Neural network physiology in cortex and basal ganglia

皮层和基底神经节的神经网络生理学

• 批准号: 7312886
• 负责人: Dietmar Plenz
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7312886
• 关键词: Neural; network; physiology; cortex; basal

Research in the Unit of Neural Network Physiology is primarily concerned with functions of the neocortex and the basal ganglia. These brain regions are involved in higher cognitive functions e.g. executive decisions and working memory, as well as in movement control and reward mediated behavior. Our work focuses on the function of the neurotransmitters glutamate and dopamine at the network level. These neurotransmitters are involved in a variety of disease states. Dopaminergic and glutamatergic dysfunctions of the cortex are found in e.g. schizophrenia and epilepsy. A dopaminergic imbalance in the striatum, which is part of the basal ganglia, is correlated with severe movement disorders such as seen in Parkinson?s disease and Chorea Huntington. More specifically, research in our unit seeks to determine the function of microcircuits in the cortex and the striatum in order to address two related questions: (1) How does the cortex achieve and maintain activity states that allow it to encode and process information? (2) How are cortical network dynamics decoded by the striatum? We address these questions at the network level because many of the computational properties of the cortex and the striatum are predicted to emerge out of the collective action of thousands of neurons and cannot be predicted from the behavior of single neurons alone. We use a variety of experimental and computational techniques to monitor and analyze the dynamics of networks in vitro in organotypic co-cultures and acute slices. For example, we reconstruct parts of the cortex-basal ganglia systems in vitro by culturing young rat or mouse brains for up to several months on multi-electrode arrays. These neuronal co-cultures provide the most complex in vitro system that exists to date: a 6-layered cortical network that drives activity in a striatal network and also receives dopaminergic inputs from the substantia nigra. The system comprises of several hundred thousand of neurons and replicates network activity that strongly resembles that seen in vivo. Taking advantage of this approach, we are in the unique position to study single neuron electrophysiology, synaptic transmission between neurons, and neuronal populations within and across nuclei under in vivo-like conditions. This year?s research further developed the following two aspects of information processing in the cortex-basal ganglia system. (A) Dynamics in cortical networks We recently provided the first demonstration that cortical networks operate in a ?critical state?. At this stable state, the network is maximally excitable without being epileptic. Using multi-electrode arrays in combination with organotypic cultures and acute slices, we demonstrated that propagation of synchronized activity in the critical state takes on the form of ?neuronal avalanches?, which are neither wave-like, nor rhythmic, or random. These ?neuronal avalanches? are described by a power law with slope ?3/2 and a branching parameter of 1 at which they retain maximal information as they propagate through the network (Beggs and Plenz, 2003). These ?neuronal avalanches? are highly diverse, yet temporally precise at the millisecond time scale and reoccur over many hours. They thus fulfill many of the