Cortical Synaptic Dynamics during Learning in the Aging Brain

衰老大脑学习过程中的皮质突触动力学

基本信息

批准号：
9924419
负责人：
Ricardo Mostany
金额：
$ 30.85万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9924419
关键词：
Accidents Action Potentials Adult Affect Age Age of Onset Aging Anatomy Area Attention Behavioral Brain Cerebral cortex Chronic Country Dangerousness Dendritic Spines Elderly Electrophysiology (science)Equilibrium Experimental Models Forelimb Future Goals Human Image Impairment Inferior Information Management Injury Interneurons Knowledge Learning Life Maintenance Mediating Memory Microscopy Modification Motor Motor Cortex Mus Neocortex Neurodegenerative Disorders Neurons Output Parvalbumins Performance Periodicity Population Quality of life Research Somatosensory Cortex Synapses Synaptic plasticity Techniques Testing Therapeutic Time Training Transgenic Mice Vibrissae Viral Vector age related aged aging brain brain cell density dexterity excitatory neuron executive function genetic approach hippocampal pyramidal neuron human subject improved in vivo innovation memory recall motor learning neuromechanism normal aging optogenetics patch clamp preservation prevent sensory discrimination somatosensory therapeutic development therapy design transmission process two-photon welfare

项目摘要

PROJECT SUMMARY/ABSTRACT The neural mechanisms that mediate the decline of brain performance with aging are poorly defined and affect many aspects of normal aging life: reductions in motor dexterity, sensory discrimination, executive function, and attention which impact the degree of independence, number of injuries, and fatal accidents. We will define mechanisms of age-related changes in synaptic plasticity and investigate their impact in memory and learning. Our hypothesis is that in the aged cerebral cortex, disruption of the excitation/inhibition balance at the level of the microcircuits of layer 5 (L5) pyramidal neurons leads to reduced formation of long-lasting stable synapses between excitatory neurons, resulting in impaired learning. We have recently described that dendritic spine density of aged mice is stable, but that their dynamics are elevated in somatosensory cortex. But, we do not if density and dynamics of dendritic spines are differentially affected by age in different brain areas. Also, the mechanisms underlying the alteration in synaptic dynamics in the aging brain are unexplored. One possibility is that the intracortical inhibition controlling synaptic plasticity in the adult brain is released with aging allowing the formation of excess synaptic contacts, many of them meaningless and subsequently be eliminated and making the handling and storing of information less effective. Thus, increasing levels of intracortical inhibition in the aged brain may prevent alterations in synaptic dynamics and preserve brain performance. We will test the following hypotheses: (a) elevated dendritic spine dynamics in the aged brain impedes the creation of memory-forming synaptic contacts and impairs the ability of cortical circuits to store/manage information; (b) age- related reduction in inhibitory transmission at the level of the local circuitry of L5 pyramidal neurons is responsible for the increased instability of dendritic spines; (c) restoring intracortical inhibition in the primary motor cortex of aged mice will stabilize dendritic spines of L5 pyramidal neurons and improve performance in a motor learning task. We will use transgenic mice for in vivo 2PE microscopy and optogenetics in the conditional expression of viral vectors, behavioral tasks, and electrophysiological recordings of synaptically connected neurons: Aim 1 will determine that the alteration of synaptic dynamics in the aged brain is a maladaptive mechanism impairing learning. Aim 2 will identify age-dependent changes in PV and SOM neurons of the L5 cortical microcircuit responsible for instability of dendritic spines in pyramidal neurons and impaired learning. Aim 3 will confirm that the age-related decrease of inhibition in L5 pyramidal neurons impairs synaptic plasticity and learning. By using state-of-the-art techniques and innovative experimental approaches will elucidate the effects of normal aging on the assembly and maintenance of cortical circuits to facilitate future development of therapeutic interventions designed to delay the onset of aging-related brain decline and prolong the quality of life and welfare of the elderly. Results from the proposed research may be applied and used for studies on other neurodegenerative disorders.

项目概要/摘要调节大脑性能随衰老而下降的神经机制很差定义并影响正常衰老生活的许多方面：运动灵活性、感觉能力下降歧视、执行功能和注意力会影响独立程度，受伤和死亡事故的数量。我们将定义与年龄相关的变化的机制突触可塑性并研究它们对记忆和学习的影响。我们的假设是，在老化的大脑皮层，兴奋/抑制平衡的破坏第 5 层 (L5) 锥体神经元的微电路导致持久稳定神经元的形成减少兴奋性神经元之间的突触，导致学习障碍。我们最近有描述老年小鼠的树突棘密度是稳定的，但它们的动态变化体感皮层升高。但是，我们不知道树突棘的密度和动力学不同大脑区域受年龄的影响不同。此外，其背后的机制衰老大脑中突触动力学的改变尚未被探索。一种可能性是控制成人大脑突触可塑性的皮质内抑制随着衰老而释放允许形成过多的突触接触，其中许多是毫无意义的并且随后被消除，从而降低信息处理和存储的效率。因此，增加老年大脑皮质内抑制水平可能会阻止大脑功能的改变。突触动力学并保持大脑性能。我们将检验以下假设：(a) 衰老大脑中树突棘动力学的升高阻碍了记忆形成的产生突触接触并损害皮质回路存储/管理信息的能力； (b) 年龄- L5 锥体局部电路水平的抑制性传递相关减少神经元导致树突棘的不稳定性增加； (c) 恢复皮质内抑制老年小鼠初级运动皮层将稳定 L5 锥体的树突棘神经元并提高运动学习任务的表现。我们将使用转基因小鼠体内 2PE 显微镜和光遗传学在病毒载体条件表达、行为任务和突触连接神经元的电生理记录：目标 1 将确定老年大脑中突触动力学的改变是一种适应不良损害学习的机制。目标 2 将确定 PV 和年龄相关的变化 L5 皮质微电路的 SOM 神经元负责树突棘的不稳定锥体神经元和学习障碍。目标 3 将确认与年龄相关的 L5 锥体神经元抑制的减少会损害突触可塑性和学习能力。通过使用最先进的技术和创新的实验方法将阐明正常老化对皮质回路组装和维护的影响，以促进未来开发旨在延缓与衰老相关的大脑发生的治疗干预措施降低并延长老年人的生活质量和福利。拟议的结果研究可应用于其他神经退行性疾病的研究。