Responses of medial olivocochlear neurons
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- Brown, M.C., de Venecia, R.K. & Guinan, J.J. Exp Brain Res (2003) 153: 491. doi:10.1007/s00221-003-1679-y
Medial olivocochlear (MOC) neurons project to outer hair cells (OHC), forming the efferent arm of a reflex that affects sound processing and offers protection from acoustic overstimulation. The central pathways that trigger the MOC reflex in response to sound are poorly understood. Insight into these pathways can be obtained by examining the responses of single MOC neurons recorded from anesthetized guinea pigs. Response latencies of MOC neurons are as short as 5 ms. This latency is consistent with the idea that type I, but not type II, auditory-nerve fibers provide the major inputs to the reflex interneurons in the cochlear nucleus. This short latency also implies that the cochlear-nucleus interneurons have rapidly conducting axons. In the cochlear nucleus, lesions of the posteroventral subdivision (PVCN), but not the anteroventral (AVCN) or dorsal (DCN) subdivisions, produce permanent disruption of the MOC reflex, based on a metric of adaptation of the distortion-product otoacoustic emission (DPOAE). This finding supports earlier anatomical results demonstrating that some PVCN neurons project to MOC neurons. Within the PVCN, there are two general types of units when classified according to poststimulus time histograms: onset units and chopper units. The MOC response is sustained and cannot be produced solely by inputs having an onset pattern. The MOC reflex interneurons are thus likely to be chopper units of PVCN. Also supporting this conclusion, chopper units and MOC neurons both have sharp frequency tuning. Thus, the most likely pathway for the sound-evoked MOC reflex begins with the responses of hair cells, proceeds with type I auditory-nerve fibers, PVCN chopper units, and MOC neurons, and ends with the MOC terminations on OHC.
KeywordsInterneuronCochleaOuter hair cellCochlear nucleusAuditory nerve
Olivocochlear neurons form a descending system that originates in the superior olivary complex of the brainstem and projects to the cochlea. Two subsystems of olivocochlear neurons exist: a medial olivocochlear (MOC) system that originates in the medial portion of the superior olive and projects mainly to outer hair cells, and a lateral olivocochlear (LOC) system that originates in the more lateral portion of the superior olive and projects mainly to the region near inner hair cells (reviewed by Warr, 1992). Most experimental data on the function and physiology of the olivocochlear neurons pertains to the MOC system (reviewed by Guinan, 1996). The action of MOC neurons on the periphery is to shift the responses of auditory-nerve fibers to higher sound levels, suggesting that they can control the dynamic range of hearing (Wiederhold and Kiang 1970; Guinan and Gifford 1988). Another action of MOC neurons is to reduce the effects of noise masking on tone burst responses, suggesting an antimasking role (Winslow and Sachs 1987; Kawase et al. 1993). Finally, MOC neurons protect the cochlea from acoustic overstimulation (Rajan 1988; Reiter and Liberman 1995).
The pathways that mediate the MOC responses to sound are known only in very general terms. The pathways must be different for Ipsi and Contra neurons (Fig. 1), because the dominant ear that evokes a response is different. For Ipsi neurons, the reflex pathway begins with hair cells in the ipsilateral cochlea. These hair cells synapse on afferent nerve fibers that project centrally to the cochlear nucleus, an obligatory synaptic site (Fekete et al. 1984). Cochlear nucleus neurons are thus the second-order neurons, or interneurons, in this reflex. The reflex pathway must project across the midline to the Ipsi neurons; in fact, anatomical studies have shown direct projections from neurons in the cochlear nucleus that cross the midline to reach MOC neurons in the periolivary areas (Warr 1969; Robertson and Winter 1988; Thompson and Thompson 1991; Ye et al. 2000). These studies and others (Adams 1996) suggest that most of the input to MOC neurons is onto their dendrites. Finally, the Ipsi neurons project axons that again cross the midline to reach the outer hair cells of the cochlea. For the Contra neurons, information from interneurons of the contralateral cochlear nucleus must reach the Contra neurons via a crossing pathway (Fig. 1, gray shading). The Contra neurons then project to the cochlea without crossing the midline. Finally, MOC neurons in both the Ipsi and Contra groups receive facilitatory inputs from the nondominant ear (Fig. 1, small arrowheads). On their own, these inputs are not strong enough to produce a response to sound and will not be further considered (Liberman 1988; Brown et al. 1998).
