Gestational Choline Levels and Sensory Inhibition

妊娠胆碱水平和感觉抑制

基本信息

批准号：
7147798
负责人：
KAREN E STEVENS
金额：
$ 24.15万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-15 至 2009-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Deficits in sensory inhibition are a common symptom of schizophrenia and are correlated with certain positive symptoms. Improvement in symptomology is seen concurrent with improvement in sensory nhibition. The sensory inhibition deficit has been modeled in DBA/2 mice which not only show the deficient sensory inhibition, but are also genotypically similar to schizophrenics in having reduced numbers of alpha7 nicotinic receptors in the hippocampus and polymorphisms in the gene coding. We have recently shown that perinatal choline supplementation in the diet of the dam, produces DBA/2 offpspring with normal sensory nhibition. Perinatal choline supplementation in rats and one mouse strain (C57/BL6) has previously been shown to improve learning and memory in offspring thoughout their lifetimes. Our preliminary data show that sensory inhibition circuitry is also permanently altered in that there is a significant increase in apha7 nicotinic receptors in the dentate gyrus and CA1 regions of the hippocampus with peri-natal choline supplementation. The underlying mechanism of the improved sensory inhibition is not known. The present application will seek to elucidate the mechanism(s) by assessing role of alpha/ receptors (using alpha7 null mutant mice), the role of non-alpha7 receptors (using an agonist at both alpha7 and non-alpha7 receptors compared to an agonist at alpha7 receptors which is also an antagonist at alpha4beta2 receptors), and the role of DNA methylation (using an alternate methyl donor, and additionally, a genetically altered mouse strain with hypermethylation). Since learning and memory effects have been observed with peri-natal choline administration, all groups will be tested for learning and memory alterations. Finally, any changes in hippocampal alpha7 receptor levels induced by any of the perinatal interventions as well as the hypermethylation mice mice will be assessed using quantitative autoradiography. The data from these studies may potentially impact guide lines for human prenatal nutrition in at-risk pregnancies for schizophrenia.

描述（由申请人提供）：感觉抑制缺陷是精神分裂症的常见症状，并且与某些阳性症状相关。症状的改善与感觉抑制的改善同时发生。在 DBA/2 小鼠中建立了感觉抑制缺陷模型，该小鼠不仅表现出感觉抑制缺陷，而且在基因型上与精神分裂症患者相似，海马中 α7 烟碱受体数量减少，且基因编码存在多态性。我们最近发现，在母猪的饮食中补充围产期胆碱，可以产生具有正常感觉抑制的 DBA/2 后代。此前已证明，对大鼠和一种小鼠品系 (C57/BL6) 进行围产期补充胆碱可以改善后代一生的学习和记忆能力。我们的初步数据表明，由于围产期补充胆碱，海马齿状回和 CA1 区域的 apha7 烟碱受体显着增加，因此感觉抑制回路也发生了永久性改变。改善感觉抑制的潜在机制尚不清楚。本申请将通过评估α/受体的作用（使用α7无效突变小鼠）、非α7受体的作用（与激动剂相比，使用α7和非α7受体的激动剂）来寻求阐明机制。 α7 受体，它也是 α4β2 受体的拮抗剂），以及 DNA 甲基化的作用（使用替代甲基供体，此外，还使用基因改造的小鼠品系，超甲基化）。由于围产期胆碱给药观察到学习和记忆效应，因此将测试所有组的学习和记忆改变。最后，将使用定量放射自显影术评估由任何围产期干预措施以及高甲基化小鼠引起的海马α7受体水平的任何变化。这些研究的数据可能会影响精神分裂症高危妊娠的人类产前营养指南。