GENETIC ANALYSIS OF SENSORY GATING

感觉门控的遗传分析

• 批准号: 2445537
• 负责人: KAREN E STEVENS
• 金额: $ 10.72万
• 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/2445537
• 关键词: atropine; auditory feedback; auditory stimulus; autoradiography; behavioral /social science research tag; 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。一个突出的问题 精神分裂症患者的问题是无法过滤或关闭感觉 信息。正常个体，当被呈现相同的配对时 刺激(点击)，具有减小的中潜伏期听觉诱发电位 与第一次点击相比，第二次点击。据说他们是 “限制他们对第二轮刺激的反应。相比之下， 精神分裂症患者和接受精神分裂疗法治疗的正常人 (苯丙胺，PCP)，对这两种点击的反应程度相似。 因此，他们不会打开大门。这种门控赤字已经被成功地模拟出来 在动物身上。大鼠表现出一种正常的感觉门控模式，这种模式发生了变化 给药后精神分裂症样的门禁丧失 类似精神分裂的药物。最近的临床研究表明， 精神分裂症患者感觉门控的一过性正常化 尼古丁注射。对大鼠模型的研究也表明， 烟碱受体，以及该受体的一个亚型，α-银环蛇毒素 结合部位，在调节感觉门控。最近，有几个 近亲交配的小鼠品系具有不同的数量 海马区的α-银环蛇毒素结合部位。这些鼠标提供了 一种评价烟碱型胆碱能神经的良好模型系统 感觉门控的调节。拟议的研究将包括 药物操纵、放射自显影和原位杂交 慢性记录模型的研究、繁育研究和开发。在……里面 实验1，海马区α-银环蛇毒素结合部位的作用 在感觉门控中将使用麻醉-准备诱发 电位记录结合药物注射影响阿尔法- 银环蛇毒素结合部位。α-半乳糖胺的海马区放射自显影 银环蛇毒素结合和alpha7mRNA的原位杂交将被 在每个记录的鼠标上执行。实验2将探索这一角色。 海马区经典烟碱受体在感觉门控中的作用 实验1.影响烟碱受体的药物将是 用药；烟碱受体放射自显影和原位 将进行alpha4和beta2mRNAs的杂交。实验三 将解决感觉门控和海马毒碱受体使用 作用于该受体的药物及其放射自显影 海马区毒扁豆碱结合。实验4将确定是否 海马区α-银环蛇毒素结合位点数的调控 会影响感官门控。慢性药物干预和 将进行育种实验。放射自显影与原位 杂交实验将在诱发电位记录之后进行。在……里面 实验5，建立小鼠慢性记录模型 允许在一个清醒且行为正常的鼠标中进行多个记录会话。 从拟议的研究中获得的知识可能有助于弥合 临床观察和特定的神经元和分子异常，以及 此外，可能有助于开发新的治疗方法 精神分裂症。