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Encoding the timing of inhibitory inputs.

Many neuronal systems represent information by the timing of individual spikes, and it is generally assumed that spike timing predominantly encodes excitatory inputs. We show here that the timing of inhibition can also be explicitly encoded in spike times using time-dependent and voltage-dependent properties of a rapidly inactivating potassium channel (I(KIF)). In vitro recordings in rat dorsal cochlear nucleus show that the effects of inhibition on spike timing can long outlast the duration of the inhibitory potential and that this depends only on the membrane voltage change during the inhibitory postsynaptic potential. Modeling results show that small neuronal populations with a heterogeneous distribution of I(KIF) voltage dependence can robustly encode intervals of >100 ms between inhibition and excitation. Thus neuronal systems can detect and represent the precise timing of inhibition, suggesting the importance of inhibition in information encoding.

Action Potentials↗

Metabolic effects of blocking tone conditioning on the rat auditory system.

The Kamin blocking phenomenon occurs when behavioral expression of conditioning to a novel stimulus fails in the presence of a previously conditioned stimulus (CS). Neural metabolic effects of a tone conditioned as an excitor were compared to the effects of the same physical tone when excitatory conditioning was blocked by previous conditioning with a light. We examined the metabolic activity of the auditory system to test the hypothesis that auditory processing of a tone CS changes during blocking. Quantitative histochemistry of cytochrome oxidase (C.O.), the final mitochondrial enzyme for oxidative metabolism, was used to evaluate cumulative changes in the metabolic capacity of the auditory system resulting from blocking. Rats (Long-Evans) in the Blocking group received pairings of a light CS with a mild footshock unconditioned stimulus (US) during Phase 1 training. Rats in the Control group received random presentations of the same stimuli during Phase 1. Both groups then received the same Phase 2 training consisting of simultaneous tone and light presentations paired with footshock. The Control group exhibited significant suppression of drinking to tone alone presentations after training, whereas the Blocking group did not. Metabolic mapping results demonstrated that blocking effects were localized to auditory regions receiving direct US somatosensory projections. Significantly greater C.O. activity in the inferior colliculus and the dorsal cochlear nucleus was found for the Blocking group relative to the Control group. Input cell layers of secondary auditory cortex also demonstrated a group difference, in that layers II/III and IV had lower levels of C.O. activity in the Blocking group. These specific changes in C.O. activity linked to behavioral training demonstrated that the blocking phenomenon produced distinct neural metabolic changes in CS processing in the auditory system localized to regions with CS-US interactions.

Animals↗

Anatomophysiology of the central auditory nervous system: basic concepts.

The purpose of this review is to provide an overview of the central auditory nervous system (CANS). Three main relay nuclei are located between the auditory nerve and the primary auditory cerebral cortex: 1- the cochlear nucleus, 2- the contralateral inferior colliculus and 3- the contralateral medial geniculate body. Some fibers of this main ascending pathway branch off to other nuclei such as the nuclei of the superior olivary complex and the nucleus of the lateral lemniscus. Fiber tracts connect the two sides of the ascending pathway at several levels, in such a manner that each ear projects heavier to the contralateral temporal cortex. As sensory information travels within the CANS, its processing occurs not only in a serial order but also in a parallel manner resulting a highly efficient and redundant system. Finally, this review put forth a model of central auditory processing that can serve as the basis for evaluating and addressing the needs of eventual revalidation.

Auditory Cortex↗

Using genetic algorithms to find the most effective stimulus for sensory neurons.

Genetic algorithms (GAs) can be used to find maxima in large search spaces in a relatively short period of time. We have used GAs in electrophysiological experiments to find the most effective stimulus (MES) for sensory neurons in the cochlear nucleus and inferior colliculus of anaesthetised guinea pigs. The MES is the stimulus that elicits the greatest number of spikes from a unit. We show that GAs provide an effective means of determining the best combination of up to four parameters for sinusoids with amplitude modulation. Using GAs, we have found tuning to modulation frequencies as a function of carrier frequency, sound level and temporal asymmetry. These results demonstrate the suitability of GAs in electrophysical experiments for estimating the position of the most effective stimulus in a specified parameter space.

