Despite the presence of large endbulb inputs, the spherical bushy cells (SBCs) of the rostral anteroventral cochlear nucleus do not function as simple auditory relays. We used the good signal-to-noise ratio of juxtacellular recordings to dissect the intrinsic and network mechanisms controlling the input-output relationship of SBCs in anesthetized gerbils. The SBCs generally operated close to action potential (AP) threshold and showed no evidence for synaptic depression, suggesting that the endbulbs of Held have low release probability in vivo. Analysis of the complex waveforms suggested that in the absence of auditory stimulation, postsynaptic spike depression and stochastic fluctuations in EPSP size were the main factors determining jitter and reliability of the endbulb synapse. During auditory stimulation, progressively larger EPSPs were needed to trigger APs at increasing sound intensities. Simulations suggested hyperpolarizing inhibition could explain the observed decrease in EPSP efficacy. Synaptic inhibition showed a delayed onset and generally had a higher threshold than excitatory inputs, but otherwise inhibition and excitation showed mostly overlapping frequency-response areas. The recruitment of synaptic inhibition caused postsynaptic spikes to be preferentially triggered by well-timed, large EPSPs, resulting in improved phase locking despite more variable EPSP-AP latencies. Our results suggest that the lack of synaptic depression, caused by low release probability, and the apparent absence of sound-evoked synaptic inhibition at low sound intensity maximize sensitivity of SBCs. At higher sound intensities, the recruitment of synaptic inhibition constrains their firing rate and optimizes their temporal precision.

GABA and glycine are the major inhibitory transmitters that attune neuronal activity in the CNS of mammals. The respective transmitters are mostly spatially separated, that is, synaptic inhibition in the forebrain areas is mediated by GABA, whereas glycine is predominantly used in the brainstem. Accordingly, inhibition in auditory brainstem circuits is largely mediated by glycine, but there are few auditory synapses using both transmitters in maturity. Little is known about physiological advantages of such a two-transmitter inhibitory mechanism. We explored the benefit of engaging both glycine and GABA with inhibition at the endbulb of Held-spherical bushy cell synapse in the auditory brainstem of juvenile Mongolian gerbils. This model synapse enables selective in vivo activation of excitatory and inhibitory neuronal inputs through systemic sound stimulation and precise analysis of the input (endbulb of Held) output (spherical bushy cell) function. The combination of in vivo and slice electrophysiology revealed that the dynamic AP inhibition in spherical bushy cells closely matches the inhibitory conductance profile determined by the glycine-R and GABA A -R. The slow and potent glycinergic component dominates the inhibitory conductance, thereby primarily accounting for its high-pass filter properties. GABAergic transmission enhances the inhibitory strength and shapes its duration in an activity-dependent manner, thus increasing the inhibitory potency to suppress the excitation through the endbulb of Held. Finally, in silico modeling provides a strong link between in vivo and slice data by simulating the interactions between the endbulb-and the synergistic glycine-GABA-conductances during in vivo-like spontaneous and sound evoked activities.

Sensory processing in the lower auditory pathway is generally considered to be rigid and thus less subject to modulation than central processing. However, in addition to the powerful bottom-up excitation by auditory nerve fibers, the ventral cochlear nucleus also receives efferent cholinergic innervation from both auditory and nonauditory top–down sources. We thus tested the influence of cholinergic modulation on highly precise time-coding neurons in the cochlear nucleus of the Mongolian gerbil. By combining electrophysiological recordings with pharmacological application in vitro and in vivo, we found 55–72% of spherical bushy cells (SBCs) to be depolarized by carbachol on two time scales, ranging from hundreds of milliseconds to minutes. These effects were mediated by nicotinic and muscarinic acetylcholine receptors, respectively. Pharmacological block of muscarinic receptors hyperpolarized the resting membrane potential, suggesting a novel mechanism of setting the resting membrane potential for SBC. The cholinergic depolarization led to an increase of spike probability in SBCs without compromising the temporal precision of the SBC output in vitro. In vivo, iontophoretic application of carbachol resulted in an increase in spontaneous SBC activity. The inclusion of cholinergic modulation in an SBC model predicted an expansion of the dynamic range of sound responses and increased temporal acuity. Our results thus suggest of a top–down modulatory system mediated by acetylcholine which influences temporally precise information processing in the lower auditory pathway.

