A noradrenergic-hypothalamic neural substrate for stress-induced sleep disturbances

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Significance

Good-quality sleep is essential for our well-being. Sleep disturbances can negatively affect our mental and physical health. Here, we show that acute psychosocial stress in mice disrupts sleep, by causing frequent arousals, disrupting slow (∼minute) oscillations in the electroencephalogram and suppressing REMs. These changes are reflected in a frequent activation of noradrenergic neurons in the locus coeruleus (LC-NE) during NREMs. Activating LC-NE neurons disrupted sleep quality similar to stress, while inhibiting them after stress improved sleep partially through their projections to the preoptic area, a crucial sleep center. Our study reveals that LC-NE neurons and their interactions with hypothalamic sleep neurons orchestrate the sleep microarchitecture and play a crucial role in mediating the negative impact of stress on sleep.

Abstract

In our daily life, we are exposed to uncontrollable and stressful events that disrupt our sleep. However, the underlying neural mechanisms deteriorating the quality of non-rapid eye movement sleep (NREMs) and REM sleep are largely unknown. Here, we show in mice that acute psychosocial stress disrupts sleep by increasing brief arousals (microarousals [MAs]), reducing sleep spindles, and impairing infraslow oscillations in the spindle band of the electroencephalogram during NREMs, while reducing REMs. This poor sleep quality was reflected in an increased number of calcium transients in the activity of noradrenergic (NE) neurons in the locus coeruleus (LC) during NREMs. Opto- and chemogenetic LC-NE activation in naïve mice is sufficient to change the sleep microarchitecture similar to stress. Conversely, chemogenetically inhibiting LC-NE neurons reduced MAs during NREMs and normalized their number after stress. Specifically inhibiting LC-NE neurons projecting to the preoptic area of the hypothalamus (POA) decreased MAs and enhanced spindles and REMs after stress. Optrode recordings revealed that stimulating LC-NE fibers in the POA indeed suppressed the spiking activity of POA neurons that are activated during sleep spindles and REMs and inactivated during MAs. Our findings reveal that changes in the dynamics of the stress-regulatory LC-NE neurons during sleep negatively affect sleep quality, partially through their interaction with the POA.

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Most cited references 114

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An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance.

Gary Aston-Jones, Jonathan D. Cohen (2005)

Historically, the locus coeruleus-norepinephrine (LC-NE) system has been implicated in arousal, but recent findings suggest that this system plays a more complex and specific role in the control of behavior than investigators previously thought. We review neurophysiological and modeling studies in monkey that support a new theory of LC-NE function. LC neurons exhibit two modes of activity, phasic and tonic. Phasic LC activation is driven by the outcome of task-related decision processes and is proposed to facilitate ensuing behaviors and to help optimize task performance (exploitation). When utility in the task wanes, LC neurons exhibit a tonic activity mode, associated with disengagement from the current task and a search for alternative behaviors (exploration). Monkey LC receives prominent, direct inputs from the anterior cingulate (ACC) and orbitofrontal cortices (OFC), both of which are thought to monitor task-related utility. We propose that these frontal areas produce the above patterns of LC activity to optimize utility on both short and long timescales.

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Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle.

G Aston-Jones, FE Bloom (1981)

Spontaneous discharge of norepinephrine-containing locus coeruleus (NE-LC) neurons was examined during the sleep-walking cycle (S-WC) in behaving rats. Single unit and multiple unit extracellular recordings yielded a consistent set of characteristic discharge properties. (1) Tonic discharge co-varied with stages of the S-WC, being highest during waking, lower during slow wave sleep, and virtually absent during paradoxical sleep. (2) Discharge anticipated S-WC stages as well as phasic cortical activity, such as spindles, during slow wave sleep. (3) Discharge decreased within active waking during grooming and sweet water consumption. (4) Bursts of impulses accompanied spontaneous or sensory-evoked interruptions of sleep, grooming, consumption, or other such ongoing behavior. (5) These characteristic discharge properties were topographically homogeneous for recordings throughout the NE-LC. (6) Phasic robust activity was synchronized markedly among neurons in multiple unit populations. (7) Field potentials occurred spontaneously in the NE-LC and were synchronized with bursts of unit activity from the same electrodes. (8) Field potentials became dissociated from unit activity during paradoxical sleep, exhibiting their highest rates in the virtual absence of impulses. These results are generally consistent with previous proposals that the NE-LC system is involved in regulating cortical and behavioral arousal. On the basis of the present data and those described in the following report (Aston-Jones, G., and F. E. Bloom (1981) J. Neurosci.1: 887-900), we conclude that these neurons may mediate a specific function within the general arousal framework. In brief, the NE-LC system may globally bias the responsiveness of target neurons and thereby influence overall behavioral orientation.

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The locus coeruleus and noradrenergic modulation of cognition.

Susan Sara (2009)

Mood, attention and motivation co-vary with activity in the neuromodulatory systems of the brain to influence behaviour. These psychological states, mediated by neuromodulators, have a profound influence on the cognitive processes of attention, perception and, particularly, our ability to retrieve memories from the past and make new ones. Moreover, many psychiatric and neurodegenerative disorders are related to dysfunction of these neuromodulatory systems. Neurons of the brainstem nucleus locus coeruleus are the sole source of noradrenaline, a neuromodulator that has a key role in all of these forebrain activities. Elucidating the factors that control the activity of these neurons and the effect of noradrenaline in target regions is key to understanding how the brain allocates attention and apprehends the environment to select, store and retrieve information for generating adaptive behaviour.

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Author and article information

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc Natl Acad Sci U S A

Journal ID (hwp): pnas

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Electronic): 4 November 2022

Publication date (Print): 8 November 2022

Publication date PMC-release: 4 May 2023

Volume: 119

Issue: 45

Electronic Location Identifier: e2123528119

Affiliations

[1] ^aDepartment of Neuroscience, Chronobiology, and Sleep Institute, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104;

[2] ^bDepartment of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia Research Institute , Philadelphia, PA 19104;

[3] ^cDepartment of Physiology and Biophysics, School of Medicine, University of California , Irvine, CA 92617;

[4] ^dDepartment of Pharmacology, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104

Author notes

¹To whom correspondence may be addressed. Email: shinjaec@ 123456pennmedicine.upenn.edu .

Edited by Joseph Takahashi, The University of Texas Southwestern Medical Center, Dallas, TX; received January 12, 2022; accepted August 19, 2022

Author contributions: H.A., F.W., and S.C. conceived the study; H.A., F.W., and S.C. designed research; H.A., F.W., and S.C. designed the methodology; J.B. and F.W. contributed software; H.A., I.K., A.C., A.P., and I.C. performed research; J.B., A.E., K.B., and S.T. contributed reagents/analytic tools; H.A., F.W., and S.C. analyzed data; H.A. created the visualization; H.A., A.E., K.B., S.T., F.W., and S.C. wrote and edited the paper; F.W. and S.C. supervised the study; and S.C. acquired the funding.