Acute spiral ganglion lesions change the tuning and tonotopic organization of cat inferior colliculus neurons

Hearing Research 147 (2000) 200^220 www.elsevier.com/locate/heares

Acute spiral ganglion lesions change the tuning and tonotopic organization of cat inferior colliculus neurons Russell L. Snyder a

a;

*, Donal G. Sinex b , JoAnn D. McGee c , Edward W. Walsh

c

Epstein Laboratory, P.O. Box 0526, U490, University of California, San Francisco, CA 94143-0526, USA b Department of Speech and Hearing Science, Arizona State University, Tempe, AZ 85287-1908, USA c Boys Town National Research Hospital, Omaha, NE 68131, USA Received 1 September 1999; received in revised form 21 January 2000; accepted 28 January 2000

Abstract Many studies have reported plastic changes in central auditory frequency organization after chronic cochlear lesions. These studies employed mechanical, acoustic or drug-induced disruptions of restricted regions of the organ of Corti that permanently alter its tuning and sensitivity and require an extended recovery period before central effects can be measured. In this study, mechanical lesions were made to 1 mm sectors of the spiral ganglion (SG). These lesions remove a restricted portion of the cochlear output, but leave the organ of Corti and basilar membrane intact. Multiunit mapping assessed the pre- and post-lesion tonotopic organization of the inferior colliculus (IC). Immediately after SG lesions, IC neurons previously tuned to the lesion frequencies became less sensitive to those frequencies but more sensitive to lesion edge frequencies, resulting in a shift in their characteristic frequencies (CFs). Notches in the excitatory response areas at frequencies corresponding to the lesion frequencies and expansion of spatial tuning curves were also observed. CFs of neurons tuned to unlesioned frequencies were unchanged. These results suggest that `plastic' changes similar to those observed after long survival times in previous studies require little or no experience and occur within minutes to hours following the lesion. ß 2000 Elsevier Science B.V. All rights reserved. Key words: Plasticity ; Inferior colliculus ; Hearing loss; Tonotopic reorganization; Cochlear lesion

1. Introduction An understanding of the role that extrinsic alterations in sensory input play in the formation and maintenance of cortical and subcortical organization is essential to any analysis of central nervous system organization. Chronic sensory alterations in neonates or very young mammals have long been known to produce functional and structural changes in the nervous system, especially cerebral cortex (see Rauschecker and Marler, 1987 ; Snow and Wilson, 1991 for review). However, more recent studies have shown that alterations in adult sensory input (usually in the form of focal ablations of the sensory epithelium) result in signi¢cant functional changes in many sensory systems (see Kaas,

* Corresponding author. Tel.: +1 (415) 476-1726; Fax: +1 (415) 476-2169; E-mail: [email protected]

1994 for review). These functional changes include the production of silent areas (`scotomas', or `holes') in the topographic representations of the ablated epithelial regions, of expanded representations of adjacent intact epithelial regions which `¢ll-in' these silent areas, and of enlarged receptive ¢elds for neurons representing intact sensory regions. For example, chronic focal lesions of the retina have been shown to produce scotomas and reorganization in primary visual cortex of adult cats and monkeys (Kaas et al., 1990; Heinen and Skavenski, 1991 ; Chino et al., 1992, 1995; Gilbert and Wiesel, 1992 ; Calford et al., 1999). These acute changes are, however, not static. After a period of recovery, retinal lesion-induced scotomas are at least partially `¢lled-in' by expanded representations of other nearby cortical areas (Chino et al., 1992, 1995 ; Darian-Smith and Gilbert, 1995). In some cases, the expanded representations are of adjacent peripheral areas (e.g. expansion of the representation of the intact dorsal surface of digit D3 in

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a monkey into the representation of its denervated glabrous surface, Merzenich et al., 1983a). In others, the dea¡erented areas are ¢lled-in by adjacent cortical areas, whose peripheral receptive ¢elds are widely separated (e.g. expansion of the face representation into the denervated forepaw representation, Silva et al., 1996). Although these adult plasticity studies have focused primarily on chronic ( s 24^48 h) sensory alterations and their cortical and subcortical consequences (see Snow and Wilson, 1991; Kaas, 1994 for review), some studies have examined acute ( 6 24 h) alterations and the cortical reorganization that results (Metzler and Marks, 1979; Kelahan et al., 1981; Carson et al., 1981 ; Rasmusson and Turnbull, 1983; Merzenich et al., 1983a; Kelahan and Doetsch, 1984; Calford and Tweedale, 1988, 1991a, 1991b; Turnbull and Rasmusson, 1990 ; Byrne and Calford, 1991; Heinen and Skavenski, 1991; Chino et al., 1992; Gilbert and Wiesel, 1992 ; Silva et al., 1996; Calford et al., 1999, among others). However, fewer studies have demonstrated acute changes in topographic organization at subcortical levels and most of these subcortical plasticity studies have been conducted in the somatosensory system (Nakahama et al., 1966; Dostrovsky et al., 1976; Millar et al., 1976 ; McMahon and Wall, 1983; Garraghty and Kaas, 1991 ; Rasmusson et al., 1993; Nicolelis et al., 1993 ; Northgrave and Rasmusson, 1996; Rasmusson, 1996a,b; Pettit and Schwark, 1993, 1996). Although some subcortical studies have been conducted in the visual (see Darian-Smith and Gilbert, 1995) and auditory (see Kaltenbach et al., 1992, 1996; Salvi et al., 1996 ; Irvine and Rajan, 1994; Rajan and Irvine, 1996, 1998b) systems, most of these have been chronic studies and have been unable to observe any changes that could be interpreted as plasticity. Topographic plasticity in the adult central auditory system has been reported using a wide variety of techniques that result in partial ablation of the auditory periphery. Among these techniques are mechanical disruption of the organ of Corti (Robertson and Irvine, 1989 ; Rajan et al., 1993; Rajan and Irvine, 1996, 1998a,b), administration of cochleotoxic drugs (Harrision et al., 1991, 1993, 1995, 1996; Schwaber et al., 1993), exposure to high intensity sounds (Kaltenbach et al., 1992, 1996 ; Calford et al., 1993; Salvi et al., 1996) or genetically induced progressive hearing loss (Willott et al., 1993; Willott, 1984, 1996). These procedures damage or destroy outer hair cells in the basal, high frequency region of the cochlea. In the periphery, these procedures lead to regional (primarily high frequency) changes in tuning and sensitivity of the basilar membrane and primary a¡erent neurons. In the central nervous system, these procedures result in expansions of the representations of frequencies located at the edge(s)

