The Cochlear Nuclei: Synaptic Plasticity in Circuits and Synapses in the Ventral Cochlear Nuclei
Abstract and Keywords
Plasticity in neuronal circuits is essential for optimizing connections as animals develop and for adapting to injuries and aging, but it can also distort the processing, as well as compromise the conveyance of ongoing sensory information. This chapter summarizes evidence from electrophysiological studies in slices and in vivo that shows how remarkably robust signaling is in principal cells of the ventral cochlear nucleus. Even in the face of short-term plasticity, these neurons signal rapidly and with temporal precision. They can relay ongoing acoustic information from the cochlea to the brain largely independently of sounds to which they were exposed previously.
The ventral cochlear nucleus (VCN) serves as the brain’s port of entry for acoustic information. The VCN performs two tasks. First, individual neurons extract biologically useful features of sounds from signals in auditory nerve fibers. Some neurons sharpen the encoding of the fine structure of sounds, others detect the onset of spectrally complex sounds that arise from a single source, and a third group tracks spectral peaks and valleys. Second, the VCN distributes acoustic information along parallel ascending pathways to brainstem nuclei, the inferior colliculi and the thalamus. In this chapter we review what is known about responses to sound in view of what has been learned about synaptic plasticity from slices in vitro.
Plasticity is crucial in the functioning of the brain for it allows neuronal circuits to be optimized as animals develop and to adapt to changes as animals suffer injuries. On the other hand, adjustment of the strength of synapses influences the way synapses convey information. Synapses in the VCN balance the need for adjustment with the need to convey ongoing acoustic information robustly. For the purposes of this chapter we will distinguish several distinct types of plasticity that differ in how they are driven, how long they last, and by what mechanisms they are regulated.
1. Over development some neurons die apoptotic deaths while others make or withdraw synaptic connections that can increase or decrease in size and strength. Developmental plasticity takes place as animals develop at all stages of the auditory pathway and the consequences last over the lifetime of the animals, months and years. That plasticity will be reviewed in (see Friauf, this volume). Such plasticity is usually rapid early in life and then slows. In development, plastic changes are accompanied by maturation in the morphology of dendritic and axonal arbors of neurons.
2. Plasticity in the adult brain is particularly evident when the brain responds to injury. In the auditory system it is evident when animals suffer hearing loss. Responses to hearing loss are evident over days, months or years and are considered in many other chapters of this book and will thus not be reviewed here (see chapters by Caspary & Llano, Manis, and Rubio, this volume).
3. In many parts of the brain, famously in the hippocampus and cerebral cortex where it is thought to underlie the ability to learn and remember, synapses undergo long-term plasticity, long-term potentiation and long-term depression. Long-term plasticity adjusts the strength of synapses upward or downward as a function of synaptic traffic they convey and can last for hours and days. This type of plasticity takes place at synapses on spines that form separate biochemical compartments for synapses. It is largely synapse specific but also shows cooperativity and associativity with nearby synapses. Such long-term plasticity occurs in the molecular layer of the dorsal cochlear nucleus (DCN; see Trussell, this volume) but not in the ventral cochlear nucleus (VCN). Neurons in the VCN lack spines and neither long-term potentiation or long-term depression have been observed in electrophysiological recordings from the VCN.
4. Synaptic plasticity can also occur over short periods. Short-term plasticity affects the strength of synapses temporarily over tens of milliseconds to seconds. This kind of plasticity will be discussed here.
This chapter summarizes evidence that the synapses that convey acoustic information from auditory nerve fibers to targets in the VCN are striking for how faithfully they convey signals even when signaling is rapid. Neurons differ in manifestation of short-term plasticity of their auditory nerve inputs in their responses to sound. In some neurons plasticity is not evident whereas in others the subtle effects of short-term depression are evident. It also discusses what little is known about plasticity of interconnections between neurons in the VCN.
Spiral Ganglion Cells Impose a Tonotopic Organization on the VCN
Myelinated spiral ganglion cells receive sensory inputs through a peripheral process from a tiny segment of the tonotopic array of inner hair cells, in mice about ~1/3000. Auditory nerve fibers, the axons of spiral ganglion cells, enter the brainstem and bifurcate to innervate the anteroventral cochlear nucleus (aVCN) with the ascending branch and the posteroventral cochlear nucleus (pVCN) and the dorsal cochlear nucleus (DCN) with the descending branch. Like other sensory neurons that innervate the hind brain and spinal cord, auditory nerve fibers grow into the brain from the periphery and bifurcate upon reaching the brain (Lu et al., 2014; Schmidt et al., 2007; Ter-Avetisyan, Rathjen, & Schmidt, 2014). The sturdy ascending branch contacts neurons in the aVCN through collateral branches that end in clusters of boutons, the end bulbs of Held, or with individual terminals while the thinner descending branch innervates neurons in the pVCN and DCN through boutons on collateral branches. In mice that lack npr2, neither auditory nerve fibers nor sensory neurons in the spinal cord bifurcate while still generating collateral branches, indicating that the bifurcation of auditory nerve fibers in the nerve root is regulated by mechanisms distinct from collateral branching (Lu et al., 2014).