requirements of a substrate for memory, and suggest that they play a central role in both information transmission and storage in cortex (Beggs and Plenz, 2004). During the last year, we demonstrated that ?neuronal avalanches? emerge in superficial layers of rat medial prefrontal cortex. The spontaneous recurrence of avalanches follows an inverted-U profile of non-linear dopamine-NMDA interaction. These avalanches thus fulfill the first network level dynamics that follows a similar pharmacological profile as know for cognitive functions e.g. working memory (Stewart and Plenz, 2006). A comment was necessary to correct wrongly reported facts on neuronal avalanche states (Plenz, 2005). Ongoing current avalanche projects: A. In July 2005, we entered into a collaboration with Miguel Nicolelis?s group at Duke University. We have demonstrated that neuronal avalanches describe the awake, desynchronized local EEG activity in awake macaque monkeys. A manuscript with these findings is currently under revision at Nature Neuroscience (Thiagarajan T, Peterman T, Plenz D). B. In January 2004, we started to analyze the occurrence of neuronal avalanches in the developing cortex. We have now found that as soon as superficial cortex layers mature, neuronal avalanches in the form of nested theta/gamma-oscillations occur and are regulated by balanced dopamine D1/D2-receptor activation. A manuscript, summarizing these findings is currently in preparation (Dharmaraj GE, Plenz D) C. The participation of single neurons in cortex in a neuronal avalanche is of greatest importance to understand the avalanche dynamics. Together with a number of postbac students, we have established an electrophysiological setup which allows for the simultaneous recording of neuronal avalanches and intracellular membrane potential of identified neurons. This study is the first demonstration of percolation in neuronal networks and will be presented in abstract form at the upcoming Society for Neuroscience conference (Falco J, Bellay T, Monzon A, Plenz D) (B) Striatal processing of cortical inputs Using calcium imaging from distal dendrites, we were the first to demonstrate that number of back propagating spikes controls dendritic calcium during ?up? states, the characteristic network state of the striatum in response to cortical inputs, (Kerr and Plenz, 2002). This last year, we demonstrated that the precise timing between ?up-state onset and delay to first action potential also determines dendritic calcium through an NMDA mediated mechanism (Kerr and Plenz, 2004). These findings pave the way for spike-time dependent plasticity rules in striatal processing of cortical inputs. We also demonstrated that GABAergic synapses between striatal neurons are important for processing of cortical inputs to the striatum. The specific local circuitries formed by these synapses can be classified into feedforward and feedback networks with unique temporal properties. During the last year, we have published an extensive study on the electrophysiology of feedforward and feedback signaling of these GABAergic synapses in the striatum. This study is the most comprehensive electrophysiological study for these connections to date, solving several discrepancies reported from other groups regarding striatal synaptic transmission (Gustafson et al., 2006). Two book chapters summarizing our striatal findings have been published (see Biblio). Similarly, in my ongoing collaboration with Prof. A. Blackwell, we