The present study seeks to more precisely specify the neural pathway responsible for the MOC response to sound. The approach taken is to study the responses of MOC neurons, because their response characteristics will place constraints on the types of inputs that could generate them. Also, recent results from cochlear-nucleus lesion studies have greatly assisted in defining the sites of the cochlear-nucleus interneurons. When combined, information from studies of responses and lesions gives a much clearer picture of the MOC reflex pathway and also points to future work needed in this area.
All experimental procedures on animals were in accordance with the National Institutes of Health guidelines for the care and use of laboratory animals, and were performed under approved protocols at the Massachusetts Eye & Ear Infirmary. Methods for recording single MOC neurons from guinea pigs are described in previous publications (Brown 1989; Brown et al. 1998). Briefly, single MOC neurons were recorded with glass micropipettes in the intraganglionic spiral bundle of one cochlea, the “ipsilateral” cochlea. The recordings were made from guinea pigs anesthetized with either a combination of Nembutal (15 mg/kg), fentanyl (0.2 mg/kg), and droperidol (10 mg/kg), or with a combination of urethane (1,500 mg/kg), fentanyl, and droperidol. Responses were measured to sound stimuli that were presented in either the ipsilateral ear, contralateral ear, or both. Sound stimuli were tone or noise bursts with rise/fall times of 2.5 ms and duration 50 ms repeated at 10/s.
Methods for lesion studies of the cochlear nucleus have been described previously (de Venecia et al. 2001). Guinea pigs were anesthetized with urethane (1500 mg/kg) and fentanyl (0.2 mg/kg). Using methods described previously (Liberman et al. 1996), the 2f1-f2 distortion-product otoacoustic emission (DPOAE) was recorded from the ear canal in response to high frequencies (f2=10 or 12 kHz; f2/f1=1.2). Samples were taken at time intervals of approximately 10 ms, beginning with the onset of stimuli. Level combinations (60–85 dB SPL) that resulted in large adaptations of the DPOAE were used (Kujawa and Liberman 2001) and the adaptations to a small matrix of L1/L2 combinations in this region were recorded (Boyev et al. 2002). Kainic acid (5 mM in PBS, pH=7) was pressure-injected into the ipsilateral cochlear nucleus via a micropipette (total injection volume 0.5–1.0 µl) and the DPOAE measurements were recorded for the following 10–13 h. The region of cell loss in the cochlear nucleus was confirmed histologically using frozen sections (Melcher et al. 1996).
Reflex pathways have rapidly conducting axons
Lesion studies identify PVCN as the site of the reflex interneurons
Responses of MOC neurons suggest that PVCN choppers are the reflex interneurons
We now consider which PVCN neurons are the likely interneurons of the MOC reflex. The PVCN contains at least five types of neurons: granule cells, small cells, giant cells, octopus cells, and stellate cells (Osen 1969; Brawer et al. 1974; Hackney et al. 1990). Granule cells are not the interneurons because their axons do not project out of the cochlear nucleus—rather, their thin, unmyelinated axons project to the DCN (Mugnaini et al. 1980). The projections of small cells have not been well studied. They may be locally projecting interneurons or they may project with such small axons that they cannot be the MOC interneurons on the basis of the latency arguments made above. Similarly, giant multipolar cells are considered unlikely to be the interneurons, because many of them project to the contralateral cochlear nucleus (Cant and Gaston 1982; Schofield and Cant 1996) and because these neurons are glycinergic (Wenthold 1987). Such inhibitory neurons and others are unlikely to be the interneurons of the MOC reflex, because the interneurons must cause an excitatory response to sound. Thus, we are left with the two main types of PVCN neurons, octopus and stellate cells, as being possible MOC reflex interneurons.