A fundamental feature of the growth of spiral ganglion cells into the cochlear nuclei is the tonotopic organization. Spiral ganglion cells that receive input from the apical part of the cochlea and encode the lowest frequencies, innervate the most ventral region of the ventral and dorsal cochlear nuclei (Bourk, Mielcarz, & Norris, 1981). Those that receive input from the base of the cochlea and that encode the highest frequencies innervate the most dorsal regions of VCN and DCN. The orderly topographic organization of connections between the cochlea and cochlear nuclear targets develops before animals hear and exists even in animals in which hair cells never function (X. J. Cao, McGinley, & Oertel, 2008) and in which synapses between hair cells and spiral ganglion cells function only weakly over a short period (Beurg et al., 2008; Wright, Hwang, & Oertel, 2014). The tonotopic organization of connections between auditory nerve fibers and their cochlear nuclear targets is thus not dependent on auditory experience but rather on molecular cues (Lu, Appler, Houseman, & Goodrich, 2011). Mutant mice that lack npr2, whose auditory nerve fibers fail to bifurcate normally (Lu et al., 2014), mutant mice in which neurons in the VCN are deprived of Hox2 genes (Karmakar et al., 2017), or where netrin signaling is disrupted (Kim et al., 2016) have a blurred tonotopic organization.
Through collateral branches auditory nerve fibers innervate four types of principal neurons, three excitatory and one inhibitory. The three major groups of excitatory principal cells that transmit acoustic information along separate ascending pathways are bushy cells, T stellate cells, and octopus cells (J. R. Brawer, Morest, & Kane, 1974; Cant & Morest, 1979; Lorente de No, 1933; Osen, 1969). D Stellate cells also project out of the VCN to the ipsilateral DCN and to the contralateral cochlear nuclei but these cells are inhibitory (Needham & Paolini, 2003; Wenthold, 1987). The organization is illustrated schematically in Figure 1A.
Differences in the way target cells process acoustic information is evident in the transformation of responses to tones at the frequency to which they are tuned, the characteristic frequency (CF; Figure 1C–F). In mature mammals auditory nerve fibers have characteristic “primary-like” firing patterns in that they fire rapidly at the onset of a sound and then the firing slows (Figure 1B; Liberman, 1978; Rhode & Smith, 1985). Globular bushy cells convert primary-like patterns of auditory nerve fibers to “primary-like with notch” patterns that have a sharply timed first spike followed by a refractory period (Figure 1C; P. H. Smith & Rhode, 1987). Octopus cells respond only at the onsets of tones with “onset” patterns when those tones are > 1 kHz (Figure 1D; Rhode, Oertel, & Smith, 1983; P. H. Smith, Massie, & Joris, 2005). T Stellate cells fire steadily throughout the tone without conveying information about the fine structure of sounds with “chopper” patterns except at low frequencies (Figure 1E; Blackburn & Sachs, 1989; P. H. Smith & Rhode, 1989). D Stellate cells also fire tonically but with a more sharply timed initial spike to produce an “Onset chopper” response (Figure 1F; P. H. Smith & Rhode, 1989).
The patterns of convergence of auditory nerve inputs differ as shown schematically in Figure 1. Bushy and T stellate cells receive input from a small number of similarly tuned inputs making them sharply tuned whereas octopus and D stellate cells receive input from large numbers of inputs and are broadly tuned. The dynamics of the synaptic currents differs (Figure 2). Repeated stimulation of auditory nerve inputs in bushy and octopus cells evokes strong synaptic depression whereas in T and D stellate cells synaptic currents show weak synaptic depression. Neurons also differ in the contribution of inhibitory inputs and in the way the electrical properties of target neurons shape the voltage responses to synaptic currents determine the firing patterns in responses to sounds of the principal cells of the VCN.
It is now possible to assign general functions to the various VCN neurons at least tentatively, as we shall discussed. Bushy cells preserve or sharpen information in the firing patterns of auditory nerve fibers that conveys the fine structure of sounds, including phase locking at low frequencies. Octopus cells detect the coincident firing of large groups of auditory nerve fibers, signaling the presence of onsets and broadband transients. Individual T stellate cells detect the amplitude of sounds over a narrow frequency range and as a population they detect the ongoing spectrum of sounds impinging on the ear. D Stellate cells detect coincident firing from many auditory nerve fibers but the temporal and spatial summation of inputs obscures temporal fine structure.
Connections between Auditory Nerve Fibers and Bushy Cells
Bushy cells sharpen the representation of the fine structure of sounds. The sharpened representations serve as the basis for the comparison of interaural time and intensity in the superior olivary complex that underlie our ability to localize sounds in the horizontal plane (Yin, 2002).
The characteristic “bush” of dendrites gives bushy cells their name (J. R. Brawer et al., 1974; Lorente de No, 1933). Bushy cells are most common in the aVCN. They are of three subtypes that differ in their targets within the brain stem. Large spherical bushy cells, most common ventrally and anteriorly in the aVCN, terminate bilaterally in the medial superior olivary nuclei (MSO). Small spherical bushy cells terminate ipsilaterally in the vicinity of the ipsilateral lateral superior olive (LSO; Cant & Casseday, 1986). Globular bushy cells terminate in the contralateral medial nucleus of the trapezoid body (Tolbert, Morest, & Yurgelun-Todd, 1982). Consistent with their lying ventrally, the tuning of large spherical bushy cells is biased toward the low frequencies, as are their targets in the MSO. Animals that have little low-frequency hearing, as for example mice and bats, have relatively few large spherical bushy cells. Lying more dorsally, small spherical bushy cells are biased toward tuning to the higher frequencies and are numerous in the aVCN of mice and bats.
