GABAergic and glycinergic inhibitory synaptic transmission in the ventral cochlear nucleus studied in VGAT channelrhodopsin-2 mice

Both glycine and GABA mediate inhibitory synaptic transmission in the ventral cochlear nucleus (VCN). In mice, the time course of glycinergic inhibition is slow in bushy cells and fast in multipolar (stellate) cells, and is proposed to contribute to the processing of temporal cues in both cell types. Much less is known about GABAergic synaptic transmission in this circuit. Electrical stimulation of the auditory nerve or the tuberculoventral pathway evokes little GABAergic synaptic current in brain slice preparations, and spontaneous GABAergic miniature synaptic currents occur infrequently. To investigate synaptic currents carried by GABA receptors in bushy and multipolar cells, we used transgenic mice in which channelrhodopsin-2 and EYFP is driven by the vesicular GABA transporter (VGAT-ChR2-EYFP) and is expressed in both GABAergic and glycinergic neurons. Light stimulation evoked action potentials in EYFP-expressing presynaptic cells, and evoked inhibitory postsynaptic potentials (IPSPs) in non-expressing bushy and planar multipolar cells. Less than 10% of the IPSP amplitude in bushy cells arose from GABAergic synapses, whereas 40% of the IPSP in multipolar neurons was GABAergic. In voltage clamp, glycinergic IPSCs were significantly slower in bushy neurons than in multipolar neurons, whereas there was little difference in the kinetics of the GABAergic IPSCs between two cell types. During prolonged stimulation, the ratio of steady state vs. peak IPSC amplitude was significantly lower for glycinergic IPSCs. Surprisingly, the reversal potentials of GABAergic IPSCs were negative to those of glycinergic IPSCs in both bushy and multipolar neurons. In the absence of receptor blockers, repetitive light stimulation was only able to effectively evoke IPSCs up to 20 Hz in both bushy and multipolar neurons. We conclude that local GABAergic release within the VCN can differentially influence bushy and multipolar cells

Synaptic transmission at the endbulb of Held deteriorates during age-related hearing loss: Synaptic transmission deteriorates during age-related hearing loss

Age-related hearing loss (ARHL) is associated with changes to the auditory periphery that raise sensory thresholds and alter coding, and is accompanied by alterations in excitatory and inhibitory synaptic transmission, and intrinsic excitability in the circuits of the central auditory system. However it remains unclear how synaptic transmission changes at the first central auditory synapses during ARHL. Using mature (2-4 months) and old (20-26 months) CBA/CaJ mice, we studied synaptic transmission at the endbulb of Held. Mature and old mice showed no difference in either spontaneous quantal synaptic transmission or low-frequency evoked synaptic transmission at the endbulb of Held. However, when challenged with sustained high frequency stimulation, synapses in old mice exhibited increased asynchronous transmitter release and reduced synchronous release. This suggests that the transmission of temporally precise information is degraded at the endbulb during ARHL. Increasing intraterminal calcium buffering with EGTA-AM, or decreasing calcium influx with ω-agatoxin IVA decreased the amount of asynchronous release and restored synchronous release in old mice. In addition, recovery from depression following high frequency trains was faster in old mice, but was restored to a normal time course by EGTA-AM treatment. These results suggest that intraterminal calcium in old endbulbs may rise to abnormally high levels during high rates of auditory nerve firing, or that calcium-dependent processes involved in release are altered with age. These observations suggest that ARHL is associated with a decrease in temporal precision of synaptic release at the first central auditory synapse, which may contribute to perceptual deficits in hearing. This article is protected by copyright. All rights reserved

Hearing loss alters quantal release at cochlear nucleus stellate cells

Auditory nerve synapses in ventral cochlear nucleus end on two principal cell types, bushy and stellate cells. While the effects of hearing loss on bushy cells has been well studied, little is known about the effects of hearing loss on synaptic input to the stellate cells. Based on prior observations in bushy cells, we hypothesized that noise-induced hearing loss (NIHL) would decrease quantal release onto stellate cells

Inhibitory projections from the ventral nucleus of the lateral lemniscus and superior paraolivary nucleus create directional selectivity of frequency modulations in the inferior colliculus: A comparison of bats with other mammals

This review considers four auditory brainstem nuclear groups and shows how studies of both bats and other mammals have provided insights into their response properties and the impact of their convergence in the inferior colliculus (IC). The four groups are octopus cells in the cochlear nucleus, their connections with the ventral nucleus of the lateral lemniscus (VNLL) and the superior paraolivary nucleus (SPON), and the connections of the VNLL and SPON with the IC. The theme is that the response properties of neurons in the SPON and VNLL map closely onto the synaptic response features of a unique subpopulation of cells in the IC of bats whose inputs are dominated by inhibition. We propose that the convergence of VNLL and SPON inputs generates the tuning of these IC cells, their unique temporal responses to tones, and their directional selectivities for frequency modulated (FM) sweeps. Other IC neurons form directional properties in other ways, showing that selective response properties are formed in multiple ways. In the final section we discuss why multiple formations of common response properties could amplify differences in population activity patterns evoked by signals that have similar spectrotemporal features

