Cells Of Dorsal Cochlear Nucleus Research Articles

Descending Axonal Projections from the Inferior Colliculus Target Nearly All Excitatory and Inhibitory Cell Types of the Dorsal Cochlear Nucleus.

The dorsal cochlear nucleus (DCN) integrates auditory nerve input with nonauditory sensory signals and is proposed to function in sound source localization and suppression of self-generated sounds. The DCN also integrates activity from descending auditory pathways, including a particularly large feedback projection from the inferior colliculus (IC), the main ascending target of the DCN. Understanding how these descending feedback signals are integrated into the DCN circuit and what role they play in hearing requires knowing the targeted DCN cell types and their postsynaptic responses. In order to explore these questions, neurons in the DCN that received descending synaptic input from the IC were labeled with a trans-synaptic viral approach in male and female mice, which allowed them to be targeted for whole-cell recording in acute brain slices. We tested their synaptic responses to optogenetic activation of the descending IC projection. Every cell type in the granule cell domain received monosynaptic, glutamatergic input from the IC, indicating that this region, considered an integrator of nonauditory sensory inputs, processes auditory input as well and may have complex and underappreciated roles in hearing. Additionally, we found that DCN cell types outside the granule cell regions also receive descending IC signals, including the principal projection neurons, as well as the neurons that inhibit them, leading to a circuit that may sharpen tuning through feedback excitation and lateral inhibition.SIGNIFICANCE STATEMENT Auditory processing starts in the cochlea and ascends through the dorsal cochlear nucleus (DCN) to the inferior colliculus (IC) and beyond. Here, we investigated the feedback projection from IC to DCN, whose synaptic targets and roles in auditory processing are unclear. We found that all cell types in the granule cell regions, which process multisensory feedback, also process this descending auditory feedback. Surprisingly, all except one cell type in the entire DCN receive IC input. The IC-DCN projection may therefore modulate the multisensory pathway as well as sharpen tuning and gate auditory signals that are sent to downstream areas. This excitatory feedback loop from DCN to IC and back to DCN could underlie hyperexcitability in DCN, widely considered an etiology of tinnitus.

Chemical synaptic transmission onto superficial stellate cells of the mouse dorsal cochlear nucleus

The dorsal cochlear nucleus (DCN) is a cerebellum-like auditory brain stem region whose functions include sound localization and multisensory integration. Although previous in vivo studies have shown that glycinergic and GABAergic inhibition regulate the activity of several DCN cell types in response to sensory stimuli, data regarding the synaptic inputs onto DCN inhibitory interneurons remain limited. Using acute DCN slices from mice, we examined the properties of excitatory and inhibitory synapses onto the superficial stellate cell, a poorly understood cell type that provides inhibition to DCN output neurons (fusiform cells) as well as to local inhibitory interneurons (cartwheel cells). Excitatory synapses onto stellate cells activated both NMDA receptors and fast-gating, Ca(2+)-permeable AMPA receptors. Inhibition onto superficial stellate cells was mediated by glycine and GABAA receptors with different temporal kinetics. Paired recordings revealed that superficial stellate cells make reciprocal synapses and autapses, with a connection probability of ∼ 18-20%. Unexpectedly, superficial stellate cells co-released both glycine and GABA, suggesting that co-transmission may play a role in fine-tuning the duration of inhibitory transmission.

Tonotopic organization of vertical cells in the dorsal cochlear nucleus of the CBA/J mouse

The systematic and topographic representation of frequency is a first principle of organization throughout the auditory system. The dorsal cochlear nucleus (DCN) receives direct tonotopic projections from the auditory nerve (AN) as well as secondary and descending projections from other sources. Among the recipients of AN input in the DCN are vertical cells (also called tuberculoventral cells), glycinergic interneurons thought to provide on- or near-best-frequency feed-forward inhibition to principal cells in the DCN and various cells in the anteroventral cochlear nucleus (AVCN). Differing lines of physiological and anatomical evidence suggest that vertical cells and their projections are organized with respect to frequency, but this has not been conclusively demonstrated in the intact mammalian brain. To address this issue, we retrogradely labeled vertical cells via physiologically targeted injections in the AVCN of the CBA/J mouse. Results from multiple cases were merged with a normalized 3D template of the cochlear nucleus (Muniak et al. [2013] J. Comp. Neurol. 521:1510-1532) to demonstrate quantitatively that the arrangement of vertical cells is tonotopic and aligned to the innervation pattern of the AN. These results suggest that vertical cells are well positioned for providing immediate, frequency-specific inhibition onto cells of the DCN and AVCN to facilitate spectral processing.

