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

层层总结：对认知行为的灵活控制是一种更高级的大脑功能，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连接的大脑区域产生的，大脑皮层的前额叶区域充当枢纽。在过去的十年里，我们和其他人已经确定了神经递质受体以及神经亚型的电生理和神经化学特性，这些特性有助于认知灵活性；然而，负责这种认知控制系统的单个脑区的确切功能和分子机制尚不清楚。在这项拟议的研究中，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背后的神经生物学机制。特别是，我们的目标是全面分析前额叶皮质神经元中介导认知灵活性的分子级联，以及丘脑核团对微调这一控制功能的关键影响。我们将使用最先进的技术，包括(1)使用病毒将设计好的受体直接运送到成年大鼠的大脑区域，以抑制特定脑区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(如学习和记忆形成)的磷酸化蛋白质的细胞内定位；以及(3)使用一系列计算机控制的行为分析和数据收集系统。我们的结果将首次揭示认知行为灵活控制背后的精确分子机制；认知行为是一种核心大脑功能，可能会随着年龄的增长而中断。因此，所提出的研究将对建立正常认知功能模型有很大的帮助。总体而言，预计我们提议的研究将提供一个令人兴奋的研究平台，培训2名博士生、5-6名本科生和研究技术人员掌握一些神经生物学的尖端技术。***********

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. ***********