The number of converging inputs differs between subtypes of bushy cells. Large and small spherical bushy cells that lie anteriorly in the anterior VCN receive input from about 2-4 fibers (J. R. Brawer & Morest, 1975; X. J. Cao & Oertel, 2010; Sento & Ryugo, 1989). They respond to tones resemble those in auditory nerve fibers and are thus termed “primary-like” (P. H. Smith, Joris, & Yin, 1993). Globular bushy cells that lie more caudally near the nerve root receive more inputs, ≥ 5 in mice (X. J. Cao & Oertel, 2010) and about 25 in cats (Ostapoff & Morest, 1991; Spirou, Rager, & Manis, 2005). They respond to tones with an initial well-timed action potential that is followed by a “notch” that reflects the refractory period of auditory nerve inputs (Figure 1C; P. H. Smith, Joris, Carney, & Yin, 1991).
Auditory nerve fibers innervate bushy cells through large clusters of terminals, the end bulbs of Held (Held, 1893), that engulf the cell body. End bulbs are capable of releasing large amounts of neurotransmitter that evoke large postsynaptic currents, up to 6 nA in wild type mice and up to 12 nA in deaf mice, through numerous release sites (Cant & Morest, 1979; X. J. Cao & Oertel, 2010; Spirou et al., 2005; Wright et al., 2014). In animals that never hear, end bulbs are smaller and less branched (Lee, Cahill, & Ryugo, 2003; Ryugo, Pongstaporn, Huchton, & Niparko, 1997; Wright et al., 2014). At these synapses, synaptic currents are larger and synaptic depression is greater than in hearing mice reflecting a higher probability of release (Oleskevich & Walmsley, 2002; Wright et al., 2014; Zhuang, Sun, & Xu-Friedman, 2017).
Bushy cells sharpen the encoding of the fine structure of sounds. The presence of a low-voltage-activated K+ conductance gives bushy cells low input resistances that cause EPSPs to rise and fall rapidly, to minimize temporal summation (X. J. Cao, Shatadal, & Oertel, 2007; Manis & Marx, 1991). Bushy cells are differentiators of excitatory postsynaptic potentials (EPSPs); large, summed synchronous EPSPs rise most rapidly and evoke action potentials most reliably (McGinley & Oertel, 2006). Extracellular recordings often indicate that the firing of bushy cells often follows the firing of auditory nerve fibers, accounting for the similarity of auditory nerve fibers and bushy cells in their responses to tones (Bourk, 1976; Kopp-Scheinpflug, Dehmel, Dorrscheidt, & Rubsamen, 2002). The relatively small number of inputs is consistent with their narrow tuning (Rhode et al., 1983; Rhode & Smith, 1986). However, the responses are subtly altered by convergence. The standard deviation in the first spike latency in the population of globular bushy cells is 0.58 msec compared to 0.73 msec for auditory nerve fibers (Rhode & Smith, 1986). Phase-locked responses to low-frequency sounds, presumably from large spherical bushy cells, are also sharpened (P.X. Joris, Carney, Smith, & Yin, 1994; P. X. Joris, Smith, & Yin, 1994). Tuning is sharpened by inhibitory sidebands, probably from D stellate cells (Caspary, Backoff, Finlayson, & Palombi, 1994; Kopp-Scheinpflug et al., 2002; Oertel, 1983; Oertel, Wu, Garb, & Dizack, 1990).
Responses of bushy cells to sound have long been explored by presenting tones many times in rapid succession and constructing a peristimulus time histogram (PSTH), which plots the probability of the cell’s firing with respect to the presentation of the tone. The observation that responses to tones are not perceptibly affected by the rate at which tones are presented shows how subtle the role of plasticity is. The peristimulus time histograms illustrated in Figure 1 were generated by summing firing in responses to 250 repetitions of a 50-msec tone at the frequency to which they are tuned. They were generated from responses to tones that were repeated at 150 ms intervals (6.7/sec). These are not substantially different from those generated by others from responses at higher rates (9.5/sec; Rhode & Smith, 1985, 1986), or slower rates (5/sec; Blackburn & Sachs, 1989; Winter & Palmer, 1990). The response of a globular bushy cell (Figure 1C) shows that the timing of the first action potential is sharp, sharper than that of auditory nerve fibers, most falling into one 250 µsec bin of the PSTH. The dot raster on the right shows that the first spikes occur over a window that does not change even as the cell responds to a rapid succession of tones. The fact that responses are stable even during stimulation at high rates is an indication that synaptic transmission shows little sign of long-term synaptic plasticity. Large spherical bushy cells also signal with sharp timing (P. X. Joris, Smith, & Yin, 1998).
The question whether short-term plasticity plays a role in vivo has been examined with elegant experiments in large spherical bushy cells. A series of studies has shown that in extracellular recordings three events, the presynaptic action potential, the postsynaptic current, and the postsynaptic action potential, can be separately and reliably monitored, as illustrated in Figure 3A (Kuenzel, Borst, & van der Heijden,, 2011). The relationship between them can thus also be measured. Short-term synaptic depression or facilitation would be expected to cause correlation of the slope of the EPSP with the interval between responses. Figures 3C and 3D show that there is little correlation (Keine, Rubsamen, & Englitz, 2016; Kuenzel et al., 2011).
