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.