Functional Properties of the Lateral Entorhinal Cortex in Learning and Aging

项目总结/摘要 衰老通常与学习和记忆障碍有关。然而，一些老年人仍然没有 任何损害。目前的项目旨在研究这种现象背后的神经生物学机制 与年龄相关的损伤，以及有损伤的人（老年受损-AI）与没有损伤的人的区别 (aged未受损--Au）。以前的研究集中在海马体上，这是一个重要的区域， 记忆形成目前的项目将集中在内嗅皮层（EC），另一个重要的区域， 记忆，因为它是皮层区域和海马体之间的中继站。欧盟不仅 它对支持记忆很重要，但也是与衰老有关的主要变化的部位。例如在 正常老化时，EC体积与较差的记忆性能直接负相关。阿尔茨海默 疾病，一种神经退行性疾病，其主要风险因素是年龄的增加，最初表现在 EC。目前的项目将侧重于欧共体的横向划分。建议横向EC支撑 时间联想记忆的形成，这是一项许多老年人受损的任务。这些 有证据表明LEC内存在神经生物学变化， 学习和随着年龄的增长而改变的神经元生理学可能是无法经历这些变化的基础， 从而导致学习缺陷。因此，目前的项目旨在确定生物物理变化， 这种现象发生在成功学习（Y和Au）的年轻和老年动物的LEC神经元中， 这是不可能的。该项目将重点关注神经元内的变化，这些变化通过贯穿路径投射到神经元。 齿状回，作为穿通路径构成三突触回路的第一步，三突触回路是用于 海马体中的记忆形成虽然以前的研究已经电生理特征， LEC的神经元，穿孔路径神经元的身份尚未得到明确的确定。我会的 因此，首先通过将逆行荧光示踪剂注射到 青年和老年动物的齿状回（目的1）。荧光示踪剂将确认 神经元，也允许在全细胞电流钳记录过程中靶向，允许确认神经元的功能。 电生理特征在整个细胞记录过程中，我还将测量神经元的兴奋性，如前所述。 研究已经确定海马内神经元兴奋性的老化相关变化 阻止了老年动物的成功学习。然后，我将训练年轻的成年和老年动物的时间 联想学习任务，以测量与学习相关的兴奋性在perforant路径的变化 神经元（Aim 2）。记录将揭示Y和Au动物的LEC如何支持学习， 识别阻止人工智能动物成功学习的机制。这项研究的结果将提供一个 作为缓解衰老相关学习缺陷和痴呆症的潜在治疗剂的靶点。

Project Summary/Abstract Aging is often associated with learning and memory impairments. Yet, some aged individuals remain free of any impairment. The current project seeks to investigate the neurobiological mechanisms that underlie the aging-related impairments and what separates those with impairments (aged impaired--AI) from those without (aged unimpaired--AU). Previous research has focused on the hippocampus, a major region necessary for memory formation. The current project will focus on the entorhinal cortex (EC), another important region for memory, as it serves as the relay station between cortical regions and the hippocampus. The EC is not only important for supporting memory, but is also a site for major aging-related changes. For example, within normal aging, EC volume is directly inversely correlated with poorer memory performance. Alzheimer’s disease, a neurodegenerative disorder whose major risk factor is increasing age, initially manifests itself within the EC. The current project will focus on the lateral division of the EC. The lateral EC is suggested to support the formation of temporal associative memory, a task on which many aged individuals are impaired. These converging pieces of evidence suggest the presence of neurobiological changes within the LEC that support learning and that altered neuronal physiology with aging may underlie the inability to undergo those changes, thus resulting in learning deficits. The current project, therefore, seeks to identify the biophysical alterations that occur in LEC neurons from young and aged animals that successfully learn (Y and AU) and from those that cannot (AI). The project will focus on changes within the neurons that project via the perforant path to the dentate gyrus, as the perforant path makes up the first step of the trisynaptic loop, the classic circuit for memory formation in the hippocampus. While previous studies have electrophysiologically characterized the neurons of the LEC, the identity of the perforant path neuron has not yet been definitively identified. I will, therefore, first establish the identity of the perforant path neuron by injecting a retrograde fluorescent tracer into the dentate gyrus of young and aged animals (Aim 1). The fluorescent tracer will confirm the morphology of the neuron and also allow for targeting during whole-cell current clamp recordings, allowing for confirmation of the electrophysiological profile. During whole cell recordings, I will also measure neuronal excitability, as previous research has determined that aging-related changes in neuronal excitability within the hippocampus have prevented successful learning in aged animals. I will then train young adult and aged animals on a temporal associative learning task in order to measure learning-related changes in excitability in the perforant path neuron (Aim 2). Recordings will reveal how learning is supported in the LEC of Y and AU animals and also identify mechanisms that prevent successful learning in AI animals. The results of this study will provide a target for potential therapeutics in alleviating aging-related learning deficits and dementia.