Computational model of response maps in the dorsal cochlear nucleus

The neurons in the mammalian (gerbil, cat) dorsal cochlear nucleus (DCN) have responses to tones and noise that have been used to classify them into unit types. These types (I-V) are based on excitatory and inhibitory responses to tones organized into plots called response maps (RMs). Type I units show purely excitatory responses, while type V units are primarily inhibited. A computational model of the neural circuitry of the mammalian DCN, based on the MacGregor neuromime, was used to investigate RMs of the principal cells (P-cells) that represent the fusiform and giant cells. In gerbils, fusiform cells have been shown to have primarily type III unit response properties; however, fusiform cells in the cat DCN are thought to have type IV unit response properties. The DCN model is based on a previous computational model of the cat (Hancock and Voigt Ann Biomed Eng 27: 73-87, 1999) and gerbil (Zheng and Voigt Ann Biomed Eng 34: 697-708, 2006) DCN. The basic model for both species is architecturally the same, and to get either type III unit RMs or type IV unit RMs, connection parameters were adjusted. Interestingly, regardless of the RM type, these units in gerbils and cats show spectral notch sensitivity and are thought to play a role in sound localization in the median plane. In this study, further parameter adjustments were made to systematically explore their effect on P-cell RMs. Significantly, type I, type III, type III-i, type IV, type IV-T and type V unit RMs can be created for the modeled P-cells. Thus major RMs observed in the cat and gerbil DCN are recreated by the model. These results suggest that RMs of individual DCN projection neurons are the result of specific assortment of excitatory and inhibitory inputs to that neuron and that subtle differences in the complement of inputs can result in different RM types. Modulation of the efficacy of certain synapses suggests that RM type may change dynamically.

Differentiation of simple spike waveforms in the hamster dorsal cochlear nucleus

The dorsal cochlear nucleus (DCN) consists of many cell types with different morphologies and properties. DCN cells belonging to different morphological classes are distinguished by differences in their physiological characteristics such as their spectral and temporal response patterns, their levels of spontaneous activity, and certain biophysical properties. Recent studies suggest that they may also exhibit different action potentials, such as simple and complex spikes. In the present study, we systematically examined the spike waveforms of spontaneously active DCN neurons using extracellular recording methods. Neurons were found to exhibit simple spikes consisting of trains of individual action potentials. Spikes fell into two discrete groups of opposite polarity, those with M-shaped and those with W-shaped waveforms. The shapes of these waveforms recorded from a given unit remained constant, despite large changes in amplitude that occurred as the electrode was moved along its axis of penetration. A quantitative analysis of the fine details of the waveforms demonstrated that, although the durations of W- and M-shaped spikes exhibited considerable variation, the variants within each category fell along a continuous gradient rather than into discrete subgroups. Both M- and W-shaped waveforms were found predominantly in the fusiform cell and deep layers, with smaller numbers found in the dorsal acoustic stria. Consideration of their depths of occurrence, their response properties, and levels of spontaneous activity of the recorded neurons suggests that W-shaped waveforms probably are associated with fusiform cells, whereas M-shaped spikes likely originate from more than one cell type.

Fluorescent labeling of rat auditory brainstem circuits for synaptic and electrophysiological studies

We visualized neurons with fluorescent agents, both retrogradely and anterogradely, to identify the input and output neuronal pathways in the rat auditory system. Output neurons of dorsal cochlear nucleus (DCN) were labeled retrogradely by injecting fluorescent microspheres into the inferior colliculus. Electrical recordings were made from the labeled fusiform cells of DCN with the whole-cell patch-clamp recording technique in slice preparations. DiI and Sindbis virus expressing membrane-targeted green fluorescent protein (GFP) were adopted for anterograde labeling. Auditory nerve fibers (ANFs) were labeled by injecting DiI into the cochlea, and the contralateral projection to the medial nucleus of the trapezoid body (MNTB) by injecting DiI and GFP into the ventral cochlear nucleus. A single ANF projecting to a DCN fusiform cell was electrically stimulated by a glass electrode and EPSCs were recorded using whole-cell patch-clamp recording methods. EPSCs were sensitive to the positioning of the electrode, and the size of EPSCs was constant irrespective of stimulus intensity, indicating that a single fiber was stimulated. Large EPSCs were generated from MNTB principal cells by stimulating the labeled fiber with a Calyx of Held terminal. The membrane excitability and EPSCs recorded after fluorescence labeling were similar to those previously reported. We confirm that the fluorescence labeling is effective to visualize neural networks and is useful to investigate the electrophysiological properties of neurons and synapses.

