NEUROTROPHIC REGULATION OF NEURONAL SIGNALING

近年来，神经营养因子在短期内（几分钟到几小时）调节突触功能的能力得到了广泛的研究，但对于神经营养因子在调节可能在数天到数周或更长时间内发生的长期突触修饰中所起的潜在作用，人们知之甚少。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神经元存活和分化方面的传统作用。在这种情况下，神经营养因子的存在和作用只是允许其他信号过程编码信息，并在神经回路中发生变化。另外，神经营养素可能选择性地调节可兴奋性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，本建议的目标是区分这两种选择，以了解神经营养素如何长期调节神经元和神经回路功能。为此，该提案的三个具体目标将确定，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，如果神经营养因子调节可兴奋性和突触功能显示：选择性，即给定的神经营养因子仅调节目标神经元中可兴奋性和突触功能的特定方面；神经营养因子特异性，即每种神经营养因子在给定的目标神经元中诱导不同的功能变化，即使该神经元对多种因素有反应；以及活动依赖性，即神经营养物质的作用可以与特定的电和/或突触活动模式和模式联系起来。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.