The functional organization of motor cortex: development, circuitry and plasticity

记忆是如何被编码到大脑中的？大多数行为神经学家一致认为，记忆是通过神经元之间连接强度的变化在大脑中实例化的，这反过来又导致神经回路的重组。我对这种“突触可塑性和记忆假说”非常感兴趣，我选择在哺乳动物的运动皮质中探索它。运动皮质是一个很容易研究的结构。运动皮质的输出是可以直接观察和测量的行为。运动表征，也称为运动地图，与行为功能有关，按地形图组织，提供丰富的信息，可以进行实验操作。最后，V层内的神经元网络与锥体神经元建立突触连接，我们可以在体外进行操作和测量，实验控制程度非常高。因此，我建议在三个相互关联的分析水平上分析运动皮质的功能：a)前肢的行为，b)使用短串和长串皮质内微刺激分别产生标准和复杂的运动图的前肢的运动表示(运动图)，以及c)使用我们开发的体外切片制备来检测V层锥体细胞的电生理特性。我将通过确定：a)经验对发育的影响，b)专门用于复杂动作和熟练行为学习的运动皮质区域的作用，c)皮质区域与复杂动作表征之间的解剖关系，以及丘脑和脊髓是否存在解剖学上的分离，以及d)内源性大麻素在熟练学习和运动图表达中的作用，来提高我们对学习和记忆的认识。我的实验室采用了几项新的创新。我们采用了一种皮质降温方法，允许我们在急性和慢性准备中选择性和可逆地停用运动皮质上的特定区域。我们执行标准(短)和长训练皮质内微刺激技术，以获得大鼠和转基因小鼠品系的运动图。我们已经开发出一种来自运动皮质的切片制剂，它概括了皮质内微刺激的基本特征，并允许对运动皮质输出层进行深入的电生理分析。也许最重要的是，所有这些方法都是在同一个实验室中进行的，将使我们能够更好地了解哺乳动物新皮质中负责学习和记忆的机制。

How is it that memories are encoded into the brain? Most behavioural neuroscientists agree that memories are instantiated in the brain through changes in the connection strengths between neurons which in turn causes a restructuring of neural circuits. I am intensely interested in this “synaptic plasticity and memory hypothesis” and I choose to explore it within the mammalian motor cortex. The motor cortex is a highly amenable structure to investigate. The output of motor cortex is behaviour which can be directly observed and measured. Motor representations, also known as motor maps, are related to behavioural functioning, topographically organized, provide a wealth of information and can be experimentally manipulated. Finally networks of neurons within layer V make synaptic connections with pyramidal neurons that we can manipulate and measure in vitro with an extraordinary high degree of experimental control. Thus, I propose to analyze the functioning of motor cortex at three inter-related levels of analysis; a) behaviour of the forelimb, b) motor representations (motor maps) of the forelimb using both short- and long-train intracortical microstimulation which give rise to standard and complex motor maps respectively, and c) by examining the electrophysiological properties of layer V pyramidal cells using an in vitro slice preparation that we have developed. I will advance our knowledge of learning and memory by determining; a) the consequences of experience on development, b) the role of the areas of motor cortex specialized for complex movements and in the learning of skilled behaviours, c) the anatomical relationship between areas of cortex and the representations of complex movements, as well as whether there is anatomical segregation in the thalamus and spinal cord, and d) the role of endocannabinoids on skilled learning and the expression of motor maps. There are several new innovations that my laboratory incorporates. We have adapted a cortical cooling methodology that allows us to selectively and reversibly inactivate specific areas on motor cortex both in acute and chronic preparations. We perform both standard (short) and long-train intracortical microstimulation techniques to derive motor maps in rats and genetically modified mouse strains. We have developed a slice preparation from motor cortex that recapitulates the essential features of intracortical microstimulation and allows for an in depth electrophysiological analysis of the output layer of motor cortex. Perhaps most importantly all of these methodologies are performed within the same laboratory and will allow us to achieve a better understanding of the mechanisms responsible for learning and memory in the mammalian neocortex.