Optogenetic control of human neurons in organotypic brain cultures

Optogenetics is one of the most powerful tools in neuroscience, allowing for selective control of specific neuronal populations in the brain of experimental animals, including mammals. We report, for the first time, the application of optogenetic tools to human brain tissue providing a proof-of-concept for the use of optogenetics in neuromodulation of human cortical and hippocampal neurons as a possible tool to explore network mechanisms and develop future therapeutic strategies

Lynx1 and Aβ1–42 bind competitively to multiple nicotinic acetylcholine receptor subtypes

AbstractLynx1 regulates synaptic plasticity in the brain by regulating nicotinic acetylcholine receptors (nAChRs). It is not known to which extent Lynx1 can bind to endogenous nAChR subunits in the brain or how this interaction is affected by Alzheimer's disease pathology. We apply affinity purification to demonstrate that a water-soluble variant of human Lynx1 (Ws-Lynx1) isolates α3, α4, α5, α6, α7, β2, and β4 nAChR subunits from human and rat cortical extracts, and rat midbrain and olfactory bulb extracts, suggesting that Lynx1 forms complexes with multiple nAChR subtypes in the human and rodent brain. Incubation with Ws-Lynx1 decreases nicotine-mediated extracellular signal–regulated kinase phosphorylation in PC12 cells and striatal neurons, indicating that binding of Ws-Lynx1 is sufficient to inhibit signaling downstream of nAChRs. The effect of nicotine in PC12 cells is independent of α7 or α4β2 nAChRs, suggesting that Lynx1 can affect the function of native non-α7, non-α4β2 nAChR subtypes. We further show that Lynx1 and oligomeric β-amyloid1–42 compete for binding to several nAChR subunits, that Ws-Lynx1 prevents β-amyloid1–42–induced cytotoxicity in cortical neurons, and that cortical Lynx1 levels are decreased in a transgenic mouse model with concomitant β-amyloid and tau pathology. Our data suggest that Lynx1 binds to multiple nAChR subtypes in the brain and that this interaction might have functional and pathophysiological implications in relation to Alzheimer's disease

GDNF Increases Inhibitory Synaptic Drive on Principal Neurons in the Hippocampus via Activation of the Ret Pathway

Glial cell line-derived neurotrophic factor (GDNF) has been shown to counteract seizures when overexpressed or delivered into the brain in various animal models of epileptogenesis or chronic epilepsy. The mechanisms underlying this effect have not been investigated. We here demonstrate for the first time that GDNF enhances GABAergic inhibitory drive onto mouse pyramidal neurons by modulating postsynaptic GABAA receptors, particularly in perisomatic inhibitory synapses, by GFRα1 mediated activation of the Ret receptor pathway. Other GDNF receptors, such as NCAM or Syndecan3, are not contributing to this effect. We observed similar alterations by GDNF in human hippocampal slices resected from epilepsy patients. These data indicate that GDNF may exert its seizure-suppressant action by enhancing GABAergic inhibitory transmission in the hippocampal network, thus counteracting the increased excitability of the epileptic brain. This new knowledge can contribute to the development of novel, more precise treatment strategies based on a GDNF gene therapy approach

Safety and EEG data quality of concurrent high-density EEG and high-speed fMRI at 3 Tesla

Concurrent EEG and fMRI is increasingly used to characterize the spatial-temporal dynamics of brain activity. However, most studies to date have been limited to conventional echo-planar imaging (EPI). There is considerable interest in integrating recently developed high-speed fMRI methods with high-density EEG to increase temporal resolution and sensitivity for task-based and resting state fMRI, and for detecting interictal spikes in epilepsy. In the present study using concurrent high-density EEG and recently developed high-speed fMRI methods, we investigate safety of radiofrequency (RF) related heating, the effect of EEG on cortical signal-to-noise ratio (SNR) in fMRI, and assess EEG data quality.The study compared EPI, multi-echo EPI, multi-band EPI and multi-slab echo-volumar imaging pulse sequences, using clinical 3 Tesla MR scanners from two different vendors that were equipped with 64- and 256-channel MR-compatible EEG systems, respectively, and receive only array head coils. Data were collected in 11 healthy controls (3 males, age range 18-70 years) and 13 patients with epilepsy (8 males, age range 21-67 years). Three of the healthy controls were scanned with the 256-channel EEG system, the other subjects were scanned with the 64-channel EEG system. Scalp surface temperature, SNR in occipital cortex and head movement were measured with and without the EEG cap. The degree of artifacts and the ability to identify background activity was assessed by visual analysis by a trained expert in the 64 channel EEG data (7 healthy controls, 13 patients).RF induced heating at the surface of the EEG electrodes during a 30-minute scan period with stable temperature prior to scanning did not exceed 1.0° C with either EEG system and any of the pulse sequences used in this study. There was no significant decrease in cortical SNR due to the presence of the EEG cap (p > 0.05). No significant differences in the visually analyzed EEG data quality were found between EEG recorded during high-speed fMRI and during conventional EPI (p = 0.78). Residual ballistocardiographic artifacts resulted in 58% of EEG data being rated as poor quality.This study demonstrates that high-density EEG can be safely implemented in conjunction with high-speed fMRI and that high-speed fMRI does not adversely affect EEG data quality. However, the deterioration of the EEG quality due to residual ballistocardiographic artifacts remains a significant constraint for routine clinical applications of concurrent EEG-fMRI

