Cholinergic modulation of cortical visual processing

描述(由申请人提供)：拟议的研究结合了分子、细胞和网络尺度的建模，以解决潜在的基本行为状态的机制：注意力。自愿注意对于感官引导的行为和记忆的形成是必不可少的。神经递质乙酰胆碱(ACh)被认为是大脑皮层注意调节的重要贡献者。该项目旨在了解大脑皮层时空弥散的ACh系统如何实现注意等行为任务所要求的时空特异性。这项研究概述的研究将广泛地旨在检验这样一个假设，即胆碱能系统通过协调其分子成分(酶、受体、转运体)的表达和定位而实现所需的时空精确度，而不是通过与FAST精确连接的传统方法 突触传递。指导阶段将涉及检查大脑皮层胆碱能系统的解剖组织如何塑造其传输的时空分布。目前的胆碱能传递模型已经隐含地被ACh机制的知识所指导，尤其是神经肌肉接头的酶作用。反应-扩散系统的分子水平模型将被用来测试皮层细胞外空间中的可用酶如何塑造从非突触位置释放的ACh的时间分布。该项目旨在为大脑皮层超微结构中胆碱能系统的空间组织产生预测。受候选人先前工作的启发，指导ACh受体亚细胞结构域调节作用的计算原理将在独立阶段进行研究。候选人将使用树突、离子通道和神经递质受体的生物物理模型进行这些研究。在指导和早期独立阶段取得的进展将导致对网络动力学的胆碱能调节机制的研究。详细的生物物理和现象学网络模型将被用来探索这一假设，即已知的细胞类型特异性和初级视皮层AChR表达的亚细胞模式是网络振荡的注意调制的基础。为了实现这些目标，应聘者需要进一步的培训，特别是高级分子建模技术以及视觉和分子神经生物学的理论基础。指导实验室和本研究所是实现这些目标的理想培训环境。这位候选人的导师是世界神经生物学计算研究的先驱之一。该研究所的神经生物学部门非常重视视觉研究。候选人的主要合作者是视觉皮质胆碱能系统的领先专家之一。在这种令人兴奋的环境中度过一小段时间后，候选人希望准备好开始独立的研究生涯，并将在神经科学领域寻求终身教职。

DESCRIPTION (provided by applicant): The proposed research combines modeling at molecular, cellular and network scales to address the mechanisms underlying a fundamental behavioral state: attention. Voluntary attention is essential for sensory- guided behavior and memory formation. The neurotransmitter Acetylcholine (ACh) is considered an important contributor to attentional modulation in the cortex. This project aims to understand how the spatio- temporally diffuse ACh system in the cortex achieves spatial and temporal specificity demanded by behavioral tasks such as attention. The studies outlined in this research will broadly aim to test the hypothesis that the cholinergic system achieves the required spatio-temporal precision by coordinating the expression and localization of its molecular components (enzymes, receptors, transporters) rather than the 'classical' approach of precise wiring with fast synaptic transmission. The mentored phase will involve examining how the anatomical organization of the cholinergic system in the cortex shapes the spatio-temporal profile of its transmission. Current models of cholinergic transmission have been implicitly guided by the knowledge of ACh machinery, especially that of enzymatic action, at the neuromuscular junction. Molecular-level models of reaction-diffusion systems will be used to test how the available enzymes in the cortical extracellular space shape the temporal profile of ACh released from non-synaptic sites. The project will aim to generate predictions for the spatial organization of the cholinergic system in the cortical ultra-structure. Inspired by previous work by the candidate, the computational principles guiding the modulatory role of sub-cellular domains of ACh receptors will be investigated in the independent phase. The candidate will use biophysical models of dendrites, ion channels and neurotransmitter receptors for these investigations. The progress made in the mentored and early independent phase will lead to investigation of the mechanisms of cholinergic modulation of network dynamics. Detailed biophysical and phenomenological network models will be used to explore the hypothesis that the known cell-type specificity and sub-cellular patterns of AChR expression in the primary visual cortex underlie the attention-modulation of network oscillations. To achieve these aims the candidate needs further training, specifically in advanced molecular modeling techniques and theoretical foundations of visual and molecular neurobiology. The mentoring lab and the present institute is the ideal training environment for the achievement of these goals. The candidate's mentor is one of the world's pioneers in the computational investigation of neurobiology. The neurobiology division at the institute has a strong focus on vision research. The candidate's main collaborator is one of the leading experts in the cholinergic system in the visual cortex. After a short period n this exciting environment, the candidate expects to be ready to embark upon an independent research career and will seek a tenure-track position in Neuroscience.