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理化学研究所・脳科学総合研究センター Joshua Johansen 平成29年9月18日発表

Modular organization of the brainstem noradrenaline system coordinates opposing learning states

  • ◯Akira Uematsu, ◯Bao Zhen Tan, Edgar A. Ycu, Jessica Sulkes, Jenny Koivumaa, Felix Junyent, Eric J. Kremer, Ilana B. Witten, Karl Deisseroth and ◎Joshua P. Johansen
    (◯:筆頭著者名, ◎:代表著者名)

Nature Neuroscience 20(11) (2017)

The neuromodulator noradrenaline modulates both emotional responding and cognitive/behavioral flexibility Noradrenaline supply to the forebrain arises from a small collection of neurons in the brainstem locus coeruleus (LC), but it is unclear how this small population of cells coordinates these opposing functions. Using a comprehensive technical approach we found that distinct populations of LC-noradrenaline neurons innervate the amygdala and medial prefrontal cortex (mPFC). Amygdala projecting cells facilitate emotional fear learning, while mPFC projecting cells extinguished aversive emotional responses to promote flexible behaviors. LC neurons exhibited context dependent response properties, with moderate discrete activation of specific cell populations by fear or safety cues and strong, global recruitment by strong aversive stimuli. This was reflected in the activation patterns of projection defined cells as amygdala projecting LC neurons were more strongly activated during high fear states while mPFC projecting cells were preferentially engaged during extinction of fear responses. These results reveal a modular organization in the LC-noradrenaline system in which context dependent activation modes are coordinated with anatomically and functionally defined cell populations allowing for the adaptive tuning of emotional responding and behavioral flexibility.




Figure 1: LC neurons exhibit distinct response modes during fear learning and extinction. Top: Experimental design schematic. Bottom: Heat plot showing auditory evoked responses of all LC neurons (each neuron aligned vertically) recorded before fear conditioning ('Pre'), in 'Early' extinction where fear responses were high and 'Late' extinction where fear responses were reduced (grey bar and '0' denote auditory onset/duration). Neurons are aligned vertically according to response type before or during extinction (Fear ('Fear) and Extinction ('Ext') cells as well as those which were responsive before conditioning ('Pre') or did not respond during extinction ('NR')). Far right heat plot shows shock-evoked responses in the same neurons (orange bar and '0' denote shock onset/duration)


Figure 2: Functionally distinct populations of LC-noradrenaline neurons project to amygdala or mPFC. a: Different colored retrograde tracers were injected into infralimbic (IL) mPFC (green) or lateral/basal (LA/B) nucleus of amygdala (red). Coronal section of LC (TH stained in white) show distinct cell populations projecting to IL or mPFC. b: reconstruction of all retrogradely labeled cells in LC from one animal. c: Schematic showing approach to optogenetically inhibit mPFC or amygdala projecting LC neurons. Retrograde rabies virus was injected into either region which caused expression of archaerhodopsin (ArchT3.0) in projection define LC neurons. Optical fibers delivered light to inhibit each cell population. d: Optogenetic inhibition of amygdala projecting cells during the shock period of fear conditioning blocked fear memory formation (y-axis=% behavioral freezing during tone period). e: Inhibition of mPFC projecting cells during the tone period of fear extinction blocked extinction.


Figure 3: New model of LC-noradrenaline function in different behavioral/sensory contexts. Intense aversive states which occur during fear conditioning strongly activate most LC neurons and transmit a global arousal signal ('Global broadcast mode'). In more ambiguous conditions such as during moderate fear states early in extinction (middle) or during later extinction when fear responses become suppressed (right) distinct populations of LC neurons are activated more moderately ('Discrete coding mode'). Yellow highlights denote activated cells, line width/arrowhead size indicates strength of activation.

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