Plasticity of Neuronal Function and Form in Drosophila

描述（由申请人提供）：遗传和环境因素对生物体表型的贡献是先天和后天争论的一个永恒主题。现在人们普遍认为，环境因素在基因型决定表型方面是重要的，或者说是通过后天培养决定的。探索基因-环境相互作用的复杂网络的最佳切入点之一是通过神经元和行为可塑性的研究。神经系统被赋予了对经验和外部刺激做出反应的自我修改能力。在环境挑战或系统扰动引起的应激或损伤时，神经元和网络功能组织中的内在可塑性引起神经保护和稳态机制。本研究的具体目的是：1）研究外部因素，包括环境温度升高和社会剥夺，影响神经元的生长和兴奋性，如影响不同K+通道亚基的Hk和Sh突变的显着表型所揭示的。在发展过程中，这些应激反应的细胞机制将被分析，以证明神经可塑性的不同形式的基本共同特征。2)研究神经元在离子通道功能和膜兴奋性突变扰动后恢复功能的内在发育调节机制。惊人的可塑性恢复突触的稳定性是揭示了由Sh和Sh突变，这提供了机会，以确定在相关的稳态过程中的信号转导通路中的相互作用的基因。这些结果将提供独特的机会来测试三个主要假设的共同线程连接不同形式的神经元可塑性：1）膜兴奋性机制是一个主要的球员在神经元的稳态调节响应环境压力或遗传扰动。2)由ROS积累反映的代谢应激触发神经元兴奋性和神经回路功能的改变。3)活动依赖性Ca积累激活Ca/CaM依赖性腺苷酸环化酶（由rut编码），该酶在稳态修饰中启动不同级联事件以调节或合成下游效应物（例如离子通道）方面发挥关键作用。公共卫生相关性：本研究的目的是解开连接不同形式的神经元和行为可塑性的共同线索。我们专注于神经元兴奋性和突触功效的稳态调节机制，使神经系统功能在环境或突变扰动下的调整和恢复。这些发现将直接影响环境压力、社会剥夺和行为条件对身心健康的影响。

DESCRIPTION (provided by applicant): The contributions of genetic and environmental factors to the phenotypes of an organism are a perennial subject of the nature and nurture debate. It is now generally accepted that environmental factors are important in the determination of phenotypes by the genotypes, or nature through nurture. One of the best entry points to exploring the complex network of gene-environment interactions is through studies of neuronal and behavioral plasticity. Nervous systems are endowed with the capacity of self-modification in response to experience and external stimuli. Upon stress or injury by environmental challenges or system perturbations, neuro-protective and homeostatic mechanisms are evoked by intrinsic plasticity in neuronal and network functional organization. The specific aims of this proposal are: 1) To investigate extrinsic factors, including elevated environmental temperature and social deprivation, that influence neuronal growth and excitability as revealed by the striking phenotypes of Hk and Sh mutations affecting different K+ channel subunits. The cellular mechanisms in response to these stressors during development will be analyzed to demonstrate the underlying common features of the diverse forms of neural plasticity. 2) To study the intrinsic developmental regulation mechanisms that enable neuronal adjustment for recovering function upon mutational perturbations of ion channel function and membrane excitability. Striking plasticity in restoring synaptic stability is revealed by slo and Sh mutations, which provide opportunities to identify interacting genes in signal transduction pathways in the associated homeostatic processes. The results will provide unique opportunities to test three major hypotheses for the common threads linking different forms of neuronal plasticity: 1) Membrane excitability mechanism is a major player in neuronal homeostatic regulation in response to environmental stresses or genetic perturbations. 2) Metabolic stress as reflected by ROS accumulation triggers modifications of neuronal excitability and neural circuit function. 3) Activity-dependent Ca accumulation activates Ca/CaM-dependent adenylyl cyclase (encoded by rut) that plays a pivotal role in initiating different cascade events for modulation or synthesis of downstream effectors, such as ion channels, in homeostatic modifications. PUBLIC HEALTH RELEVANCE: The purpose of this study is to unravel the common threads linking different forms of neuronal and behavioral plasticity. We focus on mechanisms of homeostatic regulation of neuronal excitability and synaptic efficacy that enable adjustment and restoration of nervous system function upon environmental or mutational perturbations. The findings will have direct implications in the influence of environmental stress, social deprivation, and behavioral conditioning on mental and physical health.