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Current Biology : CB Nov 2015The release of the neurotransmitter norepinephrine throughout the mammalian brain is important for modulating attention, arousal, and cognition during many behaviors.... (Review)
Review
The release of the neurotransmitter norepinephrine throughout the mammalian brain is important for modulating attention, arousal, and cognition during many behaviors. Furthermore, disruption of norepinephrine-mediated signaling is strongly associated with several psychiatric and neurodegenerative disorders in humans, emphasizing the clinical importance of this system. Most of the norepinephrine released in the brain is supplied by a very small, bilateral nucleus in the brainstem called the locus coeruleus. The goal of this minireview is to emphasize the complexity of the locus coeruleus beyond its primary definition as a norepinephrine-producing nucleus. Several recent studies utilizing innovative technologies highlight how the locus coeruleus-norepinephrine system can now be targeted with increased accuracy and resolution, in order to better understand its role in modulating diverse behaviors.
Topics: Animals; Attention; Brain; Brain Stem; Cognition; Humans; Locus Coeruleus; Norepinephrine
PubMed: 26528750
DOI: 10.1016/j.cub.2015.09.039 -
Brain : a Journal of Neurology Mar 2022There is strong comorbidity between chronic pain and depression, although the neural circuits and mechanisms underlying this association remain unclear. By combining...
There is strong comorbidity between chronic pain and depression, although the neural circuits and mechanisms underlying this association remain unclear. By combining immunohistochemistry, tracing studies and western blotting, with the use of different DREADDS (designer receptor exclusively activated by designer drugs) and behavioural approaches in a rat model of neuropathic pain (chronic constriction injury), we explore how this comorbidity arises. To this end, we evaluated the time-dependent plasticity of noradrenergic locus coeruleus neurons relative to the site of injury: ipsilateral (LCipsi) or contralateral (LCcontra) locus coeruleus at three different time points: short (2 days), mid (7 days) and long term (30-35 days from nerve injury). Nerve injury led to sensorial hypersensitivity from the onset of injury, whereas depressive-like behaviour was only evident following long-term pain. Global chemogenetic blockade of the LCipsi system alone increased short-term pain sensitivity while the blockade of the LCipsi or LCcontra relieved pain-induced depression. The asymmetric contribution of locus coeruleus modules was also evident as neuropathy develops. Hence, chemogenetic blockade of the LCipsi→spinal cord projection, increased pain-related behaviours in the short term. However, this lateralized circuit is not universal as the bilateral chemogenetic inactivation of the locus coeruleus-rostral anterior cingulate cortex pathway or the intra-rostral anterior cingulate cortex antagonism of alpha1- and alpha2-adrenoreceptors reversed long-term pain-induced depression. Furthermore, chemogenetic locus coeruleus to spinal cord activation, mainly through LCipsi, reduced sensorial hypersensitivity irrespective of the time post-injury. Our results indicate that asymmetric activation of specific locus coeruleus modules promotes early restorative analgesia, as well as late depressive-like behaviour in chronic pain and depression comorbidity.
Topics: Animals; Comorbidity; Depression; Humans; Locus Coeruleus; Neuralgia; Neurons; Rats
PubMed: 34373893
DOI: 10.1093/brain/awab239 -
Optics Express Apr 2022In this paper, directly following from Gage [J. Opt. Soc. Am.23, 46(1993)10.1364/JOSA.23.000046], we study the design of a particular theoretical filter for photography,...
In this paper, directly following from Gage [J. Opt. Soc. Am.23, 46(1993)10.1364/JOSA.23.000046], we study the design of a particular theoretical filter for photography, that we call the locus filter. It is built in such a way that a Wien-Planckian light (of any temperature) is spectrally mapped to another Wien-Planckian light. We provide a physical basis for designing such a filter based on the Wien approximation of Planck's law, and we prove that there exists a unique set of filters that have the desired property. While locus filtered Wien-Planckian lights are on the locus, the amount they shift depends both on the locus filter used and on the color temperature of the light. In experiments, we analyze the nature of temperature change when applying different locus filters and we show that real lights shift more or less as if they were Planckians in terms of the changes in their correlated color temperatures. We also study the quality of the filtered light in terms of distance from the Planckian locus and color rendering index.