Multisensory integration in the dorsal cochlear nucleus: unit responses to acoustic and trigeminal ganglion stimulation

A necessary requirement for multisensory integration is the convergence of pathways from different senses. The dorsal cochlear nucleus (DCN) receives auditory input directly via the VIIIth nerve and somatosensory input indirectly from the Vth nerve via granule cells. Multisensory integration may occur in DCN cells that receive both trigeminal and auditory nerve input, such as the fusiform cell. We investigated trigeminal system influences on guinea pig DCN cells by stimulating the trigeminal ganglion while recording spontaneous and sound-driven activity from DCN neurons. A bipolar stimulating electrode was placed into the trigeminal ganglion of anesthetized guinea pigs using stereotaxic co-ordinates. Electrical stimuli were applied as bipolar pulses (100 micros per phase) with amplitudes ranging from 10 to 100 microA. Responses from DCN units were obtained using a 16-channel, four-shank electrode. Current pulses were presented alone or preceding 100- or 200-ms broadband noise (BBN) bursts. Thirty percent of DCN units showed either excitatory, inhibitory or excitatory-inhibitory responses to trigeminal ganglion stimulation. When paired with BBN stimulation, trigeminal stimulation suppressed or facilitated the firing rate in response to BBN in 78% of units, reflecting multisensory integration. Pulses preceding the acoustic stimuli by as much as 95 ms were able to alter responses to BBN. Bimodal suppression may play a role in attenuating body-generated sounds, such as vocalization or respiration, whereas bimodal enhancement may serve to direct attention in low signal-to-noise environments.

Intracellularly labeled fusiform cells in dorsal cochlear nucleus of the gerbil. I. Physiological response properties.

Fusiform cells in the dorsal cochlear nucleus (DCN) of barbiturate-anesthetized Mongolian gerbils were characterized physiologically and labeled with neurobiotin. This report is based on 17 fusiform cells for which there was reasonable confidence in the association between physiological data and recovered anatomy. The qualitative morphology of these cells was no different from that reported in previous studies. The acoustic response properties were generally consistent with those described in the barbiturate-anesthetized cat. Most responses were of the pauser or buildup type, but a dependence on stimulus frequency and intensity was observed. Stimulus-evoked sustained depolarizations and large, long-lasting afterhyperpolarizations were common membrane potential features. The cells in this study showed a greater tendency to discharge regularly than did those of the cat, likely as a result of the longer interstimulus interval used. Barbiturate anesthesia appears to mask an interspecies difference in DCN physiology that is apparent in unanesthetized, decerebrate preparations. The response of these fusiform cells to a depolarizing current pulse could be altered by the presence of a hyperpolarizing prepulse. Buildup, pauser, and chopper patterns could each be created using appropriate combinations of hyperpolarizing and depolarizing pulse amplitudes. Thus the adult gerbil appears to express the inactivating potassium conductance previously shown to affect fusiform cell firing patterns in vitro. The results further demonstrate that the effects of these potassium currents are readily observed in vivo. Finally, the fusiform cells in this study were quite variable with respect to a number of response properties, including the resting potential, input resistance, spontaneous activity, relative noise index, normalized tone slope, and regularity histogram shape. This diversity likely results from cell-to-cell variations in the balance of activity within the relatively complex network to which the fusiform cells belong, although effects of impalement may contribute to the extent of the diversity.

Pharmacological evidence of inhibitory and disinhibitory neuronal circuits in dorsal cochlear nucleus.

