Cholinergic overload and resilience to attentional capacities in aging

描述(申请人提供)：皮质投射的基底前脑(BF)胆碱能神经元是大脑注意系统的重要组成部分。最近来自成像研究的证据表明，大脑活动试图应对与年龄相关的功能变化。然而，尚不清楚前额叶皮质(PFC)驱动的胆碱能机制是否能弥补与年龄相关的注意力能力下降。R21的应用寻求探索性研究的支持，以确定后-前移位和胆碱能超负荷在衰老过程中认知代偿中的作用。皮质乙酰胆碱(ACh)的释放以时相和紧张性模式进行，以培养注意力表现。具体地说，阶段ACh编码有关需要注意的线索的信息，而皮层ACh的紧张释放与输入加工的唤醒和效率有关。我假设，衰老扰乱了整个皮质的紧张性胆碱能活动，为了弥补随后觉醒和感觉处理过程中的损失，以及维持时相胆碱能活动，衰老增加了皮质胆碱能输入的自上而下的招募。这种适应性胆碱能负荷的中断会导致注意能力的持续性损害。这项研究将采用基于操作者的认知任务来评估与年龄相关的大鼠学习能力和注意力表现的变化。基于酶的生物传感器和固定电位安培法将被用来实时研究皮质胆碱能传递的动力学。由于通过原肌球蛋白相关激酶(TrkA)受体的神经生长因子(NGF)信号对胆碱能神经元的调节和功能至关重要，我还将利用基于载体的RNA干扰方法来产生对这些受体的持续抑制，以试图削弱皮质顶叶胆碱能神经元。目标1的实验将证明，部分胆碱能去传入PFC，而不是后顶叶皮质(PPC)，会损害训练的老年大鼠的注意行为，扰乱ACh的时相释放，而不是年轻大鼠。此外，PFC或PPC胆碱能输入的适度丢失会干扰后前移位，从而延迟任务的获得。目的2研究表明，无论是用蝇草酚使PFC失活或拮抗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，都会损害老年动物的注意功能。另一方面，激活TrkA沉默的老年动物的前脑NMDA受体有望恢复注意力缺陷。此外，TrkA抑制或与年龄相关的唤醒基础上的紧张性ACh释放的减少将被BF NMDA输注逆转。总而言之，这项研究将证明，在衰老中对注意力能力的适应性反应涉及到产生前额叶胆碱能超负荷的适应性反应，而在这一补偿过程中的中断会产生注意力障碍。此外，预期的结果将为阿尔茨海默病等与年龄相关的神经退行性疾病导致注意力下降的细胞机制提供见解。

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.