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of long standing chronic lesions. The representations of these edge frequencies (usually at frequencies just below the lesion frequencies) have been reported to expand in the auditory cortex, inferior colliculus (IC) and cochlear nucleus. However, some of these changes may re£ect alterations in peripheral sensitivity resulting in `pseudoplasticity' (Kaltenbach et al., 1992, 1996) and recordings of residual responses (Robertson and Irvine, 1989; Rajan et al., 1993, 1998b). Nevertheless, in some cases (e.g. Robertson and Irvine, 1989; Rajan et al., 1993; Willott et al., 1993 ; Rajan and Irvine, 1998a,b), careful documentation has revealed expansions of cortical representations of lesion edge frequencies without signi¢cant elevations in thresholds. Thus topographic reorganization at cortical levels in the auditory system has been convincingly demonstrated in chronic preparations. However, studies of subcortical auditory areas have either failed to detect topographic plasticity (Kaltenbach et al., 1992, 1996; Rajan and Irvine, 1998b) or failed to detect it consistently (Salvi et al., 1996; Irvine and Rajan, 1994; Rajan and Irvine, 1996). Moreover, almost all of these studies (see Robertson and Irvine, 1989 ; Snyder et al., 1996 as exceptions) looked for lesion-induced changes only after intervals of 1 to several months. The question of subcortical topographic plasticity, its time of appearance and its time course is important and strongly in£uences the interpretation of cortical plasticity speci¢cally, and central nervous system plasticity in general. For example, if cortical reorganization occurs before or without comparable subcortical changes, then the cortical changes may be viewed as intrinsic to the cortex. However, if subcortical topographic reorganization occurs and is comparable to that seen in the cortex, then cortical plasticity may simply be a re£ection of subcortical reorganization. Moreover, if both cortical and subcortical reorganizations are immediate (occurring immediately or within minutes of the alterations), then certain anatomical and physiological mechanisms, which might underlie the observed changes, may be ruled out and the observed changes may be viewed as passive `release' or `unmasking' phenomena. If the observed changes occur over the course of days to months and require prolonged exposure to the altered sensory input, then they might be more appropriately viewed as adaptive `re-calibration' or cognitive `learning' phenomena (Gilbert et al., 1996). Therefore, we have examined the tonotopic organization of the IC after mechanical destruction of restricted sectors of the spiral ganglion (SG). Unlike lesions that damage outer hair cells, these lesions leave intact the frequency processing mechanisms of the cochlea as well as the tuning and sensitivity of the basilar membrane and remaining auditory nerve ¢bers. Although SG le-

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sions could signi¢cantly alter e¡erent function (and therefore cochlear function), the cochlear hair cells, the organ of Corti and the basilar membrane are una¡ected at least in principle by these lesions. Therefore, the e¡ects of these lesions can be examined acutely in a map/lesion/re-map paradigm with the pre-lesion maps serving as controls for post-lesion changes in individual animals. We conducted these acute experiments in a single sitting with as little time elapsing between the pre- and post-lesion measurements as possible. Our results indicate that IC neurons, which are tuned to frequencies that are una¡ected by the lesion, have response areas (RAs) that are similarly una¡ected. However, neurons that are tuned to lesion frequencies become immediately (within 4^5 h) less sensitive to those frequencies and rapidly more sensitive to the intact lesion edge frequencies. These sensitivity changes result in a shift in the characteristic frequency (CF) of these neurons and produce rapid alterations in the tonotopic organization of the IC. These changes in the IC occur as rapidly as they could be measured (within hours of the lesion) and are comparable to cortical changes seen after chronic cochlear lesions, which have existed for periods of weeks to months. 2. Materials and methods Experiments were conducted in six prior normal cats. All animals were maintained in a facility approved by the American Association for Accreditation of Laboratory Animal Care. All procedures were approved by the UCSF Committee on Animal Research and were conducted in accordance with the guidelines provided by the PHS/NIH Guide for the Care and Use of Laboratory Animals. 2.1. Surgical preparation Each animal was tranquilized with an intramuscular injection of ketamine HCl (25 mg/kg) and acepromazine (0.2 mg/kg). Then an intravenous catheter was inserted into the cephalic vein and a surgical level of anesthesia was induced and maintained by infusion of sodium pentobarbital. A tracheal canula inserted via a tracheostomy. Blood oxygenation, respiratory rate and heart rate were continuously monitored using a blood oximeter. Body temperature was maintained using a servo-controlled warm water re-circulating blanket. In addition, somatic re£exes (e.g. corneal re£ex and forelimb withdrawal re£exes) were monitored to insure that a standardized surgical (are£exive) level of anesthesia was maintained. A urinary catheter was inserted into the urethra and the urine output monitored. Lactated Ringer solution was continuously infused throughout

the experiments to maintain the level of hydration necessary to maintain stable heart rate and blood pressure, and prophylactic injections of antibiotics (e.g. cefazolin 22 mg/kg) were administered twice daily. In addition, prophylactic doses of dexamethasone (1 mg/kg/h IV) and mannitol (1^2 mg/kg/day IV) were given to prevent cerebral edema. The head was positioned and immobilized using a mouth-bar head-holder mounted in a magnetic base. The external ear canals on both sides were opened near the bony annulus and rigid plastic tubes connected to sealed earphones were inserted into them and sealed in place. The auditory bulla on the left side was surgically exposed and then opened to permit clear visualization of the round window. 2.2. Sound generation and delivery A PC/AT compatible computer controlled presentation of acoustic stimuli with custom hardware for generating digital waveforms. Early experiments were conducted at the Boys Town National Research Hospital (BTNRH), and later experiments were conducted at the University of California (UC). The computer systems in use and the stimulus waveforms presented in the two laboratories were generally similar but not identical. Despite di¡erences in hardware and software, completely consistent results were obtained in the two different laboratories. Two waveform channels were used to deliver stimuli to the two ears. When waveforms were presented to both ears, they were presented in phase and at the same SPL. Waveforms were presented through a closed acoustic system consisting of a Beyer DT48 (BTNRH) or Stax 51 (UC) earphone, mounted in a metal case with a plastic tube that could be inserted into external auditory meatus, as noted above. The assembly used at BTNRH incorporated a B and K probe tube microphone with a known transfer function, and the acoustic system was calibrated for each individual experiment. For the assembly used at UC, a standard calibration obtained in a rigid coupler was used. 2.3. Compound action potential (CAP) audiograms A silver ball `active' electrode was placed in the round window niche and ¢xed in place with cyanoacrylate glue. A silver wire `reference' electrode was placed in the skin of the neck and a silver wire ground electrode was inserted into the skin below the contralateral ear. The output of these electrodes was ampli¢ed (BTNRH : Grass P511; UC: WPI, DAM50 and Tektronix 5A22N) with band-pass settings of 100 Hz^10 kHz and ampli¢ed 100 000U. The ampli¢ed output was displayed on an oscilloscope and digitized using an A/D converter sampling at a rate of 20 kHz. The

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cochlea was stimulated with 15 ms tone bursts with 1 ms rise/fall times; the phases of individual tone bursts were varied in order to cancel the cochlear microphonic. Responses to 50^100 tone bursts were averaged at each stimulus frequency and level. Frequency was usually varied in steps of 0.25 octave. Averaged responses from below threshold to 40 dB above threshold were obtained for each tone frequency. CAP audiograms were recorded both at the beginning of an experiment and immediately after the lesion. In some cases, a third CAP audiogram was recorded at the end of the experiment. 2.4. Electrophysiological mapping Electrophysiological mapping was conducted in adult cats using procedures described in previous publications (see Snyder et al., 1990, 1997). Through a mid-line skin incision, the dorsal lateral aspect of the right calvarium was exposed and a craniotomy was made in the parietal bone over the occipital cortex. The dura was excised and re£ected. The occipital cortex was removed by aspiration and a wedge of the bony tentorium cerebelli was removed exposing the entire dorsal and dorsolateral surface of the IC. The distribution of IC multiple unit activity evoked by pure tones was mapped using conventional recording techniques. Parylene-C insulated tungsten microelectrodes (1^2 M6 at 1 kHz from Microprobe, Inc.) were held in a micromanipulator (Narishige) and advanced using a hydraulic microdrive (BTNRH: TrentWells; UC: Kopf Model 650). Electrodes were driven across the IC along a standardized trajectory, tilted 45³ o¡ the sagittal plane in the coronal plane. This trajectory compensates for the tilt of the `frequency band lamina' in the central nucleus of the IC (ICC). On this axis, penetration tracks pass through the full range of frequencies represented in the IC (Snyder et al., 1990). Along this trajectory, multiunit neural activity was ampli¢ed (100 000^200 000 times) with a bandpass of 300 Hz^3 kHz using a battery-powered preampli¢er (BTNRH : WPI DAM50; UC: DAM50 and Tektronix 5A22N). Neural activity was isolated from background activity using a spike window discriminator (BTNRH : WPI 121; UC: BAK DIS-1). The responses, the acoustic stimuli and the discrimination acceptance pulses were monitored on an oscilloscope. The time of occurrence of each pulse from the window discriminator was recorded and stored using an accuracy of 10 Ws. At 100 Wm intervals, a response map (described below) was recorded in response to stimulation of the contralateral, ipsilateral and both ears.