The dorsal cochlear nucleus (DCN) is rich in both glycine and GABA inhibitory neurotransmitter systems, and the response properties of its principal cells (pyramidal and giant cells) are strongly shaped by inhibitory inputs. For example, DCN principal cells often display highly nonmonotonic (so-called type IV) input-output functions in response to best-frequency (BF) tones. In this study, the inhibitory inputs onto the principal cell types and onto response types of known inhibitory interneurons were compared before and during iontophoretic application of the glycine- and GABA(A)-receptor antagonists, strychnine and bicuculline. Strychnine eliminates the central (on-BF) inhibitory area in type IV units, resulting in monotonic BF rate-level curves. Unexpectedly, bicuculline primarily enhances inhibition in principal-cell types; for example, type IV units are inhibited at lower sound levels in the presence of bicuculline. Principal cell types with weaker inhibitory inputs (type IV-T and type III units) are more strongly inhibited in the presence of bicuculline and usually are converted into type IV units. This enhancement of on-BF inhibition by bicuculline suggests a disinhibitory process involving GABA(A) action on a non-GABA(A)ergic inhibitory pathway. This latter pathway is probably glycinergic and involves type II units (deep-layer vertical cells) and/or complex-spiking units (superficial cartwheel cells) because both of these unit types are disinhibited by bicuculline. One intrinsic GABA(A) source could be the superficial stellate cells in DCN because bicuculline partly blocks the inhibition evoked by somatosensory-stimulated activation of the superficial granule-cell circuitry in DCN. Taken together, the results suggest that glycinergic circuits mediate directly the inhibition of DCN principal cells, but that GABA(A)ergic circuits modulate the strength of the inhibition.

Acoustic and current-pulse responses of identified neurons in the dorsal cochlear nucleus of unanesthetized, decerebrate gerbils.

In an effort to establish relationships between cell physiology and morphology in the dorsal cochlear nucleus (DCN), intracellular single-unit recording and marking experiments were conducted on decerebrate gerbils using horseradish peroxidase (HRP)- or neurobiotin-filled micropipettes. Intracellular responses to acoustic (tone and broadband noise bursts) and electric current-pulse stimuli were recorded and associated with cell morphology. Units were classified according to the response map scheme (type I to type V). Results from 19 identified neurons, including 13 fusiform cells, 2 giant cells, and 4 cartwheel cells, reveal correlations between cell morphology of these neurons and their acoustic responses. Most fusiform cells (8/13) are associated with type III unit response properties. A subset of fusiform cells was type I/III units (2), type III-i units (2), and a type IV-T unit. The giant cells were associated with type IV-i unit response properties. Cartwheel cells all had weak acoustic responses that were difficult to classify. Some measures of membrane properties also were correlated with cell morphology but to a lesser degree. Giant cells and all but one fusiform cell fired only simple action potentials (APs), whereas all cartwheel cells discharged complex APs. Giant and fusiform cells all had monotonic rate versus current level curves, whereas cartwheel cells had nonmonotonic curves. This implies that inhibitory acoustic responses, resulting in nonmonotonic rate versus sound level curves, are due to local inhibitory interactions rather than strictly to membrane properties. A complex-spiking fusiform cell with type III unit properties suggests that cartwheel cells are not the only complex-spiking cells in DCN. The diverse response properties of the DCN's fusiform cells suggests that they are very sensitive to the specific complement of excitatory and inhibitory inputs they receive.

Spatial organization of the reciprocal connections between the cat dorsal and anteroventral cochlear nuclei

We are studying the interconnections between the anteroventral cochlear nucleus (AVCN) and the dorsal cochlear nucleus (DCN). Biotinylated dextran was injected into the DCN, where the best frequency of responses was also recorded. Ventrotubercular neurons in AVCN were labeled, along with cochlear nerve fibers and the axons of cells in DCN. In AVCN, a central band of labeled cochlear nerve axons and large endbulbs was labeled. Bordering this band was a `fringe' of smaller tuberculoventral axonal endings forming pericellular nests. Most AVCN neurons projecting to DCN were stellate, elongate, or giant cells, located in the posterior division of AVCN, regardless of the DCN injection site. About 75% of the labeled AVCN cells lay within the bands of labeled cochlear nerve fibers. Another 15% were in the outer fringes on either side of these bands, while 10% were outside the bands and the fringes. These findings suggest that most AVCN neurons projecting to the DCN conform to the tonotopic map. A significant portion of the ventrotubercular neurons occupy side-bands in AVCN. Reciprocally, the tuberculoventral tract forms a robust fringe of axonal endings flanking the central bands. The neuronal and axonal bands and side-bands may underlie excitatory and inhibitory signal transformations.

Postnatal development of GABA- and glycine-like immunoreactivity in the cochlear nucleus of the Mongolian gerbil (Meriones unguiculatus).

