Interactive effects of stress and aging on prefrontal cortex

描述（由申请人提供）：这些研究的主要目的是进一步了解衰老如何影响大脑的神经可塑性。虽然最初的研究表明，新皮层神经元随着年龄的增长而丢失，但现在很清楚，最小的神经元丢失伴随着正常的衰老。一种可行的假设是，在完好无损的新皮层回路中，形态分子可塑性丧失了，这些改变导致了与年龄相关的认知能力下降。然而，令人惊讶的是，人们对衰老大鼠新皮层中与年龄相关的突触变化知之甚少，而且目前还缺乏老年大脑适应性可塑性降低的直接证据。我建议使用压力作为适应性新皮层可塑性的模型；在幼龄动物中，我假设应激诱导的新皮质神经元萎缩和随后的行为障碍是可逆的。然而，我推测，在衰老的大脑中，可逆地重塑新皮层神经元树突和突触的能力将会减弱，这将反映在行为表现的下降上。另一个重点将是检查新皮质神经调节受体系统的改变，这也被认为是压力和年龄相关的认知能力下降的机制。这些研究将为未来的治疗干预提供坚实的神经生物学框架，旨在恢复老化大脑中的神经元可塑性。由于NIA的使命是改善和帮助老年人的生活质量，了解老化大脑变化背后的基本生物学机制是必不可少的。为了验证这些假设，我将使用一项行为任务，该任务具有良好的特征，并且先前被证明既依赖于特定的新皮层区域，又对压力敏感。对于神经生物学的研究，我将使用单细胞染色填充技术和无偏立体电子显微镜技术，这些技术在我们实验室之前的实验中已经被证明是非常成功的。这些技术的使用很重要，因为随着年龄的增长，树突棘形态和受体表达谱的变化将得到很大的重视。我们人口中增长最快的部分是老年人，尽管付出了很多努力，但对衰老如何影响大脑的确切理解仍然缺乏。本应用程序中提出的研究将使用行为和细胞测量来研究老年人的大脑对挑战的反应与年轻人的大脑有何不同。这些实验将为旨在减少衰老过程对大脑功能的有害影响的治疗性研究奠定基础。

DESCRIPTION (provided by applicant): The broad aim of these studies is to further the understanding of how aging affects neuroplasticity in the brain. While initial studies suggested that neocortical neurons are lost with age, it is now clear that minimal neuron loss accompanies normal aging. A working hypothesis is that morphomolecular plasticity is lost within otherwise intact neocortical circuits, and these alterations drive age-related cognitive decline. However, surprisingly little is known about age-related synaptic changes in the aging rat neocortex, and direct evidence for reductions in adaptive plasticity in the aged brain is currently lacking. I propose to use stress as a model of adaptive neocortical plasticity; in young animals, I hypothesize that stress-induced neocortical neuron atrophy and subsequent behavioral impairments are reversible with recovery. However, I hypothesize that the ability to reversibly remodel neocortical neuronal dendrites and synapses will be diminished in the aged brain, and this will be reflected in diminished behavioral performance. An additional focus will be examining alterations of neocortical neuromodulatory receptor systems, which have also been posited as a mechanism for stress- and age-related cognitive decline. These studies will provide a solid neurobiological framework for future therapeutic interventions that aim to restore neuronal plasticity in the aging brain. As the mission of the NIA is to improve and aid in the quality of life of the elderly, an understanding of the fundamental biological mechanisms behind alterations in the aging brain is essential. To test these hypotheses, I will use a behavioral task that is well-characterized and previously shown to be both dependant on specific neocortical regions and sensitive to stress. For neurobiological investigations, I will use single cell dye-filling techniques and unbiased stereological electron microscope techniques that have proven highly successful in previous experiments in our laboratory. The use of these techniques is important because a large emphasis will be placed on alterations of dendritic spine morphological and receptor expression profiles with aging. The fastest growing segment of our population is the elderly, and despite much effort, a solid understanding of exactly how aging affects the brain is lacking. The research proposed in this application will use behavioral and cellular measures to study how the aged brain responds differentially to challenge than the young brain. These experiments will set the stage for therapeutic studies that will aim to lessen the deleterious impact of the aging process on brain function.