David L Braff
University Of California San Diego
Project start date: 2009-04-16
Project end date: 2013-01-31
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to David L Braff
Gating And Inhibition In Schizophrenia
David L Braff, Professor
Psychiatryuniversity Of California San Diego
9500 Gilman Dr, Dept 0934
la Jolla, Ca 920930934
Grant 5R01MH042228-21 from National Institute Of Mental Health IRG: ZRG1
Abstract: This cross-species translational research project will use specific laboratory-based measures of gating and inhibitory functions to better understand the convergence and divergence of information-processing abnormalities in schizophrenia patients, and elucidate the clinical significance and neurobiological substrates of these abnormalities. The measures are 1) prepulse inhibition of startle (PPI); 2) P50 (humans) and N40 (animals) event-related potential suppression; 3) startle habituation and 4) oculomotor antisaccade performance. Although groups of schizophrenia patients have deficits on each of these 4 measures, any single patient may exhibit deficits in some but not all of the measures. Similarly, in animals, pharmacological, neuroanatomical, and genetic manipulations have differential effects on these measures. Hence, 300 medicated, 100 non-medicated patients, and 200 normal subjects will be tested on all 4 inhibitory measures. The human research aims are to 1) confirm and extend findings of inhibitory deficits in schizophrenia patients; 2) identify subgroups of schizophrenia patients based on patterns of deficits in the 4 inhibitory measures; 3) determine how subgroup membership and individual inhibitory deficits relate to clinical domains of demographic, symptom, neurocognitive, and functional status; 4) study patients over time to examine the stability and clinical importance of both subgroups and inhibitory measures. In animals, the project will assess similarities and differences among PPI, N40 suppression, and habituation measures, using parametric, pharmacological, and molecular biological manipulations in mice, rats, and marmosets. Simultaneous measures of PPI, N40 suppression, and/or habituation will be used in rats to assess the effects of psychotomimetic dopaminergic, serotonergic, and glutamatergic drugs. The role of specific receptors in the effects of antipsychotic drugs on inhibitory measures will be assessed in genetically engineered mice. Differential neural substrates of inhibitory measures will be identified using anatomically specific manipulations of the thalamus or ventral hippocampus in rats. Thus, this proposal is designed to "parse" groups of schizophrenia patients according to convergence and divergence of inhibitory deficits, to examine both "bottom up" applications (e.g. assessing the relationships of inhibitory measures to predict symptoms, neurocognitive deficits, functional status, and outcome) and "top down" applications (e.g. applying these measures to understand the neural substrates of schizophrenia using lesion, pharmacological, and genetic manipulations) by using the interactive human and animal experiments
Keywords: mental disorder chemotherapy, neural information processing, neural inhibition, nonhuman therapy evaluation, schizophrenia antipsychotic agent, cognition, drug receptor, hippocampus, thalamus Callithricidae, clinical research, genetically modified animal, human subject, laboratory mouse, laboratory rat, longitudinal human study, neuropsychological test, questionnaire
Project start date: 1987-01-01
Project end date: 2009-02-28
5R01MH042228-21 (2007): $628467
5R01MH042228-19 (2005): $598119
5R01MH042228-18 (2004): $609761
2R01MH042228-17A1 (2003): $663917
5R01MH042228-20 (2006): $472063
5/5: A GENOME-WIDE METHYLATION SCAN FOR EPIGENETIC CONTRIBUTIONS TO SCHIZOPHRENIA
David L Braff, Professor
University Of California San Diego, 9500 Gilman Dr, Dept 0934, La Jolla, Ca 92093-0934
Grant 5U01MH085265-02 from National Institute Of Mental Health
Abstract: Schizophrenia is a common, profoundly disabling disorder that carries a heavy burden for patients and families and is the subject of intensive genetic studies. The study of epigenetic variation is an essential complement to conventional genetic disease studies, since the phenotypic consequence of DNA sequence depends on its epigenetic context. Unlike sequence variation, epigenetic marks, i.e. chemical modifications of DNA and associated proteins, are affected by age and the environment, providing an important link between the genetic predisposition to disease and crucially important risks related to lifetime epigenetic exposures. The importance of epigenetic marks in cancer is well established, and the