The relationship between the slopes of EPSPs and the threshold of action potentials did change with activity, however. When auditory nerve fibers were driven slowly by soft tones (20 dB SPL; Figure 3C) the threshold slope of EPSPs required to evoke action potentials was lower than when auditory nerve fibers were driven rapidly by loud tones (70 dB SPL; Figure 3D; Kuenzel et al., 2011). Findings like these led to the conclusion that while short-term synaptic plasticity does not play a major role, inhibition influences the dynamics of responses to sound in vivo (Englitz, Tolnai, Typlt, Jost, & Rubsamen, 2009; Keine et al., 2016; Keine, Rubsamen, & Englitz, 2017; Kopp-Scheinpflug et al., 2002; Kuenzel et al., 2011; Kuenzel, Nerlich, Wagner, Rubsamen, & Milenkovic, 2015; Winter & Palmer, 1990). Such detailed analyses have not been performed on small spherical or on globular bushy cells.
In contrast with the subtlety or absence of synaptic plasticity in vivo, synaptic transmission between auditory nerve fibers and bushy cells in slices in vitro consistently reveals short-term synaptic depression (Figure 2A; Bellingham & Walmsley, 1999; X. J. Cao & Oertel, 2010; Chanda & Xu-Friedman, 2010; Klug et al., 2012; Oleskevich, Clements, & Walmsley, 2000; Y. Wang & Manis, 2008; Y. Wang, Ren, & Manis, 2010; H. Yang & Xu-Friedman, 2008, 2009). While most recordings from bushy cells in slices are from mice that have few large spherical bushy cells and are thus likely to be from small spherical or globular bushy cells, there is no reason to think the difference in synaptic plasticity reflects a difference in the type of bushy cell. Synaptic depression is a feature of synapses that have a high probability of neurotransmitter release (Oleskevich & Walmsley, 2002; Schneggenburger, Meyer, & Neher, 1999; Silver, Momiyama, & Cull-Candy, 1998). The high probability of release implies that when a resting synapse is stimulated with a train of shocks, a relatively large proportion of the readily releasable pool of vesicles is released in response to the first shock, leaving the pool depleted for subsequent stimuli (Taschenberger, Scheuss, & Neher, 2005). Much has been learned about short-term synaptic depression as investigators have grappled with the question why synaptic plasticity looks so different in large spherical bushy cells in vivo and in vitro.
Synaptic depression is variable. It differs between bushy cells but is matched at inputs that converge on one cell (H. Yang & Xu-Friedman, 2009). It is greater at younger than at more mature synapses (Wu & Oertel, 1987); in vivo studies are generally done on mature animals whereas measurements in slices are generally done on immature rodents.
Desensitization of the AMPA receptors that mediate transmission causes synaptic depression. Especially at immature end bulbs, EPSCs are reduced as a result of progressive desensitization of AMPA receptors (Chanda & Xu-Friedman, 2010; Trussell, Zhang, & Raman, 1993; H. Yang & Xu-Friedman, 2008). It has been demonstrated that the presence of NMDA receptors at these synapses can counteract synaptic depression in that while AMPA receptors become depressed, currents through NMDA receptors sum and strengthen (Pliss, Yang, & Xu-Friedman, 2009).
Spontaneous firing of auditory nerve fibers could put synapses into a depressed state in vivo but not in slices in vitro. In vivo many auditory nerve fibers fire spontaneously even in the absence of sound stimuli. Spontaneous firing rates vary from 0 to > 100 Hz, with the proportions of fibers firing at low and high rates varying between species and also between strains of mice (Liberman, 1978; Taberner & Liberman, 2005; Tsuji & Liberman, 1997). In mice 30%–50% of fibers fire >20/sec (Taberner & Liberman, 2005) suggesting that in vivo many end bulb synapses are probably in a constantly depressed state so that depression is less evident. Stimulation of synapses at rates similar to those in vivo resulted in reduced synaptic depression (Y. Wang et al., 2010).
Differences in short-term plasticity in vivo and in vitro are exacerbated by differences in the extracellular calcium concentrations in the extracellular fluids. Recordings in slices are often done at > 2 mM Ca2+ while in vivo physiological extracellular Ca2+ concentrations are lower, between 1.2 and 1.7 mM. High extracellular Ca2+ concentrations result in artificially high release probability and artificially high synaptic depression (Borst, 2010; H. Yang & Xu-Friedman, 2015).
In slices, even at physiological extracellular Ca2+ concentrations, EPSCs suffer from presynaptically mediated synaptic depression. In an elegant experiment in which investigators presented naturalistic stimulus trains and compared responses when a single stimulus about midway through the train was skipped, it was possible to relate the size of synaptic currents to the length of the previous interstimulus interval (Figure 3E; H. Yang & Xu-Friedman, 2015). Figure 3E illustrates how lengthening the preceding interval increased the size of EPSPs even when the extracellular Ca2+ concentration was near physiological at 1.5 mM. While synaptic depression was evident, recovery from depression was rapid, occurring over about 60 msec, because activity accelerates recovery from inactivation (H. Yang & Xu-Friedman, 2008, 2015).
Sodium channel inactivation also contributes to failure of EPSPs to evoke action potentials (H. Yang & Xu-Friedman, 2015). During the refractory period of an action potential, larger and faster depolarizations are required reach threshold.
