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Molecular Psychiatry Jan 2022This work provides an overview of the most consistent alterations in bipolar disorder (BD), attempting to unify them in an internally coherent working model of the... (Review)
Review
This work provides an overview of the most consistent alterations in bipolar disorder (BD), attempting to unify them in an internally coherent working model of the pathophysiology of BD. Data on immune-inflammatory changes, structural brain abnormalities (in gray and white matter), and functional brain alterations (from neurotransmitter signaling to intrinsic brain activity) in BD were reviewed. Based on the reported data, (1) we hypothesized that the core pathological alteration in BD is a damage of the limbic network that results in alterations of neurotransmitter signaling. Although heterogeneous conditions can lead to such damage, we supposed that the main pathophysiological mechanism is traceable to an immune/inflammatory-mediated alteration of white matter involving the limbic network connections, which destabilizes the neurotransmitter signaling, such as dopamine and serotonin signaling. Then, (2) we suggested that changes in such neurotransmitter signaling (potentially triggered by heterogeneous stressors onto a structurally-damaged limbic network) lead to phasic (and often recurrent) reconfigurations of intrinsic brain activity, from abnormal subcortical-cortical coupling to changes in network activity. We suggested that the resulting dysbalance between networks, such as sensorimotor networks, salience network, and default-mode network, clinically manifest in combined alterations of psychomotricity, affectivity, and thought during the manic and depressive phases of BD. Finally, (3) we supposed that an additional contribution of gray matter alterations and related cognitive deterioration characterize a clinical-biological subgroup of BD. This model may provide a general framework for integrating the current data on BD and suggests novel specific hypotheses, prompting for a better understanding of the pathophysiology of BD.
Topics: Bipolar Disorder; Brain; Brain Mapping; Humans; Magnetic Resonance Imaging; White Matter
PubMed: 33859358
DOI: 10.1038/s41380-021-01091-4 -
Journal of Cachexia, Sarcopenia and... Oct 2023The functional deterioration and loss of motor neurons are tightly associated with degenerative motor neuron diseases and aging-related muscle wasting. Motor neuron...
BACKGROUND
The functional deterioration and loss of motor neurons are tightly associated with degenerative motor neuron diseases and aging-related muscle wasting. Motor neuron diseases or aging-related muscle wasting in turn contribute to increased risk of adverse health outcomes in the elderly. Cdon (cell adhesion molecule-downregulated oncogene) belongs to the immunoglobulin superfamily of cell adhesion molecule and plays essential roles in multiple signalling pathways, including sonic hedgehog (Shh), netrin, and cadherin-mediated signalling. Cdon as a Shh coreceptor plays a critical role in motor neuron specification during embryonic development. However, its role in adult motor neuron function is unknown.
METHODS
Hb9-Cre recombinase-driven motor neuron-specific Cdon deficient mice (mnKO) and a compound mutant mice (mnKO::SOD1 ) were generated to investigate the role of Cdon in motor neuron degeneration. Motor neuron regeneration was examined by using a sciatic nerve crush injury model. To investigate the phenotype, physical activity, compound muscle action potential, immunostaining, and transmission electron microscopy were carried out. In the mechanism study, RNA sequencing and RNA/protein analyses were employed.
RESULTS
Mice lacking Cdon in motor neurons exhibited middle age onset lethality and aging-related decline in motor function. In the sciatic nerve crush injury model, mnKO mice exhibited an impairment in motor function recovery evident by prolonged compound muscle action potential duration (4.63 ± 0.35 vs. 3.93 ± 0.22 s for f/f, P < 0.01) and physical activity. Consistently, neuromuscular junctions of mnKO muscles were incompletely occupied (49.79 ± 5.74 vs. 79.39 ± 3.77% fully occupied neuromuscular junctions for f/f, P < 0.0001), suggesting an impaired reinnervation. The transmission electron microscopy analysis revealed that mnKO sciatic nerves had smaller axon diameter (0.88 ± 0.13 vs. 1.43 ± 0.48 μm for f/f, P < 0.0001) and myelination defects. RNA sequencing of mnKO lumbar spinal cords showed alteration in genes related to neurogenesis, inflammation and cell death. Among the altered genes, ErbB4 and FgfR expressions were significantly altered in mnKO as well as in Cdon-depleted NSC34 motor neuron cells. Consistently, Cdon-depleted NSC34 cells exhibited elevated levels of cleaved Caspase3 and γH2AX proteins, as well as Bax transcription. Cdon-depleted NSC34 cells also exhibited impaired activation of Akt in response to neuregulin-1 (NRG1) treatment.
