Locus coeruleus anchors a trisynaptic circuit controlling fear-induced suppression of feeding

Yang, Ben; Sanches-Padilla, Javier; Kondapalli, Jyothisri; Morison, Sage L.; Delpire, Eric; Awatramani, Rajeshwar; Surmeier, D. James

doi:10.1016/j.neuron.2020.12.023

Cited by 52 publications

(95 citation statements)

References 86 publications

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“…To the best of our knowledge, the slow LC-triggered membrane depolarizations described here are the sole exclusively noradrenergically mediated postsynaptic effects described so far. LC fibers release glutamate to generate fast glutamatergic currents in parabrachial nucleus 54 , with the release of NE remaining minor unless light pulses were applied repetitively at higher frequencies. We found instead that thalamic LC-fiber-elicited responses were relatively uniform in amplitude and time course over the 1 – 10 Hz frequency range.…”

Section: Discussionmentioning

confidence: 99%

“…To the best of our knowledge, the slow LC-triggered membrane depolarizations described here in the thalamus are the sole postsynaptic effects mediated exclusively by NE described so far. LC afferents to parabrachial nucleus release glutamate to generate fast glutamatergic currents, 61 and the release of NE remained minor unless fibers were stimulated at 20 Hz. Thalamic LC-fiber-elicited responses were present and relatively uniform in amplitude and time course over the 1 -10 Hz frequency range.…”

Section: The Cellular and Ionic Mechanisms Underlying Noradrenergic Control Of Sleep Spindle Clusteringmentioning

confidence: 99%

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Noradrenergic circuit control of non-REM sleep substates

Osorio-Forero

Cardis

Vantomme

et al. 2021

Preprint

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The continuity of non-rapid-eye-movement sleep (NREMS) is essential for its functions. However, many mammalian species, including humans, show NREMS fragility to maintain environmental vigilance. The neural substrates balancing NREMS continuity and fragility substates are unexplored. We show that the locus coeruleus (LC) is necessary and sufficient to generate infraslow (~50 s) continuity-fragility fluctuations in mouse NREMS. Through machine-learning-guided closed-loop optogenetic LC interrogation, we suppressed, locked, or entrained continuity-fragility fluctuations, as evident by LC-mediated regulation of sleep spindle clustering and heart rate variability. Noradrenergic modulation of thalamic but not cortical circuits was required for infraslow sleep spindle clustering and involved rapid noradrenaline increases that activated both α1- and β-adrenergic receptors to cause slowly decaying membrane depolarizations. The LC thus coordinates brain and bodily states during NREMS to engender continuity-fragility, accentuating its role in the physiology of sleep-related sensory uncoupling and as target in sleep disorders showing abnormal cortical and/or autonomic arousability.

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Section: Discussionmentioning

confidence: 99%

Section: The Cellular and Ionic Mechanisms Underlying Noradrenergic Control Of Sleep Spindle Clusteringmentioning

confidence: 99%

Noradrenergic circuit control of non-REM sleep substates

Osorio-Forero

Cardis

Vantomme

et al. 2021

Preprint

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“…We thus speculate that altered noradrenergic transmission in LC projection regions and LC terminals due to LC degeneration could affect psychiatric symptomatology in prodromal DLB with predominant non-motoric features (Figure 1 for an overview of noradrenergic LC function in relation to neurodegeneration due to DLB). Many animal studies employing diverse methodologies proved that anxiety is dependent on the noradrenergic LCamygdala (McCall et al, 2015(McCall et al, , 2017Llorca-Torralba et al, 2019), the LC-parabrachial nucleus (PBN) (Yang et al, 2021) and the orexinergic LC-thalamus circuits (Heydendael et al, 2014). In addition, the damage to noradrenergic LC cells resulted in increased anxiety in addition to defective social capacities (Song et al, 2019) as well as depressive behavior (Itoi et al, 2011) in rodents.…”

Section: Noradrenergic Mechanisms Inducing Psychiatric Symptoms In Prmentioning

confidence: 99%

Locus Coeruleus Malfunction Is Linked to Psychopathology in Prodromal Dementia With Lewy Bodies

Hansen

2021

Front. Aging Neurosci.

