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Neurobiol Learn Mem. 2019 May;161:1-11. doi: 10.1016/j.nlm.2019.02.009. Epub 2019 Feb 22.

DREADD-mediated modulation of locus coeruleus inputs to mPFC improves strategy set-shifting.

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Department of Psychiatry, University of California San Diego, 9500 Gilman Dr. MC 0804, La Jolla, CA 92093-0804, United States.
Department of Biology, University of Massachusetts, 611 North Pleasant St, Amherst, MA 01003, United States.
Department of Psychology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2136 West Mall, Vancouver, BC V6T 1Z4, Canada.
Brain Health Institute, Rutgers University/Rutgers Biomedical and Health Sciences, 683 Hoes Lane West, Office 259A, Piscataway, NJ 08854, United States. Electronic address:


Appropriate modification of behavior in response to our dynamic environment is essential for adaptation and survival. This adaptability allows organisms to maximize the utility of behavior-related energy expenditure. Modern theories of locus coeruleus (LC) function implicate a pivotal role for the noradrenergic nucleus in mediating switches between focused behavior during periods of high utility (exploit) versus disengagement of behavior and exploration of other, more rewarding opportunities. Two modes of activity in LC neurons have been characterized as elements in an Adaptive Gain Theory (AGT) of LC function. In this theory, during periods of accurate and focused behavior, LC neurons exhibit task-related phasic bursts. However, as behavioral utility wanes, phasic activity is suppressed and baseline (tonic) impulse activity increases to facilitate exploration. Our experiments sought to exogenously induce an elevated pattern of activity in LC neurons and their medial prefrontal cortical (mPFC) targets to test the tenets of the AGT. This theory posits that tonic activation immediately following a rule change should increase exploration and thereby improve performance on a set-shifting task. Indeed, DREADD mediated stimulation of LC terminals within mPFC decreased trials to reach criterion. However, this effect resulted from improved application of the new rule once the original rule is jettisoned rather than earlier disengagement from the old, ineffective strategy. Such improvements were not seen with global manipulation of LC, consistent with the view that LC-mediated exploration involves specific sub-circuits targeting mPFC. These findings extend our understanding of the role of LC in PFC and flexible behavior.


Behavioral flexibility; DREADD; Intracerebral; Locus coeruleus; Microinjection; Prefrontal cortex; Set shifting

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