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

• 批准号: 9177545
• 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
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9177545
• 关键词: Accidents; Action Potentials; Adult; Affect; Age; Aging; Area; Attention; Behavioral; Brain; Cerebral cortex; Country; Dendritic Spines; Development; Elderly; Electrophysiology (science); Equilibrium; Experimental Models; Fatal injury; Forelimb; Future; Goals; Human; Image; Inferior; Injury; Interneurons; Knowledge; Learning; Life; Maintenance; Mediating; Memory; Microscopy; Modification; Motor; Motor Cortex; Mus; Neocortex; Neurodegenerative Disorders; Neurons; Output; Parvalbumins; Performance; Population; Quality of life; Research; Social Welfare; Somatosensory Cortex; Synapses; Synaptic plasticity; Techniques; Testing; Therapeutic; Therapeutic Intervention; 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; prevent; sensory discrimination; somatosensory; therapy design; transmission process; two-photon

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.

项目总结/摘要 调节大脑性能随年龄增长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 影响独立程度的辨别力、执行功能和注意力， 受伤人数和致命事故。我们将定义与年龄相关的变化机制， 突触可塑性，并研究其对记忆和学习的影响。我们的假设是 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的形成减少 兴奋性神经元之间的突触，导致学习受损。我们最近 描述了老年小鼠的树突棘密度是稳定的，但它们的动力学是 在躯体感觉皮层中升高。但是，如果树突棘的密度和动力学 在不同的大脑区域受到年龄的不同影响。此外， 老化大脑中突触动力学的改变尚未探索。一种可能是 控制成人大脑中突触可塑性的皮质内抑制随着年龄的增长而释放 允许形成过多的突触接触，其中许多是毫无意义的， 随后被消除，并使信息的处理和存储效率降低。 因此，增加老年大脑皮质内抑制水平可能会阻止大脑皮质内抑制的改变。 突触动力学和保持大脑性能。我们将测试以下假设：（a） 老年大脑中树突棘动力学的升高阻碍了记忆形成的创造， 突触接触并损害皮层回路存储/管理信息的能力;（B）年龄- L5锥体神经节局部回路水平的抑制性传递相关减少 神经元负责增加树突棘的不稳定性;（c）恢复皮质内 抑制老年小鼠的初级运动皮层将稳定L5锥体的树突棘 神经元和提高性能的运动学习任务。我们将使用转基因小鼠 体内2 PE显微镜和光遗传学在病毒载体的条件表达、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的年龄依赖性变化， L5皮层微回路中负责树突棘不稳定性的SOM神经元 锥体神经元和学习障碍。目标3将确认与年龄有关的 L5锥体神经元中抑制的降低损害突触可塑性和学习。 通过使用最先进的技术和创新的实验方法将阐明 正常老化对大脑皮层回路组装和维持的影响， 开发旨在延迟与衰老相关的大脑发病的治疗干预措施 降低和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。