CONCLUSIONS
Our current data demonstrate the functional importance of Cdon in motor neuron function and nerve repair. Cdon ablation causes alterations in neurotrophin signalling that leads to motor neuron degeneration.
PubMed: 37559423
DOI: 10.1002/jcsm.13308 -
Clinical Science (London, England :... Mar 2018Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) (ME/CFS) is a disabling and debilitating disease of unknown aetiology. It is a heterogeneous disease... (Review)
Review
Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) (ME/CFS) is a disabling and debilitating disease of unknown aetiology. It is a heterogeneous disease characterized by various inflammatory, immune, viral, neurological and endocrine symptoms. Several microbiome studies have described alterations in the bacterial component of the microbiome (dysbiosis) consistent with a possible role in disease development. However, in focusing on the bacterial components of the microbiome, these studies have neglected the viral constituent known as the virome. Viruses, particularly those infecting bacteria (bacteriophages), have the potential to alter the function and structure of the microbiome via gene transfer and host lysis. Viral-induced microbiome changes can directly and indirectly influence host health and disease. The contribution of viruses towards disease pathogenesis is therefore an important area for research in ME/CFS. Recent advancements in sequencing technology and bioinformatics now allow more comprehensive and inclusive investigations of human microbiomes. However, as the number of microbiome studies increases, the need for greater consistency in study design and analysis also increases. Comparisons between different ME/CFS microbiome studies are difficult because of differences in patient selection and diagnosis criteria, sample processing, genome sequencing and downstream bioinformatics analysis. It is therefore important that microbiome studies adopt robust, reproducible and consistent study design to enable more reliable and valid comparisons and conclusions to be made between studies. This article provides a comprehensive review of the current evidence supporting microbiome alterations in ME/CFS patients. Additionally, the pitfalls and challenges associated with microbiome studies are discussed.
Topics: Bacteria; Bacteriophages; Dysbiosis; Fatigue Syndrome, Chronic; Gastrointestinal Microbiome; Host Microbial Interactions; Humans; Inflammation; Models, Biological
PubMed: 29523751
DOI: 10.1042/CS20171330 -
BioRxiv : the Preprint Server For... Jun 2023Protein synthesis is a fundamental cellular process in neurons that is essential for synaptic plasticity and memory consolidation. Here, we describe our investigations...
UNLABELLED
Protein synthesis is a fundamental cellular process in neurons that is essential for synaptic plasticity and memory consolidation. Here, we describe our investigations of a neuron- and muscle-specific translation factor, e ukaryotic E longation F actor 1a2 (eEF1A2), which when mutated in patients results in autism, epilepsy, and intellectual disability. We characterize three most common patient mutations, G70S, E122K, and D252H, and demonstrate that all three mutations decrease protein synthesis and elongation rates in HEK293 cells. In mouse cortical neurons, the mutations not only decrease protein synthesis, but also alter neuronal morphology, regardless of endogenous levels of eEF1A2, indicating that the mutations act via a toxic gain of function. We also show that eEF1A2 mutant proteins display increased tRNA binding and decreased actin bundling activity, suggesting that these mutations disrupt neuronal function by decreasing tRNA availability and altering the actin cytoskeleton. More broadly, our findings are consistent with the idea that eEF1A2 acts as a bridge between translation and the actin skeleton, which is essential for proper neuron development and function.
SIGNIFICANCE STATEMENT
E ukaryotic E longation F actor 1A2 (eEF1A2) is a muscle- and neuron-specific translation factor responsible for bringing charge tRNAs to the elongating ribosome. Why neurons express this unique translation factor is unclear; however, it is known that mutations in cause severe drug-resistant epilepsy, autism and neurodevelopmental delay. Here, we characterize the impact of three common disease-causing mutations in and demonstrate that they cause decreased protein synthesis via reduced translation elongation, increased tRNA binding, decreased actin bundling activity, as well as altered neuronal morphology. We posit that eEF1A2 serves as a bridge between translation and the actin cytoskeleton, linking these two processes that are essential for neuronal function and plasticity.
PubMed: 37333416
DOI: 10.1101/2023.06.06.543912 -
Aging Pathobiology and Therapeutics Mar 2021Genetic variation does not entirely address the consistent divergence of healthy and unhealthy aging in heterogeneous and homogeneous mammalian populations. The...
Genetic variation does not entirely address the consistent divergence of healthy and unhealthy aging in heterogeneous and homogeneous mammalian populations. The alteration of gene function through modification of histone DNA infrastructure is a logical extending explanation for this divergence. Since epigenetic alterations are reversible, therapeutic interventions that target the right gene or gene products could reverse aging, at the very least in the population of older people with poor health.
