Cholinergic overload and resilience to attentional capacities in aging

描述（由申请人提供）：皮质投射基底前脑（BF）胆碱能神经元构成大脑注意力系统的重要组成部分。最近的成像研究证据表明，大脑活动试图科普与年龄相关的功能变化。然而，目前尚不清楚是否前额叶皮层（PFC）驱动的胆碱能机制补偿与年龄相关的注意力下降的能力。该R21申请寻求对探索性研究的支持，以确定后前位移位和胆碱能超负荷在衰老期间认知补偿中的作用。皮层乙酰胆碱（ACh）的释放以阶段性和紧张性的模式来促进注意力的表现。具体而言，相位ACh编码有关注意力要求线索的信息，而紧张性释放的皮质ACh与唤醒和输入处理的功效。我假设，老化破坏紧张性胆碱能活动皮质范围内，并补偿随之而来的损失，唤醒和感觉处理，以及保持阶段性胆碱能活动，老化增加自上而下的招聘皮质胆碱能输入。这种适应性胆碱能负荷的中断会导致注意力能力的持续损害。本研究将采用基于操作的认知任务来评估大鼠学习能力和注意表现的年龄相关变化。基于酶的生物传感器和固定电位安培法将被用来研究皮层胆碱能传递的动力学在真实的时间。由于神经生长因子（NGF）信号通过原肌球蛋白相关激酶（trkA）受体的调节和胆碱能神经元的功能是至关重要的，我也将利用基于载体的RNA干扰方法来产生持久的抑制这些受体，试图削弱皮质胆碱能神经元。目的1的实验将证明，部分胆碱能去传入PFC，但不是后顶叶皮层（PPC）会损害注意力的表现和中断相ACh释放的训练老年大鼠，但不是年轻的。此外，PFC或PPC的胆碱能输入的中度损失会通过干扰后-前移位而延迟任务获得。目的2将证明通过蝇蕈醇失活PFC或拮抗BF N-甲基D-天冬氨酸（NMDA）谷氨酸受体阻断BF胆碱能神经元自上而下的募集会损害老年动物的注意功能。另一方面，在trkA沉默的老年动物中前脑NMDA受体的激活预期恢复注意力缺陷。此外，trkA抑制或年龄相关的觉醒为基础的紧张性ACh释放的减少将被逆转BF NMDA输注。总的来说，这项研究将证明，在老龄化的注意力能力的弹性涉及一个适应性反应，产生前额叶胆碱能过载，在这个补偿过程中的中断产生注意力障碍。此外，预期的结果将提供与年龄相关的神经退行性疾病，如阿尔茨海默病相关的注意力下降的细胞机制的见解。

DESCRIPTION (provided by applicant): Cortically-projecting basal forebrain (BF) cholinergic neurons constitute a crucial component of the brain's attentional system. Recent evidence from imaging studies suggested that brain activity attempts to cope up with functional age-related changes. However, it is not known whether prefrontal cortex (PFC)-driven cholinergic mechanisms compensate for age-related decline in attentional capacities. This R21 application seeks support for exploratory research to determine the contribution of posterior-anterior shift and cholinergic overload in cognitive compensation during aging. Cortical acetylcholine (ACh) release operates in phasic and tonic modes to foster attentional performance. Specifically, phasic ACh encode information concerning attention-demanding cues whereas tonic release of cortical ACh is linked to arousal and efficacy of input processing. I hypothesize that, aging disrupts tonic cholinergic activity cortex-wide, and to compensate for consequent loss in arousal and sensory processing, as well as to maintain phasic cholinergic activity, aging increases top-down recruitment of cortical cholinergic inputs. Disruption in this adaptive cholinergic burden produces persistent impairments in attentional capacities. This research will employ an operant-based cognitive task to assess age-related changes in learning abilities and attentional performance of rats. Enzyme- based biosensors and fixed-potential amperometry will be employed to study the dynamics of cortical cholinergic transmission in real time. As nerve growth factor (NGF) signaling via tropomyosin-related kinase (trkA) receptor is critical for the regulation and function of cholinergic neurons, I will also utilize vector-based RNA interference approaches to produce persistent suppression of these receptors in an attempt to weaken corticopetal cholinergic neurons. The experiments of aim 1 will demonstrate that partial cholinergic deafferentation of the PFC but not posterior parietal cortex (PPC) would impair attentional performance and disrupt phasic ACh release of trained aged but not young rats. Moreover, moderate loss of cholinergic inputs either the PFC or PPC would delay task acquisition by interfering with the posterior-anterior shift. Aim 2 will demonstrate that blockade f top-down recruitment of BF cholinergic neurons either by muscimol inactivation of the PFC or the antagonism of BF N-methyl D-aspartate (NMDA) glutamate receptors would impair attentional functions in aged animals. On the other hand, activation of forebrain NMDA receptors in trkA- silenced aged animals is expected to restore attentional deficits. Furthermore, trkA suppression- or age-related reduction in arousal-based tonic ACh release will be reversed by BF NMDA infusions. Collectively, this research will demonstrate that resilience to attentional capacities in aging involves an adaptive response that produces prefrontal cholinergic overload, and disruption in this compensatory process produces attentional impairments. Furthermore, the expected results would provide insights into the cellular mechanisms underlying attentional decline associated with age-related neurodegenerative disorders such as Alzheimer's disease.