Basal forebrain and cognitive aging: Novel experimental and theraptutic avenues

描述（由申请人提供）：在上个世纪，对寿命的期望增加了两倍，据估计，超过25%的65岁以上的人表现出某种形式的认知缺陷。术语轻度认知障碍（MCI）已被采用来描述认知功能障碍，该认知功能障碍先于或在没有与破坏性年龄相关疾病（如阿尔茨海默病（AD））相关的深刻记忆丧失的情况下发生，但仍然可以严重损害一个人的生活质量。然而，重要的是，这种认知能力下降并不是衰老过程的必然结果，因为许多人在进入老年后仍能保持与年轻人相当的记忆功能。在老年人和啮齿动物群体中，基底前脑胆碱能投射神经元完整性的测量与认知障碍相关，特别是在外显/空间记忆中。然而，共分布的GABA能神经元，包括至少一半的投影从基底前脑皮质的目标，并涉及在相同的记忆过程作为胆碱能神经元，仍然在很大程度上未研究的背景下老化。此外，基底前脑神经元功能障碍的机制和时间，因为它涉及到整个生命周期的认知缺陷的出现仍然不清楚。在某种程度上，缺乏这样的数据是由于有限的能力，以检测认知缺陷的啮齿动物在年龄之前的最后阶段，他们的生命。然而，我们已经开发了一种新的认知老化啮齿动物模型，该模型可靠地检测到一些中年和老年Fischer 344大鼠的认知下降，而其他两个年龄段的大鼠表现良好。我们推测，胆碱能和GABA能基底前脑投射系统的联合缺陷有助于年龄相关的认知缺陷的出现。为了检验这一假设，我们将在行为特征的年轻、中年和老年大鼠中评价以下指标：（i）胆碱能和GABA能神经元数量、形态和表型表达的完整性（使用组合的体视学/共聚焦显微镜）（ii）在来自通过基底前脑获取的切片的记录中胆碱能和GABA能神经元的突触特性，和（iii）基底前脑及其皮质靶区中的毒蕈碱胆碱能和GABA（B）受体表达和功能。最后，我们将用胆碱能和GABA能药物分别和联合治疗中年和老年大鼠，以逆转与年龄相关的认知障碍。

DESCRIPTION (provided by applicant): Expectations of longevity have increased two-fold in the last century and it is estimated that upwards of 25% of people over age 65 exhibit some form of cognitive deficit. The term mild cognitive impairment (MCI) has been adopted to describe cognitive dysfunction that precedes or occurs in the absence of profound memory loss associated with devastating age-related conditions such as Alzheimer's disease (AD), but that can nevertheless severely compromise one's quality of life. Importantly, however, such cognitive decline is not an inevitable consequence of the aging process, as many people maintain mnemonic function on par with young adults well into advanced age. Among aged human and rodent populations, measures of basal forebrain cholinergic projection neuron integrity correlate with cognitive impairment, particularly in explicit/spatial memory. However, co-distributed GABAergic neurons, that comprise at least half of the projection from basal forebrain to cortical targets and that are implicated in the same mnemonic processes as cholinergic neurons, remain largely unstudied within the context of aging. Moreover, the mechanisms and timing of basal forebrain neuronal dysfunction as it relates to emergence of cognitive deficits across the lifespan is still unclear. In part, absence of such data has been due to a limited ability to detect cognitive deficits in rodents at ages preceding the latest stages of their lifespan. However, we have developed a novel rodent model of cognitive aging that reliably detects cognitive decline in some middle-aged and aged Fischer 344 rats while other rats at both ages perform as well as young cohorts. We hypothesize that combined deficiencies in cholinergic and GABAergic basal forebrain projection systems contribute to the emergence of age-related cognitive deficits. To test this hypothesis, we will evaluate the following measures in behaviorally-characterized young, middle-aged and aged rats: (i) integrity of cholinergic and GABAergic neuronal number, morphology, and phenotypic expression (using combined stereology/confocal microscopy) (ii) synaptic properties of cholinergic and GABAergic neurons in recordings from slices taken through basal forebrain, and (iii) muscarinic cholinergic and GABA(B) receptor expression and function in basal forebrain and its cortical target fields. Finally, we will treat middle-aged and aged rats with cholinergic and GABAergic drugs, both separately and in concert, to reverse age-related cognitive impairments.