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2.5. Data collection and analysis Window discriminator pulses were stored in a bu¡er in a commercial (BTNRH: Cambridge Electronic Design 1401) or custom (UC) data acquisition system. The contents of this bu¡er were transferred to the PC/AT for display as RAs, and were saved in a disk ¢le along with stimulus information for later analyses. The RA program presented tones in a randomized order over a range of frequency and SPL, and counted the number of multiunit response events elicited by each tone. The range of frequencies usually varied over a range of three octaves or more. The exact frequency limits varied, depending upon the CF of the recording site. SPL usually varied over a range of 60^80 dB. RAs were displayed in frequency vs. SPL space by lines whose length represents the normalized magnitude of the response elicited by a frequency-SPL pair, plotted at the appropriate frequency-SPL coordinate. CF and threshold at CF were estimated by eye from these plots. 2.6. SG lesions Acute SG lesions were created after recording an initial CAP audiogram and after an initial map of the IC had been constructed. The SG was visualized directly by excising the round window membrane, partial aspiration of the perilymph and viewing the osseous spiral lamina using an operating microscope (Zeiss, OPMI). The bone overlying an approximate 1 mm segment of Rosenthal's canal was removed by manual curettage using a 34-gauge hypodermic needle and the subjacent SG destroyed. After the lesion was complete and all bleeding was stopped, the intracochlear location of the lesion was recorded using a high-resolution color video camera (Panasonic, KS102) attached to the operating microscope. The video image was digitized and stored on a Macintosh Quadra 800. After the perilymph had been replenished, the round window was re-sealed using a disk of Suranwrap1 to prevent further leakage of the perilymph. 2.7. Preparation of cochlear specimens Following the acute recording experiments, cochleas, oval and round windows were opened and an intrascalar perfusion with a ¢xative consisting of 0.1 M phosphate-bu¡ered 0.5% paraformaldehyde and 2.5% glutaraldehyde was performed. This cochlear perfusion was followed by a transcardiac vascular perfusion with the same ¢xative but with 4% sucrose added. After the vascular perfusion, temporal bones are removed and perfused with fresh ¢xative. The cochleas were left overnight in ¢xative and dissected in phosphate bu¡er. Following decalci¢cation for 6 18 h, additional

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Fig. 1. A view of the hook region of the osseous spiral lamina (osl) in a cat cochlea as seen through the round window. For the purposes of this ¢gure, the round window membrane and all the perilymph have been removed. The basilar membrane is visible as the medium gray crescent (black arrows). The basal end of the cochlear spiral is toward the top. The scala tympani spirals counter-clockwise and away into the basal turn at the bottom. The modiolus (asterisk) is toward the right. The white arrows indicate the basal to apical extent of a 1 mm SG lesion. The lesion is visible due to blood clots in Rosenthal's canal. Extravasated blood can also be seen as dark blotches lying under (on the scala tympani side of) the basilar membrane.

micro-dissection is required to isolate the cochlear sectors that contained the lesion (Snyder and Leake, 1997). Dissected specimens were post-¢xed in 0.1 M phosphate bu¡er containing 1% osmimum tetroxide and 1.5% potassium ferricyanide. The cochleas were dehydrated in increasing concentrations of ethanol and embedded in epoxy resin. Blocks containing the SG and organ of Corti were mounted on blank gelatin capsules ¢lled with polymerized epoxy and sectioned radial to the cochlear spiral at a thickness of 1^2 Wm. These radial sections were stained with toluidine blue and examined with a Zeiss photomicroscope III. 3. Results 3.1. SG lesions and CAP audiograms We have examined the tonotopic organization of the IC immediately after acute focal lesions of the SG in the basal, hook region of adult cats. An example of such a lesion is illustrated in Fig. 1, which shows a

view of the osseous spiral lamina in the hook of a cat cochlea as seen through the round window. In this view, the round window membrane has been completely removed and the perilymph completely aspirated. The basilar membrane can be seen as a medium gray crescent (black arrows). The basal-most end (hook) of the osseous spiral lamina (osl) can be seen in en-face view in the upper right of the round window. The scala tympani spirals counter-clockwise and away (bottom) from the observer. The beginning of the ¢rst (basal) turn of the cochlea can be seen at the bottom of the round window. The white arrows indicate the extent of a 1 mm SG lesion. Radial sections through the osseous spiral lamina, SG and organ of Corti apical to the lesion (Fig. 2A) and at the level of the lesion (Fig. 2B) indicate that, although the SG is virtually destroyed, the basilar membrane, organ of Corti, and inner and outer hair cells are intact. The anatomical e¡ects of lesions such as that illustrated in Figs. 1 and 2 suggest that despite a regional loss of cochlea output, the overall tuning and sensitivity

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Fig. 2. Semi-thin radial sections through the SG (black outline) and organ of Corti (asterisk) from a cochlea with a lesion similar to the one shown in Fig. 1. A: Section through the intact SG apical to the lesion. There is a post-mortem bend in the tissue at the arrow. B: Section through the lesion. The extent of the lesion is outlined black. Surviving SG cells are indicated by the white asterisks. The arrow indicates the intact basilar membrane and organ of Corti. Bar = 250 Wm.

of the cochlea should be una¡ected by the lesion. This suggestion is corroborated by tone-evoked CAP audiograms taken before and after the lesion. Fig. 3 illustrates three such audiograms using CAP thresholds at various frequencies from 0.5 to 32 kHz. Three time intervals are illustrated : (1) after the bulla has been opened but the cochlea is intact, (2) after the round window membrane has been removed, and (3) after a 1 mm SG lesion has been made. These audiograms indicate that opening of the round window alone can have little e¡ect on the sensitivity of the cochlea. However, in this case, a 1 mm SG lesion beginning at approximately 4 mm from the cochlear base produces CAP thresholds that are elevated by approximately 40 dB. The frequencies with elevated thresholds (lesion frequencies) are centered at approximately 16 kHz and range from approximately 12 kHz to 20 kHz. This audiogram is typical of those observed in our experiments, although one post-lesion audiogram could not be reconstructed due to technical dif¢culties.

3.2. Normal pre-lesion RAs The tonotopic organization of the IC was examined in a total of six animals. In four animals, the neural responses in the IC have been examined in detail and the tonotopic organization in their central nuclei was mapped in map/lesion/re-map paradigms. In one animal (our ¢rst), the IC neural responses were mapped only immediately after the lesion was produced and the hearing de¢cit documented; so in this animal no pre-lesion map is available. However, its post-lesion responses can be compared with those obtained from normal animals. In a sixth animal, a pre-lesion map was obtained, a lesion was made and documented, but the post-lesion data could not be analyzed. A series of normal IC RAs are illustrated in Fig. 4A (the post-lesion RAs in Fig. 4B will be discussed later). These RAs are a subset of those recorded at 100 Wm intervals along one penetration through the IC of cat#5298. They were recorded following stimulation with contralateral tones and recorded at sequential lo-

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Fig. 3. CAP audiograms from cat#9403 at three time intervals: when its cochlea was intact, immediately after the round window (RW) has been opened and immediately after a restricted lesion (V1 mm) was made in its SG. The post-lesion audiogram indicates that the lesion produced a 35 dB elevation in tone-evoked thresholds across a restricted range of frequencies centered at 16 kHz (arrow).

