STDP in the Developing Sensory Neocortex

Spike timing-dependent plasticity (STDP) has been proposed as a mechanism for optimizing the tuning of neurons to sensory inputs, a process that underlies the formation of receptive field properties and associative memories. The properties of STDP must adjust during development to enable neurons to optimally tune their selectivity for environmental stimuli, but these changes are poorly understood. Here we review the properties of STDP and how these may change during development in primary sensory cortical layers 2/3 and 4, initial sites for intracortical processing. We provide a primer discussing postnatal developmental changes in synaptic proteins and neuromodulators that are thought to influence STDP induction and expression. We propose that STDP is shaped by, but also modifies, synapses to produce refinements in neuronal responses to sensory inputs

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 Cochlear Nucleus Endbulb Synapse During Age-Related Hearing Loss in Mice

Age-related hearing loss (AHL) typically starts from high frequency regions of the cochlea and over time invades lower frequency regions. During this progressive hearing loss, sound-evoked activity in spiral ganglion cells is reduced. DBA mice have an early onset of AHL. In this study, we examined synaptic transmission at the endbulb of Held synapse between auditory nerve fibers and bushy cells in the anterior ventral cochlear nucleus (AVCN). Synaptic transmission in hearing-impaired high frequency areas of the AVCN was altered in old DBA mice. The spontaneous mEPSC frequency was greatly reduced (∼60%), and mEPSCs were significantly slower (∼115%) and smaller (∼70%) in high frequency regions of old (average age 45d) DBA mice compared to tonotopically matched regions of young (average age 22d) DBA mice. Moreover, synaptic release probability was about 30% higher in high frequency regions of young DBA than that in old DBA mice. Auditory nerve-evoked EPSCs showed less rectification in old DBA mice, suggesting recruitment of GluR2 subunits into the AMPA receptor complex. No similar age-related changes in synaptic release or EPSCs were found in age matched, normal hearing young and old CBA mice. Taken together, our results suggest that auditory nerve activity plays a critical role in maintaining normal synaptic function at the endbulb of Held synapse after the onset of hearing. Auditory nerve activity regulates both presynaptic (release probability) and postsynaptic (receptor composition and kinetics) function at the endbulb synapse after the onset of hearing

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

Spatial organization of excitatory synaptic inputs to layer 4 neurons in mouse primary auditory cortex

Layer 4 (L4) of primary auditory cortex (A1) receives a tonotopically organized projection from the medial geniculate nucleus of the thalamus. However, individual neurons in A1 respond to a wider range of sound frequencies than would be predicted by their thalamic input, which suggests the existence of cross-frequency intracortical networks. We used laser scanning photostimulation and uncaging of glutamate in brain slices of mouse A1 to characterize the spatial organization of intracortical inputs to L4 neurons. Slices were prepared to include the entire tonotopic extent of A1. We find that L4 neurons receive local vertically organized (columnar) excitation from layers 2 through 6 (L6) and horizontally organized excitation primarily from L4 and L6 neurons in regions centered ~300–500 μm caudal and/or rostral to the cell. Excitatory horizontal synaptic connections from layers 2 and 3 were sparse. The origins of horizontal projections from L4 and L6 correspond to regions in the tonotopic map that are approximately an octave away from the target cell location. Such spatially organized lateral connections may contribute to the detection and processing of auditory objects with specific spectral structures

Action Potential Timing Precision in Dorsal Cochlear Nucleus Pyramidal Cells

Many studies of the dorsal cochlear nucleus (DCN) have focused on the representation of acoustic stimuli in terms of average firing rate. However, recent studies have emphasized the role of spike timing in information encoding. We sought to ascertain whether DCN pyramidal cells might employ similar strategies and to what extent intrinsic excitability regulates spike timing. Gaussian distributed low-pass noise current was injected into pyramidal cells in a brain slice preparation. The shuffled auto-correlation-based analysis was used to compute a correlation index of spike times across trials. The noise causes the cells to fire with temporal precision (standard deviation ≅ 1-2 msec) and high reproducibility. Increasing the coefficient of variation of the noise improved the reproducibility of the spike trains, whereas increasing the firing rate of the neuron decreased the neurons' ability to respond with predictable patterns of spikes. Simulated IPSPs superimposed on the noise stimulus enhanced spike timing for > 300 msec, although the enhancement was greatest during the first 100 msec. We also found that populations of pyramidal neurons respond to the same noise stimuli with correlated spike trains, suggesting that ensembles of neurons in the DCN receiving shared input can fire with similar timing. These results support the hypothesis that spike timing can be an important aspect of information coding in the DCN

Endbulb synaptic depression within the range of presynaptic spontaneous firing and its impact on the firing reliability of cochlear nucleus bushy neurons

