Redefining Noradrenergic Neuromodulation of Behavior: Impacts of a Modular Locus Coeruleus Architecture

Chandler, Daniel J.; Jensen, Patricia; McCall, Jordan G.; Pickering, Anthony E.; Schwarz, Lindsay A.; Totah, NK

doi:10.1523/jneurosci.1164-19.2019

Cited by 163 publications

(151 citation statements)

References 134 publications

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“…Our optogenetic experiments targeted LC cell bodies, and future studies are needed to determine the roles of NE (and dopamine) release at specific projection targets. While LC has been typically regarded as a relatively homogeneous nucleus, some recent studies challenge this view and suggest that LC subpopulations have distinct projections that serve different functions (31). Downstream effects of LC on SEAs could be mediated through direct cortical projections, where -adrenergic receptors mediate cortical desynchronization (32).…”

Section: Mechanisms Controlling Sensory-evoked Awakeningmentioning

confidence: 99%

Locus coeruleus norepinephrine activity mediates sensory-evoked awakenings from sleep

et al. 2020

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A defining feature of sleep is reduced responsiveness to external stimuli, but the mechanisms mediating sensory-evoked arousal remain unclear. We hypothesized that reduced locus coeruleus (LC) norepinephrine (NE) activity during sleep mediates unresponsiveness, and its action promotes sensory-evoked awakenings. We tested this using electrophysiological, behavioral, pharmacological, and optogenetic techniques alongside auditory stimulation in freely behaving rats. We found that systemic reduction in NE signaling lowered probability of sound-evoked awakenings (SEAs). The level of tonic LC activity during sleep anticipated SEAs. Optogenetic LC activation promoted arousal as evident in sleep-wake transitions, EEG desynchronization, and pupil dilation. Minimal LC excitation before sound presentation increased SEA probability. Optogenetic LC silencing using a soma-targeted anion-conducting channelrhodopsin (stGtACR2) suppressed LC spiking and constricted pupils. Brief periods of LC opto-silencing reduced the probability of SEAs. Thus, LC-NE activity determines the likelihood of sensory-evoked awakenings, and its reduction during sleep constitutes a key factor mediating behavioral unresponsiveness.

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Section: Mechanisms Controlling Sensory-evoked Awakeningmentioning

confidence: 99%

Locus coeruleus norepinephrine activity mediates sensory-evoked awakenings from sleep

et al. 2020

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“…The present experiments reveal aversive valence at 25-Hz, but not 10-Hz tonic activation, in rats, and, for the first time, questions for future investigations. The physiological mechanisms illuminated in these experiments will need to be integrated with the recent structural evidence of greater specificity of LC subpopulation targeting than previously suspected (23,25). The interaction of these more selective physiological and structural features of LC modulation of brain networks promises a broad array of insights to come with novel functional implications for both basic and clinical brain science.…”

Section: Discussionmentioning

confidence: 99%

“…The brains were extracted and kept in 4% paraformaldehyde. Brains were then sectioned in a vibratome (Leica VT 1000P; Leica Biosystems, Ontario, Canada) in 50 µm 23 thick coronal slices and saved in polyvinylpyrrolidone solution. For immunohistochemistry with Npas4 and DBH, slices were washed in PBS, and then incubated with primary antibodies.…”

Section: Immunohistochemistry and Histologymentioning

confidence: 99%

Locus coeruleus patterns differentially modulate learning and valence in ratviathe ventral tegmental area and basolateral amygdala respectively

Ghosh

Massaeli

Power

et al. 2020

Preprint

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The locus coeruleus (LC), the main source of forebrain norepinephrine, produces phasic and tonic firing patterns that are theorized to have distinct functional consequences. However, how different firing modes affect learning and valence coding of sensory information are unknown. Here bilateral optogenetic activation of rat LC neurons using 10-Hz phasic trains of either 300 msec or 10 sec accelerates acquisition of a food-rewarded similar odor discrimination, but not a dissimilar odor discrimination, consistent with LC-supported enhanced pattern separation and plasticity. Similar odor discrimination learning is impaired by noradrenergic blockade in the piriform cortex (PC). However, here 10-Hz LC phasic light-mediated learning facilitation is prevented by a dopaminergic antagonist in the PC, or by ventral tegmental area (VTA) silencing with lidocaine, suggesting an LC-VTA-PC dopamine circuitry mediates 10-Hz phasic learning facilitation. Tonic stimulation at 10 Hz did not alter odor discrimination acquisition, and was less effective in activating VTA DA neurons. For valence encoding, tonic stimulation at 25 Hz induced freezing, anxiety and conditioned odor aversion, while 10-Hz phasic stimulation produced an odor preference consistent with positive valence. Noradrenergic blockade in the basolateral amygdala (BLA) prevented conditioned odor preference and aversion induced by 10-Hz phasic and 25-Hz tonic light respectively. CTB retro-labeling showed relatively larger engagement of nucleus accumbens projecting neurons over central amygdala projecting neurons in the BLA with 10-Hz LC phasic activation, compared to 25-Hz tonic. These outcomes argue that LC pauses, as well as LC firing frequencies, differentially influence both target networks and behaviour.

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“…Taken together, these results suggest that pupil signal may be related to a functionalspecific portion of LC in humans. This possibility is worth exploring in future studies since functional specialization within LC has been suggested by recent animal studies (for a review see Chandler et al 2019).…”

Section: Lc Pupil Maskmentioning

confidence: 97%

Uncovering the locus coeruleus: comparison of localization methods for functional analysis

Maeki-Marttunen

Espeseth

2020

Preprint

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Functional neuroimaging of small brainstem structures in humans is gaining increasing interest due to their potential importance in aging and many clinical conditions. Researchers have used different methods to measure activity in the locus coeruleus (LC), the main noradrenergic nucleus in the brain. However, the reliability of the different methods for identifying this small structure is unclear. In the present article, we compared four different approaches to estimate localization of the LC in a large sample (N = 98): 1) a probabilistic map from a previous study, 2) masks segmented from neuromelanin-sensitive scans, 3) components from a masked-independent components analysis of the functional data, and 4) a mask from pupil regression of the functional data. The four methods have been used in the community and find some support as reliable ways of assessing the localization of LC in vivo in humans by using functional imaging. We report several measures of similarity between the LC masks obtained from the different methods. In addition, we compare the similarity between functional connectivity maps obtained from the different masks. We conclude that sample-specific masks appear more suitable than masks from a different sample, that masks based on structural versus functional methods may capture different portions of LC, and that, at the group level, the creation of a "consensus" mask using more than one approach may give a better estimate of LC localization. KeywordsLocus coeruleus, brainstem, MRI, neuromelanin, functional connectivity Figure 1. Illustration of approaches for LC localization. Group approaches emphasize voxels of highest probability of containing LC at the group level. Individual approaches focus on identifying LC-containing voxels in the individual brainstem.A recent systematic review of imaging studies of LC (Liu et al., 2017) highlights the large variety in the methods used to identify the region that more closely corresponds to the LC. A majority of the reviewed studies used coordinates or masks

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Redefining Noradrenergic Neuromodulation of Behavior: Impacts of a Modular Locus Coeruleus Architecture

Cited by 163 publications

References 134 publications

Locus coeruleus norepinephrine activity mediates sensory-evoked awakenings from sleep

Locus coeruleus norepinephrine activity mediates sensory-evoked awakenings from sleep

Locus coeruleus patterns differentially modulate learning and valence in ratviathe ventral tegmental area and basolateral amygdala respectively

Uncovering the locus coeruleus: comparison of localization methods for functional analysis

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