Plasticity of Neuronal Function and Form in Drosophila

描述(由申请人提供)：遗传和环境因素对有机体表型的贡献是先天和后天争论的长期主题。现在人们普遍认为，环境因素在通过基因类型或通过后天培养来确定表型方面是重要的。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研究神经元和行为的可塑性。神经系统被赋予了对经验和外部刺激做出自我调整的能力。在受到环境挑战或系统扰动的应激或损伤时，神经元和网络功能组织的内在可塑性激活了神经保护和稳态机制。这一建议的具体目的是：1)研究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，这是由影响不同K+通道亚基的HK和Sh突变的显著表型所揭示的。将分析在发育过程中对这些应激源做出反应的细胞机制，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引起的神经元功能恢复的内在发育调节机制。Slo和Sh突变揭示了突触恢复稳定性的显著可塑性，这为在相关的稳态过程中识别信号转导途径中相互作用的基因提供了机会。这一结果将为检验连接不同形式神经元可塑性的共同线索的三个主要假说提供独特的机会：1)膜兴奋性机制是响应环境应激或遗传扰动的神经元内稳态调节的主要参与者。2)ROS积聚所反映的代谢应激引起神经元兴奋性和神经回路功能的改变。3)活性依赖性钙积累激活钙/钙调素依赖性腺酰环化酶(由RUT编码)，该酶在调节或合成动态平衡修饰的下游效应物(如离子通道)的不同级联事件中起着关键作用。公共卫生相关性：这项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。我们着重于神经元兴奋性和突触效能的动态平衡调节机制，这些机制使神经系统功能能够在环境或突变扰动下进行调整和恢复。这些发现将对环境压力、社会剥夺和行为限制对心理和身体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.