In neuroprosthetic implants, PEDOT-CNT may allow for smaller electrodes, effective stimulation in a safe voltage regime and lower energy-consumption. Our study also indicates, that the charge transferred at threshold or the charge injection capacity per se does not determine stimulation efficacy.
Our results suggest the following guidelines for retinal prosthetics employing biphasic current pulses. The encoding of small objects may be achieved through the activation of a confined set of different retinal ganglion cells, with individual stimulation thresholds spanning a wide range of charge densities. The encoding of increasing object sizes may be achieved by decreasing stimulation charge density.
In order to obtain functional parameters relevant to the designing of a subretinal implant, we carried out electrical stimulation experiments with isolated chicken retina. The median threshold for network activation with planar disc electrodes (diameter 10 microm) was 0.5 nC (625 microC cm(-2)) for anodal voltage impulses and 1.6 nC (2 mC cm(-2)) for cathodal impulses. Above threshold, the number of spikes evoked by a single voltage impulse increased up to saturation within a range of injected charge from 0.1 nC to 1 nC for anodal impulses and from 1 nC to 10 nC for cathodal impulses. Using needle electrodes with a tip diameter of 1 microm, we determined the electrical point spread function (EPSF) for subretinal stimulation. It had a half width in the range of 100 microm, which corresponds to a visual angle of 21' and to a visual acuity of 20/417 in the human eye. It is reasonable to conclude that with subretinal implants the minimum separable will be of the same dimension.
The postsynaptic scaffold protein gephyrin is clustered at inhibitory synapses and serves for the stabilization of GABA A receptors. Here, a comprehensive kinome-wide siRNA screen in a human HeLa cell-based model for gephyrin clustering was used to identify candidate protein kinases implicated in the stabilization of gephyrin clusters. As a result, 12 hits were identified including FGFR1 (FGF receptor 1), TrkB, and TrkC as well as components of the MAPK and mammalian target of rapamycin (mTOR) pathways. For confirmation, the impact of these hits on gephyrin clustering was analyzed in rat primary hippocampal neurons. We found that brain-derived neurotrophic factor (BDNF) acts on gephyrin clustering through MAPK signaling, and this process may be controlled by the MAPK signaling antagonist sprouty2. BDNF signaling through phosphatidylinositol 3-kinase (PI3K)-Akt also activates mTOR and represses GSK3, which was previously shown to reduce gephyrin clustering. Gephyrin is associated with inactive mTOR and becomes released upon BDNFdependent mTOR activation. In primary neurons, a reduction in the number of gephyrin clusters due to manipulation of the BDNFmTOR signaling is associated with reduced GABA A receptor clustering, suggesting functional impairment of GABA signaling. Accordingly, application of the mTOR antagonist rapamycin leads to disinhibition of neuronal networks as measured on microelectrode arrays. In conclusion, we provide evidence that BDNF regulates gephyrin clustering via MAPK as well as PI3K-Akt-mTOR signaling.
Background
Hypoxia contributes to retinal damage in several retinal diseases, including central retinal artery occlusion, with detrimental consequences like painless, monocular loss of vision. Currently, the treatment options are severely limited due to the short therapy window, as the neuronal cells, especially the retinal ganglion cells (RGCs), are irreversibly damaged within the first few hours. Hypothermia might be a possible treatment option or at least might increase the therapy window.
Methods
To investigate the neuroprotective effect of hypothermia after retinal hypoxia, an easy‐to‐use ex vivo retinal hypoxia organ culture model developed in our laboratory was used that reliably induced retinal damage on a structural, molecular and functional level. The neuroprotective effect of hypothermia after retinal hypoxia was analysed using optical coherence tomography scans, histological stainings, quantitative real‐time polymerase chain reaction, western blotting and microelectrode array recordings.
Results
Two different hypothermic temperatures (30°C and 20°C) were evaluated, both exhibited strong neuroprotective effects. Most importantly, hypothermia increased RGC survival after retinal hypoxia. Furthermore, hypothermia counteracted the hypoxia‐induced RGC death, reduced macroglia activation, attenuated retinal thinning and protected from loss of spontaneous RGC activity.
Conclusions
These results indicate that already a mild reduction in temperature protects the RGCs against damage and could function as a promising therapeutic option for hypoxic diseases.
Recording neural signals from delicate autonomic nerves is a challenging task that requires the development of a low-invasive neural interface with highly selective, micrometer-sized electrodes. This paper reports on the development of a three-dimensional (3D) protruding thin-film microelectrode array (MEA), which is intended to be used for recording low-amplitude neural signals from pelvic nervous structures by penetrating the nerves transversely to reduce the distance to the axons. Cylindrical gold pillars (Ø 20 or 50 µm, ~60 µm height) were fabricated on a micromachined polyimide substrate in an electroplating process. Their sidewalls were insulated with parylene C, and their tips were optionally modified by wet etching and/or the application of a titanium nitride (TiN) coating. The microelectrodes modified by these combined techniques exhibited low impedances (~7 kΩ at 1 kHz for Ø 50 µm microelectrode with the exposed surface area of ~5000 µm²) and low intrinsic noise levels. Their functionalities were evaluated in an ex vivo pilot study with mouse retinae, in which spontaneous neuronal spikes were recorded with amplitudes of up to 66 µV. This novel process strategy for fabricating flexible, 3D neural interfaces with low-impedance microelectrodes has the potential to selectively record neural signals from not only delicate structures such as retinal cells but also autonomic nerves with improved signal quality to study neural circuits and develop stimulation strategies in bioelectronic medicine, e.g., for the control of vital digestive functions.
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