such as cerebral palsy, epilepsy, and schizophrenia
Keywords: Ablation; Acoustic Stimulation; Address; Adult; Age; Architecture; Area; Attention; Auditory; Auditory area; auditory stimulus; Brain; Brain Injuries; Cerebral Palsy; Characteristics; Child; Complex; Cortical Column; critical period; Development; Epilepsy; experience; Frequencies (time pattern); Goals; Health; Hearing; Hypoxia; Image; imaging modality; Imaging Techniques; In Vitro; in vivo; Inhibitory Synapse; Injury; Knowledge; Language; Language Disorders; language perception; Lead; Learning Disabilities; Lesion; Life; Link; Maps; Mediating; Microelectrodes; Mus; Neonatal; Neurodevelopmental Disorder; Neurons; novel; Penetration; Physiological; Play; postnatal; prenatal; Process; public health medicine (field); research study; response; Role; Schizophrenia; Sensory; Series; Shapes; Signal Transduction; Somatosensory Cortex; sound; Speech; Speech Perception; Synapses; Synaptic plasticity; Testing; Thalamic structure; Time; two-photon; Visual Cortex; Work
Relevance: Relevance to public health: Injury to the developing brain leads to deficits in speech and language perception that might originate in altered function of the primary auditory cortex. Such injury in early life damages subplate neurons, which are critical for normal development. The proposed experiments for the first time elucidate the connectivity and functional role of subplate neurons in the developing auditory cortex by physiological and imaging methods and thus they lay the groundwork for better understanding of auditory cortical development. Results should also add to knowledge of normal development in children and to understanding causes of neurodevelopmental disorders such as cerebral palsy, epilepsy, and schizophrenia. 1
Project start date: 2009-04-01
Project end date: 2014-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-07-070
5R01DC009607-03 (2011): $328898
CROSS-MODAL CHANGES IN AUDITORY CORTEX BY VISUAL DEPRIVATION
O Patrick, Associate Professor
University Of Maryland College Pk Campuscity: College Park country: United States (us)
Grant 5R21NS070645-02 from National Institute Of Neurological Disorders And Stroke
Abstract: Proper integration of multiple senses is critical for providing a coherent perception of the environment. Cross-modal relay of sensory information is not only critical for multisensory integration, but provide substrates for cross-modal compensation when losing a sensory modality. For example, in blind individuals cross-modal compensation is observed as enhanced functionality in the remaining senses as well as recruitment of visual areas by Braille reading. While cross-modal plasticity is largely beneficial to blind individuals, it poses a challenge when attempting to recover function by clinical interventions. For instance, the success of recovering hearing by cochlear implants is reported to be inversely correlated with the extent of cross-modal sensory compensation. It is likely that recovery of vision will encounter similar obstacles. Most studies of cross-modal plasticity focuses on systems level analyses, hence cellular and circuit level mechanistic understanding is quite limited. We previously reported that depriving rodents of vision by dark-rearing not only alters synaptic transmission in primary visual cortex (V1), but also produces opposite changes in primary auditory cortex (A1). In particular, we observed an increase in excitatory synaptic transmission in the superficial layers of V1, but a decrease in excitatory synaptic transmission in the superficial layers of A1 following dark-rearing. While our data suggest that visual deprivation can globally alter excitatory synaptic transmission across different primary sensory cortices, it is unclear how these changes affect cortical function. In this proposal, we will test the hypothesis that visual deprivation-induced decrease in excitatory synaptic transmission alters the receptive field properties of A1 neurons. We will test our hypothesis by combining in vitro whole-cell recordings to assess specific circuit properties of layer 2/3 neurons in A1, and in vivo single unit recordings of these neurons from awake mice. Specifically, we will determine whether visual deprivation alters the functional circuitry (Aim 1) and the receptive field properties (Aim 2) of layer 2/3 neurons in A1. Results from our project will provide a cellular and circuit level mechanistic understanding of how loss of vision affects the functionality of A1 neurons. In addition, it will provide evidence that cross-modal changes occur in primary sensory cortices. Blind individuals display enhanced functionality in the remaining senses, such as better sound localization and pitch discrimination. We will examine how loss of vision affects the function of primary auditory cortex, an area of the brain involved in sound processing. Results from our work will benefit the development of therapeutics for recovering vision, as extensive sensory compensation is known to impede the recovery of the lost sense
Keywords: Affect; AMPA Receptors; Animals; Area; area striata; Auditory; Auditory area; awake; Biological Neural Networks; Blindness; braille; Brain; Clinical; Cochlear Implants; dark rearing; Data; design; Environment; Event; extrastriate visual cortex; Financial compensation; Hearing; In Vitro; in vivo; Intervention; Light; Mediating; Modality; multisensory; Mus; neural prosthesis; Neurons; Perception; Pitch Discrimination; Process; Property; Prosthesis; public health relevance; Reading; receptive field; Recovery; relating to nervous system; Reporting; Rodent; Role; Sensory; sensory cortex; sensory mechanism; sensory system; somatosensory; sound; Sound Localization; success; Synapses; Synaptic Transmission; System; Tactile; Testing; therapeutic development; Vision; Visual Cortex; visual deprivation; Visually Impaired Persons; Whole-Cell Recordings; Work
Project start date: 2010-05-01
Project end date: 2012-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-09-164
5R21NS070645-02 (2011): $168750
GENE EXPRESSION IN CANCER BY MICROARRAY HYBRIDIZATION