Acoustic Stimulation↗

Glutamate receptors are selectively targeted to postsynaptic sites in neurons.

The objective of the present study was to determine if a neuron that expresses multiple glutamate receptors targets the same receptors to all glutamatergic postsynaptic populations, or if the receptors are differentially targeted to specific postsynaptic populations. As a model for this study, we chose the fusiform cell of the dorsal cochlear nucleus. This neuron expresses multiple glutamate receptors and receives two distinct glutamatergic inputs: parallel fibers synapse on apical dendrites, and auditory nerve fibers synapse on basal dendrites. Pre- and postembedding immunocytochemistry were combined with retrograde tracing to identify the receptors expressed on postsynaptic membranes of parallel fiber and auditory nerve synapses. Most receptors were found at both populations of synapses, but the AMPA receptor subunit, GluR4, and the metabotropic receptor, mGluR1 alpha, were found only at the auditory nerve synapse. These results demonstrate that glutamate receptors are targeted to specific postsynaptic populations of glutamatergic synapses.

Animals↗

Effects of prolonged exposure to an augmented acoustic environment on the auditory system of middle-aged C57BL/6J mice: cochlear and central histology and sex differences.

Genetic progressive sensorineural hearing loss in mice of the C57BL/6J (B6) inbred strain begins at high frequencies during young adulthood and is severe by 12 months (middle age). Nightly treatment with an augmented acoustic environment (AAE)--12-hour periods of exposure to repetitive noise bursts of moderate intensity, begun at age 25 days--resulted in less severe hearing loss compared with control mice. Cochlear histopathological correlates of AAE treatment, assessed at 12-14 months of age, included lessened severity of progressive loss of outer hair cells in both sexes as well as small savings of spiral ganglion cells in females and inner hair cells in males. AAE effects on the number of surviving neurons (age 12-14 months) in the anterior ventral cochlear nucleus (AVCN) depended on sex. Compared with controls, the loss of AVCN neurons that typically accompanies the initial period of hearing loss (between 2 and 7 months of age) was not significantly affected by AAE treatment in females. In contrast, males treated with the AAE exhibited more severe loss of neurons in the dorsal and ventral extremes of the AVCN than male controls of the same age. AAE treatment begun at age 3-5 months resulted in significant but less severe loss of AVCN neurons in 1-year-old male mice.

Acoustic Stimulation↗

Protein kinase A and calcium/calmodulin-dependent protein kinase II regulate glycine and GABA release in auditory brain stem nuclei.

We reported previously that unilateral cochlear ablation (UCA) in young adult guinea pigs induced protein kinase C (PKC)-dependent plastic changes in the electrically evoked release of exogenous [14C]glycine ([14C]Gly) or [14C]-gamma-aminobutyric acid ([14C]GABA) in several brain stem auditory nuclei. The present study assessed whether such changes depended on protein kinase A (PKA) and calcium/calmodulin-dependent protein kinase II (CaMKII). In the major subdivisions of the cochlear nucleus (CN) and the main nuclei of the superior olivary complex (SOC) dissected from intact animals, dibutyryl-cyclic adenosine monophosphate (DBcAMP) (0.2 mM), a PKA activator, elevated release by 1.6-2.3-fold. The PKA inhibitor, H-89 (2 microM), did not alter the release but blocked the stimulatory effects of DBcAMP. These findings suggested that PKA could positively regulate glycinergic and GABAergic release. After UCA, PKA regulation declined and failed in the ventral CN but persisted in the SOC nuclei. After 145 postablation days, H-89 reversed elevations of [14C]GABA release in the medial nucleus of the trapezoid body (MNTB). A CaMKII inhibitor, KN-93, reversed depressions of [14C]Gly release in the DCN. Thus, the postablation plasticities in these nuclei probably depended on PKA or CaMKII. Both H-89 and KN-93 depressed [14C]Gly release in the lateral superior olive (LSO) and ipsilateral medial superior olive (MSO), suggesting that either kinase was used by endogenous mechanisms in these nuclei to upregulate glycinergic release. In contrast, KN-93 elevated [14C]GABA release in the contralateral MNTB, suggesting a downregulatory action of CaMKII, an action opposite to that of PKA.

