Adrenergic transmission properties and implication

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PROJECT SUMMARY Norepinephrine (NE) and epinephrine (Epi) have been implicated in complex cognitive functions, such as sensory processing, sleep-wake/arousal state transition and attention, in the brain, and other biological processes in various tissues and organs, including the heart, pancreas and spleen. Dysregulation of adrenergic transmission is linked to a number of neurological diseases, including Alzheimer’s disease, depressive disorders and schizophrenia, as well as many other health problems, including cardiovascular diseases, immune-deficiency and tumorigenesis. Despite the potential involvement of NE/Epi in myriad physiological and pathological conditions, the precise regulation and exact functional role of adrenergic transmission remain poorly defined, due primarily to limitations of available tools for monitoring NE/Epi. We have recently developed a family of intensity-based G-protein-coupled receptor (GPCR) activation-based genetically encoded NE (GRABNE) sensors by coupling a circular permutated green fluorescent protein (cpGFP) with a human adrenergic receptor. While these GRABNE sensors allowed the first visualization of adrenergic transmission, the sensors were suboptimal in determining synaptic properties of adrenergic transmission. To facilitate NE/Epi research, we recently engineered high-performance GRABNE sensors that allowed high-sensitivity and high-resolution visualization of adrenergic transmission events at single release sites. The new sensors and preliminary data build up our confidence to test the hypothesis that high-performance GRABNE sensors may resolve the adrenergic transmission properties that could deduce the adrenergic functional role. This application follows two specific aims: Aim 1 is to determine whether high-performance GRABNE sensors may resolve adrenergic transmission properties, and Aim 2 is to test whether adrenergic transmission plays an essential role in the precision- and attention-demanding behaviors. We expect the proposed experiments to characterize the first set of fundamental synaptic properties of a new form of neuronal transmission and define a novel, unique functional role for adrenergic transmission.