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GENETIC LINKAGE OF AUDITORY GATING

听觉门控的遗传联系

基本信息

批准号：
6392375
负责人：
KAREN E STEVENS
金额：
$ 19.15万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-04-01 至 2004-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6392375
关键词：
auditory feedback chromosomes disease /disorder etiology gene expression genetic markers genetic strain genotype laboratory mouse linkage mapping neural information processing phenotype polymerase chain reaction restriction fragment length polymorphism schizophrenia sensory feedback

项目摘要

Schizophrenia is a disease of unknown etiology which does not occur in animals. However, some aspects of the disorder are amenable to study in both animals and schizophrenia patients. An example is abnormal processing of sensory information; a hallmark of schizophrenia. Schizophrenics concentrate poorly and are often overloaded by incoming sensory information. The resultant flood of input may lead to personality decompensation. Deficient sensory processing can be assessed in both humans and animals using a conditioning-test paradigm and comparing the electrophysiological responses to paired auditory stimuli. Normal humans and most mouse strains show a reduced response to the second stimulus, thus, they are filtering or "gating" their response to this stimulus. Schizophrenia patients, some of their first degree relatives, and certain inbred mouse strains show responses to both stimuli which are of the same magnitude; thus, they do not gate. Traditional neuroleptic treatment does not normalize the gating deficit in schizophrenics, however, recent studies in both humans and animals have demonstrated involvement of the nicotinic receptor, specifically the alpha7 subtype, in the modulation of sensory gating. In a recent study of human pedigrees, the gating deficit was shown to be linked to chromosomal position 15q13-14, the site to which the human alpha7 receptor maps. Thus, data suggest that the alpha7 nicotinic receptor may be modulating auditory gating in both humans and rodents, however, other systems cannot be ruled out. In a classical breeding study using 2 strains of inbred mice, gating capacity was shown to be a heritable trait with a single gene, autosomal dominant pattern. This proposal will seek to identify chromosomal loci in the mouse genome which are linked to the auditory gating deficit. The segregation data suggesting the single gene model used a cross between the C3H mouse (a gating strain) and the DBA/2 mouse (a non-gating strain). I have a significant volume of data on auditory gating with the parental strains, F1, F2 and backcross generations, and the current proposal would extent these studies as well as assess the relationship between an identified restriction fragment length polymorphism (RFLP), near the alpha7 nicotinic receptor gene in the mouse, and auditory gating (Expt. 1). Also, a full genome scan will attempt to link auditory gating with any other chromosomal loci (Expt. 2). Another study will assess auditory gating and linkage to any loci in a second genetic cross between C57BL/6 mice (a gating strain) and DBA/2 mice, allowing assessment of the DBA/2 gating pattern on another genetic background with the same RFLP as C3H mice. This cross also has recombinant inbred (RI) strains which allows precise determination of gating for each RI strain. Part of the variance in auditory gating is non-genetic, and assessment of RI strains will reduce this component. In addition, assessment of true F2 generation mice will confirm sites identified in the RI strain study (Expt. 3). Identified loci in mice may lead to isolation of the gene(s) controlling schizophrenia in humans. Such information could be important in understanding of the etiology of the disorder and in determining future therapeutic interventions.

精神分裂症是一种病因不明的疾病，在动物身上不会发生。然而，这种障碍的某些方面可以在动物和精神分裂症患者身上进行研究。一个例子是感觉信息的异常处理；这是精神分裂症的一个特征。精神分裂症患者注意力不集中，经常被输入的感觉信息超负荷。由此产生的大量投入可能会导致人格失代偿。在人类和动物中，都可以使用条件性测试范式并比较电生理反应对成对的听觉刺激的反应，来评估感觉处理的缺陷。正常人和大多数品系的小鼠对第二次刺激的反应减弱，因此，他们对第二次刺激的反应进行了过滤或“门控”。精神分裂症患者、他们的一些一级亲属和某些近交系小鼠对这两种刺激都表现出相同的反应；因此，他们不会产生反应。传统的抗精神病药治疗不能使精神分裂症患者的门控缺陷正常化，然而，最近在人类和动物中的研究表明，尼古丁受体，特别是α7亚型，参与了感觉门控的调节。在最近对人类家系的一项研究中，门控缺陷被证明与染色体位置15q13-14有关，人类Alpha7受体所在的位置。因此，数据表明，α7尼古丁受体可能在调节人类和啮齿动物的听觉门控，然而，不能排除其他系统。在两个品系近交系小鼠的经典育种研究中，门控能力被证明是一个单基因遗传性状，常染色体显性模式。这项提议将寻求确定小鼠基因组中与听觉门控缺陷有关的染色体位点。分离数据表明，单基因模型使用了C3H小鼠(门控品系)和DBA/2小鼠(非门控品系)之间的杂交。我有大量关于听觉门控的亲本品系、F1、F2和回交世代的数据，目前的提议将扩大这些研究，并评估小鼠中靠近α7尼古丁受体基因的已识别的限制性片段长度多态性(RFLP)与听觉门控(Expt.1)。此外，全基因组扫描将试图将听觉门控与任何其他染色体基因座联系起来(例如。2)。另一项研究将评估C57BL/6小鼠(门控品系)和DBA/2小鼠之间的第二个遗传杂交中的听觉门控和与任何基因座的连锁，从而允许在另一个遗传背景上评估DBA/2门控模式，该遗传背景与C3H小鼠具有相同的RFLP。该杂交还拥有重组自交系(RI)品系，这使得可以精确地确定每个RI品系的门控。听觉门控的部分变异是非遗传的，RI菌株的评估将减少这一成分。此外，对真正的F2代小鼠的评估将确认RI品系研究中确定的位置(例如。3)。在老鼠身上发现的基因位点可能导致分离控制人类精神分裂症的基因(S)。这些信息可能对了解疾病的病因和确定未来的治疗干预措施很重要。