Animals↗

A characterization of the effects on neuronal excitability due to prolonged microstimulation with chronically implanted microelectrodes.

Localized, long-lasting stimulation-induced depression of neuronal excitability (SIDNE) is a consequence of prolonged, high-frequency microstimulation in the central nervous system (CNS). It represents a persisting refractory state in the neurons and axons near the stimulating microelectrode, that occurs in the absence of histologically detectable tissue injury. It does not involve a change in synaptic efficacy and, in this respect, it differs from the more familiar phenomenon of long-term depression (LTD). Although SIDNE is ultimately reversible (after several days), it must be taken into account in the design of neural prostheses based on microstimulation in the central nervous system and in animal studies that require prolonged microstimulation in the CNS. In this study, we have characterized the phenomenon, using as the paradigm, iridium microelectrodes implanted chronically in the cat's posteroventral cochlear nucleus. Although the SIDNE may persist for several days after the end of the stimulation protocol, it does not become more severe from day to day when the stimulation protocol is repeated on successive days. The severity of the SIDNE is strongly dependent upon both the instantaneous frequency and the duty cycle of the electrical stimulation. The character of the SIDNE, including its localization to the immediate vicinity of the stimulating microelectrodes, suggests that the phenomenon is a direct consequence of the prolonged electrical excitation of the neurons close to the microelectrode. The problem of designing microstimulation systems that allow high-frequency stimulation of a neural substrate, while minimizing SIDNE are discussed.

Animals↗

Ultrastructural analysis of primary endings in deaf white cats: morphologic alterations in endbulbs of Held.

Changes in structure and function of the auditory system can be produced by experimentally manipulating the sensory environment, and especially dramatic effects result from deprivation procedures. An alternative deprivation strategy utilizes naturally occurring lesions. The congenitally deaf white cat represents an animal model of sensory deprivation because it mimics a form of human deafness called the Scheibe deformity and permits studies of how central neurons react to early-onset cochlear degeneration. We studied the synaptic characteristics of the endbulb of Held, a prominent auditory nerve terminal in the cochlear nucleus. Endbulbs arise from the ascending branch of the auditory nerve fiber and contact the cell body of spherical bushy cells. After 6 months, endbulbs of deaf white cats exhibit alterations in structure that are clearly distinguishable from those of normal hearing cats, including a diminution in terminal branching, a reduction in synaptic vesicle density, structural abnormalities in mitochondria, thickening of the pre- and postsynaptic densities, and enlargement of synapse size. The hypertrophied membrane densities are suggestive of a compensatory response to diminished transmitter release. These data reveal that early-onset, long-term deafness produces unambiguous alterations in synaptic structure and may be relevant to rehabilitation strategies that promote aural/oral communication.

Animals↗

Deafness induced cell size changes in rostral AVCN of the guinea pig.

The right cochleae of 250-350 g guinea pigs were lesioned by topical administration of neomycin in the middle ear cavity. Eight weeks after the lesion, the cochleae and cochlear nuclei were analyzed. Cochlear hair cell loss was assessed, and cell areas of spherical bushy cells in the rostral anteroventral cochlear nucleus (AVCN) were compared between the lesioned and normal hearing sides for each animal. In five animals with both inner and outer hair cell loss in the lesioned cochlea, the average area of neuronal somata in the rostral AVCN in the lesioned side was 22% smaller than the average area of these cells in the normal hearing side. In two animals with outer hair cell loss but inner hair cells remaining, there was no difference in cell size between the lesioned and non-lesioned AVCN. These results provide evidence that there is significant shrinkage in AVCN cell size in the mature mammal after hearing loss associated with inner hair cell loss.

