In vivo studies of Neuregulin 1 in addiction pathways

描述(由申请者提供)：美国吸烟最严重的人群包括精神分裂症(SZ)患者。研究表明，尼古丁可能构成这类患者的一种重要的自我用药形式，特别是在它对感觉门控的致病记忆缺陷的影响方面。最近的研究表明，与对照人群相比，SZ人群对尼古丁的依赖程度更高。α7烟碱型乙酰胆碱受体(A7*-nAChR)的遗传变异与SZ相关的感觉门控缺陷有关。同样，神经调节蛋白1(Nrg1)是(A7*-nAChRs)的关键调节因子，其基因变异最近被认为与遗传型SZ有关。这些观察结果促使我们提出了Nrg1和A7*-在尼古丁滥用和神经精神障碍易感性(如SZ)的共同发病率中表达的趋同效应。CEBRA第一阶段资金旨在启动单一和复合转基因小鼠的体内电生理学和行为研究。待检测的转基因品系包括Ill-Nrg1型杂合突变体(Nrg1)和A7nAChR亚单位突变体chrna7()。拟议的研究开始测试Nrg1和A7调控的假设趋同，作为尼古丁效应易感性、烟草依赖性和SZ表型方面的遗传成分，通过比较小鼠出生前尼古丁暴露。因此，这一阶段1应用的目的是启动Nrg1缺陷(有和没有A7缺陷)是否改变体内海马-伏隔神经回路的发育、维持和/或可塑性的测试。对完整系统中突触回路和尼古丁诱导的兴奋性的基因型依赖性变化的评估使用活体细胞内和多单位记录来检查腹侧海马-纹状体的相互作用。遗传特征对兴奋性输入门控到腹侧纹状体的影响和尼古丁的影响将在并行的行为研究和成年小鼠的尼古丁暴露和/或急性尼古丁暴露的记录中进行评估。

DESCRIPTION (provided by applicant): The heaviest smoking populations in the US include patients with schizophrenia (SZ). Research indicates that nicotine may constitute an important form of self-medication for such patients, particularly in its effects on the pathognemonic deficits of sensory-gating. Recent studies demonstrate a higher degree of dependence on nicotine in SZ vs. control populations. Genetic variations in the alpha 7 nicotinic acetylcholine receptor (a7*-nAChR) are linked with the sensory gating deficits associated with SZ. Likewise, genetic variants of Neuregulin 1 (Nrg1), a key regulator of (a7*-nAChRs), have recently been associated with heritab e forms of SZ. These observations prompt our proposal of convergent effects on Nrg1 and a7*-expression in the co-morbidity of nicotine abuse and susceptibility to neuropsychiatric disorders such as SZ. CEBRA stage 1 funding is sought to initiate in vivo electrophysiology and behavioral studies in single and compound genetically-modified mice. The genetically altered lines to be examined include the isoform specific: Type Ill-Nrg1 heterozygous mutant (Nrg1) and the a7 nAChR subunit mutant Chrna7(). Proposed studies begin tests of the hypothesized convergence of Nrg1 and a7 regulation as heritable components of susceptibility to nicotine effects, tobacco dependence and facets of SZ phenotypes by comparison of mice prenatal nicotine exposure. Thus, the AIM of this STAGE 1 Application is to initiate tests of whether deficits in Nrg1 (with and without deficits in a7) alter the development, maintenance and/or plasticity of hippocampal-accumbens circuits in vivo. Assessment of genotype dependent changes in synaptic circuits and nicotine-induced excitability in intact systems examine ventral hippocampal-striatal interactions using in vivo intracellular and multi unit recordings. The impact of genetic profile on excitatory-input gating to the ventral striatum and on the effects of nicotine will be assessed in parallel behavioral studies and recordings from adult mice subjected to prenatal and/or acute nicotine exposure.