cations separated by 400^500 Wm across the high frequency region of the ICC. They are arranged with the most super¢cial locations on the left and the deepest locations on the right. These RAs are typical of those we and others have recorded in the cat IC. Typically, an RA consists of a single `V'-shaped excitatory region surrounded by a `silent' region in which there is no driven activity but some spontaneous activity. For each normal RA, there is a single minimum threshold that de¢nes a CF for that RA. In Fig. 4A,B, an arrow in each RA indicates an estimate of CF and minimum threshold. The values of those estimates are indicated at the lower left of each plot. As would be expected from the well-described tonotopic organization of the ICC (Rose et al., 1963), the more super¢cially located neurons in the ICC have relatively low CFs whereas those located more deeply have higher CFs. Moreover, in normal penetrations, there is an orderly progression of CFs with CFs increasing smoothly from low to high frequency. 3.3. Normal frequency gradient If a standardized penetration trajectory is used, plots of CF as a function of penetration depth are relatively uniform (Snyder et al., 1990). We have termed these plots frequency gradient curves (FGCs). Fig. 5 illustrates four FGCs from four penetrations in four normal cats. The data illustrated in Fig. 4A are included as one of these penetrations. These FGCs were superimposed by shifting them horizontally along the depth axis to compensate for di¡erences in external nucleus thickness and variability in determination of nuclear surface. No other normalization has been applied. The shapes of

these curves are remarkably similar and smooth. CFs increase consistently and progressively once the electrode enters the central nucleus (ICC) that usually occurs at a depth of about 1000^1500 microns from the surface of the IC. In the normal ICCs, there are few in£ections, reversals or other consistent irregularities in the FGCs. 3.4. Normal spatial tuning curves (STCs) Typically, cochlear excitation by stimulation with pure, high frequency tones produces activation of restricted regions of the auditory nerve array (Kim and Parham, 1991). Such stimuli also excite limited regions of the ICC tonotopic organization as we have shown previously (Snyder et al., 1990). Thus in addition to estimating CF and minimum threshold (threshold at CF), the threshold for any arbitrary frequency (e.g. 10 kHz) can be estimated in each RA. In the series of RAs illustrated in Fig. 4A, the arrowheads indicate our estimate of threshold for a 10 kHz tone. When these 10 kHz thresholds are plotted as a function of penetration depth, an STC for 10 kHz is generated (¢lled diamonds in Fig. 6A). STCs from normal animals are uniformly `V'-shaped functions with the location of the apex of the V corresponding the depth at which the neurons with CFs equal to the stimulation frequency are found (Fig. 6). STCs for lower frequencies (7.5 kHz, triangles in Fig. 6A) are located more super¢cially. STCs for higher frequencies are located deeper (15 kHz, circles in Fig. 6A). If standardized penetration trajectories are used, STCs provide a measure of IC areas excited by acoustic stimuli and are a useful way to compare frequency repre-

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Fig. 4. A: A series of ¢ve pre-lesion frequency RAs recorded from neurons located at sequential penetration depths ranging from 2400 Wm (A-1) to 4100 Wm (A-5). The CFs (arrows and lower left of each plot) at these locations range from 7 kHz (A-1) to 31 kHz (A-5). The arrowheads indicate the threshold for 10 kHz in each plot. B: A series of ¢ve RAs recorded after a small lesion in the SG centered at a frequency of 16 kHz (Fig. 11B). These RAs were recorded from the same animal along the same penetration trajectory as those in A. The RAs are arranged as in `A' with penetration depths ranging from 2600 Wm (B-1) to 4100 Wm (B-5). The CF for each RA is indicated as in `A'. A clear gap in the sequence of CFs can be seen between B-3 and B-4, if their CFs are compared with those in A-3 and A-4. The lesion center frequency is indicated by the open arrowheads.

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Fig. 5. FGCs recorded along a standardized penetration trajectory through the ICC in four normal cats. The CF of each ICC location is plotted as a function of penetration depth for a single penetration in each animal. The curves have been shifted along the depth axis in order to superimpose them, but no other normalization has been applied. The curves indicate that the CF gradient within the ICC is highly consistent among animals.

The RA in the middle was recorded from neurons located 400 Wm further along the penetration at 3000 Wm, a location that would have a pre-lesion CF of 16 kHz corresponding to the center of the lesion frequencies. The RA on the right was recorded from neurons located an additional 400 Wm deeper at 3400 mm with a CF of 25 kHz which is above the lesion frequencies. The arrow in each RA indicates the 16 kHz center of the lesion frequencies. The excitatory responses appear to be reduced across a narrow range of frequencies, i.e. those a¡ected by the lesion, in each RA. In the left RA (Fig. 7A), the excitatory region is centered at 10 kHz and appears to have an especially steep high frequency slope, as though the responses to tones above CF have been eliminated. In this case, the reduced excitation results in an increase in the sharpness of the frequency tuning at this location. In the middle RA (Fig. 7B), the excitatory region is centered at the lesion frequencies and the reduction in excitation results in a clear notch at its center. The notch is a few kHz wide and 20^30 dB deep and occurs across the frequencies that would normally contain the CF. Thus, the notch results in an

sentations in the ICC. STCs for tones between 5 and 20 kHz have a similar shape and their widths for each frequency are comparable from animal to animal. Fig. 6B illustrates three pre-lesion 10 kHz STCs from three cats in this study. These curves are typical of STCs. They are asymmetrical with the steep slopes on the more super¢cial side and shallower slopes on the deeper side. This asymmetry derives from the asymmetry of the excitatory regions of RAs which tend to have steeper high frequency slopes. The width of these STCs is comparable both to each other and to those illustrated in Fig. 6A. Thus at a standard level above minimum threshold, STC widths provide a rough, relative measure of the amount of the ICC activated by tones between 5 and 20 kHz. 3.5. Post-lesion RAs Lesions of the SG have several e¡ects on RAs of IC neurons. The ¢rst of these e¡ects is reduction of excitatory input to these neurons at the lesion frequencies. Fig. 7 illustrates three RAs recorded along a single post-lesion penetration from one cat (C9403). The pre- and post-lesion CAP audiograms for this cat are shown in Fig. 3. This audiogram indicates that the lesion produced an elevation in CAP thresholds across a narrow range of frequencies from 13 to 19 kHz centered at 16 kHz. The RA on the left was recorded from neurons located at 2600 Wm along the penetration. It has a CF of 10.5 kHz, which is below the lesion frequencies.

Fig. 6. A: STCs recorded following stimulation at three frequencies separated by 1/2 octave (7.5, 10 and 15 kHz) in one penetration through the IC of cat C5298. B: STCs recorded following stimulation using a 10 kHz tone along a standardized penetration trajectory through the IC of three normal (unlesioned) cats.

