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未知的复杂疾病。 一个突出 精神分裂症患者之间的问题是无法过滤或门，感觉 信息。 正常个体，当带有相同的配对时 刺激（点击），中等听觉诱发的潜力降低 与第一次单击相比，第二次点击。 据说他们是 “控球'他们对第二个刺激的反应。相比之下， 精神分裂症患者和普通人管理精神病学 （苯丙胺，PCP），具有与两次点击相似的响应。 因此，他们不登机。 这种门控赤字已成功建模 在动物中。 大鼠显示正常的感觉门控模式，该模式被改变 在给药时类似精神分裂症的门控损失 精神病药物。 最近的临床研究表明 精神分裂症患者中感觉门控的瞬态归一化 尼古丁给药。 大鼠模型中的研究也暗示了 烟碱受体和该受体的亚型，α-甲状腺毒素 结合位点，在感觉门控的调制中。 最近，几个 近交小鼠的菌株的表征有不同的数字 海马中的α-肺毒素结合位点。 这些老鼠提供 一个出色的模型系统，用于评估烟碱胆碱能 感觉门控的调解。 拟议的研究将包括 药理操作，放射自显影和原位杂交 慢性记录模型的研究，育种研究和开发。 在 实验1，海马alpha-bungarotoxin结合位点的作用 在感官门控将使用麻醉预先制备评估 潜在记录以及对α-的药物注射 Bungarotoxin结合位点。 α-的海马放射自显影 Bungarotoxin的结合和原位杂交α7mRNA将是 在每个记录的鼠标上执行。 实验2将探讨 同一感觉门控的海马经典烟碱受体 作为实验的方式1。影响烟碱受体的药物将是 管理；烟碱受体和原位的放射自显影 将进行α4和beta2 mRNA的杂交。 实验3 将使用使用感官门控和海马毒蕈碱受体来解决 活跃在该受体上的药物以及自显影的可视化 海马毒蕈碱结合。 实验4将确定是否是否 操纵海马α-bungarotoxin结合位点的数量 将影响感官门控。 慢性药理干预和 将进行育种实验。 放射自显影和原位 杂交实验将遵循引起的潜在记录。 在 实验5，将开发出鼠标中的慢性记录模型 允许在清醒和行为鼠标中进行多个记录会话。 从提议的研究中获得的知识可能有助于弥合 临床观察以及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。