Mullenhardison7842

The brain shows a complex multiscale organization that prevents a direct understanding of how structure, function and dynamics are correlated. To date, advances in neural modeling offer a unique opportunity for simulating global brain dynamics by embedding empirical data on different scales in a mathematical framework. The Virtual Brain (TVB) is an advanced data-driven model allowing to simulate brain dynamics starting from individual subjects' structural and functional connectivity obtained, for example, from magnetic resonance imaging (MRI). The use of TVB has been limited so far to cerebral connectivity but here, for the first time, we have introduced cerebellar nodes and interconnecting tracts to demonstrate the impact of cerebro-cerebellar loops on brain dynamics. Indeed, the matching between the empirical and simulated functional connectome was significantly improved when including the cerebro-cerebellar loops. This positive result should be considered as a first step, since issues remain open about the best strategy to reconstruct effective structural connectivity and the nature of the neural mass or mean-field models generating local activity in the nodes. For example, signal processing is known to differ remarkably between cortical and cerebellar microcircuits. Tackling these challenges is expected to further improve the predictive power of functional brain activity simulations, using TVB or other similar tools, in explaining not just global brain dynamics but also the role of cerebellum in determining brain states in physiological conditions and in the numerous pathologies affecting the cerebro-cerebellar loops.For a long time, post-mortem analysis of human brain pathologies has been purely descriptive, limiting insight into the pathological mechanisms. However, starting in the early 2000s, next-generation sequencing (NGS) and the routine application of bulk RNA-sequencing and microarray technologies have revolutionized the usefulness of post-mortem human brain tissue. This has allowed many studies to provide novel mechanistic insights into certain brain pathologies, albeit at a still unsatisfying resolution, with masking of lowly expressed genes and regulatory elements in different cell types. The recent rapid evolution of single-cell technologies has now allowed researchers to shed light on human pathologies at a previously unreached resolution revealing further insights into pathological mechanisms that will open the way for the development of new strategies for therapies. BLU9931 mouse In this review article, we will give an overview of the incremental information that single-cell technologies have given us for human white matter (WM) pathologies, summarize which single-cell technologies are available, and speculate where these novel approaches may lead us for pathological assessment in the future.The fibroblast growth factor (FGF) family polypeptides play key roles in promoting tissue regeneration and repair. FGF5 is strongly up-regulated in Schwann cells of the peripheral nervous system following injury; however, a role for FGF5 in peripheral nerve regeneration has not been shown up to now. In this report, we examined the expression of FGF5 and its receptors FGFR1-4 in Schwann cells of the mouse sciatic nerve following injury, and then measured the effects of FGF5 treatment upon cultured primary rat Schwann cells. By microarray and mRNA sequencing data analysis, RT-PCR, qPCR, western blotting and immunostaining, we show that FGF5 is highly up-regulated in Schwann cells of the mouse distal sciatic nerve following injury, and FGFR1 and FGFR2 are highly expressed in Schwann cells of the peripheral nerve both before and following injury. Using cultured primary rat Schwann cells, we show that FGF5 inhibits ERK1/2 MAP kinase activity but promotes rapid Schwann cell migration and adhesion via the upregulation of N-cadherin. Thus, FGF5 is an autocrine regulator of Schwann cells to regulate Schwann cell migration and adhesion.The inferior colliculus (IC) is an auditory midbrain structure involved in processing biologically important temporal features of sounds. The responses of IC neurons to these temporal features reflect an interaction of synaptic inputs and neuronal biophysical properties. One striking biophysical property of IC neurons is the rebound depolarization produced following membrane hyperpolarization. To understand how the rebound depolarization is involved in spike timing, we made whole-cell patch clamp recordings from IC neurons in brain slices of P9-21 rats. We found that the percentage of rebound neurons was developmentally regulated. The precision of the timing of the first spike on the rebound increased when the neuron was repetitively injected with a depolarizing current following membrane hyperpolarization. The average jitter of the first spikes was only 0.5 ms. The selective T-type Ca2+ channel antagonist, mibefradil, significantly increased the jitter of the first spike of neurons in response to repetitive depolarization following membrane hyperpolarization. Furthermore, the rebound was potentiated by one to two preceding rebounds within a few hundred milliseconds. The first spike generated on the potentiated rebound was more precise than that on the non-potentiated rebound. With the addition of a calcium chelator, BAPTA, into the cell, the rebound potentiation no longer occurred, and the precision of the first spike on the rebound was not improved. These results suggest that the postinhibitory rebound mediated by T-type Ca2+ channel promotes spike timing precision in IC neurons. The rebound potentiation and precise spikes may be induced by increases in intracellular calcium levels.Hearing loss is the third most common chronic health condition in the United States and largely results from damage to sensory hair cells. Major causes of hair cell damage include aging, noise exposure, and