Abnormal Eye Movement in Schizophrenia: Genome –Wide Scan 12/1/03-11/30/08
The aims of the proposal are to perform a genome-wide scan looking for a linkage to a schizophrenia-associated endophenotype, an elevated frequency of leading saccades during a smooth pursuit eye movement (SPEM) task. SPEM abnormalities have been associated with schizophrenia for almost 100 years, and have been suggested as a potential marker of genetic risk for over 20 years. Dr. Leonard’s laboratory will perform the genome scan on these families.
Age-27 Follow-Up of Early Preventive Intervention 6/1/04-12/31/08
Longitudinal follow-up of 340 young men and women who have participated in a randomized controlled trial of prenatal and infancy home visiting by nurses in Elmira, New York. Dr. Leonard’s laboratory will genotype variants in 4 genes related to stress, including MAO-A, 5HTT, DAT, and CHRNA7.
Alcohol Modulation of Brain NMDA Receptors 4/1/03 - 3/31/06
The major goal of this project is to evaluate the role of the NMDA receptor in alcohol sensitivity in ethanol-sensitive and ethanol-insensitive strains of mice and rats. The possible involvement of protein kinase C (PKC) in ethanol modulation of neurotransmitter receptors will also be examined.
Alcohol Modulation of Cerebellar Synaptic Currents 4/01/05 - 3/31/07
The major goals of this project are to determine the acute effects of alcohol on two major neurotransmitter receptor-mediated activity on cerebellar function in mice differentially sensitive to the behavioral effects of ethanol.
Atypical Antipsychotics and P50 Sensory Gating 7/1/04 – 6/30/09
The focus of this project is to assess whether adding ondansetron, a 5HT3 antagonist, will enhance P50 auditory gating and result in clinical symptom improvement in schizophrenic patients treated with atypical antipsychotics other than Clozapine. The proposed experiments are designed to test the hypothesis that 5HT3 receptor blockade is an underlying mechanism to this effect on P50 gating that is also related to clinical improvement, and that such an effect involves nicotinic mechanisms implicated in a number of other pre-clinical, clinical, and genetic studies. The investigators will provide statistical analysis on mixed effects Analyses of Variance (ANOVA) and advanced methods for repeated measures data.
Brain Mapping and genetics of Executive Function in ADHD (Subcontract to Dr. Banich) 08/15/04 – 08/14/09
This subcontract provides responsibility for the stable functioning of the magnet, for aid in creation and implementation of pulse sequences and quality control of images on this brain mapping project.
Center for Basic and Clinical Investigation of Schizophrenia 10/1/99 – 9/30/06
The Center provides support for training of new investigators, including postdoctoral fellows and graduate students. These projects involve the molecular biology of neuronal abnormalities in mental illness. These projects include:
- Analysis of genes expressed in linkage areas in schizophrenia
- Promoter function of the human a7 nicotinic receptor
- Affinity column purification of transcription factors binding to the a7 promoter
- Effects of prenatal stress on gene expression
Electrophysiology of Sensory Gating 4/1/84 - 4/30/06
This project compares siblings of schizophrenia and probands on a variety of measures, including MRI imaging, catecholamine metabolites, and neurophysiological performance, to determine what defects, in addition to sensory gating defects, are required to produce schizophrenia.
The Effects of Cannabis Use in People with Schizophrenia on Clinical, Neuropsychological and Physiological Phenotypes 7/1/05 – 6/30/07
This proposal examines if clinical symptoms, learning, memory, inhibition and distractibility are improved or made worse by the acute ingestion of tetrahydrocannabinol (THC).
fMRI of Auditory Gating Deficits in Schizophrenia 7/1/05 – 6/30/07
The study examines brain hemodynamic response during P50 auditory gating in schizophrenia.
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The Genetics of Endophenotypes and Schizophrenia 5/01/03-2/29/08
This project analyzes the results of phenotype data on P50 event related suppression, prepulse inhibition, of the startle response, the antisaccade task for eye movement dysfunction, CPT, working memory and verbal memory in schizophrenic patients than their families to determine interrelatedness and to test genetic hypotheses of each endophenotype separately and in composite. See the Consortium on the Genetics of Schizophrenia website for more information.
Gestational choline supplementation for the amelioration of sensory inhibition deficits 9/15/05-9/14/07
The experiments attempt to determine if developmental stimulation of α-7 receptors underlies the improvement in sensory inhibition seen in DBA/2 mice gestated on choline supplementation in the diet of the dams.
Impaired auditory sensory gating, acoustic startle response: Effects of long & short deployments on army combat readiness 9/17/01-9/16/07
The aim of this project is to assess whether impaired auditory sensory gating can affect military performance. The project evaluates whether objective neurophysiolgical parameters can measure the impact of long and short deployments on soldiers & assess whether the stress of deployment results in impaired auditory sensory gating and secondary performance decrements in tests directly relevant to military performance.
MEG Evoked Fields in Schizophrenia 02/15/04-01/31/09
The major goals of this project are to determine MEG and MRI based functional and structural brain abnormalities across multiple psychotic illnesses in adult patient groups, specifically schizophrenia. schizoaffective disorder, and bipolar disorder.