It is possible that synapses in vivo are tonically inhibited by GABA or glycine. Bushy cells are contacted by synaptic terminals that contain glycine and GABA (Juiz, Helfert, Bonneau, Wenthold, & Altschuler, 1996). Sound evoked inhibition increased the threshold of action potentials, so that only the largest and most sharply timed EPSPs evoked postsynaptic action potentials (Kuenzel et al., 2011). Such inhibition produces a depression in firing.
In summary, no long-term plasticity has been detected at synapses between auditory nerve fibers and bushy cells. Short-term depression is consistently observed in slices but is subtle or absent in vivo. Short-term plasticity at inputs to bushy cells in vivo appears to be regulated by many factors including release probability, desensitization of AMPA receptors, activation of NMDA receptors, accumulation of inhibition, and also Na+ channel inactivation. When these mechanisms act together at synapses between auditory nerve fibers and bushy cells in vivo, short-term plasticity is not obvious. The properties of auditory nerve inputs to globular bushy cells have not been studied in detail in vivo and may differ somewhat. Published studies indicate that synapses between auditory nerve fibers and bushy cells are remarkably robust, conveying ongoing, precisely timed information both when their inputs fire slowly and also when they fire rapidly.
Connections between Auditory Nerve Fibers and Octopus Cells
While their integrative role is not fully understood, it is likely that octopus cells contribute to the detection of gaps, a feature that is important in the understanding of speech (Oertel, Cao, Ison, & Allen, 2017; F. G. Zeng, Kong, Michalewski, & Starr, 2005; F.G. Zeng, Oba, Garde, Sininger, & Starr, 1999). Octopus cells occupy the most caudal and dorsal part of the VCN where auditory nerve fibers become closely bundled on their way to the DCN. They were named for the unidirectional spread of their dendrites across the tonotopically organized bundle of auditory nerve fibers (Osen, 1969). They project to the contralateral superior paraolivary nucleus (Schofield, 1995) and ventral nucleus of the lateral lemniscus where they terminate in calyceal endings (Adams, 1997).
Octopus cells splay their dendrites across the bundle of auditory nerve fibers from caudal to rostral, enabling them to detect synchronous firing among the many fibers (>60 in mice; Figure 1; Golding, Robertson, & Oertel, 1995; McGinley, Liberman, Bal, & Oertel, 2012). Inputs from fibers tuned to a wide range of frequencies generates broad tuning in octopus cells (Godfrey, Kiang, & Norris, 1975; Rhode et al., 1983; P. H. Smith et al., 2005). Each auditory nerve fiber delivers only a small current so that coincident inputs from many fibers are required for octopus cells to reach threshold. They respond to sounds that activate many auditory nerve fibers synchronously: clicks, the onsets of tones, and loud phase-locked sounds at every cycle at frequencies below 800 Hz (Oertel, Bal, Gardner, Smith, & Joris, 2000; Rhode & Smith, 1986; P. H. Smith et al., 2005). In responding at every cycle up to 800 Hz, octopus cells fire at extraordinary rates. They respond only at the onset of tones of higher frequency (Figure 1D; Godfrey et al., 1975; Rhode et al., 1983; P. H. Smith et al., 2005). That single action potential occurs with little temporal jitter, having a standard deviation of only 0.12 msec (Figure 1D; Rhode & Smith, 1986).
Short-term depression is evident in responses to sound of octopus cells. In responses to tones (Figure 1D) and clicks (Figure 4A) octopus cells fire over a time window that gradually shifts while cells are responding rapidly. Responses to tones presented at 6.7/sec shifted by about 100 µsec (Figure 1D, right panel); responses to 100 clicks at 500 Hz increased by about 200 µsec in latency between the first and the 100th click (Figure 4A; Oertel et al., 2000). While the greatest differences occurred between the first and subsequent responses, the latency continued to change with later responses. These systematic shifts parallel synaptic depression in slices.
In vitro rapid stimulation of auditory nerve fibers evokes responses in octopus cells that show synaptic depression. Synaptic currents evoked by stimulation of auditory nerve fibers diminish in size when they are evoked in rapid succession in the presence of high (2.4 mM) extracellular Ca2+ concentrations (Figure 2B; X. J. Cao & Oertel, 2010). The voltage changes produced by synaptic currents are determined by the biophysical properties of target cells. Octopus cells have exceptionally low input resistances and short time constants (Golding, Ferragamo, & Oertel, 1999; Golding et al., 1995). The short time constants are a consequence of the activation of two opposing voltage-sensitive conductances, a slow hyperpolarization-activated, mixed cation conductance and a fast depolarization-activated K+ conductance (Bal & Oertel, 2000, 2001). In octopus cells, EPSPs are faster than the currents that drive them, only about 1 msec in duration, because EPSPs are actively repolarized by the fast, low-voltage-activated K+ conductance (X. J. Cao & Oertel, 2010; Golding et al., 1995). The fast K+ conductance also gives every octopus cell a threshold rate of depolarization (M. J. Ferragamo & Oertel, 2002). To generate action potentials, small unitary EPSPs must sum on their rising phases to generate a depolarization that exceeds the threshold rate of depolarization. Action potentials are generated on the rising phase of EPSPs. This mechanism makes octopus cells excellent coincidence detectors. The need for coincidence in the submillisecond range raised the question how summing occurs for inputs that are subject to traveling wave delays of multiple milliseconds. Dendritic filtering compensates for differences in the cochlear traveling wave delay (McGinley et al., 2012).