The maturation of the morphological substrate for inhibitory interactions was investigated in the cochlear nucleus of the gerbil with immunocytochemistry for gamma aminobutyric acid (GABA) and glycine on alternating vibratome sections. The patterns of immunostaining obtained with both antibodies in the adult closely conformed to the general mammalian scheme. Qualitative analyses revealed an age-related increase in staining intensity and in the relative numbers of immunolabelled cells after birth up to the age of 3-4 weeks. As early as birth and in all subdivisions of the cochlear nucleus, a few labelled cells and puncta in the sections were stained either with the GABA or the glycine antibody. Immunoreactive puncta and cells were, however, far less abundant than in the adult, and the staining intensity of cells was only weak. The most strikingly GABA-immunolabelled cells at birth were the Golgi cells of the granule-cell domains. The numbers of weakly GABA- and glycine-immunostained cells of the dorsal cochlear nucleus clearly increased between birth and the third postnatal week. At approximately the onset of hearing (postnatal day 12-14), some cells of the dorsal cochlear nucleus and small cells of the ventral cochlear nucleus gained adult-like GABA-staining properties. Almost adult-like labelling intensity was observed in glycine-immunoreactive cells of the deep dorsal cochlear nucleus and in some small cells of the ventral cochlear nucleus. Puncta staining to both antibodies appeared adult-like throughout the cochlear nucleus. About 2 weeks after the onset of hearing (at the latest), adult-like staining of all subsets of immunoreactive cells occurred throughout the cochlear nucleus in all specimens.

Differences between guinea pig and rat in the dorsal cochlear nucleus: expression of calcium-binding proteins by cartwheel and Purkinje-like cells

This study describes differences between guinea pig and rat in the immunoreactivities for calbindin (CB-IR) and parvalbumin (PV-IR) in cartwheel (CWC) and Purkinje-like (PLC) cells of the dorsal cochlear nucleus (DCN). CWCs are the most important inhibitory interneurons of the DCN. Their soma and dendrites stain intensely for CB-IR in guinea pigs but only weakly and incompletely in rats. In both species, the CWCs do not show PV-IR. PLCs, a rare type of DCN cells often interpreted as displaced cerebellar Purkinje cells misrouted during migration, are known from rat and mouse and are here described for guinea pig DCN. PLCs are intensely and completely stained for CB-IR and PV-IR in guinea pigs. In rats, they stain with similar completeness only for CB-IR, PV-IR being weak and restricted to the cell's soma. Similar staining differences between the two species are seen with the cerebellar Purkinje cells, i.e., PLCs resemble the cerebellar Purkinje cells more than do the CWCs. Based on the present material (and preliminary findings in a primate (marmoset)), we speculate that the PLCs have their place in the circuitry of the DCN receiving input via parallel fibers, like the CWCs, and possibly projecting their axon onto the cerebellum.

The c-Fos transcription factor in the auditory pathway of the juvenile rat: effects of acoustic deprivation and repetitive stimulation

The expression of the inducible transcription factors (ITF) c-Fos and JunB was investigated in the dorsal cochlear nucleus (DCN), ventral cochlear nucleus (VCN) and inferior colliculus (IC) of juvenile and adult rats following deprivation and repetitive stimulation paradigms using 8 kHz tone bursts at 5 min duration and 70 dB, 90 dB or 120 dB sound pressure level (SPL). (1) During postnatal development without stimulation, c-Fos is absent in DCN and VCN from postnatal day (P) 12 to adulthood, but shows a strong expression in the IC which declines during maturation. A similar decrease was also seen in the pons. (2) Between P15 and P35 stimulation of rats with 8 kHz for 5 min at 70 dB SPL evoked expression of c-Fos in a moderate number of cells of DCN, VCN and IC. Higher sound pressure levels increased the number of c-Fos immunoreactive neurons as studied at P21. (3) Deprivation of acoustic stimulation up to P21 reduced the expression of c-Fos when rats were stimulated with 90 dB immediately after the restoration of acoustic input. In contrast to 90 dB SPL, c-Fos immunoreactivity (IR) did not significantly differ between deprived and normal rats following application of 120 dB SPL at P21. Stimulation at P28, i.e., 7 days after the end of the deprivation, evoked an increase of c-Fos only in the IC compared to otherwise normally stimulated rats. At P35, effects of the former deprivation on the c-Fos expression were not longer detectable. (4) In a repetitive stimulation paradigm, 8 kHz tone bursts 5 min in duration were applied each second day between P23 and P35 or each day between P29 and P35. When compared with acutely stimulated rats at P35, both repetitive acoustic stimulation protocols reduced the c-Fos immunoreactivity by 50%–75% in the DCN, VCN and IC. In adult 4-month-old rats, repetitive stimulation did not reduce the c-Fos immunoreactivity from its moderate levels as compared with acute stimulation. (5) In some experiments, we studied also the expression of the JunB protein. JunB paralleled the expression of c-Fos following single acoustic stimulation, but was expressed in a substantially lower number of cells. In contrast to c-Fos, however, repetitive stimulation as described in section 4 did not evoke a decrease of JunB in the lower acoustic pathway. © 1997 Elsevier Science B.V. All rights reserved.

