Locus coeruleus and the defensive activation theory of rapid eye movement sleep: A mechanistic perspective

Knopper, Rasmus West; Hansen, Brian

doi:10.3389/fnins.2023.1094812

Cited by 4 publications

(2 citation statements)

References 59 publications

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“…Similar disagreements are observed in the literature of stereological studies on the human LC, where studies show contradictory results on the effect of normal aging on LC ( Lohr and Jeste, 1988 ; Ohm et al, 1997 ; Kubis et al, 2000 ). See review by Knopper and Hansen (2023) .…”

Section: Discussionmentioning

confidence: 99%

Locus coeruleus ablation in mice: protocol optimization, stereology and behavioral impact

Markussen¹,

Knopper²,

Hasselholt³

et al. 2023

Front. Cell. Neurosci.

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The Locus Coeruleus (LC) is in the brainstem and supplies key brain structures with noradrenaline, including the forebrain and hippocampus. The LC impacts specific behaviors such as anxiety, fear, and motivation, as well as physiological phenomena that impact brain functions in general, including sleep, blood flow regulation, and capillary permeability. Nevertheless, the short- and long-term consequences of LC dysfunction remain unclear. The LC is among the brain structures first affected in patients suffering from neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s Disease, hinting that LC dysfunction may play a central role in disease development and progression. Animal models with modified or disrupted LC function are essential to further our understanding of LC function in the normal brain, the consequences of LC dysfunction, and its putative roles in disease development. For this, well-characterized animal models of LC dysfunction are needed. Here, we establish the optimal dose of selective neurotoxin N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (DSP-4) for LC ablation. Using histology and stereology, we compare LC volume and neuron number in LC ablated (LCA) mice and controls to assess the efficacy of LC ablation with different numbers of DSP-4 injections. All LCA groups show a consistent decrease in LC cell count and LC volume. We then proceed to characterize the behavior of LCA mice using a light-dark box test, Barnes maze test, and non-invasive sleep-wakefulness monitoring. Behaviorally, LCA mice differ subtly from control mice, with LCA mice generally being more curious and less anxious compared to controls consistent with known LC function and projections. We note an interesting contrast in that control mice have varying LC size and neuron count but consistent behavior whereas LCA mice (as expected) have consistently sized LC but erratic behavior. Our study provides a thorough characterization of an LC ablation model, firmly consolidating it as a valid model system for the study of LC dysfunction.

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Section: Discussionmentioning

confidence: 99%

Locus coeruleus ablation in mice: protocol optimization, stereology and behavioral impact

Markussen¹,

Knopper²,

Hasselholt³

et al. 2023

Front. Cell. Neurosci.

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“…Prior research has detected structural modifications in the prefrontal (17), temporal (18), and parietal lobes (19), as well as the hippocampus (20), anterior cingulate gyrus (21), and pineal gland areas (22) integral to sleep and emotion regulation. More recent studies have also noted abnormalities in the striatum (23) and locus coeruleus (24). FC analysis of these structurally abnormal regions allows for an examination of changes in functional activities, providing deeper insights into how structural abnormalities impact brain function and potentially elucidating the pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

The brain in chronic insomnia and anxiety disorder: a combined structural and functional fMRI study

Xu,

Li,

Wang

et al. 2024

Front. Psychiatry

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BackgroundChronic insomnia disorder (CID) is usually associated with Generalized Anxiety Disorder (GAD), which may change brain structure and function. However, the possible brain markers, imaging characteristics, and pathophysiology are unknown.ObjectiveTo look at the probable brain markers, imaging characteristics, and pathogenesis of CID in combination with GAD.MethodsA total of 57 patients with CID concomitant GAD and 57 healthy controls (HC) were enrolled. Voxel-based morphometry (VBM) and functional connectivity (FC) were utilized to measure gray matter volume (GMV) and functional changes. Correlation analysis was utilized to identify relationships between brain changes and clinical characteristics.ResultsPatients had decreased GMV in the left cerebellum, right cerebellar peduncle, and left insula; increased FC between the left cerebellum and right angular gyrus, as well as between the left insula and anterior left cingulate gyrus; and decreased FC in several areas, including the left cerebellum with the middle left cingulate gyrus and the left insula with the left superior postcentral gyrus. These brain changes related to CID and GAD. These data could be used to identify relevant brain markers, imaging features, and to better understand the etiology.ConclusionThe intensity of insomnia in patients was strongly related to the severity of anxiety. The lower GMV in the cerebellum could be interpreted as an imaging characteristic of CID. Reduced GMV in the insula, as well as aberrant function in the cingulate gyrus and prefrontal lobe, may contribute to the pathophysiology of CID and GAD. Abnormal function in the postcentral gyrus and angular gyrus may be associated with patients’ clinical complaints.

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The effects of locus coeruleus ablation on mouse brain volume and microstructure evaluated by high-field MRI

Knopper,

Skoven,

Eskildsen

et al. 2024

Front. Cell. Neurosci.

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The locus coeruleus (LC) produces most of the brain’s noradrenaline (NA). Among its many roles, NA is often said to be neuroprotective and important for brain upkeep. For this reason, loss of LC integrity is thought to impact brain volume and microstructure as well as plasticity broadly. LC dysfunction is also a suspected driver in the development of neurodegenerative diseases. Nevertheless, the impact of LC dysfunction on the gross structure and microstructure of normal brains is not well-studied. We employed high-field ex vivo magnetic resonance imaging (MRI) to investigate brain volumetrics and microstructure in control (CON) mice and mice with LC ablation (LCA) at two ages, representing the developing brain and the fully matured brain. These whole-brain methods are known to be capable of detecting subtle morphological changes and brain microstructural remodeling. We found mice behavior consistent with histologically confirmed LC ablation. However, MRI showed no difference between CON and LCA groups with regard to brain size, relative regional volumes, or regional microstructural indices. Our findings suggest that LC-NA is not needed for postnatal brain maturation and growth in mice. Nor is it required for maintenance in the normal adult mouse brain, as no atrophy or microstructural aberration is detected after weeks of LC dysfunction. This adds clarity to the often-encountered notion that LC-NA is important for brain “trophic support” as it shows that such effects are likely most relevant to mechanisms related to brain plasticity and neuroprotection in the (pre)diseased brain.

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Locus coeruleus and the defensive activation theory of rapid eye movement sleep: A mechanistic perspective

Cited by 4 publications

References 59 publications

Locus coeruleus ablation in mice: protocol optimization, stereology and behavioral impact

Locus coeruleus ablation in mice: protocol optimization, stereology and behavioral impact

The brain in chronic insomnia and anxiety disorder: a combined structural and functional fMRI study

The effects of locus coeruleus ablation on mouse brain volume and microstructure evaluated by high-field MRI

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