Mental Control in Schizophrenia: fMRI & Genetic Studies - Subcontract to Dr. Banich, UC Boulder 7/1/05 – 6/30/07
The goal of this project is examine how a genetic polymorphism linked to schizophrenia, CHRNA7, the gene for the α-7 nicotinic acetylcholine receptor subunit, influences neurocognitive control (a smooth pursuit eye movement task and the Stroop Color Word Task) as assessed by functional MRI (fMRI).
Mental Illness Research, Education and Clinical Center (MIRECC) - Dept. of Veterans Affairs 10/01/2004-9/30/2009
The purpose of the MIRECC is to evaluate and treat veterans, particularly those returning from Operation Iraqi Freedom and Operation Enduring Freedom and to treat their psychiatric disability aggressively, focusing on normalization of biological markers, to assess whether this will help limit later disability and suicide risk. The MIRECC is also serving as a training center for cognitive dysfunction studies and neuropsychiatry in the context of reducing suicide risk.
Molecular Biology of Neuronal Abnormalities in Schizophrenia 4/1/00-9/30/06
This project establishes a core molecular biology laboratory to support studies of schizophrenia. The laboratory provides technical assistance to investigators. To further support the molecular biology laboratory, the VA and the University of Colorado formed a CRADA with Colorado Associates Inc. that finances additional sequencing capabilities, in terms of machinery, laboratory renovations, technical personnel, and supplies, to sequence the alpha 7 nicotinic receptor gene.
Molecular Genetics of Schizophrenia 10/01/98-7/31/07
This project examines the genetic differences between 5,000 probands with schizophrenia and a comparison group of normal controls.
Neurophysiological Deficits in Schizophrenia 10/1/03-9/30/08
This project uses inbred mouse strains to characterize possible genetic differences in sensory gating physiology that mimic the deficits found in schizophrenia.
A Nicotinic Agonist (DMXB-A) as an Adjunct Antipsychotic Therapy 10/1/2003-9/30/07
This proposal seeks to assess the effects of DMXB-A administration on auditory gating, in conjunction with typical antipsychotics, atypical antipsychotics and acetylcholinesterase inhibitors in both a rat and a mouse model of deficient, schizophrenia-like auditory gating.
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Nicotinic Agonists, Cognition and Neuroimaging in Schizophrenia 06/30/2005-06/30/08
The first goal of this project is to use functional magnetic resonance imaging to assess the underlying neurobiology of Stroop Color Word Task performance in persons with Schizophrenia. The second goal is to assess any changes in performance and neurobiology during the Stroop Color Word Task following administration of a selective nicotinic agonist using functional magnetic resonance imaging.
A potential new animal model of schizophrenic hippocampal abnormalities 10/1/05-9/30/08
This project seeks to answer the questions:
- Does a decrease in a7 receptor expression alter the time course, pattern and/or density of hippocampal a7 receptor development?
- Does an alteration in a7 receptor expression affect hippocampal auditory gating?
- Does an alteration in a7 receptor expression affect hippocampal inhibitory neuron development?
Silvio Conte Center for Translational Neuroscience of Mental Disorders Molecular Neurobiology of Schizophrenia 7/1/04-6/30/09
This Center studies the effects of polymorphisms in genes related to schizophrenia, such as CHRNA7, on a variety of phenotypes associated with the illness. These phenotypes include the expression of CHRNA7 and other genes in post mortem brain, the function of olfactory neurons, the hemodynamic response of brain to complex stimuli, and sensory gating abnormalities in adults and in infants at risk for schizophrenia.
Project 1 Molecular Biology of Nicotinic Receptors
This project examines:
- The effects of functional promoter mutations in the a7 nicotinic receptor gene in postmortem brain of schizophrenic and control subjects. Expression of a7 will be examined as well as the effects on global gene expression using a microarray technology.
- Identification and characterization of DNA polymorphisms in the a7 nicotinic receptor gene, CHRNA7.
- What are the effects of CHRNA7 proximal promoter and intronic mutations on expression of the receptor in human subjects.
- What are the effects of CHRNA7 regulatory region mutations on expression of other genes implicated in schizophrenia as a microarray study?
Project 2: “Olfactory Function”
The main goals of this project are to:
- Examine the effects of alpha 7 promoter mutation on the expression levels and spatial distribution of alpha 7 receptors in the olfactory bulb of human schizophrenics and controls, and in mice with altered alpha 7 expression.
- Studying the nicotinic acetylcholine-elicited increases in intracellular calcium in cultured olfactory bulb neurons from genotyped schizophrenics and controls and from mice with altered alpha 7 receptor expression.
- Compare olfactory behavior of mice with altered alpha 7 expression.
Project 3 Developmental Psychopathology
This project focus on the relationship of a genetic polymorphism to developmental deficits in brain function. This projects coordinates with developmental studies of molecular phenotyping, imaging, and animal modeling to explore the role of CHRNA7 polymorphisms in Developmental Psychopathology. It is hoped that clarifying the developmental role of CHRNA7 will inform translational efforts in the primary prevention of schizophrenia.
Project 4 Pharmacology of Nicotine Receptors
This project's goals are to replicate and extend the relationship of genetic polymorphisms in CHRNA7 to the phenotype of inhibitory dysfunction as measured by inhibition of the P50 response to repeated auditory stimuli in schizophrenic and control subjects. Alpha-7 specific agonists are tested in schizophrenics to determine if they normalize P50 response and to what extent they also affect the symptoms of schizophrenia.
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