scholarly journals Infraslow locus coeruleus activity coordinates spindle rhythms and heart rate to gate fluctuating non-REM sleep substates

2021 ◽  
Author(s):  
Alejandro Osorio-Forero ◽  
Romain Cardis ◽  
Gil Vantomme ◽  
Aurélie Guillaume-Gentil ◽  
Georgia Katsioudi ◽  
...  
Keyword(s):  
Heart Rate ◽  
Locus Coeruleus ◽  
Mammalian Species ◽  
Neural Substrates ◽  
Sleep Spindle ◽  
Cortical Circuits ◽  
Necessary And Sufficient ◽  
Bodily States ◽  
Β Adrenergic Receptors ◽  
Noradrenergic Modulation

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.

scholarly journals Locus coeruleus to basolateral amygdala noradrenergic projections promote anxiety-like behavior

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Jordan G McCall ◽  
Edward R Siuda ◽  
Dionnet L Bhatti ◽  
Lamley A Lawson ◽  
Zoe A McElligott ◽  
...  
Keyword(s):  
Locus Coeruleus ◽  
Adrenergic Receptors ◽  
Basolateral Amygdala ◽  
Neural Substrates ◽  
Fast Scan Cyclic Voltammetry ◽  
Efferent System ◽  
Aversive Behavior ◽  
And Behavior ◽  
Β Adrenergic Receptors

Increased tonic activity of locus coeruleus noradrenergic (LC-NE) neurons induces anxiety-like and aversive behavior. While some information is known about the afferent circuitry that endogenously drives this neural activity and behavior, the downstream receptors and anatomical projections that mediate these acute risk aversive behavioral states via the LC-NE system remain unresolved. Here we use a combination of retrograde tracing, fast-scan cyclic voltammetry, electrophysiology, and in vivo optogenetics with localized pharmacology to identify neural substrates downstream of increased tonic LC-NE activity in mice. We demonstrate that photostimulation of LC-NE fibers in the BLA evokes norepinephrine release in the basolateral amygdala (BLA), alters BLA neuronal activity, conditions aversion, and increases anxiety-like behavior. Additionally, we report that β-adrenergic receptors mediate the anxiety-like phenotype of increased NE release in the BLA. These studies begin to illustrate how the complex efferent system of the LC-NE system selectively mediates behavior through distinct receptor and projection-selective mechanisms.

Loss of M2 muscarinic receptor function inhibits development of hypoxic bradycardia and alters cardiac β-adrenergic sensitivity in larval zebrafish (Danio rerio)

2009 ◽  
Vol 297 (2) ◽  
pp. R412-R420 ◽  
Author(s):  
Shelby L. Steele ◽  
Kwok Hong Andy Lo ◽  
Vincent Wai Tsun Li ◽  
Shuk Han Cheng ◽  
Marc Ekker ◽  
...  
Keyword(s):  
Heart Rate ◽  
Muscarinic Receptor ◽  
Danio Rerio ◽  
Antisense Oligonucleotides ◽  
Adrenergic Receptor ◽  
Larval Zebrafish ◽  
M2 Muscarinic Receptor ◽  
Β Adrenergic Receptors ◽  
Relative Mrna Expression

Fish exposed to hypoxia develop decreased heart rate, or bradycardia, the physiological significance of which remains unknown. The general muscarinic receptor antagonist atropine abolishes the development of this hypoxic bradycardia, suggesting the involvement of muscarinic receptors. In this study, we tested the hypothesis that the hypoxic bradycardia is mediated specifically by stimulation of the M2 muscarinic receptor, the most abundant subtype in the vertebrate heart. Zebrafish ( Danio rerio) were reared at two levels of hypoxia (30 and 40 Torr Po2) from the point of fertilization. In hypoxic fish, the heart rate was significantly lower than in normoxic controls from 2 to 10 days postfertilization (dpf). At the more severe level of hypoxia (30 Torr Po2), there were significant increases in the relative mRNA expression of M 2 and the cardiac type β-adrenergic receptors ( β1AR, β2aAR, and β2bAR) at 4 dpf. The hypoxic bradycardia was abolished (at 40 Torr Po2) or significantly attenuated (at 30 Torr Po2) in larvae experiencing M2 receptor knockdown (using morpholino antisense oligonucleotides). Sham-injected larvae exhibited typical hypoxic bradycardia in both hypoxic regimens. The expression of β1AR, β2aAR, β2bAR, and M 2 mRNA was altered at various stages between 1 and 4 dpf in larvae experiencing M2 receptor knockdown. Interestingly, M2 receptor knockdown revealed a cardioinhibitory role for the β2-adrenergic receptor. This is the first study to demonstrate a specific role of the M2 muscarinic receptor in the initiation of hypoxic bradycardia in fish.

