Cholinergic Lesions and Age-Related Cognitive Impairment

描述(由申请人提供)：阿尔茨海默氏症相关痴呆和年龄相关的认知能力下降，部分原因是海马体和额叶皮质胆碱能投射的丧失。尽管进行了多年的研究，但具体的认知过程受到基底前脑胆碱能投射损伤的影响，以及胆碱能投射缺失在多大程度上导致与年龄相关的认知功能下降，目前尚不清楚。最近，我们发现去卵巢的老年大鼠在一个简单的延迟匹配定位(DMP)T迷宫任务的获得上受到了实质性的损害。此外，我们还发现，将选择性免疫毒素192免疫球蛋白(SAP)注射到幼年大鼠体内，会严重损害雄性和雌性大鼠对DMP任务的获得性，与老年大鼠的缺陷相似。我们的初步研究表明，SAP产生的缺陷是由于基底前脑中胆碱能神经元的选择性丧失，而不是GABA能神经元，并且其表现与海马区和额叶皮质的胆碱能神经支配有关。此外，数据表明，SAP在DMP获取方面的缺陷主要不是由于空间工作记忆缺陷造成的。该提案的目的是(1)确定导致SAP导致DMP获得缺陷的特定胆碱能投射及其靶点，(2)确定受SAP损害影响并构成DMP获得缺陷的特定认知过程，以及(3)评估SAP产生的缺陷与与年龄相关的认知下降相关的缺陷。实验1和实验2将使用SAP微量注射以及组织化学和生化分析来确定男性和女性特定的基底前脑胆碱能投射，这些投射是SAP诱导的DMP获取的显著缺陷的原因。实验3a和3b将使用DMP任务的修改版本来确定SAP患者和老年动物(包括雄性和雌性)是否在采用地点与反应学习策略来获得任务的能力方面存在缺陷。此外，这些相同的动物将使用两个额外的任务进行测试，一个是测试结构性联想学习的负模式任务，另一个是评估工作记忆和参考记忆的12臂径向臂迷宫任务。通过在所有这些任务中比较相同的动物，将有可能确定受男性和女性SAP损害影响的特定认知过程，并确定间隔内注射SAP所产生的认知缺陷，这些缺陷反映了在老年动物中也观察到的缺陷。

DESCRIPTION (provided by applicant): Alzheimer's-related dementia and age-associated cognitive decline are due, in part, to a loss of cholinergic projections to the hippocampus and frontal cortex. Despite many years of study, the specific cognitive processes that are affected by damage to basal forebrain cholinergic projections, and the degree to which the loss of cholinergic projections contributes to age-related cognitive decline, are not well understood. Recently we showed that aged ovariectomized rats are substantially impaired in the acquisition of a simple delayed matching-to-position (DMP) T-maze task. In addition, we have shown that intraseptal injection of the selective immunotoxin 192 IgG-saporin (SAP) into young adult rats produces a severe impairment in acquisition of the DMP task in both male and female rats, similar to the deficit observed in aged rats. Our preliminary studies suggest that the deficit produced by SAP is due to the selective loss of cholinergic, and not GABAergic, neurons in the basal forebrain, and that performance correlates with cholinergic innervation in the hippocampus and frontal cortex. In addition, the data suggest that the deficit in DMP acquisition produced by SAP is not due primarily to a deficit in spatial working memory. The goals of this proposal are (1) to identify the specific cholinergic projections and their targets that are responsible for the SAP-induced deficit in DMP acquisition, (2) to identify specific cognitive processes that are affected by the SAP lesions and that underlie the deficit in DMP acquisition, and (3) to evaluate how the deficits produced by SAP relate to deficits associated with age-related cognitive decline. Experiments 1 and 2 will use microinjections of SAP along with histochemical and biochemical assays to identify specific basal forebrain cholinergic projections in both males and females that are responsible for the sizeable SAP-induced deficit in DMP acquisition observed. Experiments 3a and 3b will use a modified version of the DMP task to determine whether SAP-lesioned animals and aged animals (both males and females) show a deficit in the ability to adopt a place vs. a response learning strategy to acquire the task. In addition, these same animals will be tested using two additional tasks, a negative patterning task that will test configural association learning, and a 12-arm radial arm maze task that will assess working and reference memory. By comparing the same animals across all of these tasks, it will be possible to identify specific cognitive processes that are affected by the SAP lesions in males and females, and to identify those cognitive deficits produced by intraseptal injections of SAP that reflect deficits also observed in the aged animals.