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Brain : a Journal of Neurology Sep 2019Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative... (Review)
Review
Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression. In combination with neuropathological biomarkers, in vivo locus coeruleus imaging could help to understand the contribution of locus coeruleus neurodegeneration to clinical and pathological manifestations in Alzheimer's disease, atypical neurodegenerative dementias and Parkinson's disease. Moreover, as the functional sensitivity of the noradrenergic system is likely to change with disease progression, in vivo measures of locus coeruleus integrity could provide new pathophysiological insights into cognitive and behavioural symptoms. Locus coeruleus imaging also holds the promise to stratify patients into clinical trials according to noradrenergic dysfunction. In this article, we present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases. We outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases.
Topics: Biomarkers; Humans; Locus Coeruleus; Magnetic Resonance Imaging; Neurodegenerative Diseases; Norepinephrine
PubMed: 31327002
DOI: 10.1093/brain/awz193 -
Cell Reports Oct 2022Behavioral flexibility is the ability to adjust behavioral strategies in response to changing environmental contingencies. A major hypothesis in the field posits that...
Behavioral flexibility is the ability to adjust behavioral strategies in response to changing environmental contingencies. A major hypothesis in the field posits that the activity of neurons in the locus coeruleus (LC) plays an important role in mediating behavioral flexibility. To test this hypothesis, we developed a tactile-based rule-shift detection task in which mice responded to left and right whisker deflections in a context-dependent manner and exhibited varying degrees of switching behavior. Recording spiking activity from optogenetically tagged neurons in the LC at millisecond precision during task performance revealed a prominent graded correlation between baseline LC activity and behavioral flexibility, where higher baseline activity following a rule change was associated with faster behavioral switching to the new rule. Increasing baseline LC activity with optogenetic activation accelerated task switching and improved task performance. Overall, our study provides important evidence to reveal the link between LC activity and behavioral flexibility.
Topics: Mice; Animals; Locus Coeruleus; Optogenetics; Neurons; Vibrissae; Behavior, Animal
PubMed: 36288712
DOI: 10.1016/j.celrep.2022.111534 -
Journal of Pediatric Urology Jun 2022Bladder exstrophy-epispadias complex (BEEC) comprises a spectrum of anterior midline congenital malformations, involving the lower urinary tract. BEEC is usually...
INTRODUCTION
Bladder exstrophy-epispadias complex (BEEC) comprises a spectrum of anterior midline congenital malformations, involving the lower urinary tract. BEEC is usually sporadic, but families with more than one affected member have been reported, and a twin concordance study supported a genetic contribution to pathogenesis. Moreover, diverse chromosomal aberrations have been reported in a small subset of individuals with BEEC. The commonest are 22q11.2 microduplications, identified in approximately 3% of BEEC index cases.
OBJECTIVES
We aimed to refine the chromosome 22q11.2 locus, and to determine whether the encompassed genes are expressed in normal developing and mature human urinary bladders.
RESULTS
Using DNA from an individual with CBE, the 22q11.2 duplicated locus was refined by identification of a maternally inherited 314 kb duplication (chr22:21,147,293-21,461,017), as depicted in this image. Moreover, the eight protein coding genes within the locus were found to be expressed during normal developing and mature bladders. To determine whether duplications in any of these individual genes were associated with CBE, we undertook copy number analyses in 115 individuals with CBE without duplications of the whole locus. No duplications of individual genes were found.
DISCUSSION
The current study has refined the 22q11.2 locus associated with BEEC and has shown that the eight protein coding genes are expressed in human bladders both during antenatal development and postnatally. Nevertheless, the precise biological explanation as to why duplication of the phenocritical region of 22q11 confers increased susceptibility to BEEC remains to be determined. The fact that individuals with CBE without duplications of the whole locus also lacked duplication of any of the individual genes suggests that in individuals with BEEC and duplication of the 22q11.2 locus altered dosage of more than one gene may be important in BEEC etiology.
CONCLUSIONS
The study has refined the 22q11.2 locus associated with BEEC and has shown that the eight protein coding genes within this locus are expressed in human bladders.
Topics: Bladder Exstrophy; Chromosomes; Epispadias; Female; Humans; Pregnancy; Urinary Bladder
PubMed: 35491304
DOI: 10.1016/j.jpurol.2022.04.006 -
G3 (Bethesda, Md.) Sep 2021Eagle is an R package for multi-locus association mapping on a genome-wide scale. It is unlike other multi-locus packages in that it is easy to use for R users and...
