Homeostatic Stabilization of Neural Function in Health and Disease

项目摘要/摘要 大脑的复杂性和变化能力令人惊讶。似乎可以肯定的是，这种可塑性 我们的学习和记忆能力只有在其他方面稳定、可重现和 可预测的基线神经功能。现在清楚的是，动态平衡信号系统在整个 中枢神经系统和外周神经系统在一生中稳定神经功能。因此，它是 人们普遍认为，受损或适应不良的体内平衡信号将直接与病因和 神经疾病的进展，包括癫痫、自闭症和神经退行性变。然而，尽管 在整个动物界和隐含的神经功能的动态平衡控制的广泛证据 与疾病和衰老的相关性，人们对其潜在机制知之甚少。动态平衡领域 可塑性是开放的探索和潜在的变革性进展在细胞和 分子神经科学是巨大的。我们正在引领迅速崛起的动态平衡可塑性领域， 利用无偏见模型系统遗传学的力量从根本上识别和表征新的 神经系统内稳态信号的细胞和分子机制。我们的实验将 定义许多被确定为参与动态平衡信号系统的第一批信号通路 控制突触前神经递质释放和内在神经兴奋性。我们的方法揭示了一个 先天免疫信号系统的新活性，新的跨突触信号通路，新的钙 传感器，新的神经元激酶信号系统，突触前内质网和 与神经系统疾病有明显联系。因此，我们的数据将为探索影响提供基础 癫痫、自闭症和自闭症等神经系统疾病哺乳动物模型的稳态可塑性 神经退行性变。我们的数据还将直接影响当前的动态平衡信号理论和模型。 目前的理论模型已经引起了广泛的兴趣。分子洞察力将提供重要的新 下一代稳态可塑性理论模型的思想和新的制约因素 记忆。

PROJECT SUMMARY/ABSTRACT The brain is astonishing in its complexity and capacity for change. It seems certain that the plasticity that drives our ability to learn and remember can only be meaningful in the context of otherwise stable, reproducible, and predictable baseline neural function. It is now clear that homeostatic signaling systems function throughout the central and peripheral nervous systems to stabilize neural function throughout life. As a consequence, it is widely believed that impaired or maladaptive homeostatic signaling will be directly relevant to the cause and progression of neurological diseases that include epilepsy, autism and neurodegeneration. However, despite widespread evidence for the homeostatic control of neural function throughout the animal kingdom and implicit relevance to disease and aging, very little is known about the underlying mechanisms. The field of homeostatic plasticity is wide open for exploration and the potential for transformative advancement in cellular and molecular neuroscience is tremendous. We are leading the rapidly emerging field of homeostatic plasticity, harnessing the power of unbiased model system genetics to identify and characterize fundamentally new cellular and molecular mechanisms of homeostatic signaling in the nervous system. Our experiments will define many of the first signaling pathways identified to participate in the homeostatic signaling systems that control presynaptic neurotransmitter release and intrinsic neural excitability. Our approaches have uncovered a novel activity of the innate immune signaling system, new trans-synaptic signaling pathways, novel calcium sensors, novel neuronal kinase signaling systems, new roles for the presynaptic endoplasmic reticulum and tangible links to neurological disease. As such, our data will provide a foundation for exploring the impact homeostatic plasticity in mammalian models of neurological disease including epilepsy, autism and neurodegeneration. Our data will also directly impact current theories and models of homeostatic signaling. Current theoretical models have captured widespread interest. Molecular insight will provide important new ideas and new constraints for the next generation of theoretical models of homeostatic plasticity, learning and memory.