Analysis of Variance↗

Expression of NMDA, AMPA and GABA(A) receptor subunit mRNAs in the rat auditory brainstem. II. Influence of intracochlear electrical stimulation.

We investigated the effects of intracochlear electrical stimulation (ICES) on auditory pathways of neonatal rat deafened by daily amikacin injections. Expression of mRNAs encoding ionotropic glutamate receptor subunits such as alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) and N-methyl-D-aspartate (NMDA), and gamma-aminobutyric acid type A (GABA(A)) receptor subunits was assessed by in situ hybridization in the dorsal (DCN) and the ventral cochlear nucleus (VCN) and in the central nucleus of the inferior colliculus (CNIC). After 15 days of daily unilateral ICES, the expressions of NR1, NR2b and NR2c subunits of NMDA receptor, that of GluRA, B, C, D flop isoforms of AMPA receptor and that of some GABA(A) subunits (alpha1, beta1, gamma1, gamma2) were increased bilaterally in the DCN, VCN and the CNIC. These changes last over a week after stimulation for only NR1 and NR2c. These modifications might be related to long lasting synaptic plasticity of brainstem auditory pathways. As far as analogy to deaf children can be made, early electrical stimulation might be of interest to maintain neuronal networks.

Animals↗

Effects of sound level on fMRI activation in human brainstem, thalamic and cortical centers.

The dependence of fMRI activation on sound level was examined throughout the auditory pathway of normal human listeners using continuous broadband noise, a stimulus widely used in neuroscientific investigations of auditory processing, but largely neglected in neuro-imaging. Several specialized techniques were combined here for the first time to enhance detection of brainstem activation, mitigate scanner noise, and recover temporal resolution lost by the mitigation technique. The main finding was increased activation with increasing level in cochlear nucleus, superior olive, inferior colliculus, medial geniculate body and auditory cortical areas. We suggest that these increases reflect monotonically increasing activity in a preponderance of individual auditory neurons responsive to broadband noise. While the time-course of activation changed with level, the change was subtle and only significant in a part of the cortex. To our knowledge, these are the first fMRI data showing the effects of sound level in subcortical centers or for a non-tonal, non-speech stimulus at any stage of the pathway. The present results add to the body of parametric data in normal human listeners and are fundamental to the design of any fMRI experiment employing continuous noise.

Acoustic Stimulation↗

Inferior colliculus projections to pontine nuclei in guinea pig.

The present study examined the neural projection from the inferior colliculus to the pontine nuclei in guinea pig. This projection has been reported in other animals, and our goal was to establish the projection in guinea pig, a commonly used auditory model. Ultimately, we wanted to determine if the pontine nuclei could be a component of the descending auditory system from the inferior colliculus to the cochlear nucleus. The anterograde tracer Phaseolus vulgaris leucoagglutinin (PHA-L) was injected into one inferior colliculus of 10 animals and the pontine nuclei examined under a light microscope to detect PHA-L-labeled fibers. PHA-L-labeled fibers were observed in the ipsilateral pontine nuclei in 70% of the animals. While the majority of labeled fibers were smooth in appearance, a few fibers with en passant type varicosities (indicating synapses) were observed in the dorsolateral area of the pontine nuclei, adjacent to the lateral lemniscus. These findings do not support a robust projection from the inferior colliculus to the pontine nuclei in guinea pig. This is in opposition to findings in bat in which the projection may play a major role in modulating responses to sound.

Animals↗

Activity-dependent plasticity in the adult auditory brainstem.

