GENETIC LINKAGE OF AUDITORY GATING

听觉门控的遗传联系

• 批准号: 2853720
• 负责人: KAREN E STEVENS
• 金额: $ 15.52万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2853720
• 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

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，不会发生在动物身上。 然而，这种疾病的某些方面适合在动物和精神分裂症患者中进行研究。 一个例子是感觉信息的异常处理;精神分裂症的标志。 精神分裂症患者注意力不集中，经常被传入的感官信息超载。 由此产生的输入洪流可能导致人格失代偿。 在人类和动物中，可以使用条件测试范例并比较对成对听觉刺激的电生理反应来评估感觉处理缺陷。正常人和大多数小鼠品系对第二种刺激的反应降低，因此，它们对这种刺激的反应进行过滤或“门控”。 精神分裂症患者，他们的一些一级亲属，以及某些近交系小鼠品系对两种刺激都表现出相同幅度的反应，因此，他们不门控。 传统的精神抑制剂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已经证明了烟碱受体，特别是α 7亚型，参与感觉门控的调节。 在最近的人类谱系研究中，门控缺陷被证明与染色体位置15 q13 -14有关，该位点是人类α 7受体的位置。 因此，数据表明，α 7烟碱受体可能在人类和啮齿动物中调节听觉门控，然而，不能排除其他系统。 在一项使用2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种单基因常染色体显性遗传性状。 这项提议将寻求确定小鼠基因组中与听觉门控缺陷相关的染色体位点。 表明单基因模型的分离数据使用C3 H小鼠（门控品系）和DBA/2小鼠（非门控品系）之间的杂交。 我有大量关于亲本品系、F1、F2和回交世代的听觉门控的数据，目前的建议将扩展这些研究，并评估小鼠中α 7烟碱受体基因附近的已鉴定限制性片段长度多态性（RFLP）与听觉门控之间的关系（实验）。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位点联系起来（实验。2）。 另一项研究将评估听觉门控和与C57 BL/6小鼠（门控品系）和DBA/2小鼠之间的第二次遗传杂交中任何基因座的连锁，允许评估具有与C3 H小鼠相同RFLP的另一种遗传背景的DBA/2门控模式。 该杂交还具有重组近交（RI）菌株，其允许精确确定每个RI菌株的门控。 听觉门控的部分变异是非遗传性的，RI应变的评估将减少这一部分。 此外，真实F2代小鼠的评估将确认RI品系研究中鉴定的位点（实验3）。 在小鼠中鉴定的基因座可能导致控制人类精神分裂症的基因的分离。 这些信息可能是重要的，在了解疾病的病因，并在确定未来的治疗干预。