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Fig. 7. Post-lesion RAs neuron clusters recorded from cat#C9403 with a lesion centered at 16 kHz (Fig. 3). These RAs were recorded at sequential locations (separated by 400 Wm) along a standardized trajectory. The center of the excitatory regions in these RAs shifts to higher frequencies at progressively lower depths. A region of reduced excitation can be seen in the excitatory region of each RA (arrows). In RAs `B' and `C', lesion-induced reduction in excitation produces prominent notches at the lesion frequency.

excitatory region with two minima, i.e. an RA with apparently two CFs separated by a notch. If the notch was slightly shifted relative to the excitatory region, then one of these two minima would be at a substantially lower threshold than the other and an apparent shift in location CF would result. The RA on the right (Fig. 7C) has an excitatory region centered above the lesion and also has a 20^30 dB notch. Although this notch appears in the frequency region well below CF, it is located across precisely those frequencies a¡ected in the middle RA. Both notches also correspond to the lesion frequencies as indicated by the CAP audiogram. Thus an acute lesion of a restricted SG region results in a loss of excitation from IC neurons across a restricted frequency range, which corresponds to the range of lesion frequencies. In addition to the reduction of excitation across selected frequency regions, there are other e¡ects of SG lesions on IC neuronal responses. Some of these additional e¡ects are illustrated in Fig. 8, which shows representative pre- and post-lesion RAs from a cat with a lesion located slightly more basal than that of the previous animal. The pre- and post-lesion CAP audiograms from this animal are illustrated in Fig. 9A. These audiograms indicate that this lesion produced modest elevations in tone thresholds with a maximum elevation (20 dB) at about 20 kHz (arrow) and near normal thresholds at 16 and 30 kHz. Representative pre- and post-lesion RAs from this animal are plotted sequen-

tially with those from the most super¢cial locations on the left and those from progressively deeper locations on the right. All pre-lesion RAs (Fig. 8A) have normal `V'-shaped excitatory response regions with single minimal thresholds (arrows) and progressively increasing CFs. The post-lesion RAs (Fig. 8B), in contrast, have a number of highly unusual properties. For example, on average, post-lesion RAs have broader excitatory response regions, especially at higher stimulus levels than the pre-lesion RAs. In addition to broader excitatory regions, three of these post-lesion RAs have deep notches (or regions reduced excitation). These notches usually correspond to the (20 kHz) maximum lesion frequency. Three such notches can be seen in three of these RAs (arrowheads Fig. 8B, 2, 3 and 4). In addition, in some RAs (e.g. Fig. 8B, 3) there are two notches, one corresponding to 20 kHz and a second notch corresponding to 10 kHz, a sub-harmonic of 20 kHz. These notches are not seen in all the post-lesion RAs, but when they are observed they occur following both contralateral and binaural stimulation. In this case, the notches are very deep extending over a 50^ 60 dB range of intensities. In addition to being broader and having notches in their excitatory regions, this animal's post-lesion RAs have CFs that increase little or not at all over a broad range of penetration depth. Thus the three deepest post-lesion RAs (Fig. 8B, 3, 4 and 5) have CFs that are very similar 13^17 kHz, although they are separated by approximately 1200

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Fig. 8. A: A series of ¢ve pre-lesion frequency RAs recorded from neurons located at sequential penetration depths ranging from 2100 Wm (A-1) to 4900 Wm (A-5). The CFs (arrows and lower left of each plot) at these locations range from 6.1 kHz (A-1) to 29 kHz (A-5). B: A series of RAs recorded after a small lesion in the SG centered at a frequency of 20 kHz (Fig. 9A). These RAs were recorded from the same animal along the same penetration trajectory as those in A. The RAs are arranged as in `A' with penetration depths ranging from 2200 Wm (B-1) to 4200 Wm (B-5). The CF for each RA is indicated as in `A'. Clear gaps (arrowheads) in the excitatory regions corresponding to the lesion frequencies (15^25 kHz) can be seen in RAs B-2, B-3 and B-4. In addition to the gaps at the lesion frequencies, RA B-4 has a gap at a sub-harmonic of the lesion frequencies (asterisk).

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Fig. 9. A: Pre-, post-lesion and di¡erence CAP audiograms from cat#C4178. The di¡erence audiogram indicates that the SG lesion produced elevated thresholds across a narrow range of frequencies centered at 20 kHz. The lesion frequencies as indicated by di¡erence between the preand post-lesion audiograms are centered at approximately 20 kHz (indicated by the arrow). Pre- (B) and post-lesion (C) RAs from this animal. These RAs summarize the observed e¡ects of restricted SG lesions on ICC RAs. The pre-lesion excitatory response region is outlined in each ¢gure. The estimated CF and minimum threshold in ¢gure are indicated by the `+'.

Wm. By comparison, the CFs of pre-lesion RAs (Fig. 8A, 3, 4 and 5), which are distributed over the same distance, increase by more than an octave. It should be noted that the minimum thresholds for the post-lesion RAs are comparable to one another and lower on average than those of their pre-lesion counterparts.

Fig. 9 summarizes the e¡ects that we have observed in post-lesion RAs. The pre- and post-lesion CAP audiograms Fig. 9A and the arrow indicate that the lesion is centered at approximately 20 kHz. The lower left RA (Fig. 9B) was recorded in a pre-lesion penetration and the lower right RA (Fig. 9C) was recorded in a

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post-lesion penetration at approximately the same location in the same ICC. The pre-lesion RA was chosen because its CF (indicated by the plus) is approximately equal to the 20 kHz frequency maximally a¡ected by the lesion (indicated by the arrow). Its excitatory region has been outlined in order to emphasize its boundaries. This outline has been superimposed on the post-lesion RA (Fig. 9C) to suggest the pre-lesion tuning curve at this location. The post-lesion excitatory region is broader than that of the pre-lesion and has a notch in it, a notch that is similar to those observed in Figs. 7 and 8. This notch indicates that there has been a withdrawal of the `normal' excitatory input across a range of frequencies roughly corresponding to the lesion frequencies and this notch extends to a depth of 40^60 dB. In addition to the withdrawal of excitation in the presumed `normal' excitatory region, there is excitation that has been added or released outside the boundary of the pre-lesion excitatory region in the presumed silent region of the pre-lesion (normal) RA. This post-lesion addition of excitation occurs at frequencies both above and below the `normal' CF, but it is most prominent at frequencies below the presumed pre-lesion CF. If the pre-lesion excitatory region is presumed to approximate the `normal' excitatory region at this location, then the additional excitation would result in a shift downward in CF for these neurons. If this shift occurred consistently for several consecutive locations along a post-lesion penetration, then one would expect signi¢cant distortions in the STCs at the lesion and lesion edge frequencies and in£ections in the FGCs. That these distortions do indeed occur is demonstrated below.

Fig. 11. A: FGCs from one animal at three time intervals: prior to an SG lesion (solid squares), after a small lesion (open squares) which produced no change in the CAP audiogram (open squares, in `B') and after an enlarged lesion (open circles) which produced elevated thresholds across a range of frequencies centered at 25 kHz (open circles, in `B'). The FGC recorded after the small lesion is not signi¢cantly di¡erent from normal. The FGC recorded after the enlarged lesion has a clear discontinuity centered at 25 kHz and £anked by two in£ections (arrows) corresponding to the lesion edge frequencies. The vertical arrows indicate the locations at which the pre- (white arrows) and post-lesion (black arrows) RAs were recorded. B: Pre- and two post-lesion CAP audiograms. The ¢rst post-lesion audiogram (post-lesion 2, open squares) was recorded after an intentionally small lesion in the SG. The di¡erence between these audiograms (di¡ 132, open squares) indicates that such a lesion can have little or no e¡ect on CAP thresholds. The second post-lesion audiogram (post-lesion 3) was recorded after the lesion was enlarged. The di¡erence between this second post-lesion audiogram and the pre-lesion audiogram (di¡ 133, solid line) indicates that this enlarged lesion resulted in elevated thresholds across a restricted range of frequencies centered at 25 kHz.

3.6. Post-lesion frequency gradients Fig. 10. Two post-lesion FGCs (open squares, open circles) from C9403 which have a 1 mm SG lesion which produced elevations in CAP threshold centered at 16 kHz (Fig. 3). These curves are superimposed on an average of four normal FGCs (solid line, see Fig. 5). Note the in£ections in the post-lesion FGCs (arrows) at the upper and lower edges of the lesion frequency. The arrowheads indicate the locations at which the RAs in Fig. 7 were recorded.