medications such as aminoglycoside antibiotics. Due to their potent antibacterial properties and low cost, aminoglycosides are often used for the treatment of gram-negative bacterial infections, surpassing expensive antibiotics with fewer harmful side effects. However, their use is coupled with permanent hearing loss in over 20% of patients requiring these life-sustaining antibiotics. There are currently no FDA-approved drugs that prevent hearing loss from aminoglycosides. A previous study by our group identified the plant alkaloid berbamine as a strong protectant of zebrafish lateral line hair cells from aminoglycoside damage. This effect is likely due to a block of the mechanotransduction channel, thereby reducing aminoglycoside entry into hair cells. The present study builds on this previous work, invesse analogs exhibited protection when delivered after aminoglycoside removal. Based on our studies, berbamine analogs represent a promising tool to further understand the pathology of aminoglycoside-induced hearing loss and can serve as lead compounds to develop otoprotective drugs.Dominant, missense mutations in the widely and constitutively expressed GARS1 gene cause peripheral neuropathy that usually begins in adolescence and principally impacts the upper limbs. Caused by a toxic gain-of-function in the encoded glycyl-tRNA synthetase (GlyRS) enzyme, the neuropathology appears to be independent of the canonical role of GlyRS in aminoacylation. Patients display progressive, life-long weakness and wasting of muscles in hands followed by feet, with frequently associated deficits in sensation. When dysfunction is observed in motor and sensory nerves, there is a diagnosis of Charcot-Marie-Tooth disease type 2D (CMT2D), or distal hereditary motor neuropathy type V if the symptoms are purely motor. The cause of this varied sensory involvement remains unresolved, as are the pathomechanisms underlying the selective neurodegeneration characteristic of the disease. We have previously identified in CMT2D mice that neuropathy-causing Gars mutations perturb sensory neuron fate and permit mutant GlyRS to aberrantly interact with neurotrophin receptors (Trks). Here, we extend this work by interrogating further the anatomy and function of the CMT2D sensory nervous system in mutant Gars mice, obtaining several key results (1) sensory pathology is restricted to neurons innervating the hindlimbs; (2) perturbation of sensory development is not common to all mouse models of neuromuscular disease; (3) in vitro axonal transport of signaling endosomes is not impaired in afferent neurons of all CMT2D mouse models; and (4) Gars expression is selectively elevated in a subset of sensory neurons and linked to sensory developmental defects. These findings highlight the importance of comparative neurological assessment in mouse models of disease and shed light on key proposed neuropathogenic mechanisms in GARS1-linked neuropathy.Ferroptosis is an iron-dependent form of cell death characterized by the accumulation of intracellular lipid reactive oxygen species (ROS). Ferroptosis is significantly different from other types of cell death including apoptosis, autophagy, and necrosis, both in morphology and biochemical characteristics. The mechanisms that are associated with ferroptosis include iron metabolism, lipid oxidation, and other pathophysiological changes. Ferroptosis inducers or inhibitors can influence its occurrence through different pathways. Ferroptosis was initially discovered in tumors, though recent studies have confirmed that it is also closely related to a variety of neurological diseases including neurodegenerative disease [Alzheimer's disease (AD), Parkinson's disease (PD), etc.] and stroke. This article reviews the definition and characteristics of ferroptosis, the potential mechanisms associated with its development, inducers/inhibitors, and its role in non-neoplastic neurological diseases. We hope to provide a theoretical basis and novel treatment strategies for the treatment of central nervous system diseases by targeting ferroptosis.Coronavirus disease (CoVID-19), caused by recently identified severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2), is characterized by inconsistent clinical presentations. While many infected individuals remain asymptomatic or show mild respiratory symptoms, others develop severe pneumonia or even respiratory distress syndrome. SARS-CoV-2 is reported to be able to infect the lungs, the intestines, blood vessels, the bile ducts, the conjunctiva, macrophages, T lymphocytes, the heart, liver, kidneys, and brain. More than a third of cases displayed neurological involvement, and many severely ill patients developed multiple organ infection and injury. However, less than 1% of patients had a detectable level of SARS-CoV-2 in the blood, raising a question of how the virus spreads throughout the body. We propose that nerve terminals in the orofacial mucosa, eyes, and olfactory neuroepithelium act as entry points for the brain invasion, allowing SARS-CoV-2 to infect the brainstem. By exploiting the subcellular membrane compartments of infected cells, a feature common to all coronaviruses, SARS-CoV-2 is capable to disseminate from the brain to periphery via vesicular axonal transport and passive diffusion through axonal endoplasmic reticula, causing multiple organ injury independently of an underlying respiratory infection. The proposed model clarifies a wide range of clinically observed phenomena in CoVID-19 patients, such as neurological symptoms unassociated with lung pathology, protracted presence of the virus in samples obtained from recovered patients, exaggerated immune response, and multiple organ failure in severe cases with variable course and dynamics of the disease. We believe that this model can provide novel insights into CoVID-19 and its long-term sequelae, and establish a framework for further research.