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Previous Article | Next Article
The Journal of Neuroscience, September 15, 2001, 21(18):7372-7383
Cholinergic Modulation of Stellate Cells in the Mammalian Ventral Cochlear Nucleus
Kiyohiro Fujino and Donata Oertel Department of Physiology, University of Wisconsin, Madison, Wisconsin 53706
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
The main source of excitation to the ventral cochlear nucleus (VCN) is from glutamatergic auditory nerve afferents, but the VCN is also innervated by two groups of cholinergic efferents from the ventral nucleus of the trapezoid body. One arises from collaterals of medial olivocochlear efferents, and the other arises from neurons that project solely to the VCN. This study examines the action of cholinergic inputs on stellate cells in the VCN. T stellate cells, which form one of the ascending auditory pathways to the inferior colliculus, and D stellate cells, which inhibit T stellate cells, are distinguished electrophysiologically. Whole-cell recordings from stellate cells in slices of the VCN of mice demonstrate that most T stellate cells are excited by cholinergic agonists through three types of receptors, whereas all D stellate cells tested were insensitive to cholinergic agonists. Nicotinic excitation in T stellate cells has two components. The faster component was blocked by
-bungarotoxin and methyllycaconitine, suggesting that receptors contained
Key words: cholinergic efferents; ventral cochlear nucleus; auditory pathways; nicotinic;
INTRODUCTION
Neuronal feedback circuits in the afferent pathways of the auditory system are prominent at all levels of the auditory pathway. Cholinergic inputs to the cochlea and to the ventral cochlear nucleus (VCN) arise in the ventral nucleus of the trapezoid body (VNTB) (Sherriff and Henderson, 1994
). The medial olivocochlear neurons suppress firing of auditory nerve fibers through the mechanics of the cochlea (Galambos, 1956
The function of cholinergic efferent innervation is only partly understood. The reflex through the olivocochlear efferent neurons improves the detection of signals in noise in auditory nerve fibers (Winslow and Sachs, 1987
In slices it is possible to investigate the action of cholinergic inputs on stellate cells in the VCN in the absence of cochlear effects. Because the VNTB seems to be the only source of cholinergic input to the VCN in rats (Sherriff and Henderson, 1994
MATERIALS AND METHODS
All experiments were done in accordance with the protocols and guidelines of the Animal Care and Use Committee at the University of Wisconsin-Madison.
Slice preparation Coronal brainstem slices containing the VCN were prepared from ICR mice (Harlan Sprague Dawley, Madison, WI) between 18 and 21 postnatal days old. After decapitation, the brain was dissected from the skull in oxygenated normal saline at 31°C with minimal stretching of the auditory nerve. The brain was cut coronally at the level of the inferior colliculi. The rostral surface of the specimen was glued onto a Teflon block with a cyanoacrylate glue (Superglue; Loctite Corp., Rocky Hill, CT). Slices of 200 µm thickness were cut using an oscillating tissue slicer (Frederick Haer and Co., Brunswick, ME). The slices were allowed to recover at least 1 hr submerged in a holding chamber containing oxygenated normal saline at 33°C. One slice was then transferred to the recording chamber with a volume of 300 µl that was superfused continuously at a rate of ~8 ml/min with oxygenated normal saline maintained at a temperature of 33°C by a feedback-controlled heater.