The majority of auditory nerve fibers exhibit prominent spontaneous activity in the absence of sound. More than half of all auditory nerve fibers in CBA mice have spontaneous firing rates higher than spikes/sec, and some fibers exceeding 100 spikes/sec. We tested whether and to what extent endbulb synapses are depressed by activity between 10 and 100 Hz, within the spontaneous firing rates of auditory nerve fibers. In contrast to rate-dependent depression seen at rates >100 Hz, we found that the extent of depression was essentially rate-independent (~35%) between 10 and 100 Hz. Neither cyclothiazide nor γ-D-glutamylglycine altered the rate-independent depression, arguing against receptor desensitization and/or vesicle depletion as major contributors for the depression. When endbulb synaptic transmission was more than half-blocked with the P/Q Ca2+ channel blocker ω-agatoxin IVA, depression during 25 and 100 Hz trains was significantly attenuated, indicating P/Q Ca2+ channel inactivation may contribute to low frequency synaptic depression. Following conditioning with a 100 Hz Poisson train, the EPSC paired pulse ratio was increased, suggesting a reduced release probability. This in turn should reduce subsequent depletion-based synaptic depression at higher activation rates. To probe whether this conditioning of the synapse improves the reliability of postsynaptic responses, we tested the firing reliability of bushy neurons to 200 Hz stimulation after conditioning the endbulb with a 25 Hz or 100 Hz stimulus train. Although immediately following the conditioning train, bushy cells responded to minimal suprathreshold stimulation less reliably, the firing reliability eventually settled to the same level (<50%) regardless of the presence or absence of the preconditioning. However, when multiple presynaptic fibers were activated simultaneously, the postsynaptic response reliability did not drop significantly below 90%. These results suggest that single endbulb terminals do not reliably trigger action potentials in bushy cells under “normal” operating conditions. We conclude that the endbulb synapses are chronically depressed even by low rates of spontaneous activity, and are more resistant to further depression when challenged with a higher rate of activity. However, there seems to be no beneficial effect as assessed by the firing reliability of postsynaptic neurons for transmitting information about higher rates of activity

ACQ4: an open-source software platform for data acquisition and analysis in neurophysiology research

The complexity of modern neurophysiology experiments requires specialized software to coordinate multiple acquisition devices and analyze the collected data. We have developed ACQ4, an open-source software platform for performing data acquisition and analysis in experimental neurophysiology. This software integrates the tasks of acquiring, managing, and analyzing experimental data. ACQ4 has been used primarily for standard patch-clamp electrophysiology, laser scanning photostimulation, multiphoton microscopy, intrinsic imaging, and calcium imaging. The system is highly modular, which facilitates the addition of new devices and functionality. The modules included with ACQ4 provide for rapid construction of acquisition protocols, live video display, and customizable analysis tools. Position-aware data collection allows automated construction of image mosaics and registration of images with 3-dimensional anatomical atlases. ACQ4 uses free and open-source tools including Python, NumPy/SciPy for numerical computation, PyQt for the user interface, and PyQtGraph for scientific graphics. Supported hardware includes cameras, patch clamp amplifiers, scanning mirrors, lasers, shutters, Pockels cells, motorized stages, and more. ACQ4 is available for download at http://www.acq4.org

Erratum to: I h and HCN channels in murine spiral ganglion neurons: Tonotopic variation, local heterogeneity, and kinetic model (JARO - Journal of the Association for Research in Otolaryngology DOI: 10.1007/s10162-014-0446-z)

One of the major contributors to the response profile of neurons in the auditory pathways is the I h current. Its properties such as magnitude, activation, and kinetics not only vary among different types of neurons (Banks et al., J Neurophysiol 70:1420-1432, 1993; Fu et al., J Neurophysiol 78:2235-2245, 1997; Bal and Oertel, J Neurophysiol 84:806-817, 2000; Cao and Oertel, J Neurophysiol 94:821-832, 2005; Rodrigues and Oertel, J Neurophysiol 95:76-87, 2006; Yi et al., J Neurophysiol 103:2532-2543, 2010), but they also display notable diversity in a single population of spiral ganglion neurons (Mo and Davis, J Neurophysiol 78:3019-3027, 1997), the first neural element in the auditory periphery. In this study, we found from somatic recordings that part of the heterogeneity can be attributed to variation along the tonotopic axis because I h in the apical neurons have more positive half-activation voltage levels than basal neurons. Even within a single cochlear region, however, I h current properties are not uniform. To account for this heterogeneity, we provide immunocytochemical evidence for variance in the intracellular density of the hyperpolarization-activated cyclic nucleotide-gated channel α-subunit 1 (HCN1), which mediates I h current. We also observed different combinations of HCN1 and HCN4 α-subunits from cell to cell. Lastly, based on the physiological data, we performed kinetic analysis for the I h current and generated a mathematical model to better understand varied I h on spiral ganglion function. Regardless of whether I h currents are recorded at the nerve terminals (Yi et al., J Neurophysiol 103:2532-2543, 2010) or at the somata of spiral ganglion neurons, they have comparable mean half-activation voltage and induce similar resting membrane potential changes, and thus our model may also provide insights into the impact of I h on synaptic physiology

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