scholarly journals Locus coeruleus integrity in old age is selectively related to memories linked with salient negative events

2018 ◽  
Vol 115 (9) ◽  
pp. 2228-2233 ◽  
Author(s):  
Dorothea Hämmerer ◽  
Martina F. Callaghan ◽  
Alexandra Hopkins ◽  
Julian Kosciessa ◽  
Matthew Betts ◽  
...  
Keyword(s):  
Older Adults ◽  
Locus Coeruleus ◽  
Structural Integrity ◽  
Memory Task ◽  
Negative Events ◽  
Older Individuals ◽  
Healthy Older Adults ◽  
Aversive Events ◽  
Strong Motivation ◽  
Noradrenergic Modulation

The locus coeruleus (LC) is the principal origin of noradrenaline in the brain. LC integrity varies considerably across healthy older individuals, and is suggested to contribute to altered cognitive functions in aging. Here we test this hypothesis using an incidental memory task that is known to be susceptible to noradrenergic modulation. We used MRI neuromelanin (NM) imaging to assess LC structural integrity and pupillometry as a putative index of LC activation in both younger and older adults. We show that older adults with reduced structural LC integrity show poorer subsequent memory. This effect is more pronounced for emotionally negative events, in accord with a greater role for noradrenergic modulation in encoding salient or aversive events. In addition, we found that salient stimuli led to greater pupil diameters, consistent with increased LC activation during the encoding of such events. Our study presents novel evidence that a decrement in noradrenergic modulation impacts on specific components of cognition in healthy older adults. The findings provide a strong motivation for further investigation of the effects of altered LC integrity in pathological aging.

Heart rate changes mediate the embryotoxic effect of antiarrhythmic drugs in the chick embryo

2013 ◽  
Vol 304 (6) ◽  
pp. H895-H902 ◽  
Author(s):  
Radka Kockova ◽  
Jarmila Svatunkova ◽  
Jiri Novotny ◽  
Lucie Hejnova ◽  
Bohuslav Ostadal ◽  
...  
Keyword(s):  
Adverse Effect ◽  
Heart Rate ◽  
Cardiac Output ◽  
Adrenergic Receptors ◽  
Developmental Toxicity ◽  
Premature Death ◽  
Chick Embryos ◽  
In Ovo ◽  
Drug Induced ◽  
Β Adrenergic Receptors

A significant increase in cardiovascular medication use during pregnancy occurred in recent years. Only limited evidence on safety profiles is available, and little is known about the mechanisms of adverse effect on the fetus. We hypothesized that drug-induced bradycardia is the leading mechanism of developmental toxicity. Embryotoxicity was tested in ovo after administration of various doses of metoprolol, carvedilol, or ivabradine. Embryonic day (ED) 4 and 8 chick embryos were studied by video microscopy and ultrasound biomicroscopy ex ovo after intraamniotic injection of the drug for a period of 30 min. Stroke volume was calculated by the Simpson method and prolate ellipsoid formula. Significant dose-dependent mortality was achieved in embryos injected with carvedilol and ivabradine. In ED4 embryos, metoprolol, carvedilol, and ivabradine reduced the heart rate by 33%, 27%, and 55%, respectively, compared with controls (6%). In ED8 embryos this effect was more pronounced with a heart rate reduction by 71%, 54%, and 53%, respectively (controls, 36%). Cardiac output decreased in all tested groups but only proved significant in the metoprolol group in ED8 embryos. The number of β-adrenergic receptors showed a downward tendency during embryonic development. A negative chronotropic effect of metoprolol, carvedilol, and ivabradine was increasingly pronounced with embryonic maturity despite a downward trend in the number of β-adrenergic receptors. This effect was associated with reduced cardiac output in chick embryos, probably leading to premature death. Although standard doses of these drugs appear relatively safe, high doses have a potentially adverse effect on the fetus through reduced heart rate.

