Spherical harmonic based noise rejection and neuronal sampling with multi-axis OPMs

In this study we explore the interference rejection and spatial sampling properties of multi-axis Optically Pumped Magnetometer (OPM) data. We use both vector spherical harmonics and eigenspectra to quantify how well an array can separate neuronal signal from environmental interference while adequately sampling the entire cortex. We found that triaxial OPMs have superb noise rejection properties allowing for very high orders of interference (L=6) to be accounted for while minimally affecting the neural space (2dB attenuation for a 60-sensor triaxial system). To adequately model the signals arising from the cortex, we show that at least 11th order (143 spatial degrees of freedom) irregular solid harmonics or 95 eigenvectors of the lead field are needed to model the neural space for OPM data (regardless of number of axes measured). This can be adequately sampled with 75-100 equidistant triaxial sensors (225-300 channels) or 200 equidistant radial channels. In other words, ordering the same number of channels in triaxial (rather than purely radial) configuration gives significant advantages not only in terms of external noise rejection but also minimizes cost, weight and cross-talk.

FKN/CX3CR1 Axis Facilitated Migraine-like Behaviors via Activating Thalamic-cortical Network Microglia in SE Rat Models

Background: The incidence of migraines is higher among people with epilepsy than healthy people, and these two common diseases are proposed to have some shared pathophysiological mechanisms. Excitation/inhibition imbalance plays an essential role in the comorbidity of epilepsy and migraine. Microglia activation is crucial for abnormal neuronal signal transmission. However, whether and how microglia are activated, and their role in comorbidities after activation remains unclear. This study aimed to explore the characteristics and mechanism of microglia activation after seizures and its effect on migraine.Methods: Status epilepticus (SE) rat models induced by lithium chloride (LiCl)-pilocarpine intraperitoneal injection and migraine rat models induced by repeated inflammatory soup (IS) dural injections were generated and assessed for molecular and histopathologic evidence of microglial activation target of fractalkine (FKN) signaling. HT22-BV2 transwell coculture was used to explore the interaction between neurons and microglia. LPS (a microglia agonist) and FKN stimulation of BV2 microglia cells were used to evaluate changes in BDNF content after microglia activation.Results: Microglia were specifically hyperplasia and activation in the cortical-thalamus-sp5c neural circuit, which were pain-related brain regions, accompanied by the upregulation of FKN and CX3CR1 four days after seizures. Meanwhile, SE-induced increased nociceptive behavior and the FKN/CX3CR1 axis in migraine rat models. AZD8797 (a CX3CR1 inhibitor) prevented the worsening of hyperalgesia and microglia activation in migraine rat models after seizures, while FKN infusion in migraine rat models exacerbated hyperalgesia and microglia activation associated with BDNF-Trkb signaling. Furthermore, in neuron-BV2 coculture, microglial activation and FKN/CX3CR1/BDNF/iba1 expression were increased. Activating microglia with LPS and FKN stimulation increased BDNF synthesis in BV2 microglia.Conclusions: Our results indicated that epilepsy facilitated migraine through the cortical-thalamus-sp5c microglia activated and interactions with neurons by the FKN/CX3CR1 axis, resulting in BDNF release. Blocking the FKN/CX3CR1 axis and microglia activation are potential therapeutic targets for preventing and treating migraine in patients with epilepsy.

The secreted neuronal signal Spock1 regulates the blood-brain barrier

The blood-brain barrier (BBB) is comprised of a single layer of endothelial cells with uniquely restrictive properties required for maintaining a tightly controlled homeostatic environment in the brain. Classic quail-chick grafting experiments showed that BBB properties are not intrinsic to brain endothelial cells, but instead are induced by signals from the embryonic brain microenvironment. Here we have identified a neuronally produced signal, Spock1, that specifically regulates BBB functional development in both zebrafish and mice without affecting angiogenesis. Using a combination of mosaic genetic analysis, tracer leakage assays and live imaging we show that Spock1 from neurons can regulate brain vasculature permeability non-cell autonomously. Electron microscopy analyses of spock1 mutants revealed that the leakage arises predominantly through increased endothelial transcytosis of both clathrin-independent small and large vesicles due to altered pericyte-endothelial interactions. Single-cell RNA sequencing analyses revealed a reduction in vascular expression of the cell adhesion molecule mcamb in the spock1 mutants, and this down-regulation of mcamb occurred specifically in regions with increased BBB leakage. These analyses indicate that the neuronal signal Spock1 regulates BBB properties by altering vascular gene expression and cellular interactions.

SOLITARY TRANSMISSION OF NEURONAL SIGNALS APPROACHED VIA HE'S SEMI INVERSE METHOD

An investigation of neuronal signal transmission is intended in this paper through the establishment of solitary wave solutions for the improved Heimburg Jackson model governing the propagation of the mechanical wave in biomembranes. The computation of soliton solutions is carried out employing He's semi inverse variational principle. The role of nonlinearity and dispersive effects in the solitonic propation is correlated to the role of compressibility, elasticity, and inertia over the neuronal signal transmission in the unilamellar DPPC vesicles at T = 45o. The study reveals that He's semi inverse method is a direct and effective algebraic method to study the experimental features of the nerve pulse in the biomembranes.

Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses

G protein-coupled receptors (GPCRs) regulate multiple processes ranging from cell growth and immune responses to neuronal signal transmission. However, ligands for many GPCRs remain unknown, suffer from off-target effects or have poor bioavailability. Additional challenges exist to dissect cell type-specific responses when the same GPCR is expressed on different cells within the body. Here, we overcome these limitations by engineering DREADD-based GPCR chimeras that selectively bind their agonist clozapine-N-oxide (CNO) and mimic a GPCR-of-interest. We show that the chimeric DREADD-β2-adrenergic receptor (β2AR/ADRB2) triggers comparable responses to levalbuterol on second messenger and kinase activity, post-translational modifications, and protein-protein interactions. Moreover, we successfully recapitulate β2AR-mediated filopodia formation in microglia, a β2AR-expressing immune cell that can drive inflammation in the nervous system. To further dissect microglial inflammation, we compared DREADD-β2AR with two additionally designed DREADD-based chimeras mimicking GPR65 and GPR109A/HCAR2, both enriched in microglia. DREADD-β2AR and DREADD-GPR65 modulate the inflammatory response with a similar profile as endogenously expressed β2AR, while DREADD-GPR109A had no impact. Our DREADD-based approach allows investigation of cell type-dependent signaling pathways and function without known endogenous ligands.

Three-micrometer-diameter needle electrode with an amplifier for extracellular in vivo recordings

Microscale needle-electrode devices offer neuronal signal recording capability in brain tissue; however, using needles of smaller geometry to minimize tissue damage causes degradation of electrical properties, including high electrical impedance and low signal-to-noise ratio (SNR) recording. We overcome these limitations using a device assembly technique that uses a single needle-topped amplifier package, called STACK, within a device of ∼1 × 1 mm2. Based on silicon (Si) growth technology, a <3-µm-tip-diameter, 400-µm-length needle electrode was fabricated on a Si block as the module. The high electrical impedance characteristics of the needle electrode were improved by stacking it on the other module of the amplifier. The STACK device exhibited a voltage gain of >0.98 (−0.175 dB), enabling recording of the local field potential and action potentials from the mouse brain in vivo with an improved SNR of 6.2. Additionally, the device allowed us to use a Bluetooth module to demonstrate wireless recording of these neuronal signals; the chronic experiment was also conducted using STACK-implanted mice.

Axonal chemokine-like Orion induces astrocyte infiltration and engulfment during mushroom body neuronal remodeling

The remodeling of neurons is a conserved fundamental mechanism underlying nervous system maturation and function. Astrocytes can clear neuronal debris and they have an active role in neuronal remodeling. Developmental axon pruning ofDrosophilamemory center neurons occurs via a degenerative process mediated by infiltrating astrocytes. However, how astrocytes are recruited to the axons during brain development is unclear. Using an unbiased screen, we identify the gene requirement oforion, encoding for a chemokine-like protein, in the developing mushroom bodies. Functional analysis shows that Orion is necessary for both axonal pruning and removal of axonal debris. Orion performs its functions extracellularly and bears some features common to chemokines, a family of chemoattractant cytokines. We propose that Orion is a neuronal signal that elicits astrocyte infiltration and astrocyte-driven axonal engulfment required during neuronal remodeling in theDrosophiladeveloping brain.

Spontaneous Ca2+ Fluctuations Arise in Thin Astrocytic Processes With Real 3D Geometry

Fluctuations of cytosolic Ca2+ concentration in astrocytes are regarded as a critical non-neuronal signal to regulate neuronal functions. Although such fluctuations can be evoked by neuronal activity, rhythmic astrocytic Ca2+ oscillations may also spontaneously arise. Experimental studies hint that these spontaneous astrocytic Ca2+ oscillations may lie behind different kinds of emerging neuronal synchronized activities, like epileptogenic bursts or slow-wave rhythms. Despite the potential importance of spontaneous Ca2+ oscillations in astrocytes, the mechanism by which they develop is poorly understood. Using simple 3D synapse models and kinetic data of astrocytic Glu transporters (EAATs) and the Na+/Ca2+ exchanger (NCX), we have previously shown that NCX activity alone can generate markedly stable, spontaneous Ca2+ oscillation in the astrocytic leaflet microdomain. Here, we extend that model by incorporating experimentally determined real 3D geometries of 208 excitatory synapses reconstructed from publicly available ultra-resolution electron microscopy datasets. Our simulations predict that the surface/volume ratio (SVR) of peri-synaptic astrocytic processes prominently dictates whether NCX-mediated spontaneous Ca2+ oscillations emerge. We also show that increased levels of intracellular astrocytic Na+ concentration facilitate the appearance of Ca2+ fluctuations. These results further support the principal role of the dynamical reshaping of astrocyte processes in the generation of intrinsic Ca2+ oscillations and their spreading over larger astrocytic compartments.