2019 — 2021 |
Yang, Hongdian |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Locus Coeruleus-Norepinephrine Modulation of Sensory Response and Tactile Perception @ University of California Riverside
The locus coeruleus-norepinephrine (LC-NE) system has been proposed to have a critical role in regulating cognitive behavior, including arousal, perception, and decision making. However, we have limited understanding of how LC-NE modulates even simple aspects of sensory processing during perceptual behavior. Therefore, determining the fundamental neurobiology of LC-NE during quantitative perceptual behavior is a crucial first step toward understanding its role in modulating higher cognitive functions and neurological disorders. Uniquely, we have overcome several key technical limitations which have impeded fundamental mechanistic understanding of LC-NE functions. These limitations include the inability to record from chemically-defined LC- NE neurons during behavior, and the difficulty of quantifying their modulatory effects on target neurons. This proposal will test the central hypothesis that LC-NE differentially modulates cortical excitatory and inhibitory responses to facilitate sensory perception. We will determine: How does LC-NE influence behavioral outcomes? How does LC-NE modulate neuronal activity in the primary somatosensory cortex? The proposed research is innovative, in our opinion, because it allows recording and perturbing chemically-defined LC-NE neurons while simultaneously monitoring their target neurons in the cortex, during a quantitative perceptual task. This approach represents a substantive departure from the status quo. Combining dual-electrophysiological recordings, optogenetic gain-/loss-of-function, and well-controlled behavior, this novel approach allows investigating previously inaccessible mechanisms of LC-NE modulation in awake behaving mice. The research is significant because it is expected to fundamentally advance our understanding of LC-NE functions by establishing mechanistic links between LC-NE modulation of cortical sensory response and its modulation of perceptual decisions. The new techniques can be adapted to other neuromodulatory systems, and are expected to contribute to a broader understanding of brain functions. The results and new methods have the potential to help better understand LC-NE functions in higher cognitive processes, and to facilitate the development of therapeutic methods to treat neurological disorders.
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2019 — 2020 |
Yang, Hongdian |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Noradrenergic Modulation of Sensory Perception @ University of California Riverside
ABSTRACT 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.
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