relevance to neuropsychiatric disease is now emerging. An epigenetic contribution to schizophrenia (SZ) is supported by important, but often ignored discordance among MZ twins, the effects of DNA methylation (DNAm) precursors on psychotic symptoms in SZ, and evidence for DNAm variation in SZ candidate genes. While genome-wide association studies are ongoing for SZ, no similar effort has yet been pursued to identify epigenetic changes, largely due to technology limitations. Here we propose to determine the potential epigenetic contribution to SZ by combining robust experimental and statistical genome-wide methods for DNAm analysis recently developed by s, with three large and well-characterized Consortia focusing on the genetics of SZ (MGI, COGS, PAARTNERS) that have already carried out extensive genetic and phenotypic studies. Our specific aims are (1) Compare genome-wide methylation scan (GWMs) measures between SZ cases and controls using 1000 SZ cases / 1000 age/sex frequency matched control lymphocyte DNA as well as 140 SZ / 140 control brains; (2) Replicate GWM findings at 9,880 CpG sites in an independent sample of 2000 cases / 2000 controls from the NIMH Genetics Repository and fine-map the DNAm and examine expression patterns for the top 50 gene candidates; and (3) Integrate these epigenetic discoveries with the genetic data already being collected on these samples. These studies will provide the first comprehensive evaluation of the epigenetics of SZ and provide an unprecedented complement to SZ genetics data, allowing integration of genetic, environmental, and epigenetic effects on SZ. From an important treatment perspective, since epigenetic changes are potentially reversible, these studies may also lead to exciting new avenues for SZ therapy. Schizophrenia is a common, profoundly disabling disorder that carries a heavy burden for patients and families that is the subject of intensive genetic studies. The study of epigenetic variation, such as DNA methylation, is an essential complement to conventional genetic disease studies; unlike sequence variation, epigenetic marks are affected by age and the environment. This project will provide a comprehensive genome- wide approach to the epigenetics of SZ, bringing to bear state of the art experimental and statistical approaches to the analysis of DNA methylation on a sample set identified and assessed by an outstanding network of SZ phenotypic experts working together in a highly collaborative manner
Keywords: 3`-5`-CpG; AIDS; Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immuno-Deficiency Syndrome; Acquired Immunodeficiency Syndrome; Active Follow-up; Affect; African American; Afro American; Afroamerican; Age; Alabama; Ammon Horn; Applications Grants; Arts; Assay; Bears; Bioassay; Biologic Assays; Biological; Biological Assay; Black Populations; Black or African American; Blood Sample; Blood specimen; Body Tissues; Brain; Brain region; Budgets; CG-dinucleotide; California; Cancers; Candidate Disease Gene; Candidate Gene; Chemicals; Clinical Services; Collaborations; Collection; Communities; Complement; Complement Proteins; Cornu Ammonis; CpG dinucleotide; Custom; DNA; DNA Methylation; DNA Modification; DNA Modification Process; DNA Restriction Enzymes; DNA Sequence; Data; Data Banks; Data Bases; Databank, Electronic; Databanks; Database, Electronic; Databases; Deoxyribonucleic Acid; Diagnostic; Disease; Disorder; Doctor of Medicine; Doctor of Philosophy; Encephalon; Encephalons; Environment; Epigenetic; Epigenetic Change; Epigenetic Mechanism; Epigenetic Process; Evaluation; Event; Experimental Designs; Family; Fostering; Frequencies (time pattern); Frequency; Funding; GWAS; Gene Expression; Gene variant; Genes; Genetic; Genetic Alteration; Genetic Change; Genetic Condition; Genetic Diseases; Genetic Diversity; Genetic Models; Genetic Polymorphism; Genetic Predisposition; Genetic Predisposition to Disease; Genetic Susceptibility; Genetic Variation; Genetic defect; Genomics; Genotype; Grant; Grant Proposals; Grants, Applications; Gur; Hereditary Disease; Heterogeneity, Population; Hippocampus; Hippocampus (Brain); Human; Human, General; Immunologic Deficiency Syndrome, Acquired; Individual; Inherited Predisposition; Inherited Susceptibility; Investigation; Investigators; Lead; Leadership; Link; Lymphocyte; Lymphocytic; M.D.; M.P.H.; Malignant Neoplasms; Malignant Tumor; Man (Taxonomy); Man, Modern; Manuscripts; Maps; Masks; Master of Public Health; Measures; Mental disorders; Mental health disorders; Methods; Methylation; Modeling; Molecular; Molecular Disease; Molecular Genetic; Molecular Genetics; Mutation; NIH; NIH Program Announcements; NIMH; National