Peripheral Sympathetic Dysfunction in Cardiac Disease

项目摘要 心肌梗死和心力衰竭增加了室性心律失常和心源性猝死的风险。 自主神经失调和交感神经亢进伴随这些疾病，并触发致命的 心律不齐靶向中枢神经系统以抑制交感神经流出的干预措施尚未得到实施。 对患者有效，但针对外周交感神经系统的干预减少 心律失常和延长生命。我们假设中枢神经系统的活动被后- 神经节神经元在心血管疾病中增强去甲肾上腺素和神经肽Y的释放 心脏，这有助于病理学。我们发现交感神经后- 促进节前信号同步放大的神经节神经元。我们假设 疾病引起的心脏变化触发交感神经的形态和电转化 导致交感神经过度活跃的节后神经元。确定负责以下方面的机制： 交感神经功能亢进的变化，我们利用转基因小鼠模型加上神经化学，单细胞 RNAseq、膜片钳电生理学、标记神经元的逆行追踪和3D重建以连接 结构与功能我们将把神经功能与去甲肾上腺素和神经肽Y的释放联系起来， 心单细胞突触测量与小鼠遗传学和逆行追踪相结合的力量提供了 独特的机会，以解决机制负责增强传输特定于心脏 投射神经元我们将检验心肌梗死和心力衰竭驱动力增加的假设 心脏交感神经传递：通过扩张树突及其突触输入（Aim 1）; 通过增强神经元活性（Aim 2）和通过改变神经元钙处理（Aim 3）。我们有 组建了一个由有成就的专家、关键的动物模型和强大的遗传工具组成的独特团队， 完成这些研究。我们希望新的见解和治疗干预的目标将来自 这里描述的研究以及这项工作对许多疾病的治疗具有影响 以高度交感神经激活为特征。

Project Summary Myocardial infarction and heart failure increase risk for ventricular arrhythmias and sudden cardiac death. Autonomic dysregulation and sympathetic hyperactivity accompany these diseases and trigger lethal arrhythmias. Interventions that target the central nervous system to inhibit sympathetic outflow have not been effective in patients, but interventions that target the peripheral sympathetic nervous system decrease arrhythmias and prolong life. We hypothesize that central nervous system activity is amplified by post- ganglionic neurons in cardiovascular disease to enhance norepinephrine and neuropeptide Y release at the heart, which contributes to pathology. We have discovered excitatory collaterals between sympathetic post- ganglionic neurons that foster synchronous amplification of preganglionic signals. We hypothesize that disease-induced changes in the heart trigger morphological and electrical transformation of sympathetic postganglionic neurons that results in sympathetic hyperactivity. To identify the mechanisms responsible for hyper-sympathetic changes, we exploit transgenic mouse models coupled with neurochemistry, single cell RNAseq, patch clamp electrophysiology, retrograde tracing and 3D reconstruction of labeled neurons to link structure with function. We will connect neural function to norepinephrine and neuropeptide Y release in the heart. The combined power of single cell synaptic measures with mouse genetics and retrograde tracing offers unique opportunities to resolve mechanisms responsible for augmented transmission specific to cardiac projecting neurons. We will test the hypotheses that myocardial infarction and heart failure drive increased cardiac sympathetic transmission: through expanding dendritic arbors and their synaptic inputs (Aim 1); through enhancing neuronal activity (Aim 2); and through altering neuronal calcium handling (Aim 3). We have assembled a unique team of accomplished experts, key animal models, and powerful genetic tools to accomplish these studies. We expect that novel insights and targets for therapeutic intervention will come from the studies described here, and that this work with have implications for treatment of the many diseases characterized by high sympathetic activation.