Regulation of structural and functional neuronal plasticity by myelination

长期以来，大脑在发育过程中和成年期适应经验的能力一直被认为是学习和记忆的生物学基础。突触水平的神经元可塑性已经被认识和研究了几十年。最近，关于髓鞘形成的活动和学习依赖性变化的报道提出了髓鞘作为大脑可塑性的另一种形式的概念，它可以介导神经回路功能的长期变化。与此同时，髓磷脂缺陷与许多神经发育和神经退行性疾病的病因学和病理学有关。在神经发育障碍的一些啮齿动物模型中，行为缺陷可以通过用前髓鞘形成药物治疗而显著减弱，表明髓鞘形成缺陷可能是某些神经系统疾病表现的核心。尽管这些提示髓鞘形成在神经元回路成熟和功能中的重要性，但由于缺乏功能获得和丧失工具，很难评估髓鞘形成实际上如何影响潜在的神经回路。我们实验室最近的一项研究确定了髓鞘形成的程度与发育中啮齿动物皮层兴奋性突触密度之间的关系，提高了髓鞘可以通过调节突触形成和/或消除来塑造神经回路的可能性。然而，许多相关的问题仍然没有答案。髓鞘形成只影响特定的突触群吗？突触密度的变化是由突触生成或突触消除的变化引起的吗？除了结构可塑性外，髓鞘形成还能调节功能性神经元可塑性吗？为了更好地定义髓鞘形成如何影响突触动力学和皮质可塑性，该提案将使用最近开发的遗传小鼠模型来评估操纵髓鞘形成的程度对突触发生和突触丢失的影响。青少年的视觉皮层将被用作可塑性的模型，因为它显示了良好的描述功能和结构的可塑性，以响应视觉剥夺。核心假设是髓鞘形成促进突触稳定性，并限制发育中皮层的经验依赖性神经元可塑性。目的我将测试是否增强或削弱髓鞘形成的变化兴奋性和抑制性突触的密度在发育中的皮层。目的二将测试是否操纵髓鞘影响突触的产生和/或消除在正常的视觉皮层发育和视觉剥夺。目的III将测试增强或损害髓鞘形成是否可以限制或延长视觉剥夺后视觉皮层功能性神经元可塑性的关键期。这些研究的结果将进一步加深我们对髓鞘如何塑造神经元可塑性的理解，并对突触或髓鞘形成受到干扰的疾病具有广泛的意义。

The brain's ability to adapt to experience during development and in adulthood has long been considered the biological basis for learning and memory. Neuronal plasticity at the level of synapses has been recognized and studied for decades. More recently, reports of activity- and learning-dependent changes in myelination have brought forth the concept of myelin as an additional form of brain plasticity that can mediate long-lasting changes in neural circuit function. In parallel, myelin deficits have been implicated in the etiology and symptomology of numerous neurodevelopmental and neurodegenerative diseases. In some rodent models of neurodevelopmental disorders, behavioral deficits can be significantly attenuated by treatment with a pro- myelinating drug, indicating that defects in myelination could be central to the manifestation of certain nervous system diseases. Despite these hints at the importance of myelination in neuronal circuit maturation and function, due to a lack of gain and loss-of-function tools, it has been difficult to evaluate how myelination actually impacts the underlying neural circuits. A recent study from our lab identified a relationship between the extent of myelination and the density of excitatory synapses in the developing rodent cortex, raising the possibility that myelin can shape neural circuits by modulating synapse formation and/or elimination. However, many related questions remain unanswered. Does myelination only impact specific populations of synapses? Does the change in synapse density result from a change in synapse generation or synapse elimination? Can myelination modulate functional neuronal plasticity, in addition to structural plasticity? To better define how myelination affects synapse dynamics and cortical plasticity, this proposal will use recently developed genetic mouse models to evaluate the effects of manipulating the extent of myelination on synaptogenesis and synapse loss. The adolescent visual cortex will be used as a model for plasticity, as it displays well-described functional and structural plasticity in response to visual deprivation. The central hypothesis is that myelination promotes synapse stability and restricts experience-dependent neuronal plasticity in the developing cortex. Aim I will test whether enhancing or impairing myelination changes the density of both excitatory and inhibitory synapses in the developing cortex. Aim II will test whether manipulating myelination affects synapse generation and/or elimination during normal visual cortex development and following visual deprivation. Aim III will test whether enhancing or impairing myelination can restrict or prolong the critical period for functional neuronal plasticity in the visual cortex following visual deprivation. The results from these studies will further our understanding of how myelin shapes neuronal plasticity and have broad implications for diseases in which synapses or myelination are perturbed.