We have observed two types of distortion in postlesion FGCs. The ¢rst type takes the form of double in£ections in an otherwise normally smooth FGC. Fig. 10 illustrates two post-lesion FGCs from cat C9403. Since there was no pre-lesion recording, these FGCs

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are superimposed on top of the average of the four normal FGCs illustrated in Fig. 5. Each post-lesion FGC displays two in£ections (arrows), one more super¢cial and one deeper than the discontinuity. The discontinuity in each case corresponds to the 16 kHz center of the lesion frequencies (Fig. 3). Each in£ection represents a series of RAs at sequential locations within the ICC at which identical or nearly identical CFs were estimated. The arrowheads indicate the locations at which the RAs illustrated in Fig. 7 were recorded. The frequency gradients at locations more super¢cial and deeper than these in£ections correspond closely to the average normal FGC. Thus these in£ections are local distortions of a presumably otherwise normal FGC. Such in£ections and their accompanying discontinuities are never observed in FGCs of normal animals. Fig. 11A illustrates a second example of double in£ection distortion in an FGC. In this case (C5298), the frequency gradient was examined at three time points: before any lesion, after a very small lesion and after an enlarged lesion. The CAP audiograms and their di¡erence curves from this case are illustrated in Fig. 11B. The pre-lesion FGC (solid squares) corresponds closely to other normal FGCs. It is smooth with no in£ections. After the round window was opened and a very small lesion was attempted, the CAP audiogram was essentially normal. There was no consistent elevation in tone-evoked CAP thresholds (open squares, Fig. 11B) and the FGC following this small lesion (open squares, Fig. 11A) closely approximates the pre-lesion FGC. After the responses in these penetrations were recorded, the cochlea was re-opened and the lesion enlarged. Following this enlarged lesion, a modest 20 dB elevation in CAP thresholds (solid line, Fig. 11B) was observed across a narrow range of frequencies with a maximum threshold shift at 20^25 kHz. The FGC following this enlarged lesion (open circles, Fig. 11A) has two in£ections (arrows) spanning a discontinuity in the range of the lesion frequencies (20^30 kHz). Five representative RAs at 400 mm intervals are illustrated in Fig. 4B. The discontinuity closely corresponds to the range of frequencies with elevated thresholds in the second postlesion CAP audiogram. The nature of this discontinuity can be appreciated by comparing the CFs of the preand post-lesion RAs in Fig. 4. In the 500 Wm step from 3200 Wm to 3700 Wm (Fig. 4A, 3 to 4), the CF of prelesion RAs shifts 4 kHz (17 to 21 kHz). In contrast, the post-lesion CFs for RAs at approximately the same locations shift by more than an octave (12 kHz to 31 kHz, Fig. 4B, 3 to 4). A second type of lesion-induced distortion that we have observed in the FGCs is single in£ection distortion. Two examples of this type of distortion are illustrated in Figs. 12 and 13. Fig. 12A shows the pre- and post-lesion FGCs from cat C4178. The CAP audio-

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Fig. 12. A: Pre-lesion (¢lled diamonds) and post-lesion (open circles) FGCs recorded from cat C4178. The pre-lesion FGC is normal with progressive increase in CF as penetration depth increases. The post-lesion FGC has a clear discontinuity (large arrow). At depths more super¢cial than this discontinuity (light circles), CFs increase more or less normally. At depths deeper than this discontinuity (dark circles), there is a clear in£ection in the FGC along which CF changes very little and the di¡erence between pre- and post-lesion CF increases. The numbered small arrows indicate locations at which the RAs illustrated in Fig. 8 were recorded. B: Pre- and post-lesion thresholds at CF (minimum thresholds) for the locations illustrated in `A' (above) are plotted as a function of CF. The lowest pre-lesion thresholds correspond roughly to the pre-lesion CAP threshold in this animal (Fig. 9A). The post-lesion thresholds are equal to or less than the pre-lesion thresholds. Many of the minimum thresholds for RAs located deeper than the discontinuity and along the in£ection (dark circles) have thresholds below the pre-lesion thresholds. The open symbols plot CFs recorded before the lesion.

grams for this animal (Fig. 9A) indicate that the SG lesion produced threshold elevations that were centered at approximately 20 kHz. The pre-lesion FGC (¢lled diamonds, Fig. 12A) has some irregularities, but is still recognizable as a normal FGC. However, the post-le-

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sion FGC (circles) has a single large in£ection. In the central nucleus, CFs increase smoothly and progressively from approximately 5 kHz at 2200 Wm to approximately 25 kHz at 4100 Wm. These changes in CF roughly parallel to those seen in the pre-lesion penetration. However, the location at 4100 Wm (arrow) was silent, stimulation all frequencies and all levels of up to 75 dB SPL produced no response. At subsequent locations deeper than 4100 Wm, the post-lesion CFs (dark circles), instead of continuing to increase, shifted abruptly to approximately 16 kHz and remained at that frequency until the end of the penetration, approximately 1 mm deeper. The thresholds for these pre- and post-lesion RAs are plotted as a function of their CF in Fig. 12B. The prelesion thresholds are distributed from 20 to 47 dB across CFs from 6 to 32 kHz and their minima correspond roughly to the pre-lesion audiogram (Fig. 9A). Among post-lesion RAs, CFs range from 6 to 25 kHz, but there is an over-representation of RAs with CFs between 13 and 17 kHz. And the thresholds for these neurons with CFs in the 13^17 kHz range are at or below those recorded in the pre-lesion penetration. Moreover, the thresholds for locations deeper than 4200 Wm are among the lowest recorded. Thus the deepest post-lesion locations (see Fig. 8B, 5) had the lowest thresholds and the largest disparities between pre- and post-lesion CFs (dark circles). These results indicate clearly that the shifts in CF at these deep locations are not due to recording of `residual' responses of normal RAs and that the distortions in the FGCs observed after SG lesions are not a form of `pseudoplasticity'. Fig. 13A shows a pre- and a post-lesion FGC from another animal (C9508). The pre-lesion FGC appears normal with the CFs estimated after stimulation with contra-, ipsi- and binaural tones increasing progressively from approximately 1 kHz to above 30 kHz. However, the post-lesion FGC displays an extended in£ection beginning at a depth of approximately 3500 Wm and continuing until the end of the penetration (5000 Wm). This in£ection consists of a series of RAs extending across more than 1.5 mm that are tuned to a narrow range of frequencies, 12^15 kHz. Although we could not reconstruct the post-lesion CAP in this experiment, we can infer, based on the cochlear location of the lesion and extent of the lesion, that the postlesion thresholds in this animal were comparable to those seen in C4178 (Fig. 9A). In any case, the in£ection in this post-lesion FGC certainly corresponds in location and frequency to that observed in post-lesion FGC of that animal (Fig. 12A). The minimum thresholds to contralateral stimulation at CF are plotted as a function of CF in Fig. 13B. Note that the post-lesion minimum thresholds for RAs located along the postlesion in£ection in Fig. 13A are comparable to the

Fig. 13. A: Pre-lesion (¢lled diamonds) and post-lesion (open circles) FGCs recorded from cat C9508. The pre-lesion FGC is normal with progressive increase in CF as penetration depth increases. The post-lesion FGC has a clear in£ection (large arrow) at a frequency of about 15 kHz. B: Pre- and post-lesion thresholds at CF (minimum thresholds) for contralateral stimulation plotted as a function of CF. The post-lesion thresholds at lesion edge frequencies (12^15 kHz) are equal to or less than the pre-lesion thresholds.