O Patrick, Professor
Stanford Universitycity: Stanford country: United States (us)
Grant 5R01CA077097-13 from National Cancer Institute
Abstract: From the start, the goal of this program has been the development and application of genome-wide approaches to systematic and quantitative analysis of gene expression patterns in cancer. In the eight years since we began this project, the experimental and analytical tools for systematic studies of global gene expression patterns at the level of transcript abundance have developed dramatically and they have become widely available and widely used for the study of cancer. The resulting studies have produced a wealth of new insight into cancer and they are even beginning to influence patient care. Profiling mRNA transcript levels, however, provides only a partial picture of the global gene expression program. While there is abundant evidence that regulation of the translation, subcellular localization and decay of mRNA are critical elements of biological regulation, practical and robust genome-wide approaches to studying these levels of regulation remain to be developed. As a result, our knowledge of the systems architecture, molecular mechanisms and biological roles of these regulatory mechanisms, including the roles they play in human cancer, is barely in its infancy. We therefore propose to develop practical, robust, high-throughput methods using DNA microarraysto profile three critical aspects of global regulation at the post-transcriptional level translational regulation, regulation of mRNA degradation, and the specific interactions of RNA binding proteins with their targets. These studies will build on preliminary studies we´ve already begun in the Saccharomyces cerevisiae model system, but will focus on human cells. As the essential methodologies are developed, we will apply them to developing a foundational framework of knowledge, investigating the patterns in which these regulatory mechanisms are used in basic physiological and developmental programs, how they vary from one cell type to another and between individuals, and beginning to investigate the underlying molecular mechanisms. The goal is to develop both the experimental methodology and an interpretive framework to the point that these post-transcriptional levels of gene expression can be systematically profiled and studied on a genome-wide scale almost as routinely as transcript levels are today
Keywords: 4-thiouracil; Adopted; Affect; Affinity Chromatography; affinity purification; analytical tool; Arabidopsis; Architecture; Area; autocrine; Autocrine Systems; Basal cell carcinoma; base; Basiloma; BCC; Biological; Biological Models; biological signal transduction; Body Tissues; cancer cell; cancer microarray; Cancer Model; Cancer of Breast; Cancer stem cell; CancerModel; Cancers; Carcinoma Cell; Carcinoma, Basal Cell, Pigmented; Cell Communication and Signaling; Cell Culture Techniques; Cell Growth in Number; Cell Multiplication; Cell Proliferation; Cell Signaling; cell type; Cells; Cellular Proliferation; Characteristics; Chromatography, Affinity; clinical data repository; clinical data warehouse; Colon Cancer; Colon Carcinoma; Colonic Carcinoma; Data Banks; Data Bases; data repository; Databank, Electronic; Databanks; Database, Electronic; Databases; Degradation, mRNA; Deoxyribonucleic Acid; design; designing; Development; Diagnosis; DNA; DNA Chips; DNA Microarray; DNA Microarray Chip; DNA Microchips; DNA Molecular Biology; Elements; Engineering / Architecture; Epithelioma, Basal Cell; experiment; experimental research; experimental study; Forecast of outcome; frontier; Funding; Gene Expression; Gene Expression Monitoring; Gene Expression Pattern Analysis; Gene Expression Profiling; gene product; Gene Products, RNA; Genes; Genome; genome wide association scan; genome wide association studies; genome wide association study; genome-wide; genome-wide analysis; genome-wide scan; genomewide association scan; genomewide association studies; genomewide association study; genomewide scan; Goals; graduate student; Grant; GWAS; Human; Human Cell Line; Human, General; Individual; infancy; infantile; inhibitor; inhibitor/antagonist; innovate; innovation; innovative; insight; Intracellular Communication and Signaling; Investigation; Investigators; Kinetic; Kinetics; Knowledge; malignancy; malignant breast neoplasm; Malignant Cell; Malignant Epithelial Cell; Malignant neoplasm of breast; Malignant Neoplasms; Malignant Tumor; Malignant Tumor of the Breast; Man (Taxonomy); Man, Modern; Maps; Measurement; Messenger RNA; Method LOINC Axis 6; Methodology; Methods; Model System; Modeling; Models, Biologic; Molecular; Molecular Biology; mRNA; mRNA Decay; mRNA Transcript Degradation; Nature; neoplasm/cancer; new technology; Nuclear Export; outcome forecast; paracrine; Pathogenesis; Patient Care; Patient Care Delivery; Patient Care Planning; Pattern; Phase; Physiologic; Physiologic pulse; Physiological; Play; post-doc; post-doctoral; Postdoc; Postdoctoral Fellow; Profilings, Gene Expression; Prognosis; programs; Programs (PT); Programs [Publication Type]; Proteins; Pulse; Regulation; relational database; Reproducibility; Research; Research Associate; Research Personnel; research study; Researchers; Ribonucleic Acid; Risk; RNA; RNA chemical synthesis; RNA Splicing; RNA synthesis; RNA, Messenger; RNA, Non-Polyadenylated; RNA-Binding Proteins; Role; S cerevisiae; Saccharomyces cerevisiae; self-renewal; Signal Transduction; Signal Transduction Systems; Signaling; Skin Basal Cell Carcinoma; social role; Source; Specificity; Splicing; Survey Instrument; Surveys; system architecture; Tag; Testing; Time; Tissues; tool; Tracer; Transcript; Transcript Expression Analyses; Transcript Expression Analysis; Translational Regulation; Translations; Ulcer, Rodent; Variant; Variation; whole genome association studies; whole genome association study; Work; Yeast, Baker`s; Yeast, Brewer`s; Yeasts
Project start date: 1997-09-30
Project end date: 2012-03-31
Budget start date: 1-APR-2010
Budget end date: 31-MAR-2012
5R01CA077097-13 (2010): $513011