Electrophysiology. Whole-cell patch-clamp recordings in either current- or voltage-clamp mode were made with standard techniques. Patch pipettes were pulled from borosilicate glass capillaries (World Precision Instruments, Sarasota, FL) and were heat-polished before use. The pipette resistance was 5-7 M
when filled with a K-gluconate-based internal solution. Recordings were made with an Axopatch 200B amplifier and transferred to a computer via a Digidata 1200 interface (Axon Instruments, Foster City, CA). Data were simultaneously recorded with a chart recorder (TA 240; Gould Instrument Systems, Valley View, OH). Stimulus generation, data acquisition, and analyses were performed with pClamp software (version 6; Axon Instruments). Voltages and currents were low pass-filtered at 5 kHz and sampled digitally at 10-25 kHz. Series resistance was compensated to >90%. Voltages were corrected for junction potentials,
5 to
Solutions and drugs. The internal pipette solution in most experiments consisted of (in mM): 108 K-gluconate, 4.5 MgCl2, 14 Tris2-phosphocreatine, 9 HEPES, 9 EGTA, 4 Na2-ATP, and 0.3 Tris-GTP, pH adjusted to 7.25 with KOH. For studying nicotinic currents in some experiments, K-gluconate was replaced with equimolar concentration of CsCl to block potassium currents. The normal external saline contained (in mM): 130 NaCl, 3 KCl, 1.2 KH2PO4, 2.4 CaCl2, 1.3 MgSO4, 20 NaHCO3, 3 HEPES, and 10 glucose, saturated with 95% O2 and 5% CO2, pH 7.4 adjusted with NaOH. Experiments that involved extracellular application of CdCl2 and BaCl2 were performed in the following HEPES-buffered solution to prevent precipitation (in mM): 138 NaCl, 4.2 KCl, 2.4 CaCl2, 1.3 MgCl2, 10 HEPES, and 10 glucose, saturated with 100% O2, pH 7.4 adjusted with NaOH. In studies of muscarinic currents, 0.5 µM tetrodotoxin (TTX), 40 µM 6,7-dinitroquinoxaline-2,3-dione (DNQX), and 1 µM strychnine were added to the external solution to block voltage-sensitive sodium currents and glutamatergic and glycinergic synaptic currents. Because strychnine is known to block responses of some nicotinic receptors (Zhang et al., 1996
Agonists and antagonists of muscarinic and nicotinic receptors and of voltage-sensitive ion channels on which they might act were added to the extracellular saline solution in some experiments. Four cholinergic agonists were used: acetylcholine, carbachol (stable analog of acetylcholine that has both muscarinic and nicotinic actions; Taylor, 1993a
Puff application of drug. In some experiments, acetylcholine or carbachol, dissolved in normal saline, was applied locally by a pressure puff. Application was made by an air pressure pulse (100-200 cmH2O) through a pipette that had a tip diameter of 3-5 µm and was located ~30 µm from the cell body. The switching of pressure was made by a solenoid valve that was controlled by a stimulator (Master-8, AMPI, Jerusalem, Israel) triggered by the pClamp software.
Visualization of cells. The VCN of live tissue could easily be identified under the Axioskop microscope (Zeiss, Oberkochen, Germany) with a 63× water immersion lens. It is situated on the edge of the brainstem, ventral to the granule cell lamina and lateral to the restiform body. T stellate cells were routinely recorded in slices that included tissue that lay just caudal to root of the auditory nerve. In these slices, the octopus cell area that contains uniformly large cells embedded in a dense network of myelinated fibers can be distinguished from the multipolar cell area, which has smaller cells and a rough appearance. The octopus cell area is devoid of stellate cells, whereas in the multipolar cell area, most larger cells are T stellate cells. D stellate cells were found most commonly near the border of the VCN, near the granule cell lamina both anterior and posterior to the root of the auditory nerve.