PubMed: 35083451
DOI: 10.31491/apt.2021.03.048 -
Frontiers in Psychiatry 2022Conventional monoamine-based pharmacotherapy, considered the first-line treatment for major depressive disorder (MDD), has several challenges, including high rates of... (Review)
Review
Conventional monoamine-based pharmacotherapy, considered the first-line treatment for major depressive disorder (MDD), has several challenges, including high rates of non-response. To address these challenges, preclinical and clinical studies have sought to characterize antidepressant response through monoamine-independent mechanisms. One striking example is glutamate, the brain's foremost excitatory neurotransmitter: since the 1990s, studies have consistently reported altered levels of glutamate in MDD, as well as antidepressant effects following molecular targeting of glutamatergic receptors. Therapeutically, this has led to advances in the discovery, testing, and clinical application of a wide array of glutamatergic agents, particularly ketamine. Notably, ketamine has been demonstrated to rapidly improve mood symptoms, unlike monoamine-based interventions, and the neurobiological basis behind this rapid antidepressant response is under active investigation. Advances in brain imaging techniques, including functional magnetic resonance imaging, magnetic resonance spectroscopy, and positron emission tomography, enable the identification of the brain network-based characteristics distinguishing rapid glutamatergic modulation from the effect of slow-acting conventional monoamine-based pharmacology. Here, we review brain imaging studies that examine brain connectivity features associated with rapid antidepressant response in MDD patients treated with glutamatergic pharmacotherapies in contrast with patients treated with slow-acting monoamine-based treatments. Trends in recent brain imaging literature suggest that the activity of brain regions is organized into coherent functionally distinct networks, termed intrinsic connectivity networks (ICNs). We provide an overview of major ICNs implicated in depression and explore how treatment response following glutamatergic modulation alters functional connectivity of limbic, cognitive, and executive nodes within ICNs, with well-characterized anti-anhedonic effects and the enhancement of "top-down" executive control. Alterations within and between the core ICNs could potentially exert downstream effects on the nodes within other brain networks of relevance to MDD that are structurally and functionally interconnected through glutamatergic synapses. Understanding similarities and differences in brain ICNs features underlying treatment response will positively impact the trajectory and outcomes for adults suffering from MDD and will facilitate the development of biomarkers to enable glutamate-based precision therapeutics.
PubMed: 35722550
DOI: 10.3389/fpsyt.2022.864902 -
Frontiers in Neuroscience 2014In this article we present a review of current literature on adaptations to altered head-related auditory localization cues. Localization cues can be altered through ear... (Review)
Review
In this article we present a review of current literature on adaptations to altered head-related auditory localization cues. Localization cues can be altered through ear blocks, ear molds, electronic hearing devices, and altered head-related transfer functions (HRTFs). Three main methods have been used to induce auditory space adaptation: sound exposure, training with feedback, and explicit training. Adaptations induced by training, rather than exposure, are consistently faster. Studies on localization with altered head-related cues have reported poor initial localization, but improved accuracy and discriminability with training. Also, studies that displaced the auditory space by altering cue values reported adaptations in perceived source position to compensate for such displacements. Auditory space adaptations can last for a few months even without further contact with the learned cues. In most studies, localization with the subject's own unaltered cues remained intact despite the adaptation to a second set of cues. Generalization is observed from trained to untrained sound source positions, but there is mixed evidence regarding cross-frequency generalization. Multiple brain areas might be involved in auditory space adaptation processes, but the auditory cortex (AC) may play a critical role. Auditory space plasticity may involve context-dependent cue reweighting.
PubMed: 25120422
DOI: 10.3389/fnins.2014.00219 -
Clinical and Experimental... 2015Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by recurrent abdominal pain and abnormal bowel patterns. Alteration in gut... (Review)
Review
Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by recurrent abdominal pain and abnormal bowel patterns. Alteration in gut flora, visceral hypersensitivity, and abnormal bowel motility are among numerous factors in the complex pathophysiology of IBS. Antibiotics have been used adjunctively to treat IBS for many years but are associated with various systemic side effects. Rifaximin is a nonabsorbable, broad-spectrum antimicrobial that inhibits bacterial RNA synthesis by binding the β-subunit of microbial RNA polymerase. It targets the gastrointestinal tract and works by reducing the quantity of gas-producing bacteria and altering the predominant species of bacteria present. In vivo animal studies suggest additional beneficial mechanisms of rifaximin, including reducing mucosal inflammation and visceral hypersensitivity. Clinical studies have demonstrated that rifaximin improves symptoms associated with IBS, such as bloating, flatulence, stool consistency, and abdominal pain, and has a side-effect profile similar to placebo. Although additional investigation into optimal dosing, treatment duration, and potential resistance is required, rifaximin presents as a safe and beneficial addition to the current management options for IBS.