published the first interpretation of striatal fast spiking interneuron physiology in the context of corticostriatal processing (Kotaleski et al., 2005). (C) We also have several ongoing projects in which new technologies are combined to improve imaging of brain functions. For example, in a recent collaboration with the Unit of Functional Imaging, we demonstrated for the first time the ability to measure neuronal activity directly with MRI techniques. These experiments pave the way to overcome current limitations of the MRI technique, which relies on measuring neuronal activity indirectly through oxygen consumption. The paper reporting these findings has now been accepted at PNAS (Petridou et al., 2006). We also have an ongoing collaboration with Dr. Pajevic (DCB/MSCL/OC) in which we develop new mathematical tools to analyze activity in large neuronal networks such as the cortex. Finally, we started a collaboration with Dr. Peter Basser's group in which our cell culture models are used to study the flux of water molecules as a function of neuronal activity.

神经网络生理学单元的研究主要涉及新皮质和基底神经节的功能。这些大脑区域涉及更高的认知功能，例如执行决策和工作记忆，以及运动控制和奖励介导的行为。我们的工作重点是神经递质谷氨酸和多巴胺在网络水平上的功能。这些神经递质参与多种疾病状态。皮质的多巴胺能和谷氨酸能功能障碍见于例如。精神分裂症和癫痫症。纹状体是基底神经节的一部分，其多巴胺能失衡与严重的运动障碍有关，例如帕金森病和亨廷顿舞蹈病。 更具体地说，我们单位的研究旨在确定皮层和纹状体中微电路的功能，以解决两个相关问题： (1) 皮层如何实现和维持允许其编码和处理信息的活动状态？ (2)纹状体如何解码皮质网络动态？ 我们在网络层面解决这些问题，因为皮层和纹状体的许多计算特性预计是由数千个神经元的集体行为产生的，而不能仅根据单个神经元的行为来预测。我们使用各种实验和计算技术来监测和分析器官共培养和急性切片中体外网络的动态。例如，我们通过在多电极阵列上培养幼年大鼠或小鼠大脑长达几个月，在体外重建部分皮质-基底神经节系统。这些神经元共培养物提供了迄今为止最复杂的体外系统：驱动纹状体网络活动并接收来自黑质的多巴胺能输入的 6 层皮质网络。该系统由数十万个神经元组成，并复制与体内观察到的网络活动非常相似的网络活动。利用这种方法，我们处于独特的地位，可以在类似体内的条件下研究单神经元电生理学、神经元之间的突触传递以及细胞核内和细胞核间的神经元群体。 今年的研究进一步发展了皮层基底神经节系统信息处理的以下两个方面。 (A) 皮质网络的动力学 我们最近首次演示了皮质网络在“临界状态”下运行。在这种稳定状态下，网络可以最大限度地兴奋而不会癫痫。使用多电极阵列结合器官型培养物和急性切片，我们证明了临界状态下同步活动的传播采取“神经元雪崩”的形式，它既不是波状的，也不是有节奏的或随机的。这些“神经元雪崩”？由斜率为 3/2 且分支参数为 1 的幂律描述，在该幂律下，它们在通过网络传播时保留最大信息（Beggs 和 Plenz，2003）。这些“神经元雪崩”？高度多样化，但时间精确到毫秒时间尺度，并且在多个小时内重复发生。因此，它们满足了记忆基质的许多要求，并表明它们在皮层的信息传输和存储中发挥着核心作用（Beggs 和 Plenz，2004）。去年，我们证明了“神经元雪崩”。出现于大鼠内侧前额皮质的浅层。雪崩的自发复发遵循非线性多巴胺-NMDA 相互作用的倒 U 型曲线。因此，这些雪崩满足了第一个网络级动力学，该动力学遵循与已知的认知功能相似的药理学特征，例如认知功能。工作记忆（Stewart 和 Plenz，2006）。有必要发表评论来纠正有关神经元雪崩状态的错误报道事实（Plenz，2005）。 当前正在进行的雪崩项目： 答：2005 年 7 月，我们与杜克大学 Miguel Nicolelis 的团队建立了合作关系。我们已经证明，神经元雪崩描述了清醒猕猴中清醒的、不同步的局部脑电图活动。含有这些发现的手稿目前正在《自然神经科学》杂志上进行修订（Thiagarajan T、Peterman T、Plenz D）。 B. 2004年1月，我们开始分析发育中皮层中神经元雪崩的发生。我们现在发现，一旦浅层皮质层成熟，就会发生嵌套 theta/gamma 振荡形式的神经元雪崩，并受到平衡的多巴胺 D1/D2 受体激活的调节。目前正在准备总结这些发现的手稿（Dharmaraj GE，Plenz D） C. 皮层中单个神经元参与神经元雪崩对于理解雪崩动力学至关重要。我们与一些研究生一起建立了一个电生理学装置，可以同时记录神经元雪崩和已识别神经元的细胞内膜电位。这项研究是神经网络渗透的首次演示，并将在即将召开的神经科学学会会议上以摘要形式呈现（Falco J、Bellay T、Monzon A、Plenz D） (B) 皮质输入的纹状体处理 使用远端树突的钙成像，我们第一个证明反向传播尖峰的数量在“up”期间控制树突钙。状态，纹状体响应皮质输入的特征网络状态（Kerr 和 Plenz，2002）。去年，我们证明了上状态开始和第一次动作电位延迟之间的精确时间也通过 NMDA 介导的机制决定了树突状钙（Kerr 和 Plenz，2004）。这些发现为皮层输入纹状体处理中尖峰时间依赖性可塑性规则铺平了道路。我们还证明了纹状体神经元之间的 GABA 能突触对于处理纹状体的皮质输入非常重要。由这些突触形成的特定局部电路可以分为具有独特时间特性的前馈网络和反馈网络。去年，我们发表了一项关于纹状体中这些 GABA 突触的前馈和反馈信号传导的电生理学的广泛研究。这项研究是迄今为止对这些连接最全面的电生理学研究，解决了其他小组报告的有关纹状体突触传递的几个差异（Gustafson 等，2006）。总结我们纹状体发现的两本书章节已经出版（参见 Biblio）。 同样，在我与 A. Blackwell 教授的持续合作中，我们发表了在皮质纹状体处理背景下纹状体快速尖峰中间神经元生理学的第一个解释（Kotaleski et al., 2005）。 (C) 我们还有几个正在进行的项目，其中结合了新技术来改善大脑功能的成像。例如，在最近与功能成像部门的合作中，我们首次展示了使用 MRI 技术直接测量神经元活动的能力。这些实验为克服 MRI 技术目前的局限性铺平了道路，该技术依赖于通过耗氧量间接测量神经元活动。报告这些发现的论文现已被 PNAS 接受（Petridou 等，2006）。 我们还与 Pajevic 博士 (DCB/MSCL/OC) 持续合作，开发新的数学工具来分析大型神经元网络（例如皮层）的活动。 最后，我们开始与 Peter Basser 博士的团队合作，使用我们的细胞培养模型来研究水分子通量与神经元活动的关系。