Histology. In some experiments T and D stellate cells were identified morphologically by the internal dialysis of a pipette solution that included 0.1% biocytin. Slices were fixed in 4% paraformaldehyde and stored at 4°C for 2-7 d. Biocytin-filled cells were visualized with the avidin-biotinylated horseradish peroxidase complex reaction (Vectastain ABC Elite kit; Vector Laboratories, Burlingame, CA), using nickel- and cobalt-intensified DAB as a chromogen (Zhang and Oertel, 1993
RESULTS
General properties of T and D stellate cells
Stellate cells were distinguished from other classes of VCN cells, octopus and bushy cells, by the trains of action potentials evoked by depolarizing current pulses (Wu and Oertel, 1984
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Figure 1. Identification of T and D stellate cells. A-C, Voltage responses to depolarizing and hyperpolarizing current pulses in three representative T stellate cells. Action potentials were followed by single undershoots. The response to hyperpolarizing current shows weak inward rectification. D-F, Voltage responses to similar current pulses in three representative D stellate cells. In most cells, action potentials were followed by obviously biphasic undershoots. Hyperpolarizing responses show prominent inward rectification. Insets, Expanded traces of the undershoots indicated by arrows (time scale: the full length of the traces corresponds to 8 msec for all insets). Experiments were done using normal external and internal solutions. G, Correlation of features shows that T and D stellate cells form distinct populations of neurons. Left inset, Measurements were made of peak hyperpolarization (a) and steady-state hyperpolarization (b), and the sags were fit with a single exponential with time constant ( ). Open circles, Cells with biphasic undershoots; filled triangles, cells with action potentials whose undershoots are monophasic. The plot shows that cells with rapid sags toward rest (short
The differences between T and D stellate cells are apparent not only in current-clamp but also under voltage-clamp conditions (examples are illustrated in Figs. 6, 8). Hyperpolarizing voltage pulses evoked first a step change in current, the instantaneous current, and then a slowly activating inward current in all stellate cells tested. The instantaneous current reflects the conductance of the cell before the step change in voltage was made. The slowly activating current in T stellate cells was identified to be a hyperpolarization-activated, mixed cation current (Ih) by its sensitivity to 50 nM ZD7288, a specific blocker for Ih (BoSmith et al., 1993
One test of the reliability of our identification of T and D stellate cells was to assess whether the differing characteristics in the populations of T and D stellate cells covaried. An analysis of current-clamp responses of the entire sample of 340 stellate cells shows that stellate cells fall into two groups not only on the basis of the shapes of their undershoots but also on the basis of the rate and amplitude of the inward rectification (Fig. 1G). Those cells with single undershoots had slow and weak inward rectification, whereas those with double undershoots had rapid and strong inward rectification. Cells that were anatomically confirmed are plotted with contrasting symbols.
An additional test of the reliability of the electrophysiological criteria was to correlate the electrophysiological criteria for identification with anatomically identified, patch-clamped T and D stellate cells in the coronal slices used in this study. The camera lucida reconstructions of 2 of the 21 (11 T and 10 D) labeled cells are shown in Figure 2. These cells, whose responses to the injection of currents are shown in Figure 1, A and D, fulfill the criteria that were established to distinguish stellate cells. The T stellate cell has an axon that projects through the trapezoid body; the D stellate cell has an axon that projects dorsalward through the intermediate acoustic stria. D stellate cells, whose distribution can be estimated by immunocytochemical labeling with antibodies to glycine conjugates, are rare in comparison with T stellate cells in the body of the nucleus (Wickesberg et al., 1994
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Figure 2. Reconstructions of biocytin-labeled T and D stellate cells of the VCN. Left, A T stellate cell whose responses to injected current are shown in Figure 1A has a branched dendrite with a curly appearance. The axon characteristically projects out of the VCN through the trapezoid body and has collateral branches in the dorsal and ventral cochlear nuclei. Presumably some dendrites had been cut in preparing the slice. Right, D stellate cell whose responses to injected current are shown in Figure 1D. The axon characteristically runs dorsally through the intermediate acoustic stria. Presumably the dendrites had been cut in the preparation of the slice. PVCN, Posteroventral cochlear nucleus; AVCN, anteroventral cochlear nucleus; DCN, dorsal cochlear nucleus; Gr, granule cell region; ML, molecular layer of DCN; TB, trapezoid body; IAS, intermediate acoustic stria.
Cholinergic agonists excite T but not D stellate cells
Cholinergic agonists depolarized T stellate cells and increased their rate of firing. Figure 3, A-C, shows an example of the response of a T stellate cell to the application of cholinergic agonists in the bath. This cell was excited by carbachol, an agonist of both muscarinic and nicotinic receptors (Taylor, 1993a
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Figure 3. Cholinergic agonists excite a T stellate cell but do not affect a D stellate cell. Bath application of 100 µM carbachol (A), 20 µM muscarine (B), and 2 µM nicotine (C) increased the spontaneous firing rate of a single T stellate cell reversibly. D, The D stellate cell was unaffected by 100 µM carbachol. Experiments were done with normal external and internal solutions.