PubMed: 26089696
DOI: 10.2147/CEG.S67231 -
Neurogastroenterology and Motility Apr 2022Determine whether subjects with chronic nausea and orthostatic intolerance share common alterations in key brain networks associated with central autonomic control:...
BACKGROUND
Determine whether subjects with chronic nausea and orthostatic intolerance share common alterations in key brain networks associated with central autonomic control: default mode, salience, and central executive networks, and the insula, a key component of the salience network.
METHODS
Ten subjects (ages 12-18 years; 8 females, 2 males) with nausea predominant dyspepsia, orthostatic intolerance, and abnormal head-upright tilt test were consecutively recruited from pediatric gastroenterology clinic. These subjects were compared with healthy controls (n = 8) without GI symptoms or orthostatic intolerance. Resting-state fMRI and brain network modularity analyses were performed. Differences in the default mode, salience, and central executive networks, and insular connectivity were measured.
KEY RESULTS
The community structure of the default mode network and salience network was significantly different between tilt-abnormal children and controls (p = 0.034 and 0.012, respectively), whereas, no group difference was observed in the central executive network (p = 0.48). The default mode network was more consistently "intact," and the consistency of the community structure in the salience network was reduced in tilt-abnormal children, especially in the insula.
CONCLUSIONS AND INFERENCES
Children with chronic nausea and orthostatic intolerance have altered connectivity in the default mode network and salience network/insula, which supports over-monitoring of their body and altered processing of bodily states resulting in interoceptive hyper self-awareness. The connectivity of the salience network would not support optimal regulation of appropriate attention to internal and external stimuli, and the hyper-connected default mode network may result in a persistent self-referential state with feelings of emotion, pain, and anxiety.
Topics: Adolescent; Brain; Brain Mapping; Case-Control Studies; Child; Female; Humans; Magnetic Resonance Imaging; Male; Nausea; Nerve Net; Orthostatic Intolerance
PubMed: 34606665
DOI: 10.1111/nmo.14271 -
Neurogastroenterology and Motility Jul 2023The Chicago classification primarily utilizes ten 5 mL liquid swallows in a supine position as the standard high-resolution esophageal manometry (HRM) protocol. HRM...
BACKGROUND
The Chicago classification primarily utilizes ten 5 mL liquid swallows in a supine position as the standard high-resolution esophageal manometry (HRM) protocol. HRM can be performed with varying volumes and consistencies and in an upright position. We aimed to determine the impact on HRM results by (1) position, (2) swallows of differing volume and consistency, and (3) perception of bolus passage.
METHODS
HRM was performed in healthy volunteers (HV) with the following protocol of swallows: liquids 10 × 5 mL, 5 × 10 mL, and 3 × 10 mL multiple rapid swallows; applesauce 5 × 5 mL and 5 × 10 mL; and bread 5 × 2 × 2 cm and 5 × 4 × 4cm. HV rated difficulty of each swallow on a 5-point Likert scale. All HVs performed the protocol in supine position first and then in "semi-upright" (sitting 70 degrees in a bed) and "upright" (sitting in a chair) in a randomized order.
KEY RESULTS
Thirty-seven HVs, median age 27 years, 64% female completed this study. Median distal contractile integral (DCI) and integrated relaxation pressure 4 s (IRP4) of 5 mL liquid swallows significantly differed (all p < 0.01) between position performed. Large volume swallows resulted in higher DCI and lower IRP4. IRP4 results were significantly increased for 2 × 2 cm pieces of bread compared to 5 mL water swallows. DCI results were higher for 2 × 2 cm pieces of bread compared to 5 mL water swallows. Distal latency was shorter in more upright positions. Among this cohort of HV, perceived difficulty of bolus passage was more likely to occur with solid boluses.
CONCLUSIONS AND INFERENCES
The volume and consistency of a swallow and the position it is performed in, significantly alter HRM metrics. Interpretation of HRM studies should incorporate different normative values which are specific to the position and bolus type.
Topics: Humans; Female; Adult; Male; Deglutition; Esophagus; Manometry; Sitting Position; Water; Esophageal Motility Disorders
PubMed: 37036395
DOI: 10.1111/nmo.14593