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Who's lost first? Susceptibility of retinal ganglion cell types in experimental glaucoma. - Experimental eye research
The purpose of this article is to summarize our current knowledge about the susceptibility of specific retinal ganglion cell (RGC) types in experimental glaucoma, and to delineate the initial morphological and functional alterations that occur in response to intraocular pressure (IOP) elevation. There has been debate in the field as to whether RGCs with large somata and axons are more vulnerable, with definitive conclusions still in progress because of the wide diversity of RGC types. Indeed, it is now estimated that there are greater than 30 different RGC types, and while we do not yet understand the complete details, we discuss a growing body of work that supports the selective vulnerability hypothesis of specific RGC types in experimental glaucoma. Specifically, structural and functional degeneration of various RGC types have been examined across different rodent models of experimental glaucoma (acute vs. chronic) and different strains, and an emerging consensus is that OFF RGCs appear to be more vulnerable to IOP elevation compared to ON RGCs. Understanding the mechanisms by which this selective vulnerability manifests across different RGC types should lead to novel and improved strategies for neuroprotection and neuroregeneration in glaucoma.Copyright Â© 2016. Published by Elsevier Ltd.
Heat pulse excitability of vestibular hair cells and afferent neurons. - Journal of neurophysiology
In the present study we combined electrophysiology with optical heat pulse stimuli to examine thermodynamics of membrane electrical excitability in mammalian vestibular hair cells and afferent neurons. We recorded whole-cell currents in mammalian type II vestibular hair cells using an excised preparation (mouse), and action potentials (APs) in afferent neurons in vivo (chinchilla) in response to optical heat pulses applied to the crista (Î”Tâ‰ˆ0.25Â°C pulse -1). Afferent spike trains evoked by heat pulse stimuli were diverse and included asynchronous inhibition, asynchronous excitation, and/or phase-locked APs synchronized to each IR heat pulse. Thermal responses of membrane currents responsible for APs in ganglion neurons were strictly excitatory, with a Q10â‰ˆ2. In contrast, hair cells responded with a mix of excitatory and inhibitory currents. Excitatory hair cell membrane currents included a thermoelectric capacitive current proportional to the rate of temperature rise , and an inward conduction current driven by Î”Î¤. An iberiotoxin-sensitive (ibTX) inhibitory conduction current (BK) was also evoked by Î”Î¤, rising in <3ms and decaying with a time constant of ~24ms. The inhibitory component dominated whole cell currents in 50% of hair cells at -68mV, and in 67% of hair cells at -60mV. Responses were quantified and described based on first principles of thermodynamics. Results identify key molecular targets underlying heat pulse excitability in vestibular sensory organs, and provide quantitative methods for rational application of optical heat pulses to examine protein biophysics and manipulate cellular excitability.Copyright Â© 2016, Journal of Neurophysiology.
Plasticity within non-cerebellar pathways rapidly shapes motor performance in vivo. - Nature communications
Although cerebellar mechanisms are vital to maintain accuracy during complex movements and to calibrate simple reflexes, recent in vitro studies have called into question the widely held view that synaptic changes within cerebellar pathways exclusively guide alterations in motor performance. Here we investigate the vestibulo-ocular reflex (VOR) circuitry by applying temporally precise activation of vestibular afferents in awake-behaving monkeys to link plasticity at different neural sites with changes in motor performance. Behaviourally relevant activation patterns produce rapid attenuation of direct pathway VOR neurons, but not their nerve input. Changes in the strength of this pathway are sufficient to induce a lasting decrease in the evoked VOR. In addition, indirect brainstem pathways display complementary nearly instantaneous changes, contributing to compensating for the reduced sensitivity of primary VOR neurons. Taken together, our data provide evidence that multiple sites of plasticity within VOR pathways can rapidly shape motor performance in vivo.