Effects of somatosensory and parallel-fiber stimulation on neurons in dorsal cochlear nucleus.

1. Single units and evoked potentials were recorded in the dorsal cochlear nucleus (DCN) of paralyzed decerebrate cats in response to electrical stimulation at two sites: 1) in the somatosensory dorsal column nuclei (together called MSN below for medullary somatosensory nuclei), which activates mossy-fiber inputs to granule cells in superficial DCN, and 2) on the free surface of the DCN, which activates granule cell axons (parallel fibers) directly. The goal was to evaluate hypotheses about synaptic interactions in the cerebellum-like circuitry of the superficial DCN. A four-pulse facilitation paradigm was used (50-ms interpulse interval); this allows identification of three components of the responses of DCN principal cells (type IV units) to these stimuli. The latencies of the response components were compared with the latency of the evoked potential in DCN, which signals the arrival of the parallel fiber volley at the recording site. 2. The first component is a short-latency inhibitory response; this component is seen only with MSN stimulation and is seen almost exclusively in units also showing the second component, the transient excitatory response. The short-latency inhibitory component precedes the evoked potential. No satisfactory explanation for the short-latency component can be given at present; it most likely reflects a fast-conducting inhibitory input that arrives at the type IV unit before the slowly conducting parallel fibers. 3. The second component is a transient excitatory response; this component is seen with both MSN and parallel fiber stimulation; it is weak and appears to be masked easily by the inhibitory response components. The excitatory component occurs at the same latency as the evoked potential and probably reflects direct excitation of principal cells by granule cell axons. The excitatory component is seen in about half the type IV units for both stimulating sites. With MSN stimulation, the lack of excitation in some units suggests a heterogeneity of cochlear granule cells, with some carrying somatosensory information and some not carrying this information; with parallel fiber stimulation, excitation probably requires the stimulating and recording electrodes to be lined up on the same "beam" of parallel fibers. 4. The third component is a long-lasting inhibitory response that is observed in virtually all type IV units with both MSN and parallel-fiber stimulation; its latency is longer than the evoked potential. Evidence suggests that it is produced by inhibitory input from cartwheel cells. The appearance of this inhibitory component in almost all type IV units can be accounted for by the considerable spread of cartwheel-cell axons in the direction perpendicular to the parallel fibers. 5. The evoked potential and all three components of the unit response vary systematically in size over the four pulses of the electrical stimulus. These results can be accounted for by two phenomena: 1) a facilitation of the granule cell synapses on all cell types that produces a steadily growing response through the four pulses, resembles presynaptic facilitation, and is seen with both MSN and parallel-fiber stimulation; and 2) a strong reduction in the granule cell response between the first and second pulse for MSN stimulation only. This reduction probably occurs presynaptically in the glomerulus or in the granule cell itself and could reflect inhibitory inputs. 6. The response components described above are seen in type IV units recorded in both the fusiform-cell and deep layers of the DCN; this suggests that both pyramidal and giant cells are activated similarly. The simplest interpretation is that both principal cell types are activated by the cerebellum-like circuitry in superficial DCN. Alternatively, because giant cells appear to make limited contact with the granule-cell circuits of superficial DCN, this finding may suggest the existence of currently undescribed granule cell circuits in deep DCN that are si

Morphological changes in the cochlear nucleus of congenitally deaf white cats

Investigations in animal models and humans have indicated that congenital deafness produces degenerative changes in the central auditory pathway. The cochlear nucleus is the first central structure that receives cochlear input, and may be considered the origin of ascending auditory pathways. In this context, we studied congenitally deaf white cats, who express early onset cochlear receptor loss, in order to assess the nature of structural changes in cells of the cochlear nucleus. It is conceivable that pathologic alterations in higher auditory structures are transneuronally distributed through this nucleus. The cochlear nuclei of nonwhite cats with normal hearing were compared to those of deaf white cats exhibiting hearing loss in excess of 70 dB SPL. The cochlear nuclei of the deaf white cats were smaller in volume by roughly 50%, with the ventral and dorsal divisions being equally affected. Cell body silhouette area was determined for spherical bushy cells of the anteroventral cochlear nucleus (AVCN), pyramidal cells of the dorsal cochlear nucleus (DCN), sensory neurons from the principal trigeminal nucleus, and motoneurons of the facial nucleus. We found no statistical difference in neuronal cell body size between nonauditory neurons of these two groups of cats, whereas auditory neurons of deaf white cats were 30.8–39.4% smaller than those of normal cats. These data imply that neuronal changes in congenitally deaf cats are specific to the auditory pathway. Although cochlear nucleus volume loss was uniform for both divisions, there was a differential effect on cell density: AVCN cell density increased by 40%, whereas DCN cell density was relatively unaffected (10% increase). Astrocyte density was also greater in the AVCN (52%) compared to that in the DCN (5%). These observations reveal a differential impact on cells in the cochlear nucleus to congenital deafness, suggesting selective processing impairment at this level. If similar patterns of degeneration occur in humans, such pathologies may underlie reduced processing of input from cochlear implants in congenitally deaf adults.