Institute of Mental Health; National Institute of Mental Health (U.S.); National Institutes of Health; National Institutes of Health (U.S.); Nature; Nervous System, Brain; Neurocognitive; Parents; Participant; Pathogenesis; Patients; Pattern; Pb element; Pennsylvania; Ph.D.; PhD; Phenotype; Polymorphism (Genetics); Polymorphism, Genetic; Population Heterogeneity; Potassium Hydroxide; Prefrontal Cortex; Program Announcement; Protein Methylation; Proteins; Psychiatric Disease; Psychiatric Disorder; Publications; Publishing; R01 Mechanism; R01 Program; RPG; Research; Research Design; Research Grants; Research Personnel; Research Project Grants; Research Projects; Research Projects, R-Series; Research Resources; Researchers; Resources; Restriction Endonucleases; Risk; Role; Sampling; Sampling Studies; Scanning; Schizophrenia; Schizophrenic Disorders; Scientific Publication; Site; Study Type; Superior temporal gyrus; Symptoms; Technology; Testing; Tissues; Twin Multiple Birth; Twins; United States National Institute of Mental Health; United States National Institutes of Health; Universities; Unspecified Mental Disorder; Ursidae; Ursidae Family; Validation; Variant; Variation; Variation (Genetics); Washington; Work; Writing; alcohol use disorder; allelic variant; base; bisulfite; black American; brain control; brain tissue; case control; clinical data repository; clinical data warehouse; cytidine monophosphate guanosine; cytidylyl-3`-5`-guanosine; cytosine-guanine dinucleotide; data integration; data repository; dementia praecox; design; designing; disease/disorder; diverse populations; epigenetic variation; ethanol use disorder; follow-up; gene product; genetic disorder; genetic etiology; genetic mechanism of disease; genetic vulnerability; genome mutation; genome wide association scan; genome wide association studies; genome wide association study; genome-wide; genome-wide scan; genomewide association scan; genomewide association studies; genomewide association study; genomewide scan; heavy metal Pb; heavy metal lead; hereditary disorder; heterogeneous population; hippocampal; hydrogen sulfite; hydrosulfite; imprint; interdisciplinary approach; lymph cell; malignancy; member; mental illness; mind control; neoplasm/cancer; neuropsychiatric; neuropsychiatry; polymorphism; potash; proband; psychological disorder; public health relevance; relational database; repository; sample collection; schizophrenic; sex; sharing data; social role; specimen collection; study design; tool; whole genome association studies; whole genome association study
Relevance: Schizophrenia is a common, profoundly disabling disorder that carries a heavy burden for patients and families that is the subject of intensive genetic studies. The study of epigenetic variation, such as DNA methylation, is an essential complement to conventional genetic disease studies; unlike sequence variation, epigenetic marks are affected by age and the environment. This project will provide a comprehensive genome- wide approach to the epigenetics of SZ, bringing to bear state of the art experimental and statistical approaches to the analysis of DNA methylation on a sample set identified and assessed by an outstanding network of SZ phenotypic experts working together in a highly collaborative manner
Project start date: 2008-09-30
Project end date: 2013-05-31
Budget start date: 1-JUN-2009
Budget end date: 31-MAY-2010
PFA/PA: PA-07-092
5U01MH085265-02 (2009): $38625
5/5:FAMILY-BASED GENOME-WIDE METHYLATION SCAN IN NEUROCOGNITION AND SCHIZOPHRENIA
David L Braff, Professor
University Of California San Diego, 9500 Gilman Dr, Dept 0934, La Jolla, Ca 92093-0934
Grant 1RC2MH089984-01 from National Institute Of Mental Health
Abstract: Schizophrenia is a common profoundly disabling disorder that carries a heavy burden for patients and families and is the subject of intensive genetic studies. The study of epigenetic variation is an essential complement to conventional genetic disease studies, since the phenotypic consequence of DNA sequence depends on its epigenetic context. Unlike sequence variation, epigenetic marks, i.e. chemical modifications of DNA and associated proteins, are affected by age and the environment, providing an important link between the genetic predisposition to disease and crucially important risks related to lifetime epigenetic exposures. The importance of epigenetic marks in cancer is well established, and the relevance to neuropsychiatric disease is now emerging. An epigenetic contribution to schizophrenia (SZ) is supported by important, but often ignored discordance among MZ twins, the effects of DNA methylation (DNAm) precursors on psychotic