Our consideration of the responses of MOC neurons, along with results of lesion studies, has led us to propose that the MOC reflex pathway is composed of the following chain of elements, each of which responds in turn to sound: hair cells, type I auditory-nerve fibers, PVCN chopper units, MOC neurons, and outer hair cells. The idea that type I nerve fibers form the afferent limb of the reflex pathway is an inescapable conclusion given the short latency of MOC response. That PVCN chopper units are the interneurons is a somewhat more tentative conclusion, because it hinges on several pieces of knowledge that come from studies in either guinea pigs or cats. This knowledge comes from studies of lesions, cell types, response types, projections, and MOC response. Our conclusion about the interneuron identity could be better supported by studies of the physiological characteristics of MOC neurons and PVCN chopper units in the same species and experimental conditions. Specifically, adaptation characteristics of chopper units and MOC neurons need to be compared for both 500-ms and 10-s time scales. Also, a careful study of tuning and inhibition in both types of units would be helpful. If inhibition is difficult to study because of lack of spontaneous activity, two-tone paradigms could be used in which the first tone provides excitation at CF and the second tone is used to probe areas of inhibition. Such an approach might be successful if the inhibitory areas were much larger than two-tone suppression regions that are also likely to be present.
The idea that PVCN neurons provide input to MOC neurons originated with the studies of Warr (1969), who showed that PVCN neurons project to the periolivary areas in cats. More specifically, studies in guinea pig (Thompson and Thompson 1991) have shown that PVCN neurons project directly to MOC neurons. We postulate a simple, three-neuron reflex pathway for the response to sound because of this direct pathway, even though the MOC minimum latencies are not so short as to exclude an additional synapse between the cochlear nucleus and the MOC neurons. Neither of the projection studies was able to identify the type of PVCN neuron whose projections were being studied. In rats, individually labeled multipolar/stellate cells of the PVCN send branches to the rostral periolivary area (Friauf and Ostwald 1988), a nucleus that contains many MOC neurons. Projections of PVCN stellate/multipolar cells are now receiving attention (Doucet and Ryugo 2002). Certainly projections of those cells corresponding to chop-S units would be particularly interesting to investigate, since those cells are possible interneurons of the MOC reflex. It is important to remember, though, that projection studies do not always reveal the neurons that are important to evoke a response, and thus they must be accompanied by physiological and/or lesion studies (de Venecia et al. 2001) to link the underlying anatomical circuitry with physiological effects.
The arguments outlined above hold for the MOC reflex to ipsilateral sound. It is not yet clear that the cochlear nucleus interneurons for the reflex to contralateral sound are located in PVCN. However, the latency constraints of the contralateral reflex are similar to those of the ipsilateral reflex, and most physiological properties of Ipsi and Contra neurons are similar. These reasons lead us to suspect that the type of cochlear-nucleus interneuron is similar for the two reflex pathways. On the other hand, the facilitatory pathways to MOC neurons (small arrows in Fig. 1) have only been minimally explored. These inputs are not strong enough to elicit a response to sound and may well have different characteristics, perhaps because they are mediated by different interneurons or pathways. Further physiological and lesion studies of the facilitatory pathways are clearly needed for a complete understanding of the MOC reflex. Finally, although we have concentrated on the relatively simple pathway that elicits the MOC response to sound, anatomical studies have shown that higher centers provide several inputs to MOC neurons (Faye-Lund 1986; Mulders and Robertson 2000a). How these inputs modulate the response to sound mediated by the simple pathway awaits future studies.
The type of studies outlined above for the MOC reflex could also be applied to an analogous reflex, the stapedius reflex, a reflex for which the cochlear nucleus interneurons are also not known. Although there is one early study on this subject (Borg 1973), the cochlear nucleus lesions in that study were large and affected axons of passage such as those of auditory-nerve fibers. Such an approach severely limits the conclusions that can be drawn. Studies such as those we have done for the MOC reflex (de Venecia et al. 2001), using more focal lesions made with kainic acid to spare axons of passage, are needed to define the locations of interneurons for the stapedius reflex. For the tensor tympani, one study (Rouiller et al. 1986) has demonstrated inputs from the superior olivary complex, indicating a more complex pathway than for the MOC reflex. Other studies (Itoh et al. 1986; Ito and Honjo 1988) suggest that the tensor tympani receives direct projections from the cochlear nucleus. Additional projection studies like those used to study the OC inputs (Thompson and Thompson 1991) need to be done for both the stapedius and tensor tympani reflex pathways. Results of these studies, along with the known physiological characteristics of the stapedius motoneurons (Kobler et al. 1987, 1992; Vacher et al. 1989), might also more clearly elucidate the middle-ear muscle reflex pathways.
We thank Dr. M. C. Liberman for comments on the manuscript and Dr. Wen Xu for technical assistance. Supported by NIDCD grants DC 01089 and DC 0119, and a grant from the Triological Society.