GENETIC ANALYSIS OF SENSORY GATING

感觉门控的遗传分析

• 批准号: 2251427
• 负责人: KAREN E STEVENS
• 金额: $ 10.28万
• 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/2251427
• 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。 一个突出 精神分裂症患者的一个问题是无法过滤或门控感官， 信息. 正常人，当呈现相同的配对时， 刺激（点击），具有减弱的中潜伏期听觉诱发电位 第二次点击，与第一次点击相比。 据说他们正在 “门控”他们对第二个刺激的反应。 相比之下， 精神分裂症患者和服用拟精神病药的正常人 （安非他明，五氯酚），有类似的规模的反应，这两个点击。 所以他们不会关门。 这种门控缺陷已经成功地模拟了 在动物身上。 大鼠表现出正常的感觉门控模式， 给药后出现类似精神分裂症的门控丧失 拟精神病药物 最近的临床研究表明， 精神分裂症患者感觉门控的短暂正常化 尼古丁管理。 对大鼠模型的研究也表明， 烟碱受体和这种受体的一种亚型，α-银环蛇毒素 结合位点，在感觉门控的调制。 最近有数 已经表征了具有不同数量的近交系小鼠 海马体中的银环蛇毒素结合位点 这些老鼠提供 一个很好的模型系统，其中评估烟碱胆碱能 介导感觉门控。 拟议的研究将包括 药理学操作、放射自显影和原位杂交 研究、育种研究和慢性记录模型的开发。 在 实验1，海马α-银环蛇毒素结合位点的作用 在感觉门控将评估使用麻醉准备诱发 潜在的记录加上注射药物影响阿尔法- 银环蛇毒素结合位点。 海马体放射自显影法 银环蛇毒素结合和α 7 mRNA的原位杂交， 在每只记录的小鼠上进行。 实验2将探讨 海马经典烟碱受体在感觉门控中的作用 如实验1。 影响烟碱受体的药物将是 烟碱受体和原位放射自显影 进行α 4和β 2 mRNA杂交。 实验3 将使用以下方法解决感觉门控和海马毒蕈碱受体问题： 药物活性在这个受体，和放射自显影可视化 海马毒蕈碱结合。 实验4将确定 海马α-银环蛇毒素结合位点数目的操纵 会影响感官门控 慢性药物干预和 将进行育种实验。 放射自显影和原位 杂交实验将在诱发电位记录之后进行。 在 实验5，将在小鼠中开发慢性记录模型， 允许多个记录会话在一个清醒的和行为的鼠标。 从拟议的研究中获得的知识可能有助于弥合以下方面的差距： 临床观察和特异性神经元和分子异常，以及 此外，可能有助于开发新的治疗方法， 精神分裂症