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

项目摘要 化疗诱导的认知障碍（CICI）是癌症患者中常见的一种病症，其中 癌症化疗治疗后，学习、记忆、注意力和执行功能受损。到 迄今为止，与CICI相关的最常见的遗传风险因素是APOE 4基因，该基因也是最强的 阿尔茨海默病的遗传风险因素。关于APOE 4如何影响兴奋性和抑制性神经元的机制， 内嗅皮层（大脑的一个区域，对于大脑皮层之间的信息门控至关重要 以及这些差异如何使APOE 4神经元更容易受到环境的影响。 应力使用我们新的CICI小鼠模型，结合化疗挑战的效果， （阿霉素）和遗传易感性（APOE 4基因型），我假设APOE 4-TR小鼠有缺陷， 抑制神经元功能，阻止它们对化疗产生反应， 方式我将在这个提议中检验两个具体的假设：1）APOE 4-TR小鼠容易受到以下因素的影响： 化疗由于不能保留小白蛋白中间神经元树突复杂性在内嗅 皮层，导致突触兴奋-抑制（E/I）失衡，2）apoE亚型水平驱动差异， 用化疗治疗的APOE 4-TR小鼠的回路功能障碍。以下目的将研究APOE如何 基因型和化疗影响内嗅皮层回路：目的1：研究内嗅皮层回路的潜在机制 CICI的皮层回路功能障碍我会结合电生理学共聚焦显微镜 转基因小鼠，以测量E/I平衡的变化，并询问E/I失调的根本原因。 有无化疗。目的2：测试apoE水平的增加是否可以防止内嗅 CICI的皮层回路功能障碍我将使用AAV构建体将星形胶质细胞apoE 3引入APOE 3， 接受化疗的APOE 4小鼠。将测量E/I平衡的变化，以评估apoE水平是否 最大限度地减少CICI的漏洞。这些目标将共同确定CICI的基础电路机制。 该提案的结果可以提供以下临床指导：1）在化疗前识别高危患者 治疗和2）通过改变apoE水平降低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.