Basal forebrain and cognitive aging: Novel experimental and theraptutic avenues

基底前脑和认知衰老：新的实验和治疗途径

• 批准号: 7627219
• 负责人: JENNIFER Lynn BIZON
• 金额: $ 28.81万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7627219
• 关键词: Acetylcholine; Ache; Adopted; Affect; Age; Age-associated memory impairment; Aging; Aging-Related Process; Alzheimer' s Disease; Attenuated; Biochemical; Butyric Acids; Cessation of life; Cholinergic Receptors; Clinical; Clinical Treatment; Cognition; Cognitive; Cognitive aging; Cognitive deficits; Confocal Microscopy; Data; Diagnosis; Discrimination; Discrimination Learning; Disease; Early Diagnosis; Elderly; Exhibits; Experimental Designs; Figs - dietary; Functional disorder; GABA Agents; GABA-B Receptor; Hippocampus (Brain); Homeostasis; Human; Impaired cognition; Impairment; Individual; Individual Differences; Investigation; Laboratories; Learning; Longevity; Measures; Medial; Memory; Memory Loss; Modeling; Morphology; Muscarinic Acetylcholine Receptor; Muscarinics; Neurobiology; Neuronal Dysfunction; Neurons; Odors; Pathway interactions; Performance; Pharmaceutical Preparations; Phenotype; Population; Preparation; Process; Property; Proteins; Quality of life; Rattus; Receptor Signaling; Reporting; Reproducibility; Research; Research Personnel; Rodent; Rodent Model; Short-Term Memory; Signal Transduction; Slice; Staging; Structure; Synapses; Synaptic Transmission; System; Techniques; Temporal Lobe; Testing; Time; Training; Treatment Protocols; United States; age related; aged; basal forebrain; cholinergic; cholinergic neuron; cognitive function; cohort; effective therapy; efficacy testing; expectation; gamma-Aminobutyric Acid; improved; inhibitor/antagonist; interest; male; middle age; mild neurocognitive impairment; neural circuit; novel; programs; receptor; receptor expression; transmission process; young adult

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.

描述（由申请人提供）：上个世纪，人们对长寿的期望增加了两倍，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。轻度认知障碍（MCI）一词已被用来描述认知功能障碍，这种功能障碍先于或在没有与阿尔茨海默病（AD）等破坏性年龄相关疾病相关的严重记忆丧失的情况下发生，但仍然会严重损害一个人的生活质量。然而，重要的是，这种认知能力下降并不是衰老过程的必然结果，因为许多人在高龄时仍能保持与年轻人相同的记忆功能。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，特别是外显/空间记忆。然而，共同分布的 GABA 神经元（至少包含从基底前脑到皮质目标的投射的一半）并且与胆碱能神经元相同的记忆过程有关，在衰老的背景下仍然很大程度上未被研究。此外，基底前脑神经元功能障碍与整个生命周期中认知缺陷的出现有关的机制和时间仍不清楚。缺乏此类数据的部分原因是检测啮齿动物在生命最后阶段之前的认知缺陷的能力有限。然而，我们开发了一种新型的认知衰老啮齿动物模型，该模型可以可靠地检测一些中年和老年 Fischer 344 大鼠的认知能力下降，而其他两个年龄段的大鼠的表现与年轻群体一样好。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。为了检验这一假设，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（使用组合体视学/共聚焦显微镜）（ii）通过基底细胞切片记录的胆碱能和 GABA 能神经元的突触特性 (iii) 基底前脑及其皮质靶区中毒蕈碱胆碱能和 GABA(B) 受体的表达和功能。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。