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Several structures associated with the auditory pathway have been examined by radioimmunoassay for their content of somatostatin. Of these, the medial geniculate body had the highest content, followed by the cochlear nucleus, inferior colliculus, auditory cortex and cochlea. Cochlear perilymph had no detectable somatostatin-like immunoreactivity.
Impact of early post-natal deafening on auditory pathways was investigated in newborn rats deafened by daily amikacin injections from P7 to P16 inducing a complete destruction of the organ of Corti. The expression of mRNAs encoding N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) and gamma-aminobutyric acid type A (GABA(A)) receptor subunits was then studied by in situ hybridization in the dorsal and ventral cochlear nucleus and in the central nucleus of the inferior colliculus (CNIC). Early post-natal deafening decreased bilaterally the expression of mRNAs encoding NR1, NR2a, NR2b and flop isoforms of AMPA receptors. On the contrary, it increased the expression of mRNAs encoding some GABA(A) subunits (alpha1, beta1, gamma2) and flip isoforms of AMPA receptors. These changes were more pronounced in cochlear nuclei than in CNIC. They suggest that auditory sensation is essential in the normal development of central auditory pathways.
By use of several prostacyclin analogs and an in vitro autoradiographic technique, we have found a novel subtype of the prostacyclin receptor, one having different binding properties compared with those of the known prostacyclin receptor in the rat brain. Isocarbacyclin, which is a potent agonist for the known prostacyclin receptor, had high affinity for the novel subtype (dissociation constant (Kd) of 7.8 nM). However, iloprost, which is usually used as a stable prostacyclin analog, showed low affinity binding (Kd = 159 nM) for the subtype. Other prostaglandins showed no or little affinity for the subtype. [3H]Isocarbacyclin binding was high in the thalamus, lateral septal nucleus, hippocampus, cerebral cortex, striatum, and dorsal cochlear nucleus. Although the nucleus of the solitary tract and the spinal trigeminal nucleus showed a high density of [3H]isocarbacyclin binding, [3H]iloprost also had high affinity in these regions, and the binding specificity was similar to that for the known prostacyclin receptor. Hemilesion studies of striatal neurons lesioned by kainate or of dopaminergic afferents lesioned by 6-hydroxydopamine revealed that the binding sites of the novel subtype exist on neuronal cells in the striatum, but not on the presynaptic terminal of afferents or on glial cells. Electrophysiological studies carried out in the CA1 region of the hippocampus revealed that prostacyclin analogs have a facilitatory effect on the excitatory transmission through the novel prostacyclin receptor. The widespread expression of the prostacyclin receptor in the central nervous system suggests that prostacyclin has important roles in neuronal activity.
We investigated whether a unilateral inner ear lesion that destroyed the labyrinthine receptors, the cochlear receptors, and the spiral ganglion induced collateral sprouting in rat vestibular and auditory brainstem nuclei, using growth-associated protein-43 (GAP-43) as an indicator of synaptic remodeling. Both immunocytochemistry and in situ hybridization were performed to detect a potential modulation of GAP-43 and of its messenger RNA (mRNA) at different times after surgery. We failed to observe a reemergence of GAP-43 or a modulation of its mRNA in the deafferented vestibular nuclei at all survival times tested. In contrast, a substantial increase in the expression of GAP-43 was observed in the neuropil of the ipsilateral deafferented cochlear nuclei and in cell bodies of the ipsilateral superior olive. This increase was associated with an up- and downregulation of the mRNA coding for GAP-43 in the ipsilateral ventral cochlear nucleus and in the ipsilateral superior olive, respectively. These data indicate that synaptic remodeling, as assessed by GAP-43 expression, does not seem to occur in the deafferented vestibular complex during the first 6 weeks after labyrinthectomy, whereas it occurs within the first deafferented auditory relays at times as early as 4 days following spiral ganglion and cochlear receptors removal. We conclude that recovery of a normal resting discharge of the deafferented central vestibular neurons and consequently recovery of a normal resting posture and eye position may not depend on collateral sprouting of the remaining vestibular afferents. In contrast, we confirmed that a reactive synaptogenesis occurs in the brainstem auditory nuclei following cochlea and spiral ganglion removal. Its functional significance remains an open question.
Is patterned neural activity in immature, prefunctioning sensory systems a general phenomenon? Such patterning has been found in the prenatal visual and somatosensory systems. We have now identified patterning in the immature auditory system of a prehearing mammal, the tammar wallaby. Neurones recorded in vivo from the eighth nerve and cochlear nucleus at pouch days 94-122 discharged in bursts with rhythmic inter-spike intervals. Our findings are applied to the argument that neural activity is vital to sensory development.
