Gestational Choline Levels and Sensory Inhibition

妊娠胆碱水平和感觉抑制

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/7147798
• 关键词: DNA; auditory stimulus; autoradiography; behavior test; behavioral /social science research tag; bungarotoxins; choline; cochlear microphonic potentials; developmental neurobiology; dietary supplements; early experience; frontal lobe /cortex; gender difference; genetically modified animals; hippocampus; laboratory mouse; learning; mammalian embryology; memory; methylation; mother /embryo /fetus nutrition; neural inhibition; nicotinic receptors; nutrition related tag; prefrontal lobe /cortex; pregnancy; schizophrenia; sign /symptom

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，并与某些阳性症状相关。神经学的改善与感觉神经的改善同时出现。感觉抑制缺陷已经在DBA/2小鼠中建模，DBA/2小鼠不仅表现出感觉抑制缺陷，而且在海马中α 7烟碱受体数量减少和基因编码多态性方面与精神分裂症患者在基因型上相似。我们最近表明，围产期胆碱补充饮食的母亲，产生DBA/2的后代与正常的感觉神经。大鼠和一种小鼠品系（C57/BL 6）的围产期胆碱补充剂先前已被证明可以改善后代的学习和记忆。我们的初步数据表明，感觉抑制电路也永久改变，有一个显着增加apha 7烟碱受体在齿状回和海马CA 1区围产期胆碱补充。改善感觉抑制的潜在机制尚不清楚。本申请将寻求通过评估α/受体的作用来阐明机制。（使用α 7无效突变小鼠），非α 7受体的作用（使用α 7和非α 7受体的激动剂，与α 7受体的激动剂（其也是α 4 β 2受体的拮抗剂）相比），以及DNA甲基化的作用（使用替代甲基供体，此外还使用具有超甲基化的遗传改变小鼠品系）。由于在围产期胆碱给药时观察到了学习和记忆效应，因此将检测所有组的学习和记忆变化。最后，将使用定量放射自显影术评估由任何围产期干预以及高甲基化小鼠诱导的海马α 7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产前营养指南。