NEUROTROPHIC REGULATION OF NEURONAL SIGNALING

虽然神经营养因子在短期（几分钟到几小时）内调节突触功能的能力近年来得到了广泛的研究，但对神经营养因子在调节可能发生在几天到几周或更长时间内的长期形式的突触修饰中所起的潜在作用知之甚少。一个关键的问题是神经营养因子的这种长期作用是否本质上是支持性的，类似于神经营养因子在促进周围神经系统中神经元存活和分化的传统作用。在这种情况下，神经营养蛋白只会通过它们的存在和作用，允许其他信号传导过程对信息进行编码并改变神经回路。或者，神经营养因子可以选择性地调节兴奋和突触功能的关键要素，从而直接介导突触可塑性的重要方面。因此，本提案的目标是区分这两种选择，以了解神经元和神经回路功能如何长期受神经营养因子的调节。为此，该提案的三个具体目标将在原代神经元培养中使用分子生物学和电生理学方法的组合来确定神经营养因子对可兴奋和突触功能的调节是否显示：选择性，即给定的神经营养因子仅调节靶神经元中可兴奋和突触功能的特定方面;神经营养素特异性，即神经营养素各自在给定的靶神经元中诱导不同的功能变化，即使该神经元对多种因素作出反应;和活动依赖性，神经营养因子的作用可以与电和/或突触活动的特定模式和模式相联系。 这些实验将有助于我们了解神经营养因子如何参与调节突触可塑性，以及神经营养因子信号传导的缺陷如何导致神经元功能障碍和神经系统疾病。

While the ability of neurotrophins to modulate synaptic function in the short-term (minutes to hours) has been extensively studied in recent years, very much less is known about the potential roles neurotrophins play in regulating longer-term forms of synaptic modification that may occur over the time frame of days to weeks or more. A key issue is whether such long-term roles for neurotrophins are essentially supportive, resembling the traditional roles of neurotrophins in promoting neuronal survival and differentiation in the peripheral nervous system. In this case, neurotrophins would simply allow, by their presence and action, other signaling processes to encode information and change in neural circuits. Alternatively, neurotrophins may selectively regulate key elements of excitable and synaptic function and thereby directly mediate important aspects of synaptic plasticity. The goal of this proposal is thus to distinguish between these two alternatives in understanding how neuronal and neural circuit function is regulated by neurotrophins in the long-term. To this end, the three Specific Aims of the proposal will determine, using a combination of molecular biological and electrophysiological approaches in primary neuronal culture, if neurotrophin regulation of excitable and synaptic function shows: selectivity, that a given neurotrophin regulates only particular aspects of excitable and synaptic function in a target neuron; neurotrophin-specificity, that neurotrophins each induce distinct functional changes in a given target neuron, even when that neuron responds to multiple factors; and activity-dependence, a way in which neurotrophin action can be linked to particular modes and patterns of electrical and/or synaptic activity. These experiments will contribute to our understanding of how neurotrophins parLicipate in regulating synaptic plasticity and how deficiencies in neurotrophin signaling can lead to neuronal dysfunction and neurological disorders.