Cholinergic Lesions and Age-Related Cognitive Impairment

描述（由申请人提供）：阿尔茨海默氏症相关的痴呆和年龄相关的认知能力下降部分是由于海马和额叶皮质胆碱能投射的丧失。尽管多年的研究，具体的认知过程，受到损害的基底前脑胆碱能投射，以及胆碱能投射的损失在多大程度上有助于与年龄相关的认知能力下降，是没有很好的理解。最近，我们发现，老年卵巢切除大鼠在收购一个简单的延迟匹配位置（ESTA）的T-迷宫任务的实质性受损。此外，我们已经表明，选择性免疫毒素192 IgG-皂草素（SAP）到年轻的成年大鼠的隔内注射产生了严重的损害收购的任务，在男性和女性大鼠，类似的赤字中观察到的老年大鼠。我们的初步研究表明，由SAP产生的赤字是由于选择性损失的胆碱能，而不是GABA能，神经元在基底前脑，和性能相关的胆碱能神经支配的海马和额叶皮层。此外，这些数据表明，SAP产生的空间工作记忆的缺陷并不主要是由于空间工作记忆的缺陷。本研究的目的是（1）确定SAP诱导的认知功能障碍的特异性胆碱能投射及其靶点，（2）确定受SAP病变影响的特定认知过程以及认知功能障碍的基础，（3）评估SAP产生的认知功能障碍与年龄相关性认知功能减退的相关性。实验1和2将使用SAP的显微注射沿着组织化学和生物化学测定，以鉴定雄性和雌性中的特定基底前脑胆碱能投射，其负责观察到的SAP诱导的大量脑内胆碱能获得缺陷。实验3a和3b将使用修改版本的学习任务来确定SAP损伤的动物和老年动物（雄性和雌性）是否表现出采用位置与反应学习策略来获得任务的能力缺陷。此外，这些相同的动物将使用两个额外的任务进行测试，一个是测试神经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臂桡臂迷宫任务。通过在所有这些任务中比较相同的动物，将有可能确定受雄性和雌性SAP病变影响的特定认知过程，并确定由SAP间隔内注射产生的认知缺陷，这些认知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.