Basal forebrain and cognitive aging: Novel experimental and theraptutic avenues

描述（由申请人提供）：对寿命的预期在上个世纪增加了两倍，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。轻度认知障碍（MCI）这个术语已经被用来描述认知功能障碍，这种认知功能障碍是在没有与老年痴呆症（AD）等破坏性疾病相关的深度记忆丧失之前或发生的，但它仍然会严重损害一个人的生活质量。然而，重要的是，这种认知能力的下降并不是衰老过程的必然结果，因为许多人在老年时仍保持着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gaba能神经元，至少占基底前脑到皮质目标的一半，与胆碱能神经元参与相同的记忆过程，在衰老背景下仍未得到研究。此外，基底前脑神经元功能障碍在整个生命周期中与认知缺陷的出现有关的机制和时间尚不清楚。在某种程度上，这些数据的缺失是由于检测啮齿动物在其生命最后阶段之前的认知缺陷的能力有限。然而，我们已经开发了一种新的啮齿动物认知衰老模型，该模型可靠地检测了一些中年和老年Fischer 344大鼠的认知衰退，而其他两个年龄的大鼠表现得和年轻队列一样好。我们假设胆碱能和gaba能基底前脑投射系统的联合缺陷导致了与年龄相关的认知缺陷的出现。为了验证这一假设，我们将在具有行为特征的年轻、中年和老年大鼠中评估以下措施：(i)胆碱能和GABA能神经元数量、形态和表型表达的完整性（使用联合立体/共聚焦显微镜）（ii）基底前脑切片记录中胆碱能和GABA能神经元的突触特性，以及（iii）毒毒碱胆碱能和GABA(B)受体在基底前脑及其皮质靶区的表达和功能。最后，我们将分别或联合使用胆碱能和gaba能药物治疗中老年大鼠，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.