Involvement of Autophagic Pathway in the Progression of Retinal Degeneration in a Mouse Model of Diabetes. - Frontiers in cellular neuroscience
The notion that diabetic retinopathy (DR) is essentially a micro-vascular disease has been recently challenged by studies reporting that vascular changes are preceded by signs of damage and loss of retinal neurons. As to the mode by which neuronal death occurs, the evidence that apoptosis is the main cause of neuronal loss is far from compelling. The objective of this study was to investigate these controversies in a mouse model of streptozotocin (STZ) induced diabetes. Starting from 8 weeks after diabetes induction there was loss of rod but not of cone photoreceptors, together with reduced thickness of the outer and inner synaptic layers. Correspondingly, rhodopsin expression was downregulated and the scotopic electroretinogram (ERG) is suppressed. In contrast, cone opsin expression and photopic ERG response were not affected. Suppression of the scotopic ERG preceded morphological changes as well as any detectable sign of vascular alteration. Only sparse apoptotic figures were detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and glia was not activated. The physiological autophagy flow was altered instead, as seen by increased LC3 immunostaining at the level of outer plexiform layer (OPL) and upregulation of the autophagic proteins Beclin-1 and Atg5. Collectively, our results show that the streptozotocin induced DR in mouse initiates with a functional loss of the rod visual pathway. The pathogenic pathways leading to cell death develop with the initial dysregulation of autophagy well before the appearance of signs of vascular damage and without strong involvement of apoptosis.
Non-symmetrical furan-amidines as novel leads for the treatment of cancer and malaria. - European journal of medicinal chemistry
NRH:quinone oxidoreductase 2 enzyme (NQO2) is a potential therapeutic target in cancer and neurodegenerative diseases, with roles in either chemoprevention or chemotherapy. Here we report the design, synthesis and evaluation of non-symmetrical furan-amidines and their analogues as novel selective NQO2 inhibitors with reduced adverse off-target effects, such as binding to DNA. A pathway for the synthesis of the non-symmetrical furan-amidines was established from the corresponding 1,4-diketones. The synthesized non-symmetrical furan-amidines and their analogues showed potent NQO2 inhibition activity with nano-molar IC50 values. The most active compounds were non-symmetrical furan-amidines with meta- and para-nitro substitution on the aromatic ring, with IC50 values of 15Â nM. In contrast to the symmetric furan-amidines, which showed potent intercalation in the minor grooves of DNA, the synthesized non-symmetrical furan-amidines showed no affinity towards DNA, as demonstrated by DNA melting temperature experiments. In addition, Plasmodium parasites, which possess their own quinone oxidoreductase PfNDH2, were inhibited by the non-symmetrical furan-amidines, the most active possessing a para-fluoro substituent (IC50 9.6Â nM). The high NQO2 inhibition activity and nanomolar antimalarial effect of some of these analogues suggest the lead compounds are worthy of further development and optimization as potential drugs for novel anti-cancer and antimalarial strategies.Copyright Â© 2016 Elsevier Masson SAS. All rights reserved.
TMEM16A is associated with voltage-gated calcium channels in mouse retina and its function is disrupted upon mutation of the auxiliary Î±2Î´4 subunit. - Frontiers in cellular neuroscience
Photoreceptors rely upon highly specialized synapses to efficiently transmit signals to multiple postsynaptic targets. Calcium influx in the presynaptic terminal is mediated by voltage-gated calcium channels (VGCC). This event triggers neurotransmitter release, but also gates calcium-activated chloride channels (TMEM), which in turn regulate VGCC activity. In order to investigate the relationship between VGCC and TMEM channels, we analyzed the retina of wild type (WT) and Cacna2d4 mutant mice, in which the VGCC auxiliary Î±2Î´4 subunit carries a nonsense mutation, disrupting the normal channel function. Synaptic terminals of mutant photoreceptors are disarranged and synaptic proteins as well as TMEM16A channels lose their characteristic localization. In parallel, calcium-activated chloride currents are impaired in rods, despite unaltered TMEM16A protein levels. Co-immunoprecipitation revealed the interaction between VGCC and TMEM16A channels in the retina. Heterologous expression of these channels in tsA-201 cells showed that TMEM16A associates with the CaV1.4 subunit, and the association persists upon expression of the mutant Î±2Î´4 subunit. Collectively, our experiments show association between TMEM16A and the Î±1 subunit of VGCC. Close proximity of these channels allows optimal function of the photoreceptor synaptic terminal under physiological conditions, but also makes TMEM16A channels susceptible to changes occurring to calcium channels.