Deprivation of afferent input in young animals results in transneuronal degeneration of postsynaptic sensory neurons in a variety of species and sensory pathways. Transneuronal degeneration is generally not seen in adult animals. The cellular and molecular basis for this dramatic developmental change in susceptibility is not understood. One possibility is that genes involved in the apoptotic process are involved in determining cell death or survival after afferent deprivation. To further investigate this possibility, we performed unilateral cochlear ablation on wild-type and bcl-2-overexpressing mice at a variety of ages. In postnatal day 5 (P5) or P8 wild-type mice, cochlea removal resulted in a 54% or 31% neuronal loss in the anteroventral cochlear nucleus (AVCN), respectively. When the same manipulation is performed on a P30 mouse, no loss of AVCN neurons occurs. This confirmed a rather abrupt change in the sensitivity to disruption of afferent input, a critical period. However, in littermates expressing bcl-2 under a neuron-specific enolase promoter, no significant loss of AVCN neurons was observed at any age after unilateral cochlear ablation. Furthermore, wild-type mice demonstrate rapid expression of activated caspase-3 in AVCN neurons within hours of deafferentation, whereas bcl-2-overexpressing mice do not. This suggests that bcl-2 can influence cell survival after removal of afferent input during the critical period and is consistent with the hypothesis that caspase-3 is one effector of cell death under these circumstances. These data are the first to indicate that known apoptotic mediators can play a role in central neuronal plasticity in models of afferent deprivation.
CNTF receptor alpha (CNTFRalpha) is involved in the development, the maintenance and the regeneration of a variety of brain structures. However, its in vivo distribution has not been determined in the auditory system. CNTFRalpha expression was studied in developing and adult rat brainstem auditory nuclei using immunohistochemistry. At birth, the CNTFRalpha immunolabeling was clearly present in somata of the external nucleus of the inferior colliculus but was diffuse throughout brainstem auditory nuclei. The labeling was present in most brainstem auditory nuclei by post-natal day (PND) 6. The intensity of the staining subsequently increased to its highest level at PND21 and decreased to an adult-like appearance by the fourth post-natal week. In adult, CNTFRalpha labeling occurred in most neurons of the cochlear nucleus (CN), the lateral superior olive (LSO), the medial superior olive (MSO), and the medial nucleus of the trapezoid body (MNTB). CNTFRalpha labeling first appeared in the central nucleus of the inferior colliculus (IC) by the end of the fourth week. There was a general increase in the expression of CNTFRalpha that begins prior to the onset of hearing and reaches its highest level after this important developmental stage. Ultrastructural analysis in the adult ventral CN revealed the presence of CNTFR in post-synaptic sites. The presence of CNTF has been investigated in the adult using both Western blot and immunohistochemistry. Western blot showed the presence of CNTF in both peripheral and central auditory structures. The CNTF label was generally localized to the somatic compartment, in axons and as puncta surrounding neuronal cell bodies and dendrites. Differential CNTF labeling was observed between the different auditory nuclei. CNTF staining is present in neurons of the CN, the MNTB and the LSO, while it is restricted to axons and puncta surrounding neuronal somata in the IC. The clear presence of CNTFRalpha at post-synaptic terminals and that of its ligand the CNTF in axons and puncta surrounding neuronal cell bodies suggest an anterograde mode of action for CNTF in the central auditory system.
Laser interferometry was used to measure umbo velocity in the developing BALB/c mouse middle ear at 133 pure-tone frequencies between 2.0 kHz and 40.0 kHz, all at a constant 100 dB sound pressure level. Umbo velocities increased with age across the entire frequency range, and reached adult-like levels by about 19 days between 2.0 and 22.0 kHz. Velocities at 28.0 and 34.0 kHz took 27 and 52 days respectively to reach adult-like levels. A simple middle-ear model utilizing compliance, resistance, and inertia elements matched the general trends of our velocity results and provided an indication of the anatomical basis for the growth in umbo velocity. The model suggested that velocity development at the lowest frequencies may be attributed to increases in tympanic membrane compliance. The model also indicated that both the frictional resistance of the middle ear and the inertia of the tympanic membrane and ossicles decreased during the growth period. At frequencies below 20.0 kHz, age-related increases in umbo velocity coincided with improvements in N1 thresholds recorded from the round window and evoked potential thresholds obtained from the cochlear nucleus. These results indicated that the functional development of the middle-ear plays a major role in the development of hearing in the mouse.