The efficacy and safety of Xueshuantong (lyophilized) for injection in the treatment of unstable angina pectoris: A systematic review and meta-analysis

Objective: Xueshuantong (lyophilized) for injection (XST) is an effective botanical drug for treating unstable angina pectoris (UAP). However, a meta-analysis of XST combined with conventional treatment (CT) against UAP has not been conducted. Therefore, this study aimed to investigate the effectiveness and safety of XST combined with CT for UAP patients compared to CT alone.Methods: Randomized controlled trials (RCT) of XST in UAP patients were retrieved from the Cochrane Library, PubMed, Web of Science, EMBASE, CNKI, VIP, Wanfang, and Chinese Biological Medicine Database databases. A meta-analysis was performed using Revman 5.4 and Stata 16.0, and the quality of the included literature was evaluated based on the Cochrane risk-of-bias 2.0 (RoB2.0) tool. The aggregate 95% confidence intervals (CIs), mean difference (MD), and relative risk (RR) estimates were calculated. A GRADE assessment was performed using GRADEprofiler 3.6, and trial sequent analysis was performed using TSA 0.9.Results: Thirty-four studies involving 3,518 patients were included in the analysis. The combination of CT with XST improved the comprehensive clinical efficacy (RR = 1.22, 95% CI: 1.18–1.26, p < 0.00001) and ECG improvement (RR = 1.24, 95% CI: 1.18–1.31, p < 0.00001). The frequency of angina attacks was lower (MD = −0.73, 95% CI: −0.92 to −0.55, p < 0.00001), and the duration was shorter (MD = −1.08, 95% CI: −1.44 to −0.72, p < 0.00001) in the group that received CT combined with XST compared to the one without XST. Total cholesterol levels (MD = −1.30, 95% CI: −1.83 to −0.78, p < 0.00001) and triglyceride levels (MD = −0.76, 95% CI: −0.93 to −0.59, p < 0.00001) were lower in patients who received CT in combination with XST than those who received CT alone. CT combined with XST reduced whole blood viscosity (MD = −0.72, 95% CI = −0.99 to −0.44, p < 0.00001) and plasma viscosity (MD = −0.24, 95% CI: −0.46 to −0.03, p = 0.03). There was no statistically significant difference in the incidence of cardiovascular events or adverse events among patients treated with the combination of XST and CT compared to CT alone. The GRADE assessment indicated that the composite quality of the evidence was low. The trial sequent analysis showed an adequate sample size and stable findings for the clinical efficacy of CT combined with XST for unstable angina.Conclusion: The present systematic review and meta-analysis conditionally indicate that XST combined with CT improved the clinical outcomes of patients with unstable angina more than CT alone with a better safety profile. However, the results need further validation due to limitations in the quality of the included studies.Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022357395

The dominance of inhibition in the inferior colliculus

Almost all of the processing that occurs in the various lower auditory nuclei converges upon a common target in the central nucleus of the inferior colliculus (ICc) thus making the ICc the nexus of the auditory system. A variety of new response properties are formed in the ICc through the interactions among the excitatory and inhibitory inputs that converge upon it. Here we review studies that illustrate the dominant role inhibition plays in the ICc. We begin by reviewing studies of tuning curves and show how inhibition shapes the variety of tuning curves in the ICc through sideband inhibition. We then show how inhibition shapes selective response properties for complex signals, focusing on selectivity for the sweep direction of frequency modulations (FM). In the final section we consider results from in vivo whole-cell recordings that show how parameters of the incoming excitation and inhibition interact to shape directional selectivity. We show that post-synaptic potentials (PSPs) evoked by different signals can be similar but evoke markedly different spike-counts. In these cases, spike threshold acts as a non-linear amplifier that converts small differences in PSPs into large differences in spike output. Such differences between the inputs to a cell compared to the outputs from the same cell suggest that highly selective discharge properties can be created by only minor adjustments in the synaptic strengths evoked by one or both signals. These findings also suggest that plasticity of response features may be achieved with far less modifications in circuitry than previously supposed

The roles of inhibition in hierarchical processing in the auditory system and the response features of inferior colliculus neurons revealed by in vivo whole cell recordings