In responses to rapid trains of shocks to the auditory nerve, diminishing synaptic currents depolarize octopus cells more and more slowly, generating progressively smaller, albeit suprathreshold, responses (Figure 4B). The peaks of suprathreshold postsynaptic responses become smaller (Figure 4B). The peaks of responses also become increasingly delayed (Figure 4C), much as responses to clicks are delayed when they are presented in rapid succession (Figure 4A). How a reduction of extracellular Ca2+ to physiological levels affects the degree of depression in slices and whether synaptic depression reflects only depletion of neurotransmitter or also involves other factors is not known. Inhibition may or may not play a role. In guinea pigs glycinergic, but not GABAergic, terminals have been detected (Juiz et al., 1996) but in mice there is a conspicuous absence of inhibition in the octopus cell area (R. E. Wickesberg, Whitlon, & Oertel, 1994). It is also not known whether sodium channel inactivation elevates the thresholds of action potentials.
In summary, responses to tones and clicks in vivo show evidence of short-term depression, but not of long-term synaptic plasticity. Detailed comparisons of short-term plasticity in octopus cells in vivo and in vitro have not been made.
Connections between Auditory Nerve Fibers and T Stellate Cells
T Stellate cells encode features that are critical for understanding speech in humans and for understanding the significance of environmental sounds in all mammals, spectral peaks and valleys and amplitude modulation (Frisina, Smith, & Chamberlain, 1990; Rosen, 1992; Shannon, Zeng, Kamath, Wygonski, & Ekelid, 1995; X. Wang & Sachs, 1992). As a population they encode spectrum (Blackburn & Sachs, 1990; May, Prell, & Sachs, 1998; Recio & Rhode, 2000). The fact that they encode those features known to be conveyed by cochlear implants and that they fail to encode the temporal fine structure of sounds that is not conveyed by cochlear implants, suggests that T stellate cells play a particularly important role in cochlear implant users and that they are important for understanding speech in all listeners.
T Stellate cells are concentrated just caudal to the nerve root in the multipolar cell area. Their dendrites lie parallel to the path of auditory nerve fibers and their axons project out of the VCN through the trapezoid body (hence T stellate (Oertel et al., 1990)). They are known by a confusing array of names. They are referred to as multipolar cells (Osen, 1969), stellate cells (J. R. Brawer et al., 1974), type I cells (Cant, 1981), and planar multipolar cells (Doucet & Ryugo, 1997). T Stellate cells are not only numerous but they project more widely than the other principal cells. T Stellate cells excite targets in the ipsilateral DCN (Doucet & Ryugo, 1997; Oertel et al., 1990; P.H. Smith, Joris, Banks, & Yin, 1993), the contralateral ventral nucleus of the trapezoid body (P.H. Smith et al., 1993; Thompson & Thompson, 1991), the contralateral ventral nucleus of the lateral lemniscus (Schofield & Cant, 1997; P.H. Smith et al., 1993), the inferior colliculi (Adams, 1979; Oliver, 1987; Schofield, Mellott, & Motts, 2014), and the thalamus (Schofield et al., 2014).
T Stellate cells respond tonically to sound stimuli in vivo. That is, they fire at a roughly constant rate in the presence of sounds to which they are tuned (Figure 1E). The “chopping” pattern reflects the consistency of the regular firing (Blackburn & Sachs, 1989; Rhode et al., 1983; P. H. Smith & Rhode, 1989; Young, Robert, & Shofner, 1988). The first spike has a narrow range of latencies and produces the first mode in the chopping pattern; the jitter in timing of the second spike sums with the jitter in the timing of the first, producing a broader, smaller mode and so on until the modes are not resolvable. These cells respond to tones as if they are steadily depolarized by sound and fire at a rate monotonically related to the size of the depolarization. The firing pattern thus does not reflect the fine structure of sounds except at low frequencies (Blackburn & Sachs, 1989).
It was noted long ago that the responses of T stellate cells to tones in vivo occur almost 2 msec later than responses of other VCN neurons (Figure 1E; Young et al., 1988). Furthermore, the variability of the latency of the first spike is greater than that of other targets of auditory nerve fibers. The firing of T stellate cells at roughly constant rates for the duration of a tone, also stands in contrast with responses of their auditory nerve inputs, which fire most rapidly at the onset of sound stimuli and then slow. How T stellate cells convert the phasic responses of auditory nerve fibers to tonic responses is not understood (Oertel, Wright, Cao, Ferragamo, & Bal, 2011). The consistency of the firing pattern over many repetitions even when those stimuli are presented at high rates is an indication that long-term plasticity does not play a role in shaping responses to tones in T stellate cells. Dot rasters of responses to tones do show that the latency of responses shifts gradually when the cell is driven at high rates. The finding that at physiological Ca2+ concentrations, T stellate cells show facilitation rather than depression makes it unlikely that the shift is a consequence of synaptic depression (Chanda & Xu-Friedman, 2010). It could arise from accumulating inhibition.