Four different illustrative examples of single unit data from the cochlear nucleus of anesthetized cats are presented. The spontaneous activity of each of these four units can be quantitatively described by the histogram of interspike intervals and by other related measurements. Several descriptive models are suggested by these measurements.
Neural prostheses use charge recovery mechanisms to ensure the electrical stimulus is charge balanced. Nucleus cochlear implants short all stimulating electrodes between pulses in order to achieve charge balance, resulting in a small residual direct current (DC). In the present study we sought to characterize the variation of this residual DC with different charge recovery mechanisms, stimulation modes, and stimulation parameters, and by modeling, to gain insight into the underlying mechanisms. In an acute study with anaesthetised guinea pigs, DC was measured in four platinum intracochlear electrodes stimulated using a Nucleus C124M cochlear implant at moderate to high pulse rates (1200-14,500 pulses/s) and stimulus intensities (0.2-1.75 mA at 26-200 microseconds/phase). Both monopolar and bipolar stimulation modes were used, and the effects of shorting or combining a capacitor with shorting for charge recovery were investigated. Residual DC increased as a function of stimulus rate, stimulus intensity, and pulse width. DC was lower for monopolar than bipolar stimulation, and lower still with capacitively coupled monopolar stimulation. Our model suggests that residual DC is a consequence of Faradaic reactions which allow charge to leak through the electrode tissue interface. Such reactions and charge leakage are still present when capacitors are used to achieve charge recovery, but anodic and cathodic reactions are balanced in such a way that the net charge leakage is zero.
Distributions of arg3.1 and c-fos immunoreactive neurons (IRN) in gerbil auditory cortex (AC) and amygdala showed characteristic differences when comparing systemic application of the tinnitus-eliciting drug salicylate with acoustic stimulation or saline injections. In AC, arg3.1 IRN induced by stimulation focused in regions corresponding to the frequency content of the stimulus. Injections of salicylate (350 mg/kg body weight) led to accumulation of arg3.1 IRN in the high frequency domain, while saline injections produced a diffuse distribution. After all treatments, c-fos IRN outnumbered arg3.1 IRN in AC and showed a broad distribution. In subcortical auditory structures arg3.1 IRN were absent in all but one brain. In ventral cochlear nucleus, c-fos IRN were always found after stimulation and often also after saline injections, whereas none were present when injecting salicylate. Similarly, in inferior colliculus, numbers of c-fos IRN were lowest after salicylate injections. In the amygdala, c-fos and arg3.1 IRN were increased substantially after salicylate injections compared to auditory stimulation or saline injections. In particular in its central nucleus, c-fos and arg3.1 IRN were found exclusively after the tinnitus-inducing treatment, suggesting that coactivation of the AC and the amygdala may by an essential feature of tinnitus-related activation.
Voltage-gated potassium channels play an important role in shaping membrane properties that underlie neurons' discharge patterns and the ways in which they transform their input. In the auditory system, low threshold potassium currents such as those created by Kv1.1 subunits contribute to precise phaselocking and to transient onset responses that provide time markers for temporal features of sounds. The purpose of the present study was to compare information about the distribution of neurons expressing the KV 1.1 in the brainstem auditory nuclei with the distribution of neurons with known functional properties in the auditory system of the big brown bat, Eptesicus fuscus. We used immunocytochemistry and light microscopy to look at the distribution of Kv1.1 subunits in the brainstem auditory nuclei. There was prominent expression in cell types known to contain high levels of Kv1.1 in other species and known to respond to auditory signals with high temporal precision. These included octopus cells and spherical bushy cells of the cochlear nucleus and principal neurons of the medial nucleus of the trapezoid body. In addition, we found high levels of Kv1.1 in neurons of the columnar subdivision of the ventral nucleus of the lateral lemniscus and in ventral periolivary cell groups. Neurons with high levels of Kv1.1 were differentially distributed in the intermediate nucleus of the lateral lemniscus and in the inferior colliculus, suggesting that these structures contain functionally distinct cell populations, some of which may be involved in high-precision temporal processing.
