The role of the locus coeruleus in the generation of pathological anxiety

Morris, Laurel; McCall, Jordan G.; Charney, Dennis S.; Murrough, James W.

doi:10.1177/2398212820930321

Cited by 125 publications

(115 citation statements)

References 279 publications

(368 reference statements)

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“…The LC is the main location of a highly flexible, adaptable noradrenergic system projecting in many cortical and subcortical brain regions, thus explaining its highly relevant function in humans in everyday life, and essential for us humans as feeling and thinking beings. Beside its involvement in cognitive processes, a broader function recently emerged covering aspects of psychopathology, such as triggering anxiety (Morris et al, 2020 ), psychosis in alpha-synucleinopathies (Wolters, 2001 ) and demotivation in schizophrenia (Mäki-Marttunen et al, 2020 ), inattention to visual stimuli in the attention deficit-hyperactivity and autism-spectrum disorders (Boxhoorn et al, 2020 ), depressive symptoms in Alzheimer's disease (AD) (Förstl et al, 1992 ), suicide behavior (Roy et al, 2017 ) and defective emotional-memory encoding (Jacobs et al, 2020 ).…”

Section: Introductionmentioning

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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Section: Introductionmentioning

confidence: 99%

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

Hansen

2021

Front. Aging Neurosci.

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“…Norepinephrine (NE) is a stress hormone that is elevated due to activation of the hypothalamic-pituitary-adrenal axis, the locus coeruleus (LC) and involves noradrenergic neurons, the sympathetic adrenal medulla and the renin-angiotensin-aldosterone system during stress ( 23 ). NE constricts the blood vessels to change blood distribution, which is important during heat stress ( 24 ).…”

Section: Introductionmentioning

confidence: 99%

Effects of norepinephrine on colonic tight junction protein expression during heat stress

Luo

Niu

et al. 2021

Exp Ther Med

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Stress induced by changes in the internal or external environment in humans and animals leads to intestinal epithelial damage, in a manner that is associated with impaired intestinal barrier function. However, the role of the stress hormone norepinephrine (NE) in impairments in barrier function remains poorly understood. In the present study, a rat heat-exposed model was used to observe changes in the tight junction proteins Occludin and zonula occludens-1 (ZO-1), in addition to those in protease-activated receptor 2 (PAR-2) and transient receptor potential ankyrin 1 channel (TRPA1) in colon. The levels of plasma NE were detected using an ELISA kit. Different concentrations of NE were used to culture the human colon cell line Caco-2 for 6 and 24 h to investigate the cell viability using Cell Counting Kit-8 assay, whilst the expression levels of Occludin, ZO-1, PAR-2 and TRPA1 were examined using western blotting and immunofluorescence in Caco-2 cells and immunohistrochemistry in rat colon tissues. Although there was no clear histological damage to the rat colonic mucosa, there were decreased expression levels of tight junction proteins Occludin and ZO-1 after heat exposure. In addition, PAR-2 expression was increased by heat exposure. It was found that TRPA1 expression was concentrated to the luminal surface of the colon in the heat exposed group compared with that in the control group. After the administration of increasing concentrations of NE for 6 h, treatment did not affect cell viability. Furthermore, after application of NE for 24 h, cell viability gradually increased as the NE concentration was elevated from 10 to 100 µM. However, no significant increase in viability was observed when the cells were treated with 120 and 160 µM NE. Occludin expression was decreased when 10 µM NE was applied for 6 or 24 h. By contrast, 60 µM NE significantly downregulated Occludin expression in the 6 h group, but caused an insignificant decrease in the 24 h group. It was found that ZO-1 expression was upregulated after treatment with 10 µM NE for 6 h, whilst downregulation was observed after treatment with 10 µM NE for 24 h. PAR-2 protein expression was increased after application of NE for both 6 and 24 h, but not after treatment with 60 µM NE. In addition, TRPA1 expression was not affected by the treatment of NE, but increased positive staining was observed on the luminal side of the mucosa, which appeared to be concentrated in the cells of the luminal side in the rat colon after heat exposure. Collectively, the present results suggested that expression of tight junction proteins Occludin and ZO-1, in addition to that of PAR-2, can be regulated by NE, which may contribute to impairments in barrier function observed during heat stress.

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“…Gliding behaviors are thought to represent an anti-predator response [2]. Intriguingly, we find accelerated sequence evolution in the genes involved in locus cereleus development, a key region of the brain involved in alertness, anxiety and panic response in humans [14], as well as epinephrine secretion and transport and adrenergic receptor activity (Fig 3, S9 Table). Finally, flying fish have unique pyramidal corneas adapted to provide clear image resolution both above and below the water surface [15], and we observed accelerated evolutionary rate across a number of visual pathways, including camera-type eye morphogenesis, retinal development, lens development and morphogenesis, and lens fiber cell differentiation (Fig 3, S9 Table).…”

Section: Genomic Imprint Of the Evolution Of Aerial Gliding In Fishesmentioning

confidence: 79%

Novel regulators of growth identified in the evolution of fin proportion in flying fish

Blum

Lanni

et al. 2021

Preprint

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Identifying the genetic foundations of trait variation and evolution is challenging as it is often difficult to parse meaningful signals from confounding signatures such as drift and epistasis. However, identification of the genetic loci underlying morphological and physiological traits can be honed through the use of comparative and complementary genetic approaches, whereby shared sets of genes that are repeatedly implicated across large evolutionary time periods as under selection can illuminate important pathways and epistatic relationships that function as novel regulators of trait development. Here we intersect comparative genomic analyses with unbiased mutagenesis screens in distantly related species to define the control of proportional growth, as changes in the size and relative proportions of tissues underlie a large degree of the variant forms seen in nature. Through a phylogenomic analysis of genome-wide variation in 35 species of flying fishes and relatives, we identify genetic signatures in both coding and regulatory regions underlying the convergent evolution of increased paired fin size and aerial gliding behaviors, key innovations for flying fishes and flying halfbeaks. To refine our analysis, we intersected convergent phylogenomic signatures with mutants identified in distantly related zebrafish with altered fin size. Through these paired approaches, we identify a surprising role for an L-type amino acid transporter, lat4a, and the potassium channel, kcnh2a, in the regulation of fin proportion. We show that specific epistatic interaction between these genetic loci in zebrafish closely phenocopies the observed fin proportions of flying fishes. The congruence of experimental and phylogenomic findings point to a conserved, non-canonical signaling interaction that integrates bioelectric cues and amino acid transport in the establishment of relative size in development and evolution.

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The role of the locus coeruleus in the generation of pathological anxiety

Cited by 125 publications

References 279 publications

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

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

Effects of norepinephrine on colonic tight junction protein expression during heat stress

Novel regulators of growth identified in the evolution of fin proportion in flying fish

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