HUMAN PERINATAL INTERVENTION

初级预防是调查任何慢性病的目标。项目2：翻译 关于α 7烟碱受体在早期大脑发育中作用的基本神经生物学发现， 早期人类发育异常的临床评估， 生活它还正在对一种具体的围产期干预措施进行初步试验，以减少这一风险。 我们系统地研究了心理生理和神经心理的发展 与成人精神分裂症遗传易感性相关的异常。这些包括听觉感官 PSO听觉诱发电位显示门控缺陷，平滑追踪眼异常 运动，不匹配的负性，以及各种注意力测量。在这些措施中， 出现在一些父母患有精神分裂症的孩子身上，只要测试是发展可能的。 基础科学研究指出，围产期是α 7尼古丁作用的关键窗口， 受体，其最大表达发生在GABA和谷氨酸突触的成人形式 表达了。我们开发了在出生后几周内记录PSO感觉门控的技术， 这表明，这个功能已经正常存在。在拟议的目标中，我们将扩大我们最初的 观察到父母的精神病史与减少PSO听觉感觉门控有关。 项目3将对我们的受试者进行基因分型，以测试这些缺陷的遗传关联是否在早期 发展与成人的协会相同。类似的遗传关联可能支持 一种假设，即有精神分裂症风险的儿童的缺陷与缺陷具有相同的分子基础， 在精神分裂症中观察到的我们还将扩展第二个观察结果，即母亲在怀孕期间使用尼古丁， 妊娠与减少的PSO听觉感觉门控有关。这些影响是加性的， 明显的遗传风险的影响，并牵连烟碱受体的赤字，也是如此，在成人与 精神分裂症患者对慢性尼古丁暴露有反应，但PSO门控丢失。根据Project 3的 证明围产期胆碱，α 7烟碱受体激动剂，改善感觉门控， DBA/2小鼠模型的α 7烟碱受体和感觉门控的遗传缺陷，我们有 获得了FDA的许可，可以给母亲和他们的婴儿服用围产期胆碱。我们将继续这一 临床研究，这显示了早期增强感觉门控的初步前景。 项目2得到项目1的临床研究支持和项目3、4、5、6的基础研究支持。 相关性（参见说明）： 精神分裂症需要新的治疗策略来改善认知功能障碍和负性 症状和预防精神病的发展。该中心研究了一种烟碱乙酰胆碱 受体作为新的治疗靶点。研究结果用于设计一种新的药物治疗， 精神分裂症和婴儿发育期间的预防性营养干预，这两者都激活了这一点。 rprpntnr

Primary prevention is a goal for the investigation of any chronic illness. Project 2 focuses on translating basic neurobiological findings about the role of alpha 7 nicotinic receptors in early brain development into clinical assessments of early human developmental abnormalities that can progress to schizophrenia later in life. It is also conducting initial tests of a specific perinatal intervention to reduce this risk. We have systematically examined the development of psychophysiological and neuropsychological abnormalities associated with the genetic liability to schizophrenia in adults. These include auditory sensory gating deficits demonstrated with PSO auditory evoked potentials, abnormalities in smooth pursuit eye movements, mismatch negativity, and various measures of attention. Abnormalities in these measures appear in some children of parents with schizophrenia as soon as testing is developmentally possible. Basic science research points to the perinatal period as a critical window for the role of alpha 7 nicotinic receptors, with their maximal expression occurring then as the adult forms of GABA and glutamate synapses are expressed. We developed techniques to record PSO sensory gating within several weeks of birth and showed that this function is already normally present. In the proposed aims, we will extend our initial observation that parental history of psychosis is associated with diminished PSO auditory sensory gating. Project 3 will genotype our subjects to test whether the genetic associations of these deficits in early development are the same as the associations in adults. Similar genetic association may support the hypothesis that the deficits in children at risk for schizophrenia have the same molecular basis as deficits observed in schizophrenia itself. We will also extend a second observation that maternal nicotine use during pregnancy is associated with diminished PSO auditory sensory gating. These effects are additive with the effects of apparent genetic risk and implicate nicotinic receptors in the deficit, as is also true in adults with schizophrenia who respond to chronic nicotine exposure with loss of PSO gating. Based on Project 3's demonstration that perinatal choline, an alpha 7 nicotinic receptor agonist, improves sensory gating in the DBA/2 mouse model of genetic deficiencies in alpha 7 nicotinic receptors and sensory gating, we have obtained FDA permission to administer perinatal choline to mothers and their infants. We will continue this clinical investigation, which shows initial promise of early enhancement of sensory gating. Project 2 receives clinical research support from Project 1 and basic research support from Projects 3,4,5,6. RELEVANCE (See instructions): New therapeutic strategies for schizophrenia are needed to improve cognitive dysfunction and negative symptoms and to prevent the development of psychosis. The Center investigates a nicotinic acetylcholine receptor as a new therapeutic target. Investigational results are used to design a new drug treatment for schizophrenia and a preventative nutrient intervention during infant development, both of which activate this rprpntnr