Identical sensory stimuli can be perceived or neglected, depending on the level of task engagement or brain states. What are the underlying neural processes that influence our awareness of the presence or absence of the same stimulus? The ascending neuromodulator norepinephrine (NE), arising mainly from a small brainstem nucleus locus coeruleus (LC), has been proposed to have a critical role in regulating multiple aspects of cognitive behavior, including perception, attention and decision-making. In this proposal, we hypothesize that the two distinct modes of LC activity (tonic vs. phasic) differentially modulate sensory perception. By combining multi-channel extracellular recording and optogenetic perturbation of LC activity, patch-clamp recording in the downstream brain region, and well-controlled behavior, we will assess how different patterns of LC activity modulate sensory processing and perceptual decisions. Capitalizing on a sensory detection task in mice, we will determine: 1) How does LC-NE activity influence perceptual behavior performance? 2) How are LC tonic and phasic activity related? 3) How does LC-NE activity modulate cortical sensory processing? The proposed research is innovative, in our opinion, because it allows us to record and perturb NE-releasing neurons in the LC simultaneously with monitoring the activity of their downstream neurons in the cortex during quantitative perceptual behavior. Combining dual-electrophysiological recordings in the LC and its downstream brain area, precise optogenetic manipulation, and well-controlled behavior, we expect to offer novel approaches to acquiring fundamental knowledge of LC-NE functions. The new techniques can be readily adapted to other brain circuits and their downstream targets, and thus are expected to contribute to a broader understanding of neuromodulation and brain functions. The knowledge gained is expected to provide mechanistic insights into neuromodulation of perceptual behavior and cognitive dysfunctions, potentially facilitating the development of new treatments for attention- and anxiety-related disorders.
The proposed research is relevant to public health and NIH's mission, because LC-NE is implicated in many neurological diseases, including attention- and anxiety-related disorders. Insights gained here is a pivotal first step toward explaining how LC-NE is involved in higher cognitive processes, potentially facilitating the studies of neurological disorders in non-human primates and humans.