The inferior colliculus (IC) receives inputs, which include both excitatory and inhibitory projections, from almost all lower auditory nuclei and thus is the major integration center in the auditory pathway. This dissertation evaluated three questions in order to understand the roles of inhibition in shaping response features of IC neurons, and how the influences of inhibition in the IC compare to the roles that inhibition plays in shaping the response properties of neurons in two lower nuclei, the dorsal nucleus of the lateral lemniscus (DNLL) and intermediate nucleus of the lateral lemniscus (INLL). The first question asks what response features are expressed by cells in the DNLL and INLL, and to what degree those features are shaped by inhibition. The second question asks whether the response properties of IC cells are inherited from lower nuclei and to what degree are they created in the IC by the interactions of excitatory and inhibitory projections. To investigate these questions, I recorded single-unit activity evoked by the same set of stimuli in the three nuclei both before and while inhibition was blocked by iontophoresis of receptor blockers. The results showed that the response features of DNLL and INLL neurons are homogeneous and weakly influenced by inhibition. The response features of IC neurons, however, are heterogeneous and markedly shaped by inhibitory inputs. Thus, DNLL and INLL properties were either largely inherited or shaped by the convergence of excitatory projections, while IC response features were largely created in the IC by inhibition. The third question asks what intrinsic and synaptic features underlie sound-evoked response properties in IC neurons. These features were evaluated with in vivo whole-cell recordings. Consistent with extracellular studies, a variety of tuning features were revealed among the IC population by whole-cell recordings, but the spectral extent of subthreshold excitatory and inhibitory inputs was surprisingly broad. Particular attention was given to a subset of IC neurons with special features in synaptic responses, discharge features and their intrinsic properties. These features provide unique insights into how sound-evoked synaptic response features and intrinsic properties might interact to produce the discharge features of these novel cells.Institute for Neuroscienc

Target-Specific IPSC Kinetics Promote Temporal Processing in Auditory Parallel Pathways

The acoustic environment contains biologically relevant information on time scales from microseconds to tens of seconds. The auditory brainstem nuclei process this temporal information through parallel pathways that originate in the cochlear nucleus from different classes of cells. While the roles of ion channels and excitatory synapses in temporal processing have been well studied, the contribution of inhibition is less well understood. Here, we show in CBA/CaJ mice that the two major projection neurons of the ventral cochlear nucleus, the bushy and T-stellate cells, receive glycinergic inhibition with different synaptic conductance time courses. Bushy cells, which provide precisely timed spike trains used in sound localization and pitch identification, receive slow inhibitory inputs. In contrast, T-stellate cells, which encode slower envelope information, receive inhibition that is eight-fold faster. Both types of inhibition improved the precision of spike timing, but engage different cellular mechanisms and operate on different time scales. Computer models reveal that slow IPSCs in bushy cells can improve spike timing on the scale of tens of microseconds. While fast and slow IPSCs in T-stellate cells improve spike timing on the scale of milliseconds, only fast IPSCs can enhance the detection of narrowband acoustic signals in a complex background. Our results suggest that target-specific IPSC kinetics are critical for the segregated parallel processing of temporal information from the sensory environment

Radiate and Planar Multipolar Neurons of the Mouse Anteroventral Cochlear Nucleus: Intrinsic Excitability and Characterization of their Auditory Nerve Input

Radiate and planar neurons are the two major types of multipolar neurons in the ventral cochlear nucleus (VCN). Both cell types receive monosynaptic excitatory synaptic inputs from the auditory nerve, but have different responses to sound and project to different target regions and cells. Although the intrinsic physiology and synaptic inputs to planar neurons have been previously characterized, the radiate neurons are less common and have not been as well studied. We studied both types of multipolar neurons and characterized their properties including intrinsic excitability, synaptic dynamics of their auditory nerve inputs, as well as their neural firing properties to auditory nerve stimulation. Radiate neurons had a faster member time constant and higher threshold current to fire spikes than planar neurons, but the maximal firing rate is the same for both cell types upon large current injections. Compared to planar neurons, radiate neurons showed spontaneous postsynaptic currents with smaller size, and slower but variable kinetics. Auditory nerve stimulation progressively recruited synaptic inputs that were smaller and slower in radiate neurons, over a broader range of stimulus strength. Synaptic inputs to radiate neurons showed less depression than planar neurons during low rates of repetitive activity, but the synaptic depression at higher rates was similar between two cell types. However, due to the slow kinetics of the synaptic inputs, synaptic transmission in radiate neurons showed prominent temporal summation that contributed to greater synaptic depolarization and a higher firing rate for repetitive auditory nerve stimulation at high rates. Taken together, these results show that radiate multipolar neurons integrate a large number of weak synaptic inputs over a broad dynamic range, and have intrinsic and synaptic properties that are distinct from planar multipolar neurons. These properties enable radiate neurons to generate powerful inhibitory inputs to target neurons during high levels of afferent activity. Such robust inhibition is expected to dynamically modulate the excitability of many cell types in the cochlear nuclear complex