symptoms in SZ, and evidence for DNAm variation in SZ candidate genes. This coordinated application builds on a strong foundation of an existing collaboration between six groups of investigators, with an already established and funded infrastructure, without which this research would not be possible. We have previously established a collaboration to investigate the epigenetics of SZ using a case-control approach with existing samples by collaborating with three large Consortia focusing on the genetics of SZ (MGI, COGS, PAARTNERS) that have already carried out extensive genetic and phenotypic studies on well-characterized patients, including quantitative neurocognitive phenotypes. Here we approach the epigenetics of SZ in the family members of the probands currently under study, as well as the relationship of epigenetic variation to quantitative neurocognitive phenotypes such as executive function, memory, language and emotion processing. Our Specific Aims are (2) To quantitatively assess methylation of >4 million CpG sites genome-wide, across 1000 SZ families, examining an average of 3 family members per proband with a total of 3000 family members; (2) To use these data to estimate the heritability of genome-wide methylation in SZ families, to perform family-based epigenetic association with SZ and to perform family-based integration of GWAS data with DNAm; and (3) to examine neurocognitive phenotypes available across families to estimate the relationship between methylation and cognitive efficiency within and across families. The proposed research offers a novel, timely, powerful, and comprehensive strategy for determining the familial epigenetic contribution to SZ, combining expertise in epigenetic technology of human disease with a network of collaborating consortia yielding large well-characterized samples of patients with SZ and their family members. Schizophrenia is a common, profoundly disabling disorder that carries a heavy burden for patients and families that is the subject of intensive genetic studies, but the study of epigenetic variation, such as DNA methylation, is an essential complement to conventional genetic disease studies, as epigenetic marks are affected by age and the environment. This project will provide a comprehensive genome-wide approach to the familial basis of schizophrenia, leveraging our ongoing study of an existing cohort of schizophrenic patients by examining family members for heritability of schizophrenia-related methylation changes, and by relating these changes to quantitative defects in cognition in patients and family members. The research offers a novel, timely, and powerful strategy for determining the familial epigenetic contribution to schizophrenia
Keywords: Affect; Age; Cancers; Candidate Disease Gene; Candidate Gene; Case-Base Studies; Case-Comparison Studies; Case-Compeer Studies; Case-Control Studies; Case-Referent Studies; Case-Referrent Studies; Cell Communication and Signaling; Cell Signaling; Chemicals; Cognition; Cognitive; Collaborations; Complement; Complement Proteins; DNA; DNA Methylation; DNA Modification; DNA Modification Process; DNA Sequence; Data; Defect; Deoxyribonucleic Acid; Diagnosis; Disease; Disorder; Emotions; Environment; Epigenetic; Epigenetic Change; Epigenetic Mechanism; Epigenetic Process; Family; Family member; Foundations; Frequencies (time pattern); Frequency; Funding; GWAS; Genetic; Genetic Condition; Genetic Diseases; Genetic Predisposition; Genetic Predisposition to Disease; Genetic Susceptibility; Hand; Hereditary Disease; Heritability; Infrastructure; Inherited Predisposition; Inherited Susceptibility; Intracellular Communication and Signaling; Investigators; Language; Link; Lymphocyte; Lymphocytic; Malignant Neoplasms; Malignant Tumor; Memory; Methods; Methylation; Molecular Disease; NIMH; National Institute of Mental Health; National Institute of Mental Health (U.S.); Neurocognition; Neurocognitive; Patients; Phenotype; Process; Protein Methylation; Proteins; Relative; Relative (related person); Research; Research Infrastructure; Research Personnel; Researchers; Risk; Sampling; Scanning; Schizophrenia; Schizophrenic Disorders; Series; Signal Transduction; Signal Transduction Systems; Signaling; Site; Symptoms; Technology; Twin Multiple Birth; Twins; United States National Institute of Mental Health; Variant; Variation; Work; base; biological signal transduction; brain control; case control; cohort; dementia praecox; disease/disorder; epigenetic variation; executive control; executive function; gene product; genetic disorder; genetic etiology; genetic mechanism of disease; genetic vulnerability; genome wide association scan; genome wide association studies; genome wide association study; genome-wide; genome-wide scan; genomewide association scan; genomewide association studies; genomewide association study; genomewide scan; hereditary disorder; human disease; lymph cell; malignancy; mind control; neoplasm/cancer; neuropsychiatric; neuropsychiatry; novel; proband; public health relevance; repository; schizophrenic; sex; trait; whole genome association studies; whole genome association study
