Differential impact of Alzheimer disease on neuronal subpopulations in dorsal hippocampal CA1

项目总结/摘要 阿尔茨海默病（AD）早期的记忆丧失出现在病理生理学从内嗅皮层扩展时 (EC)海马CA 1区CA 1处理EC输入以产生海马输出，并承担 海马AD病理学的冲击。AD对CA 1的研究将其锥体神经元（PNs）视为一种神经元。 同质种群然而，我们和其他小组的工作确定了CA 1 PN是多样的， 由在记忆中具有独特作用的表层（sPN）和深层（dPN）组成。这两层显示 缺血和癫痫的不同变化，但我们在这个水平上对AD病理生理学的了解是 不完整这限制了我们对AD记忆缺陷的理解和我们纠正功能障碍的能力。这 知识也可以促进我们对AD和神经变性活动依赖性扩散的理解 危险因素我们发表的和初步的数据，以及文献，支持一个工作假设，即背 由于淀粉样蛋白和tau蛋白，CA 1 sPN和dPN表现出截然不同的病理生理和功能损害 病理sPN发展出衰老的病理学迹象，并且在神经元中显示出内在的和突触的低兴奋性。 老年和3xTg-AD小鼠。dPN不显示这些体征，并变得过度兴奋。在人类AD中， sPN层更容易出现斑块和缠结，两层显示出与以下相关的蛋白质组差异： 疾病途径和兴奋性。我们使用淀粉样蛋白（5xFAD）和tau（PS19）模型来测试我们的假设， 在三个水平上分别解决这些病理对sPN/dPN的影响。在目标1中，我们使用体外 光电生理学，以评价AD病理学对背侧sPN与dPN相关回路的影响。 这将把细胞和突触的特性与生理变化的方向和程度联系起来。我们预计 淀粉样蛋白/tau诱导sPN回路中的低兴奋性和dPN回路中的高兴奋性。在目标2中，我们使用 微型镜GCaMP钙成像以确定AD病理对背侧sPN与dPN的影响 活动期间，依赖于露营的行为。这将检验差分局部电路在体内的优势 在记忆缺陷的设置中，在整体减少传出输入的情况下CA 1的变化。我们预计， 在记忆引导的行为中，它们更容易受到体内活性降低的影响。在目标3中， AD病理学背景下背侧sPN与dPN的蛋白质组学变化。这将连接细胞身份， AD严重程度的分子标志物和生理变化的程度/方向。我们希望sPN 蛋白质组将在病理性AD途径中显示更严重的变化。这项工作的重要性在于， 关于AD记忆功能障碍的新的、细胞类型特异性的、机制性的知识。这也将有助于链接 生理变化发展为病理和神经变性。这些都是关键步骤， 更好的治疗。我们的战略是创新的，它结合了多种最先进的方法来解决 疾病病理生理学在不同的细胞类型在多个生物水平：电路，行为和分子。

PROJECT SUMMARY/ABSTRACT Memory loss in early Alzheimer disease (AD) appears when pathophysiology extends from entorhinal cortex (EC) into hippocampal area CA1. CA1 processes EC input to generate hippocampal output, and bears the brunt of hippocampal AD pathology. AD studies on CA1 have treated its pyramidal neurons (PNs) as a homogeneous population. However, work from our and other groups established that CA1 PNs are diverse, comprised of superficial (sPN) and deep (dPN) layers with unique roles in memory. The two layers show differential changes in ischemia and epilepsy, but our knowledge of AD pathophysiology at this level is incomplete. This limits our understanding of memory deficits in AD and our ability to correct dysfunction. This knowledge can also advance our understanding of activity-dependent spread of AD and neurodegeneration risk factors. Our published and preliminary data, and the literature, support a working hypothesis that dorsal CA1 sPNs and dPNs exhibit contrasting pathophysiological and functional compromise due to amyloid and tau pathology. The sPNs develop pathologic signs of aging, and show intrinsic and synaptic hypoexcitability in aged and 3xTg-AD mice. The dPNs do not show these signs and become hyperexcitable. In human AD, the sPN layer is more prone to plaques and tangles, and the two layers show proteomic differences related to disease pathways and excitability. We test our hypothesis using amyloid (5xFAD) and tau (PS19) models to separately address the effects of these pathologies on sPNs/dPNs at three levels. In Aim 1, we use in vitro opto-electrophysiology to evaluate the impact of AD pathology on dorsal sPN- versus dPN-associated circuits. This will relate cell and synaptic identity to the directionality and extent of physiologic change. We expect that amyloid/tau induce hypoexcitability in sPN circuits and hyperexcitability in dPN circuits. In Aim 2, we use miniscope GCaMP calcium imaging to determine the influence of AD pathology on dorsal sPN versus dPN activity during hippocampal-dependent behavior. This will test the in vivo dominance of differential local circuit changes in CA1 over globally reduced efferent input in the setting of memory deficits. We expect that sPNs are more vulnerable to reductions in their in vivo activity during memory-guided behaviors. In Aim 3, we compare proteomic changes in dorsal sPNs versus dPNs in the setting of AD pathology. This will link cell identity, molecular markers of AD severity, and the degree/directionality of physiologic change. We expect that sPN proteomes will show more severe changes in pathologic AD pathways. This work is significant by providing new, cell-type specific, mechanistic knowledge about memory dysfunction in AD. This will also help link physiologic change to development of pathology and neurodegeneration. These are critical steps towards better treatments. Our strategy is innovative by combining multiple, state-of-the-art approaches to address disease pathophysiology in distinct cell types at multiple biological levels: circuit, behavior, and molecular.