Rodent models of knee osteoarthritis for pain research.

Osteoarthritis (OA) is a chronic degenerative joint disease and a leading cause of disability worldwide. Pain is the main symptom, yet no current treatment can halt disease progression or effectively provide symptomatic relief. Numerous animal models have been described for studying OA and some for the associated OA pain.

Anoctamin 1/TMEM16A in pruritoceptors is essential for Mas-related G protein receptor-dependent itch.

Itch is an unpleasant sensation that evokes a desire to scratch. Pathologic conditions such as allergy or atopic dermatitis produce severe itching sensation. Mas-related G protein receptors (Mrgprs) are receptors for many endogenous pruritogens.

Human cortical interneuron development unraveled.

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Calcium imaging for analgesic drug discovery.

Somatosensation and pain are complex phenomena involving a rangeofspecialised cell types forming different circuits within the peripheral and central nervous systems. In recent decades, advances in the investigation of these networks, as well as their function in sensation, resulted from the constant evolution of electrophysiology and imaging techniques to allow the observation of cellular activity at the population level both and . Genetically encoded indicators of neuronal activity, combined with recent advances in DNA engineering and modern microscopy, offer powerful tools to dissect and visualise the activity of specific neuronal subpopulations with high spatial and temporal resolution.

Nav1.7 is required for normal C-low threshold mechanoreceptor function in humans and mice.

Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 present with congenital insensitivity to pain (CIP), whilst low threshold mechanosensation is reportedly normal. Using psychophysics (n = 6 CIP participants and n = 86 healthy controls) and facial electromyography (n = 3 CIP participants and n = 8 healthy controls), we found that these patients also have abnormalities in the encoding of affective touch, which is mediated by the specialized afferents C-low threshold mechanoreceptors (C-LTMRs).

Intracellularly Released Cholesterol from Polymer-Based Delivery Systems Alters Cellular Responses to Pneumolysin and Promotes Cell Survival.

Cholesterol is highly abundant within all human body cells and modulates critical cellular functions related to cellular plasticity, metabolism, and survival. The cholesterol-binding toxin pneumolysin represents an essential virulence factor of in establishing pneumonia and other pneumococcal infections. Thus, cholesterol scavenging of pneumolysin is a promising strategy to reduce   induced lung damage.

Cannabidiol activates PINK1-Parkin-dependent mitophagy and mitochondrial-derived vesicles.

The PINK1/Parkin pathway plays an important role in maintaining a healthy pool of mitochondria. Activation of this pathway can lead to apoptosis, mitophagy, or mitochondrial-derived vesicle formation, depending on the nature of mitochondrial damage. The signaling by which PINK/Parkin activation leads to these different mitochondrial outcomes remains understudied.

Chemical approach to generating long-term self-renewing pMN progenitors from human embryonic stem cells.

Spinal cord impairment involving motor neuron degeneration and demyelination can cause lifelong disabilities, but effective clinical interventions for restoring neurological functions have yet to be developed. In early spinal cord development, neural progenitors of the motor neuron (pMN) domain, defined by the expression of oligodendrocyte transcription factor 2 (OLIG2), in the ventral spinal cord first generate motor neurons and then switch the fate to produce myelin-forming oligodendrocytes. Given their differentiation potential, pMN progenitors could be a valuable cell source for cell therapy in relevant neurological conditions such as spinal cord injury.

Target specificity of selective bioactive compounds in blocking α-dystroglycan receptor to suppress Lassa virus infection: an approach.

Lassa hemorrhagic fever, caused by Lassa mammarenavirus (LASV) infection, accumulates up to 5000 deaths every year. Currently, there is no vaccine available to combat this disease. In this study, a library of 200 bioactive compounds was virtually screened to study their drug-likeness with the capacity to block the α-dystroglycan (α-DG) receptor and prevent LASV influx.

Homer1a regulates Shank3 expression and underlies behavioral vulnerability to stress in a model of Phelan-McDermid syndrome.

Mutations of SHANK3 cause Phelan-McDermid syndrome (PMS), and these individuals can exhibit sensitivity to stress, resulting in behavioral deterioration. Here, we examine the interaction of stress with genotype using a mouse model with face validity to PMS. In Shank3 mice, swim stress produces an altered transcriptomic response in pyramidal neurons that impacts genes and pathways involved in synaptic function, signaling, and protein turnover.

Pain, purines and Geoff.

The story of purinergic neurotransmission and regulation is intimately linked to studies of the somatosensory system. Burnstock's contributions to the discovery of ATP as a primary afferent neurotransmitter, as well as a signal of peripheral tissue damage that depolarised sensory neurons initiated a new period of pain research. The neuro-immune interactions that occur after tissue damage and are important for pain have now also been found to involve purinergic signalling, and adenosine has been demonstrated to have significant analgesic effects.

