GENETIC ANALYSIS OF SENSORY GATING

感觉门控的遗传分析

• 批准号: 2251428
• 负责人: KAREN E STEVENS
• 金额: $ 9.95万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2251428
• 关键词: atropine; auditory feedback; auditory stimulus; autoradiography; behavioral genetics; biological models; brain electrical activity; bungarotoxins; evoked potentials; genetic strain; hippocampus; in situ hybridization; laboratory mouse; messenger RNA; molecular psychobiology; muscarinic receptor; neuropharmacology; nicotine; nicotinic receptors; paired stimuli; receptor binding; receptor expression; receptor sensitivity; tubocurarine

Schizophrenia is a complex disorder of unknown etiology. One prominent problem among schizophrenics is an inability to filter, or gate, sensory information. Normal individuals, when presented with identical paired stimuli (clicks), have a diminished midlatency auditory evoked potential the second click, as compared to the first click. They are said to be "gating' their response to the second stimulus. By contrast, schizophrenics, and normal individuals administered psychotomimetics (amphetamine, PCP), have responses of similar magnitude to both clicks. Thus, they do not gate. This gating deficit has been successfully modeled in animals. Rats show a normal pattern of sensory gating which is altered to a schizophrenia-like loss of gating upon administration of psychotomimetic drugs. Recent clinical studies have demonstrated a transient normalization of sensory gating in schizophrenics following nicotine administration. Studies in the rat model have also implicated the nicotinic receptor, and a subtype of this receptor, the alpha-bungarotoxin binding site, in the modulation of sensory gating. Recently, several strains of inbred mice have been characterized which have differing numbers of alpha-bungarotoxin binding sites in the hippocampus. These mice offer an excellent model system in which to evaluate the nicotinic cholinergic mediation of sensory gating. The proposed studies will include pharmacologic manipulation, autoradiographic and in situ hybridization studies, breeding studies and development of a chronic recording model. In Experiment 1, the role of the hippocampal alpha-bungarotoxin binding site in sensory gating will be evaluated using anesthetized-preparation evoked potential recording coupled with injections of drugs effecting the alpha- bungarotoxin binding site. Hippocampal autoradiography for alpha- bungarotoxin binding and in situ hybridization for alpha7 mRNA will be performed on each recorded mouse. Experiment 2 will explore the role of the hippocampal classic nicotinic receptor in sensory gating in the same manner as Experiment 1. Drugs effecting the nicotinic receptor will be administered; autoradiography for the nicotinic receptor and in situ hybridization for alpha4 and beta2 mRNAs will be performed. Experiment 3 will address sensory gating and hippocampal muscarinic receptors using drugs active at this receptor, and autoradiographic visualization of hippocampal muscarinic binding. Experiment 4 will determine whether the manipulation of the number of hippocampal alpha-bungarotoxin binding sites will effect sensory gating. Both chronic pharmacologic intervention and breeding experiments will be performed. Autoradiography and in situ hybridization experiments will follow evoked potential recording. In Experiment 5, a chronic recording model in the mouse will be developed to permit multiple recording sessions in an awake and behaving mouse. Knowledge gained from the proposed research may help bridge the gap between clinical observation and specific neuronal and molecular abnormalities, and further, may aid in the development of new therapeutic approaches for schizophrenia.

精神分裂症是一种病因不明的复杂疾病。一个著名的