Eagle is an R package for multi-locus association mapping on a genome-wide scale. It is unlike other multi-locus packages in that it is easy to use for R users and non-users alike. It has two modes of use, command line and graphical user interface. Eagle is fully documented and has its own supporting website, http://eagle.r-forge.r-project.org/index.html. Eagle is a significant improvement over the method-of-choice, single-locus association mapping. It has greater power to detect SNP-trait associations. It is based on model selection, linear mixed models, and a clever idea on how random effects can be used to identify SNP-trait associations. Through an example with real mouse data, we demonstrate Eagle's ability to bring clarity and increased insight to single-locus findings. Initially, we see Eagle complementing single-locus analyses. However, over time, we hope the community will make, increasingly, multi-locus association mapping their method-of-choice for the analysis of genome-wide association study data.
Topics: Animals; Chromosome Mapping; Eagles; Genome; Genome-Wide Association Study; Mice; Polymorphism, Single Nucleotide
PubMed: 34544142
DOI: 10.1093/g3journal/jkab204 -
Neural Plasticity 2017The locus coeruleus is connected to the dorsal hippocampus via strong fiber projections. It becomes activated after arousal and novelty, whereupon noradrenaline is... (Review)
Review
The locus coeruleus is connected to the dorsal hippocampus via strong fiber projections. It becomes activated after arousal and novelty, whereupon noradrenaline is released in the hippocampus. Noradrenaline from the locus coeruleus is involved in modulating the encoding, consolidation, retrieval, and reversal of hippocampus-based memory. Memory storage can be modified by the activation of the locus coeruleus and subsequent facilitation of hippocampal long-term plasticity in the forms of long-term depression and long-term potentiation. Recent evidence indicates that noradrenaline and dopamine are coreleased in the hippocampus from locus coeruleus terminals, thus fostering neuromodulation of long-term synaptic plasticity and memory. Noradrenaline is an inductor of epigenetic modifications regulating transcriptional control of synaptic long-term plasticity to gate the endurance of memory storage. In conclusion, locus coeruleus activation primes the persistence of hippocampus-based long-term memory.
Topics: Animals; Hippocampus; Locus Coeruleus; Long-Term Potentiation; Memory; Neural Pathways; Norepinephrine
PubMed: 28695015
DOI: 10.1155/2017/2727602 -
Brain Sciences Nov 2021Descriptions of the nuclear parcellation of the locus coeruleus complex have been provided in approximately 80 mammal species spanning the phylogenetic breadth of this... (Review)
Review
Descriptions of the nuclear parcellation of the locus coeruleus complex have been provided in approximately 80 mammal species spanning the phylogenetic breadth of this class. Within the mammalian rostral hindbrain, noradrenergic neurons (revealed with tyrosine hydroxylase and dopamine-ß-hydroxylase immunohistochemistry) have been observed within the periventricular grey matter (A4 and A6 nuclei) and parvicellular reticular nucleus (A5 and A7 nuclei), with the one exception to date being the tree pangolin, where no A4/A6 neurons are observed. The alphanumeric nomenclature system, developed in laboratory rodent brains, has been adapted to cover the variation observed across species. Cross-species homology is observed regarding the nuclear organization of noradrenergic neurons located in the parvicellular reticular nucleus (A5 and A7). In contrast, significant variations are observed in the organization of the A6 neurons of the locus coeruleus proper. In most mammals, the A6 is comprised of a moderate density of neurons, but in Murid rodents, primates, and megachiropteran bats, the A6 exhibits a very high density of neurons. In primates and megachiropterans, there is an additional moderate density of A6 neurons located rostromedial to the high-density portion. These variations are of importance in understanding the translation of findings in laboratory rodents to humans.
PubMed: 34827485
DOI: 10.3390/brainsci11111486 -
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 -
Sleep Sep 2023Long-term use of sodium oxybate (SXB), (also called gamma-hydroxybutyrate [GHB]) attenuates the cataplexy and sleepiness of human narcolepsy. We had previously found...
