The contribution of zincergic neurons to cerebral cortical plasticity

我的实验室自成立以来，所有的研究都是为了更好地理解哺乳动物大脑皮层的内在机制，这种机制介导并促进了哺乳动物大脑皮层的显著可塑性。我过去的观点主要是由对大脑皮层出生后发育的研究指导的，因为在这段时间里，新皮层的可塑性最强。我们相信，这种可塑性背后的细胞和分子机制可能与后来的发展中存在的相同，在老年，那些介导学习和记忆以及从损伤中恢复的过程。大脑皮层中的神经元和神经元网络改变其组织以响应变化的感觉环境的能力的解剖、分子、生理和行为基质在很大程度上是未知的。然而，众所周知，神经元活动深刻地影响整个大脑神经元回路的建立和维持。在最近的NSERC资助的资助期间，我们已经建立了大量的证据，暗示神经元含有锌的突触囊泡（锌能），并调节锌的释放，在活动和经验依赖性的方式，可能发挥特殊的作用，在大脑皮层回路内介导突触可塑性。在这段时间里，我们还获得了一些技术，使我们能够更好地了解锌能神经元和突触锌在介导大脑皮层可塑性中的具体作用。这些工具包括锌信号通路表达改变的特定转基因和基因敲除小鼠，以及解剖学，分子和生理学技术和探针的发展，使我们能够监测锌能信号通路的激活。使用这些新的工具，与传统的生理，解剖，分子和行为的方法，我们打算继续我们的研究在啮齿动物模型中，以建立锌能神经元的作用，锌本身，在大脑皮层电路的正常功能和突触可塑性。

All of the research in my laboratory, since its inception, has been directed toward gaining a better understanding of the intrinsic mechanisms that mediate and facilitate the remarkable malleability that is characteristic of the mammalian cerebral cortex. My perspective in the past was largely guided by studies of the postnatal development of cortex, as it is during this time that the neocortex is most plastic. It is our belief that the cellular and molecular mechanisms that underlie this plasticity are likely the same as are present in later development, and in old age, those that mediate processes such as learning and memory, and recovery from injury. The anatomical, molecular, physiological, and behavioural substrates that underlie the ability of neurons and neuronal networks in the cerebral cortex to alter their organization in response to changing sensory environments are largely unknown. However, it is known that neuronal activity profoundly affects the establishment and maintenance of neuronal circuits throughout the brain. In the most recent NSERC-funded granting period we have established abundant lines of evidence that implicate neurons that contain zinc in synaptic vesicles (are zincergic), and modulate the release of zinc in an activity- and experience-dependent manner, might play a special role in mediating synaptic plasticity within cerebral cortical circuits. Across this period of time we have also acquired a number of technologies that will allow us to better understand the specific role of zincergic neurons and synaptic zinc in mediating cerebral cortical plasticity. The tools include specific transgenic and knockout mice with altered expression of zinc signaling pathways, as well as the development of anatomical, molecular and physiological techniques and probes that allow us to monitor the activation zincergic signaling pathways. Using these novel tools, together with traditional physiological, anatomical, molecular and behavioural methodologies, we intend to continue our studies in rodent models to establish the role of zincergic neurons, and zinc itself, in the normal functioning and synaptic plasticity of cerebral cortical circuits.