In contrast, no D stellate cells responded to any of these cholinergic agonists in all 18 cells tested in current-clamp experiments [0 of 3 cells tested with 1 mM acetylcholine, 0 of 10 cells tested with 100 µM carbachol (Fig. 3D), 0 of 7 cells tested with 20 µM muscarine, and 0 of 4 cells tested with 2 µM nicotine]. Additional results of tests under voltage-clamp conditions are described below. The EC50 of acetylcholine has been measured for various types of nicotinic receptors. The maximum EC50 for any nicotinic receptor was 350 µM (Role, 1992
To understand the mechanisms whereby cholinergic agonists excite T stellate cells, the currents evoked by these agonists were examined under voltage-clamp conditions. Nicotinic currents were evoked by the application of nicotine or by carbachol in the presence of 2 µM atropine. The identity of those currents was confirmed by their sensitivity to 50 µM D-TC (Taylor, 1993b
Clamping the voltage in cells with long dendrites is imperfect, but useful information can still be obtained. The capacitative transient currents were long, sometimes ~10 msec, indicating that step changes in voltage were slow in parts of the cell. Curvature in the current-voltage relationship of the instantaneous current in the depolarizing voltage range reflected the activation of a voltage-sensitive potassium conductance whose activation began before the clamp settled. In the voltage range more depolarized than
Cholinergic inputs act on muscarinic as well as fast and slow nicotinic receptors of T stellate cells
Cholinergic responses of T stellate cells had three components. The pattern of responses that was recorded most often is illustrated in Figure 4. The cell was held under voltage clamp at
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Figure 4. Rapid application of agonist reveals two nicotinic and muscarinic cholinergic currents in T stellate cells but none in a D stellate cell. Carbachol (500 µM) was applied to a T stellate cell with a pressure pulse (bar). A, Carbachol-evoked inward currents with three components. A rapidly activating and rapidly desensitizing current (a) was followed by a more slowly activating and desensitizing current (b). Some current persisted for the duration of the pulse (c). B, D-TC (50 µM) blocked the two faster components, leaving a slow component (c'). The sensitivity of some of the steady-state current to D-TC shows that the nicotinic current desensitized incompletely (c). C, The remaining slowest component (c') was blocked by 1 µM atropine. D, A D stellate cell was unaffected by the application of 500 µM carbachol with a pressure pulse. E, A different D stellate cell was unaffected by puff application 5 mM acetylcholine. The internal solution was normal; the external solution contained 0.5 µM TTX and 40 µM DNQX.
None of the three D stellate cells tested showed responses to puff application of 500 µM carbachol (n = 3) or 5 mM acetylcholine (n = 3) (Fig. 4D,E) or bath application of 1 mM acetylcholine (n = 3) (traces not shown).
Pharmacology of nicotinic receptor-mediated currents in T stellate cells
To characterize currents through nicotinic receptors, their sensitivity to antagonists of known specificity was tested. A T stellate cell was held at
Application of 500 µM carbachol with pressure pulses of 1 sec evoked inward currents in 80 (83%) of 96 T stellate cells. Biphasic responses were observed in 57 of 96 T stellate cells (Fig. 5A-E). Only slowly desensitizing currents were observed in 23 cells, and no response could be resolved in 16 cells. The fast component reached a peak rapidly (<50 msec), and desensitized within ~300 msec. The slow component reached a peak more slowly (5-10 sec) and desensitized even more slowly. The mean amplitude of the fast component was 121 ± 113 pA (n = 57), and that of the slow component was 221 ± 124 pA (n = 57).