Over the past few years we have studied the plasticity of the adult auditory brainstem in the rat following unilateral changes to the pattern of sensory activation, either by intracochlear electrical stimulation or by deafening. We discovered that modifications to afferent activity induced changes in the molecular composition and cellular morphology throughout the auditory brainstem, including its major centers: the cochlear nucleus complex, the superior olivary complex, and the inferior colliculus. The time window studied ranged from 2 h to over 1 year following induction of changes to afferent activity. The molecular markers employed include the NMDA receptor subunit type 1, the cAMP response element binding protein (CREB), the immediate early gene products c-Fos, c-Jun and Egr-1, the growth and plasticity-associated protein GAP-43 and its mRNA, the calcium binding protein calbindin, the cell adhesion molecule integrin-alpha(1), the microtubule-associated protein MAP-1b, and the neurofilament light chain (NF-L). As a consequence of the specific electrical stimulation of the auditory afferents or the loss of hearing, a cascade of events is triggered that apparently modifies the integrative action and computational abilities of the central auditory system. An attempt is made to relate the diverse phenomena observed to a common molecular signaling network that is suspected to bridge sensory experience to changes in the structure and function of the brain. Eventually, a thorough understanding of these events will be essential for the specific diagnosis of patients, optimal timing for implantation, and suitable parameters for running of a cochlear implant or an auditory brainstem implant in humans. In this report an overview of the results obtained in the past years in our lab is presented, flanked by an introduction into the history of plasticity research and a model proposed for intracellular signal cascades related to activity-dependent plasticity.

Animals↗

Fast inhibition underlies the transmission of auditory information between cochlear nuclei.

A direct commissural connection between cochlear nuclei provides a pathway by which binaural input can influence the processing of acoustic information through the ventral cochlear nucleus. Despite anatomical evidence to suggest the existence of such a pathway, its nature and behavior have not been investigated previously. This in vivo intracellular electrophysiological study provides direct evidence of monosynaptic (mean latency, 1.43 msec), inhibitory commissural input to T stellate cells. This inhibition is fast acting (duration, <10 msec), occurring with little synaptic delay ( approximately 0.3 msec). Electrical stimulation also revealed the initiation of antidromic responses in the onset chopper population, signifying D stellate neurons as a source of commissural inputs. Activation of the commissural connection was most evident in response to broadband stimuli. These results provide the first compelling evidence of a fast, monosynaptic commissural pathway arising from contralateral D stellate neurons providing broadband inhibitory input to T stellate cells.

Acoustic Stimulation↗

NT-3 combined with CNTF promotes survival of neurons in modiolus-spiral ganglion explants.

Auditory neurons depend upon the integrity of both their peripheral (auditory hair cells) and central (cochlear nucleus) targets for survival. One proposed trophic mechanism is the production of neurotrophin-3 (NT-3) by auditory hair cells. Modiolus-spiral ganglion explants from adult rats that closely mirror cell-cell interactions and in vivo tissue relationships within this ganglion provide a model for testing trophic factors. Brain derived neurotrophic factor (BDNF), NT-3 and ciliary neurotrophic factor (CNTF) were tested for their ability, both individually and in combination, to support neuronal survival. NT-3 was the strongest individual promoter of survival, while CNTF (a cytokine) with NT-3 (a neurotrophin) was the most effective combination for promoting the survival of auditory neurons.

Animals↗

Auditory brainstem implantation in primates: lessons for human surgery and application.

We report on the surgical technique for surface electro-auditory prosthesis (EAP) implantation, pathological changes occurring at the cochlear nucleus complex (CNC), and its relation with electrical stimulation. Fourteen Macaca fascicularis were operated upon for a translabyrinthine bilateral auditory neurectomy, and simultaneous unilateral EAP implantation. Six animals were not stimulated, and the remaining eight were connected to an external active device. Stimulation was planned for 1000 hours. Biotolerance to the materials was adequate without significant reactions in the CNC surface, but an ependymal reaction. Lesions attributed to surgical trauma were also found. Two animals being stimulated could not complete the planned course due to cable break or EAP extrusion. One stimulated animal developed an asymptomatic brainstem abscess. A good knowledge of CNC topography is required to avoid surgical trauma. Externally connected devices may facilitate extrusion of the EAP or ascending infections.

Animals↗