Relevance: Schizophrenia is a common, profoundly disabling disorder that carries a heavy burden for patients and families that is the subject of intensive genetic studies, but the study of epigenetic variation, such as DNA methylation, is an essential complement to conventional genetic disease studies, as epigenetic marks are affected by age and the environment. This project will provide a comprehensive genome-wide approach to the familial basis of schizophrenia, leveraging our ongoing study of an existing cohort of schizophrenic patients by examining family members for heritability of schizophrenia-related methylation changes, and by relating these changes to quantitative defects in cognition in patients and family members. The research offers a novel, timely, and powerful strategy for determining the familial epigenetic contribution to schizophrenia
Project start date: 2009-09-30
Project end date: 2011-08-31
Budget start date: 30-SEP-2009
Budget end date: 31-AUG-2010
PFA/PA: RFA-OD-09-004
1RC2MH089984-01 (2009): $32871
David L Braff
Institution:
Grant 2P30MH049671-059007 from National Institute Of Mental Health
Abstract: Psychophysiological deficits are important in understanding both schizophrenia and the aging process. The Psychophysiology Core is designed to provide a multi-factorial assessment of several important domains of psychophysiological, information processing and attentional functions of subjects in the CRC. This Core is an extension of the Motor Function Core which has been productively in place during the past three years of the CRC s existence. The newly expanded Psychophysiology Core test battery reflects our growing awareness of the central role of psychomotor, attentional, and information processing deficits in understanding the schizophrenia and other psychotic disorders in general and late-life psychoses in particular. The Psychophysiology Core will provide an initial comprehensive battery which assesses eight measures from four domains of psychophysiological function including motor function, startle plasticity, pupillometry and cerebral event-related potentials. Schizophrenia patients have been found to have deficits in all four domains and these deficits are related to the symptoms, course, and outcome of schizophrenia. In addition, these psychophysiological measures have been related to specific neural substrates that may be impaired in psychosis. The Psychophysiology Core will serve as a data acquisition and hypothesis testing module of the CRC. Since psychophysiological deficits across all of the four domains are associated with both schizophrenia and aging, this database will support the CRC themes of examining late-life psychosis cross-sectionally and longitudinally, and will add to our knowledge of treatment effects and predictors. The Psychophysiology Core will test formal hypotheses pertaining to the four Center-wide themes (1) age of onset of schizophrenia; (2) different late-onset psychoses; (3) clinical outcome; and (4) treatment outcome, and in doing so will be able to address the following specific questions (1) How does age of onset treated as a continuous variable correlate with deficits on psychophysiologic dependent measures in schizophrenia? (2) What psychophysiological deficits are observed across different late-onset psychoses? (3) What psychophysiological deficits are observed cross sectionally at baseline in patients who represent a variety of outcomes? and (4) Do the psychophysiological measures on admission to the treatment protocols predict or correlate with the subsequent treatment responses? In addition, the eight dependent measures of the Psychophysiology Core will be utilized to answer questions about cross-Core hypotheses relating to how these psychophysiological measures relate to specific deficits in clinical state, neuropsychological function, and brain imaging abnormalities. Finally, specific psychophysiological measures that appear to tap into similar processes and neural substrates will be correlated with each other. Via this cumulative effort, the significance of psychophysiological information processing and attentional abnormalities in late-life psychosis will be defined and clarified.