This study examined the combined effects of administration of exogenous GM1 ganglioside and electrical stimulation on the cochlear nucleus (CN) of cats deafened neonatally by ototoxic drugs. Five normal hearing adult cats served as controls. Another 12 cats were deafened bilaterally by daily injections of neomycin sulfate (60 mg/kg) for 17-21 days after birth until auditory brainstem testing demonstrated profound hearing loss. Six of the deaf animals comprised the GM1 group, which received daily injections of GM1 ganglioside (30 mg/kg) for 28-38 days during the period after profound deafness was confirmed, and prior to receiving a cochlear implant. The non-GM1 group (n=6) received no treatment during this interim period. All the deafened animals underwent unilateral cochlear implantation at 6-9 weeks postnatal and received several months (mean duration, 32 weeks) of chronic electrical stimulation (4 h/day, 5 days/week). Stimulation was delivered by intracochlear bipolar electrodes, using electrical signals that were designed to be temporally challenging to the central auditory system. Results showed that in the neonatally deafened animals, both the GM1 and non-GM1 groups, the volume of the CN was markedly reduced (to 76% of normal), but there was no difference between the animals that received GM1 and those that did not. The cross sectional areas of spherical cell somata in both GM1 and non-GM1 groups also showed a highly significant reduction in size, to < or =75% of normal after neonatal deafening. Moreover, in both the GM1 and non-GM1 groups, the spherical cells in the CN ipsilateral to the implanted cochlea were significantly larger (6%) than cells in the control, unstimulated CN. Again, however, there was no significant difference between the GM1 group and the non-GM1 group in spherical cell size. These results contrast sharply with previous reports that exogenous GM1 prevents CN degeneration after neonatal conductive hearing loss and partially prevents spiral ganglion cell degeneration when administered immediately after ototoxic drug deafening in adult animals. Taken together, findings to date suggest that GM1 may be effective in preventing degeneration only if the GM1 is administered immediately at the time hearing loss occurs.
In young adult guinea pigs, the effects of unilateral ossicle removal and cochlear ablation were determined on transmitter release from glutamatergic presynaptic endings and glutamate inactivation via uptake. (i) D-[3H]Aspartate release and uptake were measured in subdivisions of the cochlear nucleus (CN) and in nuclei of the superior olive (SOC) and auditory midbrain (MB) up to 145 days after placing the lesions. Activities were compared to those from age-matched unlesioned controls. Fiber degeneration was visualized histologically. (ii) In the ipsilateral CN, changes in release and uptake were governed by the type of lesion. Ossicle removal produced sparse pruning of fibers only after 112 days and decreased release and uptake at 145 days, consistent with regulatory weakening of excitatory glutamatergic transmission. Cochlear ablation deafferented the CN, producing deficient release and uptake at 2 days and abundant fiber degeneration at 7 days. Subsequently, the residual release and uptake increased in magnitude, consistent with strengthening of excitatory glutamatergic transmission. (iii) In the contralateral CN, after either lesion, changes in release and uptake usually matched those in the ipsilateral CN. Thus, the auditory pathway associated with the lesioned ear probably provided cues for the regulation of synaptic strength in the contralateral CN. (iv) Both lesions increased release in the SOC and MB, and uptake in the SOC, consistent with strengthening of excitatory glutamatergic transmission. Sparse fiber degeneration, suggesting axonal pruning, appeared in the SOC and MB after cochlear ablation. (v) The strengthening of excitatory glutamatergic transmission may facilitate and maintain symptoms such as loudness recruitment and tinnitus which often accompany hearing loss.
Recordings were made from single afferent fibers in the inferior vestibular nerve, which innervates the saccule and posterior semicircular canal. A substantial portion of the fibers with irregular background activity increased their firing in response to moderately intense clicks and tones. In responsive fibers, acoustic clicks evoked action potentials with minimum latencies of < or = 1.0 msec. Fibers fell into two classes, with the shortest latency either to condensation clicks (PUSH fibers) or to rarefaction clicks (PULL fibers). Low-frequency (800 Hz) tone bursts at moderately high sound levels (> 80 dB SPL) caused synchronization of spikes to preferred phases of the tone cycle. PUSH and PULL fibers had preferred response phases approximately 180 degrees apart. These two response classes are consistent with fibers that innervate hair cells having opposite morphological polarizations, an arrangement found in the saccule. With low-frequency tone bursts, sound levels of > or = 90 dB SPL evoked increases in mean spike rate. Spike rates increased monotonically with sound level without saturating at levels < or = 115 dB SPL. Contraction of the middle-ear muscles decreased responses to sound, consistent with the sound transmission path being through the middle ear. Several fibers were labeled with biocytin and traced. All labeled fibers had bipolar cell bodies in the inferior vestibular ganglion with peripheral processes extending toward the saccular nerve and central processes in the vestibular nerve. Two fibers were traced to the saccular epithelium. One fiber was traced centrally and arborized extensively in vestibular nuclei and a region ventromedial to the cochlear nucleus. Our results confirm and extend previous suggestions that the mammalian saccule responds to sound at frequencies and levels within the normal range of human hearing. We suggest a number of auditory roles that these fibers may play in the everyday life of mammals.