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Figure 5. Sensitivity of nicotinic receptor-mediated currents in T stellate cells to cholinergic blockers. Carbachol (500 µM) applied with pressure pulses of 1 sec (bar) evoked biphasic inward currents. A, D-TC (50 µM) blocked both fast and slow components completely and reversibly. In this cell, the fast component was small (arrow). B, MEC (2 µM) blocked both fast and slow components completely and reversibly. C, MLA (20 nM) blocked only the fast component completely and reversibly but did not affect the slow component. D,
Pharmacological tests distinguish receptors that contain
In 23 cells, only a slow nicotinic current was detected; a rapidly desensitizing component could have been undetected rather than absent. The mean amplitude of these carbachol-induced currents was 214 ± 179 pA (n = 23). They were completely blocked by 50 µM D-TC (n = 3) and 2 µM MEC (n = 3) but almost insensitive to 20 nM MLA (reduced by 3.5 ± 2.1%; n = 4), 100 nM
Biophysical properties of nicotinic receptor-mediated currents
Nicotine produced a negative shift in the holding current (11 of 14 cells tested) and an increase of the instantaneous current in response to hyperpolarizing voltage pulses (Fig. 6A). The current reached its peak amplitude (144 ± 82 pA; n = 11) within 10-20 sec. The current evoked by bath-applied nicotine (nicotine minus control) was noisy and, when averaged over the length of the trace, had a linear current-voltage relationship (Fig. 6B,C). The extrapolated reversal potential of this current was
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Figure 6. Biophysical properties of currents evoked by bath application of nicotine in a T stellate cell (A-C). A, Nicotine (5 µM) increased the instantaneous current (IINS), elicited a negative shift of the holding current, and increased membrane noise. B, The nicotine-evoked difference currents (currents in nicotine minus control currents) obtained from trace-to-trace subtraction. C, I-V relationship of the difference current. The extrapolated reversal potential was
Similar tests on two D stellate cells failed to reveal an effect on voltage-dependent or -independent conductances (Fig. 6D).
To improve the quality and voltage range of the voltage clamp, nicotinic currents were measured when K+, Ca2+, and Ih currents were blocked with a CsCl-based internal solution and by external 200 µM CdCl2 and 5 mM CsCl. Responses to bath application of 100 µM carbachol in the presence of 2 µM atropine resembled those to nicotine when voltage-sensitive currents were not blocked. Carbachol evoked inward currents in 19 of 23 cells tested (190 ± 102 pA; n = 19). An increase in noise and an increase in conductance were evident in over the entire voltage range tested between
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Figure 7. Nicotinic receptor-mediated currents measured with voltage clamp under conditions in which voltage-sensitive conductances were blocked. Pipettes contained a CsCl-based solution; the external solution contained 2 µM atropine, 0.5 µM TTX, 40 µM DNQX, 5 mM CsCl, and 200 µM CdCl2. A, Carbachol (100 µM) increased the instantaneous current, elicited a negative shift of the holding current, and increased the membrane noise. B, The difference currents are primarily voltage- and time-insensitive. C, The I-V relationship of the difference current is linear over a wide range of voltage. The current amplitudes were averaged over the whole trace. The reversal potential (
Biophysical properties of muscarinic receptor-mediated currents
Muscarinic excitation arises through a decrease in voltage-independent potassium conductance. When 20 µM muscarine was applied to the bath while the cell was held at
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Figure 8. Biophysical properties of currents evoked by bath application of muscarine in a T stellate cell (A-D). A, Muscarine (20 µM) elicited a decrease of instantaneous current (IINS) and a negative shift of the holding current. B, The muscarine-evoked difference currents were not obviously time- and voltage-dependent. C, The I-V relationship of the difference current was linear. The current amplitudes were averaged through the whole length of each trace. The reversal potential (
Similar tests on three D stellate cells failed to reveal any effect on conductance change (Fig. 8E).
To test the voltage sensitivity of the muscarine-induced response with better control over membrane voltage, Ih, voltage-sensitive Ca2+ currents, and Ca-activated K+ currents were blocked by adding 5 mM CsCl and 200 µM CdCl2 to the external solution. Muscarine reduced both inward and outward currents under these conditions (Fig. 9A). The difference current had a linear current-voltage relationship and reversed at
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Figure 9. Muscarinic currents measured with voltage clamp under conditions in which voltage-sensitive conductances were blocked. The external solution contained 0.5 µM TTX, 40 µM DNQX, 1 µM strychnine, 5 mM CsCl, and 200 µM CdCl2; the internal solution was normal. A, Muscarine (20 µM) blocked outward and inward currents and elicited a negative shift of the holding current. B, The difference current is not obviously time- or voltage-dependent. C, I-V relationship of the difference current. The current amplitudes were averaged through the whole length of each trace. The reversal potential (
Ba2+ has been reported to block the leak K+ current (Benson et al., 1988
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Figure 10. Muscarinic response is sensitive to extracellular Ba2+. The external solution contained 0.5 µM TTX, 40 µM DNQX, 1 µM strychnine, 5 mM CsCl, and 200 µM CdCl2; the internal solution was normal. A, Muscarine (20 µM) decreased the inward current and elicited a negative shift of the holding current. B, In the presence of 2 mM BaCl2, muscarine did not evoke any response.
