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辩论的长期主题。现在人们普遍认为，环境因素在基因型决定表型或后天自然决定表型中起重要作用。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研究神经元和行为可塑性。神经系统被赋予了对经验和外部刺激作出自我修正的能力。在受到环境挑战或系统扰动的应激或损伤时，神经保护和内稳态机制是由神经元和网络功能组织的内在可塑性引起的。本研究的具体目的是：1)研究影响不同K+通道亚基的Hk和Sh突变的显著表型所揭示的影响神经元生长和兴奋性的外在因素，包括环境温度升高和社会剥夺。在发育过程中，细胞机制对这些压力源的反应将被分析，以展示不同形式的神经可塑性的潜在共同特征。2)研究离子通道功能和膜兴奋性突变扰动下神经元恢复功能的内在发育调控机制。slo和Sh突变揭示了恢复突触稳定性的惊人可塑性，这为识别相关稳态过程中信号转导途径中的相互作用基因提供了机会。这一结果将为验证连接不同形式神经元可塑性的共同线索的三个主要假设提供独特的机会：1)膜兴奋性机制是神经元响应环境压力或遗传扰动的稳态调节的主要参与者。2)以ROS积累为反映的代谢应激引发神经元兴奋性和神经回路功能的改变。3)活性依赖性Ca积累激活Ca/ cam依赖性腺苷酸环化酶（由rut编码），该酶在启动调节或合成下游效应物（如离子通道）的不同级联事件中起关键作用。公共卫生相关性：本研究的目的是揭示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效能的稳态调节机制，使神经系统功能在环境或突变扰动下进行调节和恢复。研究结果将对环境压力、社会剥夺和行为调节对身心健康的影响产生直接影响。

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.