Cortical Synaptic Dynamics during Learning in the Aging Brain

项目摘要/摘要 调节大脑功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、感觉能力下降 影响独立程度的辨别力、执行功能和注意力， 受伤和致命事故的数量。我们将定义与年龄相关的变化机制 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 衰老的大脑皮层，兴奋/抑制平衡的破坏 5层(L5)锥体神经元微回路导致长时间稳定的形成减少 兴奋性神经元之间的突触，导致学习障碍。我们最近做了 描述了老龄小鼠树突棘密度是稳定的，但其动态变化是 在躯体感觉皮质中升高。但是，我们不知道树突的密度和动态 在不同的大脑区域受到年龄的不同影响。此外，潜在的机制是 老化大脑中突触动力学的变化还没有被探索。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年龄的增长而释放 允许形成过多的突触接触，其中许多是无意义的 随后会被消除，并使信息的处理和存储效率降低。 因此，增加老年人大脑皮质内抑制的水平可能会阻止 突触动力学和保存脑功能。我们将检验以下假设：(A) 老年人脑内树突棘动力学升高阻碍记忆形成的形成 突触接触并损害皮层回路存储/管理信息的能力；(B)年龄- L5锥体局部回路水平抑制性传递的相关减少 神经元负责增加树突棘的不稳定性；(C)皮质内恢复 老年小鼠初级运动皮质的抑制将稳定L5锥体的树突 并提高运动学习任务中的表现。我们将使用转基因小鼠进行In 活体2PE显微镜和光遗传学在病毒载体条件表达中的行为 任务和突触连接神经元的电生理记录：目标1将 确定老年人大脑中突触动力学的改变是一种不适应 机制损害学习。目标2将确定Pv和Pv随年龄的变化 L5皮质微路SOM神经元与树突棘不稳定相关 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的可塑性和学习能力。 通过使用最先进的技术和创新的实验方法，将阐明 正常衰老对大脑皮层环路组装和维持的影响 旨在延缓衰老相关脑发病的治疗干预措施的发展 降低和延长老年人的生活质量和福利。建议的结果 这项研究也可以应用于其他神经退行性疾病的研究。

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.