The Nicotinic Cholinergic System and Cognitive Aging

 描述（由申请人提供）：胆碱能系统已被证明是导致痴呆症认知症状的主要神经递质系统。虽然痴呆症的治疗益处是明确的，但胆碱能神经元在痴呆症中的作用仍然不确定。 烟碱系统一般在健康非痴呆老年人的认知中起作用，而烟碱系统具体在健康非痴呆老年人的认知中起作用（在本申请中称为认知老化）。这一点至关重要，因为健康老龄化人口的扩大将显示出认知能力的下降，这种认知能力低于痴呆症，但仍会影响功能能力、独立性和财务决策。了解年龄相关的功能变化对烟碱系统的影响，将阐明一个神经化学机制与年龄相关的认知变化，并将提供有关烟碱功能障碍如何影响健康老年人的认知。先前的研究表明，尼古丁系统在健康成年人的注意力和记忆力中起着重要作用。最近，随着脑功能磁共振成像（fMRI）结合精神药理学操作的使用越来越多，出现了进一步定义尼古丁系统在认知、衰老和痴呆中的作用的数据模式。 我们认为，烟碱系统的变化是负责工作记忆任务的性能和大脑激活的年龄差异。我们可以通过检查大脑对烟碱阻断和刺激的激活模式来观察烟碱系统的功能。与年轻人相比，老年人的内侧额回（MFG）激活增加。我们建议，暂时拮抗烟碱系统将模拟这种“旧模式”的受损性能和增加MFG激活。我们假设，老年人将有更大的性能障碍和增加MFG激活后，尼古丁阻滞年轻人相比。我们还提出，烟碱刺激将导致更好的性能和减少MFG激活的“年轻模式”。我们假设，尼古丁刺激将提高性能，这种改善将是更大的老年人相比，年轻的成年人。我们还将观察到MFG激活的减少，与年轻人相比，老年人的MFG激活更大。这些数据将进一步了解正常衰老中涉及的一种神经化学机制，以及大脑激活模式如何与受体功能相关。随着对安全有效的认知增强剂的研究的继续，了解烟碱系统在认知衰老中的作用以及烟碱机制是否有可能有益于健康成年人的认知将非常重要。

 DESCRIPTION (provided by applicant): The cholinergic system has been shown to be the primary neurotransmitter system responsible for cognitive symptoms in dementia. While therapeutic benefits are clear in dementia, what remains uncertain is the role that the cholinergic system in general and the nicotinic system specifically plays in cognition in healthy non-demented older adults (referred to as cognitive aging in this application). This is critical becaus the expansion of the healthy aging population will nonetheless show declines in cognition that fall short of dementia but still impact functional abilities, independence, and financial decision making. Understanding the effects of age-related functional changes on the nicotinic system will elucidate one neurochemical mechanism underlying age-related changes in cognition and will provide information about how nicotinic dysfunction affects cognition in healthy older adults. Prior research has shown that the nicotinic system has a roll in attention and memory in healthy adults. More recently, with the increased use of brain functional magnetic resonance imaging (fMRI) in combination with psychopharmacological manipulations, data patterns have emerged that further define the role of the nicotinic system in cognition, aging, and dementia. We propose that nicotinic system changes are responsible for age differences in working memory task performance and brain activation. We can observe the functioning of the nicotinic system by examining brain activation patterns in response to nicotinic blockade and stimulation. Increased medial frontal gyrus (MFG) activation has been shown in older adults compared to younger adults. We propose that temporary antagonism of the nicotinic system will model this "older pattern" of impaired performance and increased MFG activation. We hypothesize that older adults will have greater performance impairments and increased MFG activation compared to younger adults after nicotinic blockade. We also propose that nicotinic stimulation will result in "younger patterns" of better performance and decreased MFG activation. We hypothesize that nicotinic stimulation will improve performance and this improvement will be greater for older adults compared to younger adults. We will also observe decreased MFG activation that will be greater for older adults compared to younger adults. These data will further the understanding of one neurochemical mechanism involved in normal aging and how brain activation patterns relate to receptor function. As the search continues for safe and effective cognitive enhancers, it will be important to understand the role of the nicotinic system in cognitive aging and whether nicotinic mechanisms have the potential to benefit cognition in healthy adults.