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

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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.