Contribution of vestibular efferent system alpha-9 nicotinic receptors to vestibulo-oculomotor interaction and short-term vestibular compensation after unilateral labyrinthectomy in mice. - Neuroscience letters
Sudden unilateral loss of vestibular afferent input causes nystagmus, ocular misalignment, postural instability and vertigo, all of which improve significantly over the first few days after injury through a process called vestibular compensation (VC). Efferent neuronal signals to the labyrinth are thought to be required for VC. To better understand efferent contributions to VC, we compared the time course of VC in wild-type (WT) mice and Î±9 knockout (Î±9(-/-)) mice, the latter lacking the Î±9 subunit of nicotinic acetylcholine receptors (nAChRs), which is thought to represent one signaling arm activated by the efferent vestibular system (EVS). Specifically, we investigated the time course of changes in the fast/direct and slow/indirect components of the angular vestibulo-ocular reflex (VOR) before and after unilateral labyrinthectomy (UL). Eye movements were recorded using infrared video oculography in darkness with the animal stationary and during sinusoidal (50 and 100Â°/s, 0.5-5 Hz) and velocity step (150Â°/s for 7-10s, peak acceleration 3000Â°/s(2)) passive whole-body rotations about an Earth-vertical axis. Eye movements were measured before and 0.5, 2, 4, 6 and 9 days after UL. Before UL, we found frequency- and velocity-dependent differences between WT and Î±9(-/-) mice in generation of VOR quick phases. The VOR slow phase time constant (TC) during velocity steps, which quantifies contributions of the indirect component of the VOR, was longer in Î±9(-/-) mutants relative to WT mice. After UL, spontaneous nystagmus (SN) was suppressed significantly earlier in WT mice than in Î±9(-/-) mice, but mutants achieved greater recovery of TC symmetry and VOR quick phases. These data suggest (1) there are significant differences in vestibular and oculomotor functions between these two types of mice, and (2) efferent signals mediated by Î±9 nicotinic AChRs play a role during VC after UL.Copyright Â© 2015 Elsevier Ireland Ltd. All rights reserved.
A CMOS Neural Interface for a Multichannel Vestibular Prosthesis. - IEEE transactions on biomedical circuits and systems
We present a high-voltage CMOS neural-interface chip for a multichannel vestibular prosthesis (MVP) that measures head motion and modulates vestibular nerve activity to restore vision- and posture-stabilizing reflexes. This application specific integrated circuit neural interface (ASIC-NI) chip was designed to work with a commercially available microcontroller, which controls the ASIC-NI via a fast parallel interface to deliver biphasic stimulation pulses with 9-bit programmable current amplitude via 16 stimulation channels. The chip was fabricated in the ONSemi C5 0.5 micron, high-voltage CMOS process and can accommodate compliance voltages up to 12 V, stimulating vestibular nerve branches using biphasic current pulses up to 1.45Â±0.06 mA with durations as short as 10 Î¼s/phase. The ASIC-NI includes a dedicated digital-to-analog converter for each channel, enabling it to perform complex multipolar stimulation. The ASIC-NI replaces discrete components that cover nearly half of the 2nd generation MVP (MVP2) printed circuit board, reducing the MVP system size by 48% and power consumption by 17%. Physiological tests of the ASIC-based MVP system (MVP2A) in a rhesus monkey produced reflexive eye movement responses to prosthetic stimulation similar to those observed when using the MVP2. Sinusoidal modulation of stimulus pulse rate from 68-130 pulses per second at frequencies from 0.1 to 5 Hz elicited appropriately-directed slow phase eye velocities ranging in amplitude from 1.9-16.7 (Â°)/s for the MVP2 and 2.0-14.2 (Â°)/s for the MVP2A. The eye velocities evoked by MVP2 and MVP2A showed no significant difference ( t-test, p=0.34), suggesting that the MVP2A achieves performance at least as good as the larger MVP2.