Functional interaction between Lypd6 and nicotinic acetylcholine receptors

Nicotinic acetylcholine receptors (nAChRs) affect multiple physiological functions in the brain and their functions are modulated by regulatory proteins of the Lynx family. Here, we report for the first time a direct interaction of the Lynx protein LY6/PLAUR domain‐containing 6 (Lypd6) with nAChRs in human brain extracts, identifying Lypd6 as a novel regulator of nAChR function. Using protein cross‐linking and affinity purification from human temporal cortical extracts, we demonstrate that Lypd6 is a synaptically enriched membrane‐bound protein that binds to multiple nAChR subtypes in the human brain. Additionally, soluble recombinant Lypd6 protein attenuates nicotine‐induced hippocampal inward currents in rat brain slices and decreases nicotine‐induced extracellular signal‐regulated kinase phosphorylation in PC12 cells, suggesting that binding of Lypd6 is sufficient to inhibit nAChR‐mediated intracellular signaling. We further show that perinatal nicotine exposure in rats (4 mg/kg/day through minipumps to dams from embryonic day 7 to post‐natal day 21) significantly increases Lypd6 protein levels in the hippocampus in adulthood, which did not occur after exposure to nicotine in adulthood only. Our findings suggest that Lypd6 is a versatile inhibitor of cholinergic signaling in the brain, and that Lypd6 is dysregulated by nicotine exposure during early development. [Image: see text] Regulatory proteins of the Lynx family modulate the function of nicotinic receptors (nAChRs). We report for the first time that the Lynx protein Lypd6 binds to nAChRs in human brain extracts, and that recombinant Lypd6 decreases nicotine‐induced ERK phosphorylation and attenuates nicotine‐induced hippocampal inward currents. Our findings suggest that Lypd6 is a versatile inhibitor of cholinergic signaling in the brain

Interpretable surface-based detection of focal cortical dysplasias:a Multi-centre Epilepsy Lesion Detection study

One outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm interpretability. A key application is the identification of subtle epileptogenic focal cortical dysplasias (FCDs) from structural MRI. FCDs are difficult to visualize on structural MRI but are often amenable to surgical resection. We aimed to develop an open-source, interpretable, surface-based machine-learning algorithm to automatically identify FCDs on heterogeneous structural MRI data from epilepsy surgery centres worldwide. The Multi-centre Epilepsy Lesion Detection (MELD) Project collated and harmonized a retrospective MRI cohort of 1015 participants, 618 patients with focal FCD-related epilepsy and 397 controls, from 22 epilepsy centres worldwide. We created a neural network for FCD detection based on 33 surface-based features. The network was trained and cross-validated on 50% of the total cohort and tested on the remaining 50% as well as on 2 independent test sites. Multidimensional feature analysis and integrated gradient saliencies were used to interrogate network performance. Our pipeline outputs individual patient reports, which identify the location of predicted lesions, alongside their imaging features and relative saliency to the classifier. On a restricted 'gold-standard' subcohort of seizure-free patients with FCD type IIB who had T1 and fluid-attenuated inversion recovery MRI data, the MELD FCD surface-based algorithm had a sensitivity of 85%. Across the entire withheld test cohort the sensitivity was 59% and specificity was 54%. After including a border zone around lesions, to account for uncertainty around the borders of manually delineated lesion masks, the sensitivity was 67%. This multicentre, multinational study with open access protocols and code has developed a robust and interpretable machine-learning algorithm for automated detection of focal cortical dysplasias, giving physicians greater confidence in the identification of subtle MRI lesions in individuals with epilepsy

[Golf handicap score is a suitable scale for monitoring rehabilitation after apoplexia cerebri].

A 67-year-old male was examined nine, 35 and 135 days after stroke using conventional stroke scales, 18 holes of golf, functional MRI (fist closures) and translocator protein imaging of microglial function in the brain using single photon emission computed tomography. The data showed that the over 100-year-old golf handicap scale is better suited for quantifying recovery after stroke than conventional stroke assessment scales, which are prone to ceiling effect. We suggest that rating with golf handicap should be used more widely in stroke research, and we find it tremendously important that these new findings are published before Christmas