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Background: The locus coeruleus (LC) is a nucleus in the human brainstem with a variety of noradrenaline-driven functions involved in cognition, emotions, and perception. Dementia with Lewy bodies (DLB) constitutes a neurodegenerative disease involving deposits of alpha-synuclein, first appearing in the brainstem. The goal of this narrative review is to delineate the relationship between the expression of psychiatric symptoms as an early-onset of DLB and the degeneration of the LC's noradrenaline system.Methods: We searched in PubMed for relevant articles concerning LC degeneration and psychiatric symptoms in prodromal DLB in this narrative review. We rely on the McKeith criteria for prodromal psychiatric DLB.Results: We found four studies that document neuronal loss, deposits of Lewy bodies and other hints for neurodegeneration in the LC in patients with DLB. Furthermore, we reviewed theories and studies on how the degenerated noradrenaline LC system contributes to psychiatric DLB's phenotype. We hypothesized how anxiety, hallucinations, delusions, and depressive symptoms might occur in DLB patients due to degenerated noradrenergic neurons entailing consecutive altered noradrenergic transmission in the LC's projection areas.Conclusions: LC degeneration in prodromal DLB might cause psychiatric symptoms as the first and non-motor manifestation of DLB, as the LC is affected earlier by degeneration than are dopaminergic structures such as the substantia nigra, which are impaired later in the disease course.

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“…The copyright holder for this preprint this version posted October 19, 2021. ; https://doi.org/10.1101/2021.10.18.464861 doi: bioRxiv preprint contrast to LPB, MPB is reported to directly project to cortical regions without having thalamus as relay: in our results we observe both "direct" functional connectivity with the anterior insular cortex, cingulate and infralimbic cortex, and strong connectivity with the thalamus, maybe mediated by descending cortico-thalamic pathways. Expected connectivity with amygdala was present but weak, while the functional connectivity to LC was strong [Yang et al, 2021]. The connectivity to medullary reticular formation nuclei (iMRt and sMRt) and VSM was bilateral, and in line with the presence of afferents from the rostral gustatory division of the solitary nucleus (included in VSM) [Olszewski and Baxter, 2014].…”

Section: Comparison Of Connectome Links With Existing Literaturementioning

confidence: 99%

Functional connectome of brainstem nuclei involved in autonomic, limbic, pain and sensory processing in living humans from 7 Tesla resting state fMRI

Singh

Stauder

García‐Gomar

et al. 2021

Preprint

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Despite remarkable advances in mapping the functional connectivity of the cortex, the functional connectivity of subcortical regions is understudied in living humans. This is the case for brainstem nuclei that control vital processes, such as autonomic, limbic, nociceptive and sensory functions. This is because of the lack of precise brainstem nuclei localization, of adequate sensitivity and resolution in the deepest brain regions, as well as of optimized processing for the brainstem. To close the gap between the cortex and the brainstem, on 20 healthy subjects, we computed a correlation based functional connectome of 15 brainstem nuclei involved in autonomic, limbic, nociceptive, and sensory function (superior and inferior colliculi, ventral tegmental area parabrachial pigmented nucleus complex, microcellular tegmental nucleus prabigeminal nucleus complex, lateral and medial parabrachial nuclei, vestibular and superior olivary complex, superior and inferior medullary reticular formation, viscerosensory motor nucleus, raphe magnus, pallidus, and obscurus, and parvicellular reticular nucleus alpha part) with the rest of the brain. Specifically, we exploited 1.1mm isotropic resolution 7 Tesla resting state fMRI, ad hoc coregistration and physiological noise correction strategies, and a recently developed probabilistic template of brainstem nuclei. Further, we used 2.5mm isotropic resolution resting state fMRI data acquired on a 3 Tesla scanner to assess the translatability of our results to conventional datasets. We report highly consistent correlation coefficients across subjects, confirming available literature on autonomic, limbic, nociceptive and sensory pathways, as well as high interconnectivity within the central autonomic network and the vestibular network. Interestingly, our results showed evidence of vestibulo autonomic interactions in line with previous work. Comparison of 7 Tesla and 3 Tesla findings showed high translatability of results to conventional settings for brainstem cortical connectivity and good yet weaker translatability for brainstem brainstem connectivity. The brainstem functional connectome might bring new insight in the understanding of autonomic, limbic, nociceptive and sensory function in health and disease.

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Locus coeruleus anchors a trisynaptic circuit controlling fear-induced suppression of feeding

Cited by 52 publications

References 86 publications

Noradrenergic circuit control of non-REM sleep substates

Noradrenergic circuit control of non-REM sleep substates

Locus Coeruleus Malfunction Is Linked to Psychopathology in Prodromal Dementia With Lewy Bodies

Functional connectome of brainstem nuclei involved in autonomic, limbic, pain and sensory processing in living humans from 7 Tesla resting state fMRI

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