pre-lesion thresholds for locations with the same CF. Moreover, they are among the lowest thresholds recorded in this animal. Therefore, like the post-lesion FGC in Fig. 12A, the expanded lesion edge frequency indicated by the in£ection in Fig. 13A occurs without elevations in post-lesion minimum thresholds and cannot be accounted for by recording `residual' responses. 3.7. Post-lesion STCs Examination of STCs in animals with restricted SG lesions conclusively demonstrates that the in£ections in FGCs (seen above) are not `pseudoplasticity' but rather expanded representations of lesion edge frequencies. Fig. 14 illustrates three sets of pre- and post-lesion STCs generated using contralateral and binaural tones at three frequencies: one well below the lesion frequencies, one near the lesion edge, and one at the lesion edge. In Fig. 14A, the STCs were generated using a tone in an intact frequency region (5 kHz) well below the lesion edge. There is a representation of this 5 kHz

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of the ICC representation are comparable to those in the pre-lesion STCs. Thus the ICC representation of this frequency is expanded toward deeper (higher frequency) regions. Fig. 14C illustrates pre- and post-lesion STCs produced by stimulation at the lesion edge frequency of 15 kHz (Fig. 13, large arrow). Again, as occurred in the 10 kHz STCs, the pre-lesion representations of this frequency are normal in threshold and width. However, the post-lesion representations of 15 kHz at least in the ICC are greatly expanded. Moreover, this expansion occurs toward both deeper (higher frequency) and more super¢cial (lower frequency) locations, a result of the broadening of the excitatory regions of the RAs. From results such as these, we conclude that tone frequencies well below those e¡ected by the lesion are normally represented in the IC; those at frequencies progressively closer to the lesion have progressively expanded representations. Moreover, these expanded lesion edge frequencies have representations with broad minimal thresholds that are equal to or below those of pre-lesion recordings. This result is completely inconsistent with recording of `residual' responses and pseudoplasticity. 4. Discussion Fig. 14. Pre-lesion (open symbols) and post-lesion (closed symbols) STCs for three tones (5, 10 and 15 kHz) recorded in cat C9508. Responses were recorded to tones presented either to the contralateral ear (squares), ipsilateral ear (triangles) or binaurally (circles), are respectively below, near and at the lesion edge frequency. A: Pre- and post-lesion STCs generated by stimulation with a 5 kHz tone, which is far below the lesion edge frequency (large arrow, Fig. 13). B: Pre- and post-lesion STCs generated by stimulation with a 10 kHz tone, which is near the lesion edge frequency (medium arrow, Fig. 13). C: Pre- and post-lesion STCs generated by stimulation with a 15 kHz tone, which is near the lesion edge frequency (small arrow, Fig. 13).

tone super¢cially (deeper than 1000 Wm) in the external nucleus (ICX) and a representation in the ICC (at about 3000 Wm). The pre- and post-lesion STCs are comparable to each other and to normal STCs (see Fig. 6A,B) both in minimum threshold and width. Fig. 14B illustrates STCs produced by activation using a frequency near the lesion edge (10 kHz) in the same animal. Again there is a representation of this 10 kHz tone in both the external and central nuclei. It is di¤cult to assess the nature of the ICX representations due the relatively course sampling (100 Wm intervals) and compressed representation in the ICX, but those in the pre-lesion ICC are normal with low thresholds and narrow widths. However, the post-lesion ICC representations are clearly broader than normal. Despite their broader representation, the minimum thresholds

The results presented strongly indicate that acute, restricted SG lesions produce immediate alterations in the tonotopic organization in the ICC of cats. These alterations occur over restricted frequency ranges that correspond to the lesion frequencies (as indicated by CAP audiograms). Moreover, they demonstrate that the alterations are not simple re£ections of changes in sensitivity of cochlear structures (pseudoplasticity). These lesions always produced CF shifts in IC neurons across speci¢c regions and clear expansions of lesion edge frequency representations, without elevating RA thresholds. Altered FGCs and STCs were always observed in IC penetrations in which localized elevations in CAP threshold were observed. An examination of post-lesion RAs reveals at least two e¡ects of the lesion. First, there is loss of excitation within the pre-lesion excitatory region across the narrow range of frequencies a¡ected by the lesion. This loss of excitation is evident at all stimulus levels without any clear e¡ect of level on the frequency range, i.e. the withdrawal is relatively level independent. The edges of the region of loss are nearly vertical and the `tuning' of the loss is very sharp. Second, there is release (addition) of excitation in the pre-lesion silent regions at frequencies both above and below the pre-lesion excitatory frequencies. However, the addition of excitation is often strongest on the low frequency side. This preferential addition of excitation at frequencies below the pre-le-

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sion CF results in a preferential downward shift in postlesion CFs (Figs. 12 and 13). If it occurs in a succession of RA, it produces an in£ection in the FGC on the lower edge frequency and it produces preferential expansion of low frequency STCs toward deeper (higher frequency) IC regions. Although the release of excitation on the low frequency side of the pre-lesion CF occurs most frequently, such excitatory release also occurs on the high frequency side of the pre-lesion excitatory areas (compare Fig. 4A, 4 with Fig. 4A, 4). This di¡erential prevalence may be due to several factors. First, this might simply re£ect the fact that all our lesions were made through the round window and, therefore, are restricted to the high frequency end of the cochlea. Thus there are simply fewer frequencies into which the excitation can expand. Moreover, in this frequency range, threshold increases progressively as frequency increases. Second, any non-speci¢c e¡ects of the lesions (e.g. from opening the round window and/or from partially draining the perilymph from the scala tympani) would be expected to preferentially alter responses to tones on the high frequency (basal) side of the lesions. Thus the preferential shift of post-lesion CFs downward might simply re£ect a shift toward the nearest completely intact edge frequency, i.e. the edge frequency with the lowest threshold. The increased post-lesion responses to stimulation at intact cochlear locations combined with reduced excitation at lesion frequencies produce alterations in CFs of neurons across wide regions of the IC. Altered CFs are re£ected in long in£ections in frequency gradients (1^1.5 mm, in some cases) and in broad STCs. For some (perhaps smaller) lesions, the CFs of neurons located near the lower edge frequency shift upward and the CFs of neurons located near the upper edge frequency shift downward. For other (perhaps larger) lesions, all units shift their CFs to the low edge frequency. 4.1. Time course of acute response changes produced by restricted cochlear lesions In order to interpret auditory plasticity, the acute e¡ects of partial hearing losses and their time course must be determined. Several studies of partial chronic hearing losses by (1) mechanical disruption of the organ of Corti (Robertson and Irvine, 1989; Rajan et al., 1993), (2) administration of cochleotoxic drugs (Harrision et al., 1991, 1993, 1996; Schwaber et al., 1993), (3) exposure to high intensity (Salvi et al., 1996) or (4) genetically induced progressive hearing loss (Willott et al., 1993 ; Willott 1984, 1996) have reported reorganization in the auditory CNS. These procedures, which result in basal, high frequency hearing losses in cats, chin-