Muscarine has been shown to modulate several types of K+ channels. Best known is the M current (IM; Brown and Adams, 1980
Cholinergic synaptic potentials and synaptic currents were not observed. Spontaneous EPSCs recorded at or near the resting potential were blocked by DNQX, indicating that they are mediated by AMPA receptors (Gardner et al., 1999
DISCUSSION
T Stellate cells form a major excitatory ascending pathway to the inferior colliculus. They also participate in neuronal circuits that provide feedforward inhibition to the inferior colliculi through the ventral nuclei of the lateral lemniscus (Smith et al., 1993
Nicotinic cholinergic responses
Nicotinic responses are mediated through pentameric, ligand-gated receptors. Two forms of the nicotinic acetylcholine receptors predominate in the brain (Role, 1992
2 subunits and has a high affinity for acetylcholine and a low affinity for
Neither spontaneous nor evoked nicotinic EPSCs could be recorded in T stellate cells. Many medial olivocochlear fibers terminate in the vicinity of granule cell regions near the branched, distal ends of T stellate cell dendrites (Benson and Brown, 1990
Muscarinic cholinergic responses
Muscarinic cholinergic receptors are G-protein-coupled and have been shown to modulate several K+ currents. They suppress the IM, Ca2+-activated K+ current (Brown and Adams, 1980
Neuronal circuits that involve T and D stellate cells
The distinction between two types of stellate cells has been confirmed in all species that have been examined. In rodents the two classes of stellate cells have distinct dendritic morphology, projections, and shapes of undershoots (Harrison and Feldman, 1970
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Figure 11. Schematic representations of neuronal circuits that involve cholinergic innervation of the VCN and their implications. A, Representation of the feedback loop to the cochlea and to the VCN through two types of cholinergic neurons of the VNTB. The medial olivocochlear efferent neuron (filled star) innervates both the VCN and the outer hair cells of the cochlea. Acoustic information from inner hair cells is carried to the VCN through spiral ganglion cells (shaded oval) whose axons are the auditory nerve. Smaller cholinergic neurons of the VNTB (filled triangle) innervate only the VCN. T stellate cells are indicated by the scalloped quadrangle. +, Excitatory connections;
The broadly tuned D stellate cells are a major source of side band inhibition for the narrowly tuned T stellate cells. In mice, T stellate cells receive excitation through approximately five auditory nerve fibers, and they receive inhibition from D stellate cells (Ferragamo et al., 1998
The present results suggest that the VNTB forms an excitatory feedback loop that targets T but not D stellate cells (Fig. 11A,B). All cholinergic inputs to the VCN arise from the VNTB (Sherriff and Henderson, 1994
The positive feedback through the VNTB to T stellate cells would be expected to enhance signaling by T stellate cells in noisy environments. In enhancing excitation but not inhibition in noise, cholinergic feedback enhances the encoding of spectral peaks over spectral troughs (Fig. 11C). In noise, olivocochlear efferents suppress activity in the cochlea, raising thresholds and shifting and sometimes compressing the dynamic range of auditory nerve fibers inputs to T stellate cells (Guinan, 1996
FOOTNOTES Received May 22, 2001; revised June 19, 2001; accepted July 5, 2001.
This work was supported by National Institutes of Health Grant DC 00176. We are grateful to Inge Siggelkow and Joan Meister for making many liters of solutions and for processing many little tissue slices. We thank Carol Dizack for finishing the anatomical reconstruction figures. We also thank Ramazan Bal and Stephanie Gardner for helping get these experiments started and for valuable suggestions. We also acknowledge Prof. Harunori Ohmori for help with the puff application apparatus.
Correspondence should be addressed to Donata Oertel, Department of Physiology, University of Wisconsin, Medical School, 1300 University Avenue, Madison, WI 53706. E-mail: oertel{at}physiology.wisc.edu.
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