Despite the peripheral and central immaturities that limit auditory processing in juvenile animals, they are able to lateralize sounds using binaural cues. This study explores a central mechanism that may compensate for these limitations during development. Interaural time and level difference processing by neurons in the superior olivary complex depends on synaptic inhibition from the medial nucleus of the trapezoid body (MNTB), a group of inhibitory neurons that is activated by contralateral sound stimuli. In this study, we examined the maturation of coding properties of MNTB neurons and found that they receive an inhibitory influence from the ipsilateral ear that is modified during the course of postnatal development. Single neuron recordings were obtained from the MNTB in juvenile (postnatal day 15-19) and adult gerbils. Approximately 50% of all recorded MNTB neurons were inhibited by ipsilateral sound stimuli, but juvenile neurons displayed a much greater suppression of firing as compared with those in adults. A comparison of the prepotential and postsynaptic action potential indicated that inhibition occurred at the presynaptic level, likely within the cochlear nucleus. A simple linear model of level difference detection by lateral superior olivary neurons that receive input from MNTB suggested that inhibition of the MNTB may expand the response of LSO neurons to physiologically realistic level differences, particularly in juvenile animals, at a time when these cues are reduced.
The cochlear mechanics of bats with long constant-frequency components in their echolocation calls are sharply tuned to the dominant second harmonic constant frequency. Hipposiderid bats employ a shorter constant-frequency call component whose frequency is less stable than in long-constant-frequency bats. To investigate to what degree cochlear mechanics in hipposiderid bats are already specialized for the processing of constant frequencies, we recorded distortion-product otoacoustic emissions in Hipposideros lankadiva. Iso-distortion threshold curves for the 2f1-f2 distortion-product otoacoustic emission reveal a threshold maximum close to the second harmonic constant frequency, between 65.0 and 70.0 kHz, and a second insensitivity close to the first harmonic constant frequency. The group delay of the 2f1-f2 distortion is prolonged for both frequency ranges, indicating that a specialized cochlear resonance may act to absorb the constant-frequency call components. Compared to long-constant-frequency bats, the threshold maximum at the second harmonic constant frequency is less pronounced and the optimum cochlear frequency separation is larger. Distortion-product otoacoustic emission suppression tuning curves and neuronal tuning curves recorded from neurons in the cochlear nucleus display an increase of tuning sharpness close to the second harmonic constant-frequency range which is smaller than that reported for long-constant-frequency bats. Our data suggest that the cochlea of hipposiderid bats represents an intermediate state between that of non-specialized bats and long-constant-frequency bats.
To develop the BALB/c mouse strain as an animal model for the study of progressive sensorineural hearing loss, mice ranging in age from young adult through middle age were studied. Auditory brainstem response thresholds, histopathology [cytocochleograms for hair cells, the packing density of spiral ganglion cells (SGCs), the number of neurons and overall size of the anterior ventral cochlear nucleus (AVCN)], and behavioral paradigms (prepulse inhibition, fear-potentiated startle) were compared with previous data from C57BL/6J (C57) and DBA/2J (DBA) mouse strains. Progressive high frequency hearing loss in BALB/c mice was generally more rapid than C57 and slower than DBA (e.g. mean thresholds for 16 kHz: 10-month-old BALB/c mice = 71 dB SPL; 55-day-old DBA mice = 79 dB SPL; 12-month-old C57 mice = 50 dB SPL). Like the other strains, BALB/c exhibited a progressive loss of hair cells and SGCs that was most severe in the cochlear base and least severe in the middle turns; however, BALB/c mice had relatively more SGC loss in the apex. Unlike C57 and DBA, no loss of neurons was observed in the AVCN following cochlear pathology (although AVCN volume was reduced). Like the other strains, successful fear conditioning was obtained with a 12 kHz conditioned stimulus. Prepulse inhibition showed that middle and low frequency tones (4-12 kHz) became more salient as high frequency hearing declined. Similar results had been previously obtained with C57 and DBA mice and were interpreted as reflecting hearing-loss-induced plasticity in the central auditory system.