N-methyl-D-aspartate receptors at parallel fiber synapses in the dorsal cochlear nucleus.

1. N-methyl-D-aspartate (NMDA) binding and NMDA-receptors immunolocalization experiments have revealed an enhanced expression of these receptors in the outer two layers of the dorsal cochlear nucleus (DCN). The distribution of the receptors is congruent with the distribution of synapses produced by the granule cell-parallel fiber system. To determine the functional distribution and contribution of NMDA receptors at parallel fiber synapses, synaptic responses to parallel fiber stimulation were studied in in vitro brain slice preparations of the guinea pig and rat dorsal cochlear nucleus. 2. The field potential response to parallel fiber stimulation in guinea pigs includes three postsynaptic components. The short latency components (the P3(2) and N2(2)) are blocked by general excitatory receptor antagonists, including the non-NMDA-receptor blockers 6,7-dinitroquinoxaline-2,3-dione (DNQX) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), but are insensitive to NMDA-receptor antagonists. 3. A slower component (P4(2)) is revealed when the slices are washed with a low magnesium solution to eliminate the magnesium block of currents through NMDA receptors. This slow component is reduced by D- or DL-2-amino-5-phosphonovaleric acid (D-APV, DL-APV) and 3-[(+/-)-2-carboxypiperazine-4-yl] propyl-1-phosphonate, but is not blocked by DNQX or CNQX. Eliminating the voltage dependence of the NMDA receptors also results in a complex oscillatory response in some slices. This response exhibits the same pharmacological sensitivity as the slow potential. The pharmacologic sensitivity to NMDA-receptor antagonists suggest that the slow component (P4(2)) and the associated oscillatory response are mediated through activation of NMDA receptors. 4. Current source-density analysis of the parallel fiber-evoked field potentials was carried out to determine the relative spatial distributions of the fast and slow synaptic currents. Both synaptic components were associated with a superficial current sink and a deeper current source, localized within the superficial 250 microM of the nucleus. The slow (APV-sensitive) current was slightly shifted in depth relative to the fast (DNQX-sensitive) current in three of five slices with the maximum current sink and source occurring approximately 16 microns further from the surface of the DCN. These data suggest that either the NMDA receptors are not present at all of the synapses that generate the fast non-NMDA currents or that postsynaptic cells with different dendritic distributions have different densities of NMDA receptors. 5. The types of cells in layers 1 and 2 exhibiting NMDA-receptor-mediated synaptic potentials were investigated. Intracellular recordings with sharp electrodes in guinea pig slices showed that eliminating the voltage dependence of the NMDA receptors in low magnesium revealed a slow excitatory postsynaptic potential (EPSP) in both simple and complex spiking cells. The late phase of the EPSP could be reduced by APV in both cell types. These results could be explained by NMDA receptors on the postsynaptic cells or by NMDA receptors on excitatory interneurons. Attempts to demonstrate an appropriate voltage dependence of the parallel fiber synaptic response in normal magnesium medium under current clamp were confounded by the intrinsic voltage-dependent conductances of the cells. 6. To determine whether NMDA receptors were present on postsynaptic cells, the direct sensitivity of DCN cells to NMDA application was examined during intracellular recording. Both simple spiking and complex spiking cells responded to NMDA with depolarization. The response to NMDA persisted when non-NMDA receptors were blocked with CNQX or DNQX. However in all cells tested, the response to NMDA was blocked by APV. These experiments further support the postsynaptic localization of NMDA receptors on both simple and complex spiking cells. (ABSTRACT TRUNCATED)

A computational model for signal processing by the dorsal cochlear nucleus. I. Responses to pure tones