PubMed: 35472916
DOI: 10.1364/OE.448160 -
Frontiers in Neuroscience 2022Genome-wide association studies have consistently shown that the alpha-synuclein locus is significantly associated with Parkinson's disease. The mechanism by which this... (Review)
Review
Genome-wide association studies have consistently shown that the alpha-synuclein locus is significantly associated with Parkinson's disease. The mechanism by which this locus modulates the disease pathology and etiology remains largely under-investigated. This is due to the assumption that is the only driver of the functional aspects of several single nucleotide polymorphism (SNP) risk-signals at this locus. Recent evidence has shown that the risk associated with the top GWAS-identified variant within this locus is independent of expression, calling into question the validity of assigning function to the nearest gene, . In this review, we examine additional genes and risk variants present at the locus and how they may contribute to Parkinson's disease. Using the locus as an example, we hope to demonstrate that deeper and detailed functional validations are required for high impact disease-linked variants.
PubMed: 35898413
DOI: 10.3389/fnins.2022.889802 -
Proceedings of the National Academy of... Nov 2021The last decade has seen significant progress identifying genetic and brain differences related to intelligence. However, there remain considerable gaps in our... (Review)
Review
The last decade has seen significant progress identifying genetic and brain differences related to intelligence. However, there remain considerable gaps in our understanding of how cognitive mechanisms that underpin intelligence map onto various brain functions. In this article, we argue that the locus coeruleus-norepinephrine system is essential for understanding the biological basis of intelligence. We review evidence suggesting that the locus coeruleus-norepinephrine system plays a central role at all levels of brain function, from metabolic processes to the organization of large-scale brain networks. We connect this evidence with our executive attention view of working-memory capacity and fluid intelligence and present analyses on baseline pupil size, an indicator of locus coeruleus activity. Using a latent variable approach, our analyses showed that a common executive attention factor predicted baseline pupil size. Additionally, the executive attention function of disengagement--not maintenance--uniquely predicted baseline pupil size. These findings suggest that the ability to control attention may be important for understanding how cognitive mechanisms of fluid intelligence map onto the locus coeruleus-norepinephrine system. We discuss how further research is needed to better understand the relationships between fluid intelligence, the locus coeruleus-norepinephrine system, and functionally organized brain networks.
Topics: Animals; Attention; Brain; Executive Function; Humans; Individuality; Intelligence; Locus Coeruleus; Memory, Short-Term; Norepinephrine; Pupil
PubMed: 34764223
DOI: 10.1073/pnas.2110630118 -
Neural Regeneration Research Jun 2020The locus coeruleus is a pontine nucleus that produces much of the brain's norepinephrine. Despite its small size, the locus coeruleus is critical for a myriad of... (Review)
Review
The locus coeruleus is a pontine nucleus that produces much of the brain's norepinephrine. Despite its small size, the locus coeruleus is critical for a myriad of functions and is involved in many neurodegenerative and neuropsychiatric disorders. In this review, we discuss the physiology and anatomy of the locus coeruleus system and focus on norepinephrine's role in synaptic plasticity. We highlight Parkinson's disease as a disorder with motor and neuropsychiatric symptoms that may be understood as aberrations in the normal functions of locus coeruleus.
PubMed: 31823870
DOI: 10.4103/1673-5374.270297 -
International Journal of Molecular... Jun 2023The Apolipoprotein E ( locus has garnered significant clinical interest because of its association with Alzheimer's disease (AD) and longevity. This genetic association...
The Apolipoprotein E ( locus has garnered significant clinical interest because of its association with Alzheimer's disease (AD) and longevity. This genetic association appears across multiple genes in the locus. Despite the apparent differences between AD and longevity, both conditions share a commonality of aging-related changes in mitochondrial function. This commonality is likely due to accumulative biological effects partly exerted by the locus. In this study, we investigated changes in mitochondrial structure/function-related markers using oxidative stress-induced human cellular models and postmortem brains (PMBs) from individuals with AD and normal controls. Our results reveal a range of expressional alterations, either upregulated or downregulated, in these genes in response to oxidative stress. In contrast, we consistently observed an upregulation of multiple locus genes in all cellular models and AD PMBs. Additionally, the effects of AD status on mitochondrial DNA copy number (mtDNA CN) varied depending on genotype. Our findings imply a potential coregulation of locus genes possibly occurring within the same topologically associating domain (TAD) of the 3D chromosome conformation. The coordinated expression of locus genes could impact mitochondrial function, contributing to the development of AD or longevity. Our study underscores the significant role of the locus in modulating mitochondrial function and provides valuable insights into the underlying mechanisms of AD and aging, emphasizing the importance of this locus in clinical research.