Neutralization of Hv1/HVCN1 With Antibody Enhances Microglia/Macrophages Myelin Clearance by Promoting Their Migration in the Brain.

Microglia dynamically monitor the microenvironment of the central nervous system (CNS) by constantly extending and retracting their processes in physiological conditions, and microglia/macrophages rapidly migrate into lesion sites in response to injuries or diseases in the CNS. Consequently, their migration ability is fundamentally important for their proper functioning. However, the mechanisms underlying their migration have not been fully understood.

A synaptic learning rule for exploiting nonlinear dendritic computation.

Information processing in the brain depends on the integration of synaptic input distributed throughout neuronal dendrites. Dendritic integration is a hierarchical process, proposed to be equivalent to integration by a multilayer network, potentially endowing single neurons with substantial computational power. However, whether neurons can learn to harness dendritic properties to realize this potential is unknown.

Peptides Derived from Vascular Endothelial Growth Factor B Show Potent Binding to Neuropilin-1.

Vascular endothelial growth factors (VEGFs) regulate significant pathways in angiogenesis, myocardial and neuronal protection, metabolism, and cancer progression. The VEGF-B growth factor is involved in cell survival, anti-apoptotic and antioxidant mechanisms, through binding to VEGF receptor 1 and neuropilin-1 (NRP1). We employed surface plasmon resonance technology and X-ray crystallography to analyse the molecular basis of the interaction between VEGF-B and the b1 domain of NRP1, and developed VEGF-B C-terminus derived peptides to be used as chemical tools for studying VEGF-B - NRP1 related pathways.

G protein-coupled receptor GPR37-like 1 regulates adult oligodendrocyte generation.

Oligodendrocytes (OLs) continue to be generated from OL precursors (OPs) in the adult mammalian brain. Adult-born OLs are believed to contribute to neural plasticity, learning and memory through a process of "adaptive myelination," but how adult OL generation and adaptive myelination are regulated remains unclear. Here, we report that the glia-specific G protein-coupled receptor 37-like 1 (GPR37L1) is expressed in subsets of OPs and newly formed immature OLs in adult mouse brain.

Structural and Lipidomic Alterations of Striatal Myelin in 16p11.2 Deletion Mouse Model of Autism Spectrum Disorder.

Myelin abnormalities have been observed in autism spectrum disorder (ASD). In this study, we seek to discover myelin-related changes in the striatum, a key brain region responsible for core ASD features, using the 16p11.2 deletion (16p11.

Oligodendrocyte HCN2 Channels Regulate Myelin Sheath Length.

Oligodendrocytes generate myelin sheaths vital for the formation, health, and function of the CNS. Myelin sheath length is a key property that determines axonal conduction velocity and is known to be variable across the CNS. Myelin sheath length can be modified by neuronal activity, suggesting that dynamic regulation of sheath length might contribute to the functional plasticity of neural circuits.

Scanned optogenetic control of mammalian somatosensory input to map input-specific behavioral outputs.

Somatosensory stimuli guide and shape behavior, from immediate protective reflexes to longer-term learning and higher-order processes related to pain and touch. However, somatosensory inputs are challenging to control in awake mammals due to the diversity and nature of contact stimuli. Application of cutaneous stimuli is currently limited to relatively imprecise methods as well as subjective behavioral measures.

Active dendrites enable strong but sparse inputs to determine orientation selectivity.

The dendrites of neocortical pyramidal neurons are excitable. However, it is unknown how synaptic inputs engage nonlinear dendritic mechanisms during sensory processing in vivo, and how they in turn influence action potential output. Here, we provide a quantitative account of the relationship between synaptic inputs, nonlinear dendritic events, and action potential output.

Nutritional regulation of oligodendrocyte differentiation regulates perineuronal net remodeling in the median eminence.

The mediobasal hypothalamus (MBH; arcuate nucleus of the hypothalamus [ARH] and median eminence [ME]) is a key nutrient sensing site for the production of the complex homeostatic feedback responses required for the maintenance of energy balance. Here, we show that refeeding after an overnight fast rapidly triggers proliferation and differentiation of oligodendrocyte progenitors, leading to the production of new oligodendrocytes in the ME specifically. During this nutritional paradigm, ME perineuronal nets (PNNs), emerging regulators of ARH metabolic functions, are rapidly remodeled, and this process requires myelin regulatory factor (Myrf) in oligodendrocyte progenitors.

Reversal of behavioural phenotype by the cannabinoid-like compound VSN16R in fragile X syndrome mice.

Fragile X syndrome is the most common inherited intellectual disability and mono-genetic cause of autism spectrum disorder. It is a neurodevelopmental condition occurring due to a CGG trinucleotide expansion in the FMR1 gene. Polymorphisms and variants in large-conductance calcium-activated potassium channels are increasingly linked to intellectual disability and loss of FMR protein causes reduced large-conductance calcium-activated potassium channel activity leading to abnormalities in synapse function.