GENETIC STRAIN EFFECTS AND DOPAMINE CELL LOSS IN WEAVER MUTANT

对神经细胞数量和神经细胞控制机制的认识 大脑的缺失是了解中枢神经系统的核心 在健康和疾病方面的功能。神经细胞差异的证据 不同品系小鼠脑内区域的数量表明 可能的基因控制离散区域神经元数量的变异性 大脑的一部分。CBA/J品系小鼠中脑多巴胺的数量 (Da)小鼠的神经元数量比BALB/CJ小鼠低约20%。这是可以想象的 中脑DA神经元的数量也受基因调控 天哪。如果某些人被赋予较少数量的特定 神经细胞群体，比如说DA细胞群体，会不会这样的个体， 作为突变基因的结果，成为功能缺陷的受害者-帕金森 疾病--更早？有门槛吗？我们之前已经发现， 单基因突变织布者(Wv)影响中脑的生存能力 DA神经元，并导致这些细胞出生后的损失。在混合B6CBA中- WV基因纯合子的AW-J/A小鼠， 中脑DA系统大约比野生少47% 按90天龄打字。与应变相关的变异性的影响 中脑DA神经元的数量对A基因表型表达的影响 影响神经元群体单基因突变还没有得到证实 之前被调查过。我们打算确定是否有 由于WV基因的影响，出生后丢失的DA神经元是固定的， 与应变无关，或与DA神经元的数量有关 这种特定的菌株最初是被赋予的。为此，我们将 获得CBA/J株同源纯合子WV突变小鼠 BALB/CJ株，将决定神经细胞的数量 WV纯合子和成熟时对照的中脑DA系统 并将测量中脑中的神经化学多巴胺能标记物 以及突变型和野生型小鼠的纹状体。WV基因将是 在BALB/CJ和CBA/J背景下引入育种技术 这被称为回交系统。13个回交世代将是 生产同源品系所需的。当这些都能得到的时候，神经 将在#年进行DA神经元的细胞计数和统计分析 中脑。这些数据将使我们能够确定是否存在 品系特异性神经细胞数量与神经细胞数量的关系 因单一基因而被编程为死亡的细胞 突变。有了这些研究，就有可能推断出一般情况 神经生物学原理和提出新的有待检验的假说 研究人类大脑的退行性疾病，如帕金森 疾病。

Knowledge of the mechanisms controlling nerve cell number and nerve cell loss in the brain is central to the understanding of central nervous system functions in health and disease. The evidence of differences in nerve cell number within brain regions among different strains of mice indicates that putative genes control the variability of neuronal number in discrete areas of the brain. In mice of the CBA/J strain the number of midbrain dopamine (DA) neurons in some 20% lower than in BALB/cJ mice. It is conceivable that the number of midbrain DA neurons is genetically regulated also in man. If certain individuals be endowed with a lesser number of a specific nerve cell population, say the DA cell population, would such individuals, as a result of a mutant gene, fall victim to functional deficit - Parkinson Disease - earlier? Is there a threshold? We have previously found that the single gene mutation weaver (wv) affects the viability of the midbrain DA neurons and induces a postnatal loss of these cells. In hybrid B6CBA- Aw-j/A mice, homozygous for the wv gene, the neurons of the mesotelencephalic DA system are approximately 47% fewer than in the wild type by 90 days of age. The influence of the strain-associated variability of the number of midbrain DA neurons upon the phenotypic expression of a single gene mutation affecting that neuronal population, has not been previously investigated. We intend to determine whether the percentage of DA neurons lost postnatally as an effect of the wv gene is fixed, regardless of strain, or varies in relation to the number of DA neurons with which the specific strain is originally endowed. To this end we will obtain homozygous wv mutant mice congenic in the CBA/J strain as well as in the BALB/cJ strain, will determine the number of neurons of the mesencephalic DA system in wv homozygotes and controls at maturity for each strain and will measure neurochemical dopaminergic markers in the midbrain and the striatum of mutant and wild type mice. The wv gene will be introduced in the BALB/cJ and CBA/J background using the breeding technique known as the backcross system. Thirteen backcross generations will be required to produce the congenic lines. When these will be obtained, nerve cell counts and statistical analysis of DA neurons will be carried out in the midbrain. The data will allow us to determine whether there is a relation between the strain-specific nerve cell number and the number of cells that are programmed to die as a consequence of a single gene mutation. With these studies it may be possible to extrapolate general neurobiological principles and to formulate new hypotheses to be tested studying degenerative diseases of the human brain, such as Parkinson disease.