In vivo studies of Neuregulin 1 in addiction pathways

描述（由申请人提供）：美国最严重的吸烟人群包括精神分裂症患者（SZ）。研究表明，尼古丁可能是此类患者自我药疗的一种重要形式，特别是在其对感觉门控的病理性缺陷的影响方面。最近的研究表明，SZ人群对尼古丁的依赖程度高于对照人群。α 7烟碱乙酰胆碱受体（α 7 *-nAChR）的遗传变异与SZ相关的感觉门控缺陷有关。同样地，神经调节蛋白1（Nrg 1）（α 7 *-nAChR）的关键调节因子）的遗传变体最近与可遗传形式的SZ相关。这些观察结果促使我们提出了尼古丁滥用和神经精神疾病（如SZ）易感性共病中Nrg 1和a7* 表达的会聚效应。CEBRA第1阶段的资金寻求在单一和复合基因修饰小鼠中启动体内电生理学和行为研究。待检查的遗传改变品系包括亚型特异性：III型-Nrg 1杂合突变体（Nrg 1）和α 7 nAChR亚基突变体Chrna 7（）。拟议的研究开始测试假设的收敛Nrg 1和a7调节作为遗传的组成部分，尼古丁效应的易感性，烟草依赖和方面的SZ表型通过比较小鼠产前尼古丁暴露。因此，第1阶段申请的目的是启动Nrg 1缺陷（有和没有a7缺陷）是否会改变体内海马-海马神经回路的发育、维持和/或可塑性的试验。评估基因型依赖的突触电路和尼古丁诱导的兴奋性在完整的系统中的变化，研究腹侧海马-纹状体的相互作用，在体内细胞内和多个单位的记录。将在平行行为研究中评估遗传特征对腹侧纹状体兴奋性输入门控和尼古丁效应的影响，并记录产前和/或急性尼古丁暴露的成年小鼠。

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.