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(申请人提供)：上个世纪，人们的预期寿命增加了两倍，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)一词被用来描述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或发生的认知功能障碍，但这仍会严重影响一个人的生活质量。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，因为许多人在晚年仍保持着与年轻人一样的助记功能。在老年人和啮齿动物群体中，测量基底前脑胆碱能投射神经元的完整性与认知障碍有关，特别是在外显/空间记忆方面。然而，共同分布的GABA能神经元，包括至少一半的从基底前脑到皮质靶点的投射，并与胆碱能神经元参与相同的助记过程，在很大程度上仍未在衰老的背景下进行研究。此外，基底前脑神经元功能障碍的机制和时机仍不清楚，因为它与整个生命周期中认知缺陷的出现有关。在一定程度上，缺乏这样的数据是因为在啮齿动物寿命的最新阶段之前，检测其认知缺陷的能力有限。然而，我们开发了一种新的认知老化啮齿动物模型，它可靠地检测到一些中老年Fischer 344大鼠的认知衰退，而其他两个年龄段的大鼠表现与年轻队列一样好。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。为了验证这一假说，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指标：(I)胆碱能和GABA能神经元的完整性(使用体视学/共聚焦显微镜)(Ii)胆碱和GABA能神经元的突触特性(通过基底前脑获取的切片)，以及(Iii)M胆碱和GABA(B)受体在基础前脑及其皮质靶区的表达和功能。最后，我们将分别和联合使用胆碱能和GABA能药物治疗中老年大鼠，以逆转与年龄相关的认知障碍。