Keywords: aging, biomedical facility, psychophysiology, schizophrenia, age difference, antipsychotic agent, attention, evoked potential, human therapy evaluation, longitudinal human study, mental disorder chemotherapy, neural information processing, neural plasticity, psychomotor function, pupillary reflex, startle reaction, clinical research, human middle age (45-64), human old age (65+), human subject, psychometrics
Sponsored Links Excellgen http://Excellgen.com
4/4-A Genomic Approach To Schizophrenia
David L Braff, Professor
Psychiatryuniversity Of California San Diego
Grant 1R01MH084071-01A1 from National Institute Of Mental Health IRG: ZRG1
Abstract: Our goal is to identify genes that are enriched for rare or de novo genomic deletions or duplications in persons with schizophrenia and to determine the functional consequences of these mutations. Structural genomic variants are important causes of human genetic variation and are increasingly implicated in human disease. We have shown that rare deletions and duplications that impact genes are significantly more frequent among individuals with schizophrenia than among controls. These mutations disproportionately affect genes involved with neural development. Other investigators have shown that de novo structural mutations are 8-fold more frequent among individuals with sporadic schizophrenia compared to controls. Using a gene-based design, we propose to identify genes that are disproportionately altered by structural mutations in persons with schizophrenia. We anticipate that a gene important to schizophrenia will harbor different disease-causing mutations in different affected individuals (Aim 1). We also will identify genes with de novo structural mutations in patients with sporadic schizophrenia (Aim 2). The consequences of structural mutations in the most significant candidate genes will be characterized experimentally to determine the impacts of mutations on gene function (Aim 3). Cases have been assessed and sampled by four NIMH projects. These projects together have enrolled 1155 probands, 259 affected relatives, and 2965 unaffected relatives, including 431 proband-parent trios. Controls will be drawn from >3000 unrelated unaffected persons age >30 years from NIMH distribution 5. All cases and controls will be screened identically genome-wide with NimbleGen 2.1-million feature HD2 arrays, which can detect deletions and duplications as small as 3kb. Screening of the NIMH controls is supported by independent funds. If successful, our approach will identify multiple genes important for schizophrenia. Each of these genes should stimulate future efforts to develop more effective treatment and prevention strategies. Structural mutations are increasingly recognized to play an important role in human disease. Our goal is to use state-of-the-art genomic tools to detect these mutations anywhere in the genome, and to identify genes that are more often impacted by structural mutations in persons with schizophrenia compared to healthy controls
Project start date: 2009-04-16
Project end date: 2013-01-31
The Genetics Of Endophenotypes And Schizophrenia
David L Braff, Professor
Psychiatryuniversity Of California San Diego
9500 Gilman Dr, Dept 0934
la Jolla, Ca 920930934
Grant 5R01MH065571-05 from National Institute Of Mental Health IRG: ZRG1
Abstract: Neurobiological deficits that serve as informative endophenotype markers have been demonstrated in schizophrenia by a number of different paradigms. Neurophysiological deficits are prominent in P50 event related suppression, prepulse inhibition (PPI) of the startle response, and the antisaccade (AS) task for eye movement dysfunction. Neurocognitive deficits in schizophrenia are revealed by poor performance on the CPT, verbal memory, and tests of working memory. Each of these deficits has also been demonstrated in clinically unaffected relatives of schizophrenia patients, which is evidence that they may reflect part of the heritable risk for the illness. This conclusion is reinforced by findings of deficits in non-psychotic, unmedicated schizophrenia patients, and schizotypal patients. The null hypothesis is that all 6 deficits reflect a single, common underlying heritable dysfunction in all schizophrenia patients. A test of that hypothesis requires measurement of all of these deficits in the same group of schizophrenia patient probands and their relatives. If they are all manifestations of the same genetic dysfunction (although perhaps expressed in different brain areas), then a multivariate analysis would show that they all contribute to a single dimension in both relatives and schizophrenia patients. An alternative hypothesis is that only one or a small subset of deficits is present in each family, which is consistent with the heterogeneity found in current genetic linkage studies. In that case, the multivariate analysis would show the different measures or subsets of them loading onto different dimensions. Schizophrenia itself is likely to be the result of multiple deficits in any individual. Therefore, the analysis is performed in the same cohort of schizophrenia patient probands and their relatives to take advantage of Mendel´s second law, which holds that genetically independent deficits segregate independently. Hence, although schizophrenia patient probands themselves have multiple deficits, if the deficits are caused by different genetic factors, then they will segregate to different groups of relatives. This 7 site collaborative RO1 project will gather a combined total of 420 pedigrees (1680 subjects) and 525 normal subjects over 5 years (each site will contribute 1/7th of these totals). Findings of heritable deficits in specific measures will be used to guide the next generation of studies of the genetics of schizophrenia
