Interactive effects of stress and aging on prefrontal cortex

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，新皮质神经元会随着年龄的增长而丢失，但现在很明显，正常衰老过程中伴随着最小的神经元丢失。一种有效的假说是，形态分子的可塑性在其他情况下完好无损的新皮质回路中丢失，这些变化导致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质中与年龄相关的突触变化知之甚少，而且目前还缺乏直接证据证明老年大脑的适应性可塑性降低。我建议使用应激作为适应性新皮质可塑性的模型；在年轻动物中，我假设应激诱导的新皮质神经元萎缩和随后的行为障碍随着恢复是可逆的。然而，我假设，在衰老的大脑中，可逆地重塑新皮质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减弱上。另一个重点将是检查新皮质神经调节受体系统的变化，这也被认为是与压力和年龄相关的认知下降的机制。这些研究将为未来旨在恢复老化大脑神经元可塑性的治疗干预提供坚实的神经生物学框架。由于NIA的使命是改善和帮助老年人的生活质量，因此了解老化大脑变化背后的基本生物学机制是至关重要的。为了验证这些假设，我将使用一项具有良好特征的行为任务，该任务之前被证明既依赖于特定的新皮质区域，又对压力敏感。对于神经生物学研究，我将使用单细胞染料填充技术和无偏见的体视学电子显微镜技术，这些技术在我们实验室之前的实验中被证明非常成功。这些技术的使用是重要的，因为随着年龄的增长，树突棘形态和受体表达谱的变化将受到很大的重视。

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.