Spherical bushy cells (SBCs) of the anteroventral cochlear nucleus (AVCN) receive input from large excitatory auditory nerve (AN) terminals, the endbulbs of Held, and mixed glycinergic/GABAergic inhibitory inputs. The latter have sufficient potency to block action potential firing in vivo and in slice recordings. However, it is not clear how well the data from slice recordings match the inhibition in the intact brain and how it contributes to complex phenomena such as non-monotonic rate-level functions (RLF). Therefore, we determined the input-output relationship of a model SBC with simulated endbulb inputs and a dynamic inhibitory conductance constrained by recordings in brain slice preparations of hearing gerbils. Event arrival times from in vivo single-unit recordings in gerbils, where 70% of SBC showed non-monotonic RLF, were used as input for the model. Model output RLFs systematically changed from monotonic to non-monotonic shape with increasing strength of tonic inhibition. A limited range of inhibitory synaptic properties consistent with the slice data generated a good match between the model and recorded RLF. Moreover, tonic inhibition elevated the action potentials (AP) threshold and improved the temporal precision of output functions in a SBC model with phase-dependent input conductance. We conclude that activity-dependent, summating inhibition contributes to high temporal precision of SBC spiking by filtering out weak and poorly timed EPSP. Moreover, inhibitory parameters determined in slice recordings provide a good estimate of inhibitory mechanisms apparently active in vivo.

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Surgical repair of larger peripheral nerve lesions requires the use of autologous nerve grafts. At present, clinical alternatives to avoid nerve transplantation consist of empty tubes, which are only suitable for the repair over short distances and have limited success. We developed a cell-free, three-dimensional scaffold for axonal guidance in long-distance nerve repair. Sub-micron scale fibres of biodegradable poly-ε-caprolactone (PCL) and collagen/PCL (c/PCL) blends were incorporated in a gelatin matrix and inserted in collagen tubes. The conduits were tested by replacing 15-mm-long segments of rat sciatic nerves in vivo. Biocompatibility of the implants and nerve regeneration were assessed histologically, with electromyography and with behavioural tests for motor functions. Functional repair was achieved in all animals with autologous transplants, in 12 of 13 rats that received artificial implants with an internal structure and in half of the animals with empty nerve conduits. In rats with implants containing c/PCL fibres, the extent of recovery (compound muscle action potentials, motor functions of the hind limbs) was superior to animals that had received empty implants, but not as good as with autologous nerve transplantation. Schwann cell migration and axonal regeneration were observed in all artificial implants, and muscular atrophy was reduced in comparison with animals that had received no implants. The present design represents a significant step towards cell-free, artificial nerve bridges that can replace autologous nerve transplants in the clinic. Copyright © 2017 John Wiley & Sons, Ltd.

Background and purpose Using the treatment goal of “no evidence of disease activity” (NEDA) incorporating magnetic resonance imaging (MRI) re‐baselining, we aimed to assess the efficacy of ocrelizumab in patients with relapsing‐remitting multiple sclerosis with a prior suboptimal response, defined by MRI or relapse criteria, to one or two disease‐modifying therapies (DMTs). Methods CASTING was a prospective, international, multicenter, single‐arm, open‐label phase 3 trial (NCT02861014). Patients (Expanded Disability Status Scale [EDSS] score ≤ 4.0, with discontinued prior DMT of ≥6 months duration due to suboptimal disease control) received intravenous ocrelizumab 600 mg every 24 weeks for 96 weeks. The primary endpoint was NEDA (defined as absence of relapses, disability progression, and inflammatory MRI measures, with prespecified MRI re‐baselining at Week 8) over 96 weeks. Results A total of 680 patients were enrolled, 167 (24.6%) based on MRI activity only. At Week 96, 74.8% (95% confidence interval [CI] 71.3–78.0, n/N = 492/658) of patients had NEDA. NEDA was highest among patients enrolled due to MRI activity alone (80.6% [95% CI 68.6–89.6], n/N = 50/62) versus those enrolled for relapse (75.1% [95% CI 69.0–80.6], n/N = 172/229) or for relapse with MRI (70.5% [95% CI 60.0–79.0], n/N = 74/105). NEDA across subgroups was highest in patients with a baseline EDSS score <2.5 (77.2% [95% CI 72.8–81.2], n/N = 315/408). NEDA was higher in patients receiving one prior DMT (77.6% [95% CI 73.2–81.6], n/N = 312/402) versus two prior DMTs (70.3% [95% CI 64.3–75.8], n/N = 180/256). Conclusions In patients switching therapy due to suboptimal disease control, treatment with ocrelizumab led to an overall high NEDA rate across a wide range of disease‐related and demographic subgroups, regardless of prior treatment background, with no new safety signals detected.