Much information is available on the anatomical organization and neurophysiological properties of the major cell types in the dorsal cochlear nucleus (DCN). The complicated response properties of individual cells and units in the DCN indicate that substantial information processing already occurs at the level of the DCN. A large number of connectional hypotheses have been put forward to explain various aspects of the response characteristics of DCN cells, but many of the consequences of these hypotheses have not been investigated quantitatively. In this paper, we investigate these hypotheses by constructing and testing mathematical and computational models and compare our results to those of previous modeling studies. The simplest versions of our models include auditory nerve (AN) fibers, type II cells (inhibitory interneurons) and type IV cells (fusiform and giant cells). The model response maps, i.e., the pattern of output of model type IV cells, generated by the simplest model have some but not all the features of the experimental response maps of type IV neurons. In particular, the excitatory region which occurs at best frequency is not isolated and the excitatory region at low frequencies and high amplitude is narrower than observed. Since experimental evidence exists that some of the connections between these cell types are divergent or convergent across adjacent isofrequency sheets, the effect of such convergence and divergence was then investigated. Response maps so obtained reproduce many of the qualitative features of the experimental maps. Enlargement of the model by including inhibitory interneurons (e.g., stellate cells) that receive convergent input from AN fibers and which inhibit type II cells results in the generation of response maps that, with some variations in connectional patterns and physiological properties of neurons, match most of the essential features seen in the large variety of experimental maps obtained from the cat DCN.

Morphology and physiology of cells in slice preparations of the dorsal cochlear nucleus of mice.

Horseradish peroxidase (HRP) was injected into cells from which intracellular recordings were made in slices of the dorsal cochlear nucleus (DCN) in order to correlate physiology with morphology. In general, the morphology of cells labeled intracellularly with HRP corresponded to those made with Golgi impregnations in mice and other mammals. The following cells were labeled: one granule cell, four cartwheel cells, eight fusiform cells, two other cells in the fusiform cell layer, and two tuberculoventral association cells in the deep layers of the DCN. The axon of the granule cell runs parallel to isofrequency laminae with collaterals branching perpendicularly and running along the tonotopic axis. The cartwheel cells have dendrites in the molecular layer that are densely covered with spines. The axon of one cell terminates just dorsally to the cell body. Fusiform cells have the characteristic spiny, apical and smooth, basal dendrites. The basal dendrites are conspicuously oriented parallel to isofrequency laminae. Axons of the fusiform cells exit through the dorsal acoustic stria without branching. The two tuberculoventral association cells in the deep DCN have axons that terminate both in the deep DCN, within the same isofrequency lamina that contains the cell body, and in the ventral cochlear nucleus (VCN). Intracellular recordings from 11 of these cells show that they cannot be distinguished on the basis of their responses to intracellularly injected current. All cell types fired large action potentials that were followed by a fast and a slower undershoot, distinguishing them from cells of the VCN but not from one another. Most cells responded to shocks of the auditory nerve root with early EPSPs and later IPSPs. The latencies of EPSPs show that some were monosynaptic and others polysynaptic. That there was no systematic relationship between the latencies of EPSPs and the cell types from which they were recorded shows that shocks to the nerve root may have activated more than just the large, myelinated, auditory nerve fibers.

Inhibitory connections between AVCN and DCN: Evidence from lidocaine injection in AVCN

Principal cells of the dorsal cochlear nucleus (DCN) receive a variety of inhibitory influences, including some that are associated with the anteroventral cochlear nucleus (AVCN). Electrical stimulation in the caudal part of the AVCN produces long-lasting inhibition of DCN units [(1973) Exp. Brain Res. 17, 4287ndash;442], including unit type IV, which is associated with principal cells. This inhibition may be mediated either by orthodromic activation of AVCN axons that terminate in DCN or by antidromic stimulation of DCN inhibitory interneurons whose axons send collaterals to the AVCN. These two possibilities cannot be distinguished with electrical stimulation alone. In this study, microinjections of lidocaine were made in the AVCN. These injections should block AVCN to DCN axons without directly affecting the activity, within the DCN, of DCN interneurons. Two effects of lidocaine injections were observed. In some cases, all activity of DCN cells was abolished by lidocaine. These cases involved either spread of lidocaine to the recording site or into the auditory nerve. In other cases, the inhibitory responses of DCN type IV units were weakened by lidocaine without changing the units' thresholds or spontaneous activity. The latter result demonstrates that there are inhibitory pathways originating in AVCN or passing through AVCN and terminating in the DCN.