Neurobiological Mechanisms Underlying Behavioural Flexibility: From Molecular Signalling to Brain Circuits

摘要：对认知行为的灵活控制是一种高阶大脑功能，负责实现日常生活中的目标。这种灵活的控制是由许多相互联系的大脑区域产生的，大脑皮层的前额叶区域起着中枢的作用。在过去的十年中，我们和其他人已经确定了神经递质受体以及有助于认知灵活性的神经元亚型的电生理和神经化学特性；然而，个体大脑区域的确切功能和负责这种认知控制系统的分子机制尚不清楚。在本研究中，我们将进一步研究这种负责控制我们认知功能的灵活控制系统的神经生物学机制。特别是，我们的目标是全面分析介导认知灵活性的前额皮质神经元中的分子级联，以及丘脑核对微调这种控制功能所施加的关键影响。我们将采用最先进的技术，包括(1)使用病毒将设计受体直接传递到成年大鼠的大脑区域，以抑制给定大脑区域特定神经元群体的功能；(2)使用高分辨率显微镜分析控制精确神经元功能（例如，学习和记忆形成）的磷酸化蛋白的细胞内定位；(3)使用一系列计算机控制的行为分析和数据收集系统。我们的研究结果将首次揭示认知行为灵活控制背后的精确分子机制；随着年龄的增长，大脑的核心功能可能会被破坏。因此，所提出的研究将极大地帮助建模正常的认知功能。总体而言，预计我们提出的研究将提供一个令人兴奋的研究平台，培养2名博士生，5-6名本科生和研究技术人员在神经生物学的一些前沿技术。***********

LAY SUMMARY: Flexible control of cognitive behavior is a higher-order brain function, and is responsible for achieving goals in daily life. This flexible control is produced by a number of interconnected brain areas, with the prefrontal region of the cerebral cortex acting as a hub. Over the past decade, we and others have identified the neurotransmitter-receptors as well as electrophysiological and neurochemical properties of neuronal subtypes that contribute to cognitive flexibility; however, the precise function of individual brain areas and molecular mechanisms responsible this cognitive control system are not clear. In the proposed study, we will further investigate the neurobiological mechanisms underlying this flexible control system responsible for controlling our cognitive function. In particular, we aim to comprehensively analyze the molecular cascades in prefrontal cortical neurons that mediate cognitive flexibility, and the critical influence exerted by a nucleus of the thalamus to fine tune this control function. We will employ state-of-the-art techniques, including (1) using viruses to deliver designer receptors directly into brain areas of adult rats to suppress functions of specific populations of neurons in given brain areas, (2) using high-resolution microscopy to analyze the intracellular localization of phosphorylated proteins that control precise neuronal functions (e.g., learning and formation of memory), and (3) using an array of computer-controlled behavioral analyses and data collection systems. Our results, for the first time, will uncover the precise molecular mechanisms underlying the flexible control of cognitive behaviour; a core brain function which can be disrupted with old age. Thus, the proposed research will help tremendously in modeling normal cognitive function. Overall, it is expected that our proposed studies will provide an exciting research platform to train 2 PhD students, 5-6 undergraduate students and research technicians in a number of cutting-edge techniques in neurobiology. ***********