T Stellate cells/choppers are strongly influenced by inhibition. The tuning of choppers is sharpened by inhibitory sidebands (Palombi & Caspary, 1992; Paolini, Clarey, Needham, & Clark, 2005; Rhode & Greenberg, 1994b). In responses to complex sounds, inhibition would be expected to enhance the encoding of spectral peaks, consistent with the observation that choppers convey information about the spectrum of sounds (Blackburn & Sachs, 1990; May et al., 1998; Recio & Rhode, 2000). Possibly inhibition balances excitation, counteracting strong excitation at the onset of a sound and obscuring the fine structure of excitation (Paolini et al., 2005). The presence of early inhibition could also account for the longer latency of responses of choppers than responses of other VCN neurons (Figure 1E, right panel). As T stellate cells receive input directly from auditory nerve fibers and inhibition requires an extra synaptic delay, it is unclear how inhibition can affect the onset of responses to sounds. However, inhibition so rapid that it can reduce responses to single clicks has been observed in vivo (R.E. Wickesberg, 1996).
Studies in slices reveal that shocks to auditory nerve fibers evoke rapid excitation and delayed, long-lasting inhibition in T stellate cells Recordings in slices show that T stellate cells receive input from a relatively small number of auditory nerve fibers, in mice about 5.5, consistent with their sharp tuning (M. J. Ferragamo, Golding, & Oertel, 1998). The latency between shocks to auditory nerve fibers and responses are similar to those in bushy and octopus cells (Wu & Oertel, 1984). T Stellate cells fire steadily and regularly as long as they are depolarized, the firing rate being monotonically related to the injected depolarizing current (Oertel et al., 1990). In contrast with bushy and octopus cells, whose thresholds are a function of the slope of EPSPs, thresholds of action potentials in T stellate cells are more nearly a function of the peak amplitude of EPSPs as result of having somatic voltage-sensitive Na+ channels (Y. Yang, Ramamurthy, Neef, & Xu-Friedman, 2016).
In slices bathed in extracellular fluid with elevated Ca2+ concentrations, synaptic responses to stimulation of the auditory nerve show synaptic depression in T stellate cells. Under voltage-clamp at -65 mV, AMPA-receptor mediated responses can be isolated. These show some synaptic depression, but less than bushy or octopus cells (Figure 2C; X. J. Cao & Oertel, 2010). Under lower, more physiological Ca2+ concentrations, inputs to T stellate cells show facilitation rather than depression (Chanda & Xu-Friedman, 2010). Synaptic responses in T stellate cells involve not only AMPA but also NMDA receptors that can last for hundreds of milliseconds (X. J. Cao & Oertel, 2010; M. J. Ferragamo et al., 1998).
Slices confirm that inhibition affects the dynamics of signaling (M. Ferragamo, Golding, Gardner, & Oertel, 1998; Paolini et al., 2005). Glycinergic inputs are regularly activated by stimulation of the auditory nerve and can sometimes provide repeated IPSPs for long periods (Figure 5A; M. Ferragamo et al., 1998). The observation that inhibition can last for 500 msec, albeit in slices (Figure 5A), suggests that responses to tones repeated every 150 msec could be affected by inhibition evoked by previous tones (Figure 1E). While GABAergic IPSPs have not been detected in slices, bicuculline, a blocker of GABAA receptors affects choppers, suggesting that GABAA receptors affect responses to sound in vivo (Caspary et al., 1994). The presence of GABA suggests that release from auditory nerve terminals could be modulated through GABAB receptors.
In summary, T stellate cells respond robustly to sounds showing no evidence of long-term plasticity. If short-term plasticity plays a role, it is subtle. While responses to tones of T stellate cells become slightly delayed when they are presented in rapid succession, those shifts could arise from shifts in the balance between excitation and inhibition. Like the other principal cells of the VCN, T stellate cells respond robustly to ongoing sounds, largely independently of what happened previously.
Connections between Auditory Nerve Fibers and D Stellate Cells
In contrast with bushy, octopus and T stellate cells, which are excitatory and form the major ascending auditory pathways, D Stellate cells are glycinergic, inhibitory neurons that project within the ipsilateral cochlear nuclei and to the contralateral cochlear nuclei (Needham & Paolini, 2003; Paolini & Clark, 1999; Wenthold, 1987). Being inhibitory, these neurons shape the output of their targets. These neurons are thought to generate inhibitory sidebands that sharpen tuning in their targets, in T stellate cells and also in targets in pyramidal cells of the DCN (Nelken & Young, 1994).
The reach of D stellate cell dendrites across the tonotopic axis gives D stellate cells access to input from numerous auditory nerve fibers and accounts for their broad tuning (Oertel et al., 1990; Xie & Manis, 2017). D Stellate cells fire with “onset-chopper” response patterns (Figure 1F; Palmer, Jiang, & Marshall, 1996; Paolini & Clark, 1999; P. H. Smith & Rhode, 1989). In these neurons the regularity of the early spikes in responses to tones generates sharply timed modes at the onset of peristimulus time histograms. The sharpness in timing likely reflects a reduction in temporal jitter by coincidence detection (Rhode & Greenberg, 1994a; Xie & Manis, 2017). As in other VCN neurons, the firing patterns are stable even when they are stimulated rapidly, suggesting that synaptic inputs from auditory nerve fibers are not subject to long-term synaptic plasticity (Figure 1F). The dot rasters confirm the consistency in the timing of firing of responses to tones, with first spike latencies largely falling within a 300 µsec window and there being no detectable difference between the early and late responses.
