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Activity-dependent mechanisms controlling the developmental timing of spontaneous

控制自发发育时间的活动依赖机制

基本信息

批准号：
8876804
负责人：
MARTHA M BOSMA
金额：
$ 11.59万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8876804
关键词：
Addictive Behavior Autistic Disorder Automobile Driving Axon Behavior Brain Brain Stem Brain region Cells Development Developmental Process Disease Dopamine Down-Regulation Drug Prescriptions Embryo Environment Event Genes Genetic Halorhodopsins Health Invaded Ion Channel Label Laboratories Length Life Light Maintenance Mediating Mental Depression Mental disorders Midbrain structure Mitotic Modification Mood Disorders Moods Morphology Neuraxis Neurons Outcome Pacemakers Pattern Phenotype Population Positioning Attribute Potassium Channel Pregnancy Property Regulation Research Retina Rewards Role Schizophrenia Serotonin Spinal Cord Staging Stimulus Street Drugs Structure Synapses System Techniques Tegmentum Mesencephali Time Up-Regulation addiction axon growth axonal pathfinding dopaminergic neuron drug of abuse embryo culture fetal hindbrain neuron development neuronal excitability nodal myocyte optogenetics postnatal receptor relating to nervous system research study spatiotemporal synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): Spontaneous activity (SA; electrical activity independent of external stimulus) in the developing central nervous system is often recorded as waves of propagating electrical events in different brain structures. These waves are expressed only in a relatively short window of development, often occurring during a period of synaptogenesis; a change in the window of expression alters development of the relevant circuit. They have also been shown to influence neuron proliferation and phenotype, axon pathfinding and extension, and synaptic formation and maintenance. The waves of activity successively invade group of cells, allowing coincident firing between neighboring cells and mutual strengthening of developmental events. Modulation of this SA by changes in ion channels, propagation mechanisms or transmitter release would modify both the timing and the extent of SA, and would likely alter circuit development. In the embryonic brainstem, we have shown that SA originates within the developing serotonergic (5HT) hindbrain raphe; postnatally, 5HT neurons regulate of mood and behaviors such as depression and schizophrenia. 5HT-dependent waves propagate widely early in brainstem formation, at embryonic day (E) 11.5; soon after, waves begin to retract towards the pacemaker region, and disappear by E14.5. At specific stages, the waves propagate into the midbrain tegmentum, where they activate newly differentiating dopamine (DA) neurons; later in life these neurons mediate reward and addictive behaviors. This is an unusual example of SA in one brain region regulating neuronal excitability in another structure. We have shown that retraction of the 5HT-dependent waves is caused by upregulation of specific K channels, such that waves are unable to propagate into regions of the hindbrain in a defined spatiotemporal pattern. Because the initiator cells driving SA maintain their pacemaker role for the entire period of SA, we propose to use genetic labeling and optogenetic techniques to selectively silence or augment waves of SA, and ask how that modulation changes the development of serotonergic AND dopaminergic circuits. We have recently used specific 5HT genes to transgenically label live 5HT pacemaker neurons and identify the mechanisms by which they generate SA. We now propose to use the same genetic tags to introduce light- regulated ion channels that can silence (halorhodopsin) or stimulate (channelrhodopsin) the neurons. These experiments will be performed on cultured embryos, using controlled light stimulation during the culture period. We will be able to examine how modulation of SA changes the expression of the K channel that mediates wave retraction, and to characterize changes in 5HT and DA neuron number, position, axon extension and pathfinding. These experiments will demonstrate how modifications of neuronal excitability in the 5HT-dependent pacemaker population, such as might be induced during pregnancy by prescription or street drugs, can alter development of important behavior-regulating circuits.

描述（由申请人提供）：发育中的中枢神经系统中的自发活动（SA;独立于外部刺激的电活动）通常记录为不同脑结构中传播电事件的波。这些波只在相对较短的发育窗口中表达，通常发生在突触发生期间;表达窗口的变化会改变相关回路的发育。它们还被证明影响神经元增殖和表型、轴突寻路和延伸以及突触形成和维持。活动波连续侵入细胞群，使相邻细胞之间的同步放电和发育事件的相互加强。通过改变离子通道、传播机制或递质释放来调节SA，将改变SA的时间和程度，并可能改变电路的发育。在胚胎脑干中，我们已经证明SA起源于发育中的多巴胺能（5 HT）后脑中缝;出生后，5 HT神经元调节情绪和行为，如抑郁症和精神分裂症。5 HT依赖性波在脑干形成的早期广泛传播，在胚胎（E）11.5天;不久之后，波开始向起搏区收缩，并在E14.5消失。在特定阶段，波传播到中脑被盖，在那里它们激活新分化的多巴胺（DA）神经元;在以后的生活中，这些神经元介导奖励和成瘾行为。这是一个不寻常的例子，SA在一个大脑区域调节另一个结构的神经元兴奋性。我们已经表明，收缩的5 HT依赖性波是由特定的K通道的上调，使波无法传播到一个定义的时空模式的后脑区域。由于启动细胞驱动SA保持其起搏器的作用，为整个SA期间，我们建议使用遗传标记和光遗传学技术选择性沉默或增加波的SA，并询问调制如何改变的发展多巴胺能和多巴胺能电路。我们最近使用特定的5 HT基因转基因标记活的5 HT起搏神经元，并确定其产生SA的机制。我们现在建议使用相同的基因标签来引入光调节离子通道，可以沉默（盐视紫红质）或刺激（通道视紫红质）神经元。这些实验将在培养的胚胎上进行，在培养期间使用受控的光刺激。我们将能够研究SA的调制如何改变介导波回缩的K通道的表达，并表征5 HT和DA神经元数量、位置、轴突延伸和寻路的变化。这些实验将证明如何修改的神经元兴奋性的5 HT依赖性起搏器的人口，如可能会引起在怀孕期间的处方药或街头药物，可以改变重要的行为调节电路的发展。