chillas, monkeys and mice, produce expansions of the representations of frequencies located at the edge(s) of the lesions (especially at the lower edge frequencies) in the auditory cortex, IC and cochlear nucleus. Although some of these reported changes appear to merely re£ect alterations in peripheral sensitivity (`pseudoplasticity', see Kaltenbach et al., 1992, 1996), other reported changes have documented clear expansions of cortical representations without signi¢cant elevations in thresholds (e.g. Robertson and Irvine, 1989; Rajan et al., 1993 ; Willott et al., 1993). Thus topographic reorganization in the auditory cortex has been convincingly demonstrated in chronic preparations. However, they leave unresolved questions regarding the time course of reorganization and the mechanisms responsible for that reorganization (e.g. anatomical sprouting, changes in synaptic e¤cacy, etc.). Acute topographic plasticity in the auditory system at cortical levels is controversial. Some cortical studies of auditory plasticity have reported that cochlear lesions result in acute topographic changes that can all be attributed to `residual' responses and pseudoplasticity (e.g. Robertson and Irvine, 1989). Whereas other studies have found acute changes that are inconsistent with recordings of residual responses and are consistent with cortical changes observed after chronic lesions (Calford et al., 1993 ; Snyder and Sinex, 1998). Although rapid topographic reorganization following acute lesions has been questioned in the auditory cortex, it has been reported in both visual (Kaas et al., 1990; Gilbert and Wiesel, 1992; Chino et al., 1992, 1995 ; Darian-Smith and Gilbert, 1995 ; Calford et al., 1999) and somatosensory (Rasmusson and Turnbull, 1983 ; Turnbull and Rasmusson, 1990; Merzenich et al., 1983a,b; Calford and Tweedale, 1988, 1991a,b; Rasmusson et al., 1993; Silva et al., 1996) cortices. Likewise, although topographic reorganization of the auditory system at subcortical levels has been almost universally denied (Kaltenbach et al., 1996 ; Rajan and Irvine, 1996) or observed only inconsistently (Irvine and Rajan, 1994; Salvi et al., 1996), it has been described by several studies in the somatosensory system (Dostrovsky et al., 1976 ; Millar et al., 1976; Pettit and Schwark, 1993, 1996 ; Nicolelis et al., 1993). Thus the acute changes presented in this study are the ¢rst in the auditory system that are comparable with those reported in the somatosensory system at cortical and subcortical levels. Such rapid changes in deeply anesthetized animals suggest that these changes are not adaptive, do occur as a consequence of experience and do not re£ect anatomical alterations in connectivity. In any case, the shifts in CF reported here occurred as rapidly as they could be measured. Indeed, subsequent studies have shown that they occur immediately after the lesion is complete (Snyder and Sinex, 2000).

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4.2. Di¡erences between responses of auditory nerve ¢bers and IC neurons to restricted cochlear lesions It is important to recognize the di¡erences between the e¡ects of restricted SG lesions on responses of IC neurons and those that would be expected on auditory nerve responses. Recognizing these di¡erences is important not only because they indicate that these post-lesion changes are not due to pseudoplasticity, but also because they clearly di¡erentiate RAs recorded in IC neurons from those in the auditory nerve neurons (ANNs), which they super¢cially resemble. The most striking di¡erences between the post-lesion responses of these two types of neurons are seen in the loss of excitation. As we have discussed above, restricted SG lesions produce loss of excitation across a narrow frequency range in neurons widely distributed across the IC and tuned to a wide CF range (Figs. 7 and 8). The a¡ected IC neurons are not limited to the neurons with CFs within the restricted lesion frequency range. In contrast, comparable SG lesions would be expected to completely silence the relatively small number of ANNs directly damaged by the lesion. These lesions should leave the responses of the vast majority of nerve ¢bers intact (Liberman and Mulroy, 1982). Thus across the ANN population, one would expect a silent region £anked by neurons with normal RAs with normal thresholds. In addition to the withdrawal of excitation in IC neurons, there is withdrawal of inhibition or release of excitation. Post-lesion stimulation at intact, non-lesion, frequencies produces IC responses at stimulus levels below those that were e¡ective in pre-lesion stimulation. Thus the consequences of restricted SG lesions on the IC neuronal responses are strikingly di¡erent from those expected in the auditory nerve. These results strongly indicate that the excitatory RAs of IC neurons are not relayed replicas of the excitatory responses of auditory nerve ¢bers. Rather, they indicate that IC RAs are mosaics, the composite of excitatory and inhibitory drives across di¡erent, highly restricted frequency bands. The input to each band is ultimately derived from a di¡erent cochlear region. For example, the excitatory input to the 18^20 kHz band in Fig. 10B is derived from auditory nerve ¢bers innervating the 18^ 20 kHz region of the cochlea. Excitation evoked in adjacent frequency bands (e.g. 16^18 kHz and 20^22 kHz) is supplied by auditory nerve ¢bers innervating adjacent cochlear regions corresponding to these frequencies. Removal of auditory nerve ¢bers innervating the 18^20 kHz region of the cochlea results in withdrawal of excitation in this frequency band in many IC neurons (Fig. 9C), but leaves other frequency bands intact. This loss of excitation occurs at the lesion frequencies regardless of the neuron's location (CF) in the

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IC. If the IC RAs were replicas of auditory nerve RAs, then removal of a restricted sector of the auditory nerve would simply result in a silent IC region in which neurons could not be driven or could be driven only at high stimulus levels. If this silent region occurred, the CFs of its neurons would correspond to those of the damaged auditory nerve ¢bers (Liberman and Mulroy, 1982). In addition to a frequency speci¢c loss of excitation from the excitatory regions of RAs, our results indicate that restricted SG lesions produce rapid, frequency speci¢c loss of inhibition and release of excitation within the `silent' regions of IC RAs. The release of excitation indicates that these `silent' regions are silent not because there is no excitatory drive to them. Rather they are silent because the existing excitatory drive is `suppressed' by inhibition. This inhibition is supplied by activity in pathway(s), which are tuned to normally excitatory frequencies, and acts across speci¢c frequencies in normally silent regions. Thus, for example, removal of excitatory activity within the 15^20 kHz frequency range releases excitatory activity in the 10^15 kHz band of some IC neurons and in the 20^30 kHz bands of others. Such release of excitation by withdrawal of inhibition has been observed in the auditory cortex after frequency speci¢c cochlear lesions (Rajan, 1998) and IC after localized cortical stimulation or inactivation (Yan and Suga, 1998 ; Zhang et al., 1997). According to the view outlined above, both the excitatory and silent regions of an IC neuron's RA are mosaics composed of numerous inputs each of which acts upon a restricted frequency band (Zhang et al., 1997). The widths of these bands appear to be largely independent of level and in total their distribution covers a range of frequencies wider than the normal range of excitatory frequencies. This view of IC RAs is similar to that suggested for cortical neurons by Phillips and Hall (1992). They suggested that a cortical tuning curve represents `the envelope of sensitivities of a number of (independent) inputs of similar CF', i.e. that cortical RAs consist of a series of overlapping `V'-shaped inputs. Our suggestion is similar except that each input to an IC RA consists of an excitatory and an inhibitory region acting across a speci¢c frequency band whose limits change little with stimulus intensity, a series of `I'-shaped inputs. According to both views, a central auditory neurons RA is an emergent property of that neuron which emerges out of the interactions across these bands, much as their binaural properties emerge out of the interactions of the monaural inputs from the two ears. Given this view, the observed e¡ects of SG lesions, which produce e¡ects that closely mimic those reported by others following chronic cochlear lesions, do not represent plasticity. At least not plasticity in the same sense as the use dependent changes reported in numerous sensory deprivation/augmentation experi-

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ments (see Kaas, 1994). Rather, the e¡ects reported here represent acute (immediate) withdrawal and release phenomena occurring instantaneously upon completion of the lesion. Thus these e¡ects are more related to phenomena like spinal shock (withdrawal of excitation) and decerebrate rigidity (release from inhibition) than to adaptive cortical reorganization or re-calibration (Gilbert et al., 1996). These changes (withdrawal of excitation and release for inhibition) occur far too rapidly to be subserved by the mechanisms that are usually invoked to account for use dependent plasticity (sprouting, LTP, LTD, up-regulation of potassium channels, etc.) and should be factored out of any consideration of use dependent plasticity. Finally, the results presented in this study establish two important facts. First, they establish an upper limit on the time frame, a few hours (at a maximum) to a few milliseconds (at a minimum), within which some auditory topographic reorganization occurs. The molecular mechanisms, which underlie this reorganization, if any, must operate within this limit. Second, they establish the IC as one subcortical location at which one might look to observe these molecular mechanisms in operation. Acknowledgements Supported by NIDCD Grants DC03549 to R.L.S. and DC00341 to D.G.S.

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