Long-term use of sodium oxybate (SXB), (also called gamma-hydroxybutyrate [GHB]) attenuates the cataplexy and sleepiness of human narcolepsy. We had previously found that chronic opiate usage in humans and long-term opiate administration to mice significantly increased the number of detected hypocretin/orexin (Hcrt) neurons, decreased their size, and increased Hcrt level in the hypothalamus. We also found that opiates significantly decreased cataplexy in human narcoleptics as well as in narcoleptic mice and that cessation of locus coeruleus neuronal activity preceded and was tightly linked to cataplectic attacks in narcoleptic dogs. We tested the hypothesis that SXB produces changes similar to opiates and now report that chronic SXB administration significantly increased the size of Hcrt neurons, the reverse of what we had seen with opiates in humans and mice. Levels of Hcrt in the hypothalamus were nonsignificantly lower, in contrast to the significant increase in hypothalamic Hcrt level after opiates. SXB decreased tyrosine hydroxylase levels in the locus coeruleus, the major descending projection of the hypocretin system, also the reverse of what we saw with opioids. Therefore despite some similar effects on narcoleptic symptomatology, SXB does not produce anatomical changes similar to those elicited by opiates. Analysis of changes in other links in the cataplexy pathway might further illuminate SXB's mechanism of action on narcolepsy.
Topics: Humans; Mice; Animals; Dogs; Orexins; Sodium Oxybate; Cataplexy; Locus Coeruleus; Narcolepsy; Neurons; Opiate Alkaloids
PubMed: 37155728
DOI: 10.1093/sleep/zsad135 -
PloS One 2022To investigate how cancer patients' and family members' perspective and health locus of control are presented in clinical encounter decision-making.
OBJECTIVE
To investigate how cancer patients' and family members' perspective and health locus of control are presented in clinical encounter decision-making.
METHODS
Semi-structured in-depth interviews were carried out with 16 cancer patients and 6 family members living in Israel (n = 22). Interviews were transcribed verbatim, and data were analyzed using thematic analysis.
RESULTS
Following the health locus of control model, the findings were divided into an external and internal locus of control themes, and we added a theme regarding shared decision-making. Internal locus of control sub-themes included asking for a second opinion, negotiating with the doctor, asking questions, looking for information, and fighting for their rights. External locus of control sub-themes included powerful others, oncologists, and fate. The dominant approach of most of the interviewees was an external locus of control. Women demonstrated more external locus of control than men. On the direct question of who should decide on treatment-the doctor, the patient, or both jointly-the answers ranged from only the doctor (n = 8) to together (n = 7) to only the patient (n = 8).
CONCLUSIONS
This study provides insights into different aspects of locus of control in the clinical encounter involving cancer patients. The findings reflect the need to devote comprehensive attention to cancer patients' perceptions and experiences in the clinical encounter. A patient-centered care approach and a personalized framework for decision-making in cancer care are essential to achieving better treatment outcomes. Further research can engage in the development and validation of an up-to-date health locus of control questionnaire for cancer patients based on the findings of this study.
Topics: Adult; Aged; Clinical Decision-Making; Decision Making, Shared; Family; Female; Humans; Internal-External Control; Male; Middle Aged; Neoplasms; Oncologists; Qualitative Research; Surveys and Questionnaires
PubMed: 35085354
DOI: 10.1371/journal.pone.0263086 -
Animal Genetics Apr 2022The multiple teats trait is common in many species of mammals and is considered related to lactation ability in swine. However, in Hu sheep, related gene research is...
The multiple teats trait is common in many species of mammals and is considered related to lactation ability in swine. However, in Hu sheep, related gene research is still relatively limited. In this study, a genome-wide association study was used to identify genetic markers and genes related to the number of teats in the Hu sheep population, a native Chinese sheep breed. A single marker method and several multi-locus methods were utilized. A total of 61 SNPs were found to be related to the number of teats. Among these, 11 SNPs and one SNP were consistently detected by two and three multi-locus models respectively. Four SNPs were concordantly identified between the single marker and multi-locus methods. We also performed quantitative real-time PCR testing of these identified candidate genes, identifying three genes with significantly different expression. Our study suggested that the LHFP, DPYSL2, and TDP-43 genes may be related to the number of teats in sheep. The combination of single and multi-locus GWAS detected additional SNPs not found with only one model. Our results provide new and important insights into the genetic mechanisms of the mammalian multiparous teat phenotype. These findings may be useful for future breeding and understanding the genetics of sheep and other livestock.
Topics: Animals; Female; Genetic Markers; Genome-Wide Association Study; Mammary Glands, Animal; Phenotype; Polymorphism, Single Nucleotide; Sheep; Swine
PubMed: 35040155
DOI: 10.1111/age.13169