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与年龄相关的认知能力下降部分是由于海马体和额叶皮质胆碱能投射的丧失。尽管经过多年的研究，基底前脑胆碱能投射损伤对特定认知过程的影响，以及胆碱能投射的丧失在多大程度上导致与年龄相关的认知能力下降，仍未得到很好的理解。最近，我们发现去卵巢的老年大鼠在简单延迟匹配-位置（DMP） t迷宫任务的获得方面受到严重损害。此外，我们已经证明，在年轻成年大鼠中注射选择性免疫毒素192 igg皂苷（SAP）对雄性和雌性大鼠的DMP任务的获得产生严重损害，类似于在老年大鼠中观察到的缺陷。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而非gaba能神经元的选择性丧失，并且这种表现与海马和额叶皮层的胆碱能神经支配有关。此外，这些数据表明，SAP产生的DMP习得缺陷并不主要是由于空间工作记忆的缺陷。本提案的目标是(1)确定导致SAP诱导的DMP习得缺陷的特定胆碱能预测及其目标，(2)确定受SAP病变影响的特定认知过程，并确定其构成DMP习得缺陷的基础，以及(3)评估SAP产生的缺陷与年龄相关认知衰退相关的缺陷之间的关系。实验1和2将使用SAP显微注射以及组织化学和生化分析来确定男性和女性的特定基底前脑胆碱能投射，这是造成观察到的大量SAP诱导的DMP获取缺陷的原因。实验3a和3b将使用DMP任务的修改版本来确定sap损伤的动物和老年动物（雄性和雌性）在采用位置学习策略和反应学习策略来获得任务的能力方面是否表现出缺陷。此外，这些动物还将接受另外两项任务的测试，一项是测试构形联想学习的消极模式任务，另一项是评估工作记忆和参考记忆的12臂径向迷宫任务。通过比较相同动物的所有这些任务，将有可能确定雄性和雌性SAP病变影响的特定认知过程，并确定脑膜内注射SAP产生的认知缺陷，这些缺陷也反映了老年动物中观察到的缺陷。

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.