Characterizing Entorhinal Cortex Circuit Dysfunction in an APOE Mouse Model of Chemotherapy-Induced Cognitive Impairment

项目摘要 化疗引起的认知障碍(CiCi)是癌症患者常见的一种情况， 癌症化疗后，学习、记忆、注意力和执行功能受损。至 与CiCi相关的最常见的遗传风险因素是APOE4基因，它也是最强的 阿尔茨海默病的遗传危险因素。关于载脂蛋白4如何影响兴奋性和抑制性还知之甚少。 内嗅觉皮质中的神经元(大脑中对大脑皮层之间的信息门控至关重要的区域 以及这些差异如何使APOE4神经元更容易受到环境的影响 压力。使用我们的新型CiCi小鼠模型结合化疗挑战的效果 (阿霉素)和遗传易感性(APOE4基因)，我假设APOE4-tr小鼠有缺陷 在抑制神经元功能，防止他们对化疗的反应中 举止。我将检验这项提议中的两个具体假设：1)APOE4-tr小鼠容易受到 无法保存内嗅区小白蛋白间神经元间树突状复合体的化疗 大脑皮质，导致突触兴奋-抑制(E/I)失衡和2)载脂蛋白E亚型水平导致 化疗治疗的apoe4-tr小鼠的电路功能障碍。以下目标将调查APOE如何 基因分型和化疗对内嗅皮层回路的影响：目的1：研究内嗅的机制 CiCi患者的皮质回路功能障碍。我将使用电生理学、共聚焦显微镜和 转基因小鼠测量E/I平衡的变化并询问E/I失调的潜在原因 有没有化疗。目标2：测试增加载脂蛋白E水平是否能保护内嗅觉 CiCi患者的皮质回路功能障碍。我将使用AAV构建将Astercell-apoE3引入到APOE3中，并 ApoE4小鼠接受化疗。将测量E/I平衡的变化，以评估载脂蛋白E水平 最大限度地减少对CiCi的脆弱性。这些目标将共同确定CiCi背后的基于电路的机制。 这项建议的结果可以为临床提供指导：1)在化疗前识别高危患者 治疗和2)通过改变载脂蛋白E水平降低发生CiCi的可能性。

PROJECT ABSTRACT Chemotherapy-induced cognitive impairment (CICI) is a condition commonly reported in cancer patients, where learning, memory, attention, and executive functions are impaired following cancer chemotherapy treatment. To date, the most common genetic risk factor associated with CICI is the APOE4 gene, which is also the strongest genetic risk factor for Alzheimer’s Disease. Little is known about how APOE4 affects excitatory and inhibitory neurons in the entorhinal cortex (a region of the brain critical for information gating between the cerebral cortex and the hippocampus) and how those differences may make APOE4 neurons more susceptible to environmental stress. Using our novel mouse model of CICI that combines the effects of a chemotherapeutic challenge (doxorubicin) and genetic susceptibility (APOE4 genotype), I hypothesize that APOE4-TR mice have a deficit in inhibitory neuron function which prevents them from responding to chemotherapy in a protective manner. I will test two specific hypotheses in this proposal: 1) APOE4-TR mice are vulnerable to the effects of chemotherapy due to an inability to preserve parvalbumin interneuron dendritic complexity in the entorhinal cortex, leading to synaptic excitation-inhibition (E/I) imbalance and 2) apoE isoform levels drive the difference in circuit dysfunction in APOE4-TR mice treated with chemotherapy. The following aims will investigate how APOE genotype and chemotherapy affect entorhinal cortex circuitry: Aim 1: Examine mechanisms underlying entorhinal cortex circuit dysfunction in CICI. I will use a combination of electrophysiology, confocal microscopy, and transgenic mice to measure changes in E/I balance and interrogate underlying causes of E/I dysregulation in the presence and absence of chemotherapy. Aim 2: Test whether increasing apoE levels protects against entorhinal cortex circuit dysfunction in CICI. I will use an AAV construct to introduce astrocytic-apoE3 into APOE3 and APOE4 mice treated with chemotherapy. Changes to E/I balance will be measured to assess if apoE levels minimize vulnerability to CICI. These aims will collectively identify circuit-based mechanisms underlying CICI. Outcomes of this proposal can provide clinical guidance on 1) identifying at-risk patients prior to chemotherapy treatment and 2) reducing the likelihood of CICI by altering apoE levels.