Topics: Humans; Alzheimer Disease; Apolipoproteins E; Aging; Genotype; Mitochondria; Apolipoprotein E4
PubMed: 37445616
DOI: 10.3390/ijms241310440 -
Frontiers in Genetics 2019Intramuscular fat (IMF) is an important quantitative trait of meat, which affects the associated sensory properties and nutritional value of pork. To gain a better...
Intramuscular fat (IMF) is an important quantitative trait of meat, which affects the associated sensory properties and nutritional value of pork. To gain a better understanding of the genetic determinants of IMF, we used a composite strategy, including single-locus and multi-locus association analyses to perform genome-wide association studies (GWAS) for IMF in 1,490 Duroc boars. We estimated the genomic heritability of IMF to be 0.23 ± 0.04. A total of 30 single nucleotide polymorphisms (SNPs) were found to be significantly associated with IMF. The single-locus mixed linear model (MLM) and multiple-locus methods multi-locus random-SNP-effect mixed linear model (mrMLM), fast multi-locus random-SNP-effect efficient mixed model association (FASTmrEMMA), and integrative sure independence screening expectation maximization Bayesian least absolute shrinkage and selection operator model (ISIS EM-BLASSO) analyses identified 5, 9, 8, and 21 significant SNPs, respectively. Interestingly, a novel quantitative trait locus (QTL) on SSC 7 was found to affect IMF. In addition, 10 candidate genes (, , , , , , , , , and ) were found to be associated with IMF based on their potential functional roles in IMF. GO analysis showed that most of the genes were involved in muscle and organ development. A significantly enriched KEGG pathway, the sphingolipid signaling pathway, was reported to be associated with fat deposition and obesity. Identification of novel variants and functional genes will advance our understanding of the genetic mechanisms of IMF and provide specific opportunities for marker-assisted or genomic selection in pigs. In general, such a composite single-locus and multi-locus strategy for GWAS may be useful for understanding the genetic architecture of economic traits in livestock.
PubMed: 31316554
DOI: 10.3389/fgene.2019.00619 -
Philosophical Transactions of the Royal... Aug 2020All genes interact with other genes, and their additive effects and epistatic interactions affect an organism's phenotype and fitness. Recent theoretical and empirical... (Review)
Review
All genes interact with other genes, and their additive effects and epistatic interactions affect an organism's phenotype and fitness. Recent theoretical and empirical work has advanced our understanding of the role of multi-locus interactions in speciation. However, relating different models to one another and to empirical observations is challenging. This review focuses on multi-locus interactions that lead to reproductive isolation (RI) through reduced hybrid fitness. We first review theoretical approaches and show how recent work incorporating a mechanistic understanding of multi-locus interactions recapitulates earlier models, but also makes novel predictions concerning the build-up of RI. These include high variance in the build-up rate of RI among taxa, the emergence of strong incompatibilities producing localized barriers to introgression, and an effect of population size on the build-up of RI. We then review recent experimental approaches to detect multi-locus interactions underlying RI using genomic data. We argue that future studies would benefit from overlapping methods like ancestry disequilibrium scans, genome scans of differentiation and analyses of hybrid gene expression. Finally, we highlight a need for further overlap between theoretical and empirical work, and approaches that predict what kind of patterns multi-locus interactions resulting in incompatibilities will leave in genome-wide polymorphism data. This article is part of the theme issue 'Towards the completion of speciation: the evolution of reproductive isolation beyond the first barriers'.
Topics: Genetic Fitness; Genetic Speciation; Models, Genetic; Reproductive Isolation
PubMed: 32654649
DOI: 10.1098/rstb.2019.0543