Noradrenergic modulation of midbrain dopamine cell firing elicited by stimulation of the locus coeruleus in the rat

1993 ◽  
Vol 93 (1) ◽  
pp. 11-25 ◽  
Author(s):  
J. Grenhoff ◽  
M. Nisell ◽  
S. Ferr� ◽  
G. Aston-Jones ◽  
T. H. Svensson
Keyword(s):  
Locus Coeruleus ◽  
Cell Firing ◽  
Midbrain Dopamine ◽  
Noradrenergic Modulation ◽  
Dopamine Cell ◽  
Stimulation Of

scholarly journals Different functions for homologous serotonergic interneurons and serotonin in species-specific rhythmic behaviours

2008 ◽  
Vol 276 (1654) ◽  
pp. 99-108 ◽  
Author(s):  
James M Newcomb ◽  
Paul S Katz
Keyword(s):  
Related Species ◽  
Motor Pattern ◽  
Neural Substrates ◽  
Pattern Generator ◽  
Closely Related Species ◽  
Serotonin Antagonist ◽  
Tritonia Diomedea ◽  
Specific Behaviour ◽  
Species Specific ◽  
Necessary And Sufficient

Closely related species can exhibit different behaviours despite homologous neural substrates. The nudibranch molluscs Tritonia diomedea and Melibe leonina swim differently, yet their nervous systems contain homologous serotonergic neurons. In Tritonia , the dorsal swim interneurons (DSIs) are members of the swim central pattern generator (CPG) and their neurotransmitter serotonin is both necessary and sufficient to elicit a swim motor pattern. Here it is shown that the DSI homologues in Melibe , the cerebral serotonergic posterior-A neurons ( Ce SP-As), are extrinsic to the swim CPG, and that neither the Ce SP-As nor their neurotransmitter serotonin is necessary for swim motor pattern initiation, which occurred when the Ce SP-As were inactive. Furthermore, the serotonin antagonist methysergide blocked the effects of both the serotonin and Ce SP-As but did not prevent the production of a swim motor pattern. However, the Ce SP-As and serotonin could influence the Melibe swim circuit; depolarization of a cerebral serotonergic posterior-A was sufficient to initiate a swim motor pattern and hyperpolarization of a Ce SP-A temporarily halted an ongoing swim motor pattern. Serotonin itself was sufficient to initiate a swim motor pattern or make an ongoing swim motor pattern more regular. Thus, evolution of species-specific behaviour involved alterations in the functions of identified homologous neurons and their neurotransmitter.

scholarly journals Locus coeruleus toggles reciprocal prefrontal firing to reinstate fear

2019 ◽  
Vol 116 (17) ◽  
pp. 8570-8575 ◽  
Author(s):  
Thomas F. Giustino ◽  
Paul J. Fitzgerald ◽  
Reed L. Ressler ◽  
Stephen Maren
Keyword(s):  
Locus Coeruleus ◽  
Freezing Behavior ◽  
Therapeutic Interventions ◽  
Single Unit Activity ◽  
Noradrenergic Neurons ◽  
Number Of Factors ◽  
Conditioned Freezing ◽  
Noradrenergic Modulation ◽  
Spike Firing ◽  
Fear Expression

The medial prefrontal cortex (mPFC) plays an essential role in regulating emotion, including inhibiting fear when danger has passed. The extinction of fear, however, is labile and a number of factors, including stress, cause extinguished fear to relapse. Here we show that fear relapse in rats limits single-unit activity among infralimbic (IL) neurons, which are critical for inhibiting fear responses, and facilitates activity in prelimbic (PL) neurons involved in fear expression. Pharmacogenetic activation of noradrenergic neurons in the locus coeruleus mimics this shift in reciprocal IL–PL spike firing, increases the expression of conditioned freezing behavior, and causes relapse of extinguished fear. Noradrenergic modulation of mPFC firing represents a mechanism for relapse and a potential target for therapeutic interventions to reduce pathological fear.

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