Characterization of Vestibulopathy in Individuals with Type 2 Diabetes Mellitus. - Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery
Previous observational studies suggest higher rates of vestibular dysfunction among patients with type 2 diabetes mellitus (DM) compared with those without diabetes. This study aims to functionally localize vestibular dysfunction in adults with type 2 DM.Prospective cohort study.Tertiary academic medical center.Adults 50 years of age and older with â‰¥10-year history of type 2 DM were recruited (December 2011-February 2013, n = 25). Vestibular function was assessed by cervical and ocular vestibular-evoked myogenic potentials (VEMPs), testing the saccule and utricle, respectively. Head thrust dynamic visual acuity testing assessed semicircular canal (SCC) function in all canal planes. Results were compared with nondiabetic age-matched controls (n = 25).Subjects were 64.7 Â± 7.6 years old, were 40% female, and had a mean hemoglobin A1c of 8.3% Â± 1.7%. SCC dysfunction was more common than otoconial organ dysfunction, with 70% of subjects with DM demonstrating impaired performance of at least 1 SCC (Î”logMAR â‰¥0.18) and 50% demonstrating otoconial organ impairment (absent ocular VEMP and/or cervical VEMP). Adults with type 2 DM had poorer lateral and superior SCC performance (P < .05) but similar posterior SCC performance compared with controls (P = .16). Both cervical VEMP peak-to-peak amplitude and ocular VEMP n1 amplitude were also decreased with diabetes (P < .01).Adults with type 2 DM have poorer performance on tests of vestibular function related to both SCC and otoconial organ function compared with nondiabetic age-matched adults. Future studies are needed to better understand the relationship between vestibular function and functional disability in persons with diabetes.Â© American Academy of Otolaryngologyâ€”Head and Neck Surgery Foundation 2015.
Histopathologic Changes of the Inner ear in Rhesus Monkeys After Intratympanic Gentamicin Injection and Vestibular Prosthesis Electrode Array Implantation. - Journal of the Association for Research in Otolaryngology : JARO
Bilateral vestibular deficiency (BVD) due to gentamicin ototoxicity can significantly impact quality of life and result in large socioeconomic burdens. Restoring sensation of head rotation using an implantable multichannel vestibular prosthesis (MVP) is a promising treatment approach that has been tested in animals and humans. However, uncertainty remains regarding the histopathologic effects of gentamicin ototoxicity alone or in combination with electrode implantation. Understanding these histological changes is important because selective MVP-driven stimulation of semicircular canals (SCCs) depends on persistence of primary afferent innervation in each SCC crista despite both the primary cause of BVD (e.g., ototoxic injury) and surgical trauma associated with MVP implantation. Retraction of primary afferents out of the cristae and back toward Scarpa's ganglion would render spatially selective stimulation difficult to achieve and could limit utility of an MVP that relies on electrodes implanted in the lumen of each ampulla. We investigated histopathologic changes of the inner ear associated with intratympanic gentamicin (ITG) injection and/or MVP electrode array implantation in 11 temporal bones from six rhesus macaque monkeys. Hematoxylin and eosin-stained 10-Î¼m temporal bone sections were examined under light microscopy for four treatment groups: normal (three ears), ITG-only (two ears), MVP-only (two ears), and ITG + MVP (four ears). We estimated vestibular hair cell (HC) surface densities for each sensory neuroepithelium and compared findings across end organs and treatment groups. In ITG-only, MVP-only, and ITG + MVP ears, we observed decreased but persistent ampullary nerve fibers of SCC cristae despite ITG treatment and/or MVP electrode implantation. ITG-only and ITG + MVP ears exhibited neuroepithelial thinning and loss of type I HCs in the cristae but little effect on the maculae. MVP-only and ITG + MVP ears exhibited no signs of trauma to the cochlea or otolith end organs except in a single case of saccular injury due to over-insertion of the posterior SCC electrode. While implanted electrodes reached to within 50-760 Î¼m of the target cristae and were usually ensheathed in a thin fibrotic capsule, dense fibrotic reaction and osteoneogenesis were each observed in only one of six electrode tracts examined. Consistent with physiologic studies that have demonstrated directionally appropriate vestibulo-ocular reflex responses to MVP electrical stimulation years after implantation in these animals, histologic findings in the present study indicate that although intralabyrinthine MVP implantation causes some inner ear trauma, it can be accomplished without destroying the distal afferent fibers an MVP is designed to excite.
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