Interactive effects of stress and aging on prefrontal cortex

压力和衰老对前额皮质的交互影响

基本信息

批准号：
7808563
负责人：
Erik Bradley Bloss
金额：
$ 4.12万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-25 至 2012-09-24
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7808563
关键词：
21 year old Ablation Adrenergic Receptor Adult Affect Agaricales Age Age-Months Age-associated memory impairment Aging Aging-Related Process Agreement Analysis of Variance Animal Model Animals Anterior Antibody Affinity Apical Area Atrophic Axon Behavior Behavioral Binding Biological Brain Caliber Catecholamine Receptors Catecholamines Cells Classification Cognitive Cognitive aging Cognitive deficits Collaborations Computer software Control Groups Cyclic Nucleotides Data Dendrites Dendritic Spines Dimensions Discrimination Dopamine Dorsal Dyes Elderly Electron Microscope Electron Microscopy Ensure Exhibits Floor Food Future Gold Growth Head Hippocampus (Brain)Human Image Impairment Injection of therapeutic agent Investigation Label Laboratories Lesion Link Localized Lesion Longevity Maps Measures Medial Mediating Mental disorders Methods Mission Mixed Function Oxygenases Modeling Molecular Molecular Profiling Monkeys Morphology Mus Nature Neocortex Neurobiology Neuronal Plasticity Neurons Norepinephrine Norepinephrine Receptors Outcome Paper Parietal Lobe Pattern Performance Pharmaceutical Preparations Phenotype Plastics Population Prefrontal Cortex Preparation Printing Process Publications Publishing Quality of life Rattus Receptor Up-Regulation Recovery Reporting Research Resolution Rest Rewards Rodent Sampling Short-Term Memory Site Solid Staging Staining method Stains Statistical Methods Stimulus Stress Structure Surface Synapses Synaptic Receptors System Techniques Testing Therapeutic Intervention Therapeutic Studies Thinking Time Tissues Training Vertebral column Visual Work age effect age related aged aging brain base behavioral impairment beta-2 Adrenergic Receptors cognitive control cognitive function cohort cortical catecholamine density design flexibility human study improved interest juvenile animal locus ceruleus structure lucifer yellow member middle age neocortical neuron loss noradrenergic norepinephrine system normal aging particle pathological aging postsynaptic presynaptic radioligand receptor receptor expression relating to nervous system research study response restraint stress statistics vesicular monoamine transporter 2

项目摘要

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.

描述（由申请人提供）：这些研究的总体目标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，正常的衰老伴随着最小的神经元丢失。一个可行的假设是，形态分子可塑性在其他完整的新皮质回路中丢失，而这些改变会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，并且目前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质可塑性的模型；在年幼的动物中，我假设压力引起的新皮质神经元萎缩和随后的行为障碍在恢复后是可逆的。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下降上。另一个重点是检查新皮质神经调节受体系统的改变，该系统也被认为是与压力和年龄相关的认知能力下降的机制。这些研究将为未来旨在恢复衰老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，因此了解衰老大脑变化背后的基本生物学机制至关重要。为了检验这些假设，我将使用一项具有良好特征的行为任务，该任务之前已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被证明非常成功。这些技术的使用很重要，因为重点将放在树突棘形态和受体表达谱随衰老的变化上。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，但人们仍然缺乏对衰老究竟如何影响大脑的深入了解。本申请中提出的研究将使用行为和细胞测量来研究老年大脑与年轻大脑对挑战的反应有何不同。这些实验将为治疗研究奠定基础，旨在减轻衰老过程对大脑功能的有害影响。