Keywords: behavioral genetics, genetic susceptibility, phenotype, schizophrenia family genetics, gene expression, genetic disorder diagnosis, genetic polymorphism, genetic screening, linkage disequilibrium, short term memory, startle reaction behavioral /social science research tag, clinical research, electroencephalography, electrooculography, human subject
Project start date: 2003-04-04
Project end date: 2009-02-28
5R01MH065571-05 (2007): $791864
5R01MH065571-04 (2006): $756153
5R01MH065571-03 (2005): $747965
5R01MH065571-02 (2004): $730208
1R01MH065571-01A1 (2003): $745088
SENSORY GATING AND HABITUATION IN SCHIZOPHRENIA
David L Braff, Professor
University Of California San Diego 9500 Gilman Dr, Dept 0934 La Jolla, Ca 920930934
Grant 5R37MH042228-16 from National Institute Of Mental Health IRG: NSS
Abstract: Attentional and information processing deficits have frequently been implicated in the psychopathology of schizophrenia. In recent years, the hypothesis of dopamine (DA) overactivity has also assumed significance in understanding schizophrenia. This proposal specifically outlines studies with humans and related animal models that will extend our knowledge of how DA overactivity relates to the sensory gating and habituation deficits that may underlie the cognitive fragmentation and thought disorder characteristic of schizophrenia. In animal experiments, we will further explore dopaminergic, noradrenergic, and specific anatomical pathways involved in the observed sensory gating deficits. To accomplish these goals, we propose to utilize the prepulse inhibition (PPI) and habituation of the startle reaction in humans and rats using the very similar paradigms, stimulus parameters, dependent measures, and statistical analyses that we have developed in our previous work. In humans, we will use electromyographic monitoring of the blink reflex component of the startle reaction (SR). In rats, we will use measures of whole body startle. Sensory gating will be accomplished by weak prestimulation and habituation using 121-trial tests in both humans and animals. Schizophrenic and control patients will be tested longitudinally and through various phases of their illness, while their clinical, symptomatic, neuropsychological, homovanillic acid levels, radioreceptor assay levels, and other measures are obtained. As an animal model of DA overactivity, rats having 6-hydroxydopamine-induced depletions of nucleus accumbens DA will be tested in the PPI paradigm following systemic treatments with apomorphine, noradrenergic agonists, and/or various dopaminergic antagonists. Liquid chromatography will be used to confirm the DA depletions. Our objectives are to clarify the neurochemical and anatomical pathways that underlie sensory gating and habituation deficits in schizophrenia and to explore the functional importance of dopamine overactivity in schizophrenia. We intend to further our understanding of how DA overactivity and its underlying neuroanatomic correlates may relate to the specific cognitive dysfunction, symptoms, and outcome of the schizophrenic disorders.
Keywords: behavioral habituation /sensitization, cognition disorder, dopamine receptor, neural inhibition, schizophrenia, startle reaction, 6 hydroxydopamine, antipsychotic agent, apomorphine, behavioral medicine, dopamine, homovanillate, inhibitor /antagonist, mental disorder chemotherapy, methylphenidate, neural information processing, neuroanatomy, neurochemistry, neuropharmacology, nucleus accumbens, sensory disorder, serotonin receptor, stimulant /agonist, behavioral /social science research tag, disease /disorder model, electromyography, experimental brain lesion, human subject, laboratory rat, neuropsychological test
Project start date: 1987-01-01
Project end date: 2003-04-16
5R37MH042228-16 (2002): $456085
5R37MH042228-15 (2001): $442800
Sponsored Links Excellgen http://Excellgen.com
5R37MH042228-14 (2000): $429902
5R37MH042228-13 (1999): $406350
5R37MH042228-11 (1997): $348433
5R37MH042228-09 (1995): $329240
5R37MH042228-08 (1994): $330407
2R37MH042228-07 (1993): $292274
4R37MH042228-12 (1998): $360073
David L Braff
University Of California San Diego
Project start date: 2003-04-04
Project end date: 2014-01-31
SENSORY GATING AND HABITUATION IN SCHIZOPHRENIA
David L Braff, Professor
University Of California San Diego 9500 Gilman Dr, Dept 0934 La Jolla, Ca 920930934
Grant 5R37MH042228-10 from National Institute Of Mental Health IRG: CNR
Project start date: 1987-01-01
Project end date: 1998-01-31
5R37MH042228-10 (1996): $335031