In slices EPSCs activated by stimulation of auditory nerve fibers in slices are slower in D stellate cells than in the other principal cells of the VCN (Xie & Manis, 2017). In the presence of high extracellular Ca2+ some synaptic depression is evident (Figure 2D). Synaptic depression is, however, even weaker than in T stellate cells (Xie & Manis, 2017). Presumably there would be little synaptic depression or perhaps facilitation in the presence of physiological extracellular Ca2+ concentrations but that has not been measured.
In summary, neither responses to sound in vivo nor responses to trains of shocks in slices show signs of synaptic plasticity. Like excitatory neurons of the VCN, D stellate cells fire independently of previous signaling. They are thus able to provide ongoing representations of the acoustic environment.
Interconnections between T and D Stellate Cells
Less is known about the properties of synaptic connections between principal cells than between auditory nerve fibers and principal cells. In vivo two sources of inhibition were identified, with one arising from the DCN (R.E. Wickesberg, 1996). Intracellular recordings from bushy and T stellate cells show that these cells are disynaptically inhibited by shocks to the auditory nerve in slices that contain VCN and DCN (M. J. Ferragamo et al., 1998; Oertel, 1983). That inhibition is glycinergic (Wu & Oertel, 1986). Two groups of inhibitory neurons can be the source of that inhibition, tuberculoventral cells in the deep layer of the DCN (R. E. Wickesberg & Oertel, 1990; R. E. Wickesberg et al., 1994) and D stellate cells in the VCN (M. J. Ferragamo et al., 1998; Wenthold, 1987). In slices that lack the DCN, disynaptic inhibition arising from shocks to the auditory nerve is likely to arise from D stellate cells, the only known group of glycinergic neurons in the VCN (Figure 5A). Strong shocks to the root of the auditory nerve evoked brief excitation and then long trains of IPSPs in many T stellate cells. Their regularity and uniformity in amplitude suggest that these come from only a few inhibitory interneurons. Over hundreds of milliseconds, synaptic responses neither grow nor shrink systematically, showing a lack of long-term depression or potentiation. While the early inhibitory responses are obscured by excitation (Figure 5A*), the later ones are clear and seem unaffected by the previous interval. There is no indication of short-term depression or facilitation.
The finding that T stellate cells have local axonal collaterals within the same isofrequency as the dendrites within the multipolar cell area suggests that T stellate cells are interconnected within an isofrequency lamina (Oertel et al., 2011; Oertel et al., 1990). To study those connections, paired recordings were made from T stellate cells within an isofrequency lamina. To date only weak indirect connections have been found (Figure 5B). Preliminary experiments suggest that these connections are potentiated when firing of one cell is paired with depolarization of another and that this potentiation is mediated by nitric oxide signaling (X.-J. Cao, Oertel, D., 2016, 2017). What role this plasticity plays in responses to sounds in vivo is not known but an interesting possibility is that it enhances the signaling of spectral peaks.
Synaptic connections between auditory nerve fibers and their targets in the VCN show no signs of long-term potentiation or depression. Short-term plasticity varies in different targets of auditory nerve fibers in the VCN. Measurements in slices in the presence of unphysiologically high (>2 mM) Ca2+ suggest that synaptic depression between auditory nerve fibers and their targets is greatest in bushy and octopus cells and less in T stellate cells and D stellate cells (Figure 2). The story is more interesting than that, however. Not only is synaptic depression weaker in vivo because the probability of release is lower in the presence of lower, more physiological levels of extracellular Ca2+, but other mechanisms including desensitization of AMPA receptors, the presence of NMDA receptors, the presence of inhibition, and perhaps also Na+ channel inactivation make signaling dynamic. Synaptic depression in bushy cells that is strong in vitro is only subtly evident in vivo, likely because inhibition reduces the probability of release when firing is rapid. On the other hand, the threshold of action potentials is dynamic. In octopus cells that are not observed to be subject to much inhibition, short-term synaptic depression is evident in vivo as it is in vitro. In T and D stellate cells synaptic depression of auditory nerve inputs is weak in slices and would be expected to be even weaker or facilitatory in vivo in the presence of lower concentrations of Ca2+. Nevertheless, the latency of first spikes shifts in repeated responses to tones.
The usefulness of hearing depends on the faithful transmission of information about what is happening in the acoustic environment no matter what happened previously. Because VCN neurons respond so robustly, the early studies that characterized responses to sound ignored long-term and short-term plasticity. If synapses were to be strengthened or weakened as a function of the synaptic traffic, then the information they convey would be affected by what the animal heard previously. It is perhaps not surprising, therefore, that synapses in the VCN have only short-term plasticity, plasticity that recovers over milliseconds. Cells differ in the way short term plasticity is manifest in vivo. It is subtly present in the latencies of responses of octopus cells and perhaps in T stellate cells. In bushy cells, where synaptic depression is as great as in octopus cells in slices, synaptic depression is difficult to detect in vivo and inhibition seems to govern the dynamics. D Stellate cells have been less intensively studied but show no sign of long-term or short-term plasticity. Nitric oxide-mediated plasticity has been observed only at interconnections between T stellate cells, cells that do not carry information in the precise timing of firing.
While synaptic plasticity is subtle in the VCN, it is not absent. In the two cells that convey information in the timing of firing, bushy and octopus cells, plasticity is subtle or regulated by inhibition. These circuits change dramatically as they mature and when acoustic input is removed. That type of plasticity is covered in other chapters in this book, however.
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