HAL Id: jpa-00230568
https://hal.archives-ouvertes.fr/jpa-00230568
Submitted on 1 Jan 1990
HAL is a multi-disciplinary open access archive for the deposit and dissemination of sci- entific research documents, whether they are pub- lished or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.
L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
NEUROBIOLOGY OF THE COCHLEA
R. Pujol
To cite this version:
R. Pujol. NEUROBIOLOGY OF THE COCHLEA. Journal de Physique Colloques, 1990, 51 (C2),
pp.C2-99-C2-105. �10.1051/jphyscol:1990224�. �jpa-00230568�
COLLOQUE DE PHYSIQUE
Colloque C2, suppl6ment au n02, Tome 51, FQvrier 1990 ler Congrgs F r a n ~ a i s d'lcoustique 1990
NEUROBIOLOGY OF THE COCHLEA
R. PUJOL
INSERM U.254 et Universit6 de Montpellier 11, Laboratoire de
Neurobiologie de llAudition, Hapita1 St. Charles, F-34059 Montpellier Cedex, France
Resume
-
Notre conception de la physiologie cochleaire a profondement evolue au cours de ces dix dernieres annees. Deux domaines de la neurobiologie de cet organe sensoriel ont ete particulierement concernes par cette evolution des connaissances : 1)-le role contractile joue par l'un des deux types de mecanorecepteurs, les cellules ciliees externes; 2)-l'identification des principales substances neuroactives de la cochlee. Le but d e la presente revue est de replacer ces nouvelles donnees dans un schema global et reactualise de la physiologie et de la physiopathologie cochleaires.Abstract - The two major advances in the knowledge of cochlear physiology during the last decade have been: I)-the discovery of the contractile properties of outer hair cells (OHCs), one of the two types of mechanoreceptors; and 2)-the identification of most of the neuroactive substances in the cochlea. The aim of this paper is to take into account these new findings in order to give an updated summary of cochlear physiology and pathophysiology.
I
-
INTRODUCTIONThe organ of Corti, the neurosensory part of the cochlea, contains two types of hair cells, namely the inner hair cells (IHCs) and the outer hair cells (OHCs), which are precisely adapted for mechanoreception: i.e., the transduction of the vibration of the cochlear partition into a bioelectrical signal. In the human cochlea, there are more or less 3,500 IHCs regularly arranged in one row along the cochlear spiral, and more than 12,000 OHCs arranged in three, sometimes (at the apex) four rows. The neural connections of the IHCs and OHCs are quite distinct (see /I/). IHCs are linked to the majority of the 30,000 auditory nerve fibers (radial afferents) which carry the auditory messages out to the brain. In addition these IHCs receive and indirect feed back control by means of the lateral efferent system. OHCs, on the other hand, directly receive signals from the brain by means of the medial efferent system. They are also connected to the brain by means of the spiral afferents which form about 5% of the auditory nerve; the type of message (probably not auditory in the strict sense of the word) they carry out to the brain is still unknown. Figure 1 summarizes the neural connections of both IHCs and OHCs which dramatically divides the organ of Corti into two separate sensory-neural systems; the main putative neuro-active substances (see below) are also indicated.
Article published online by EDP Sciences and available at http://dx.doi.org/10.1051/jphyscol:1990224
COLLOQUE DE PHYSIQUE
R.A. [E. S: A. M.E.
Fig. 1
-
Neural connections of an inner hair cell (I) and an outer hair cell ( 0 ) at the base of the cochlea. The IHC is synaptically connected with all radial afferents (RA);the synapse could well be glutamatergic (GLU). The lateral efferents (LE) coming from the ipsilateral brain stem, synapse on the radial afferents; putative neurotransmitters are: acetylcholine (ACh), gamma aminobutyric acid (GABA), dopamine (DA), enkephalins (Enk), calcitonin gene related peptide (CGRP), dynorphins (DYN). The OHC is connected to the spiral afferents (SA) (unknown neurotransmitter). The medial efferents (ME) coming mainly from the controlateral brain stem synapse on the OHC, putative co-transmitters are ACh and CGRP.
Before going into more details of the IHC and OHC neurobiology, let us schematize the overall functioning of the organ of Corti (fig. 2). A sound vibration is transmitted to the cochlear partition (step 1) with a basic tonotopy (as described by Bekesy): i.e., with a maximal vibration which gradually affects a more apical region as the sound frequency decreases. However, if transmitted directly to the auditory nerve this basic tonotopy is far away from what is needed for a good frequency discrimination. A mechanism for enhancing the frequency selectivity of the, cochlear receptor is obviously required, as we know that messages in the auditory nerve are indeed sharply tuned.
Such a mechanism is provided by the OHCs which, due to the attachment of their cilia to the tectorial membrane, are excited first by the vibration: when the cochlear partition moves up, the tectorial membrane displaces OHC cilia in the excitative direction (step 2). Excited OHCs are depolarized (this is a classical mechano-electro transduction process), the changes in the OHC membrane potentials are transferred into
longitudinal forces (because of the specific morphology and position of these cells), this atypical electro-mechano transduction process results in the contraction of the OHCs (step 3). It is a fast motilility (calcium- and ATP-independent) which follows the frequency of the stimulus and induces, within a very restricted zone of the cochlea, an amplification of the vibration. This active mechanism gives the cochlea its exquisite properties of sensitivity and frequency selectivity: in the very restricted zone where it occurs, a small number of IHCs (sometimes even a single IHC) are excited (step 4).
This excitation depolarizes the IHC and a sharply tuned bio-electrical signal is sent to the brain (step 5). When OHCs are missing or damaged (in most traumatic conditions, they are damaged first!) the active mechanism is lost and a far more intense (of about 50 dB) vibration is needed to directly excite the IHCs: to jump from step 1 to step 4.
Worse, as only the basic tonotopy is preserved, the sharp frequency selectivity is also lost and the signal sent to the brain is too poorly tuned to allow a good frequency discrimination. Having in mind this scheme of the distinct functions of both IHCs and OHCs, we can now concentrate more precisely on their distinct neurobiology.
Fig. 2
-
Schematic representation of the overall functioning of the organ of Corti. I:inner hair cell; 0: outer hair cells; MB: basilar membrane; MT: tectorial membrane. The different arrows 1 to 5 refer to the steps described in the text. 1: vibration of the cochlear partition; 2: sharring motion of the TM on the OHC cilia (excitation of OHCs); 3: fast motility in OHCs (active mechanism); 4: displacement of the IHC cilia (excitation of the IHC); 5: firing in the auditory fiber.
COLLOQUE DE PHYSIQUE
2
-
NEUROBIOLOGY O F INNER HAIR CELLSAs seen above, the IHCs constitute the real sensory receptor elements of the cochlea.
They are able to react to vibration by sending an auditory message to the brain. It is worthwhile to recall the main steps of their neorobiological function.
2.1
-
Mechano-electro transduction at the IHC aoical ooleWhen their cilia are bent in the direction of the lateral wall, the IHC is excited.
This is due to an opening of ion channels located at the top of the small cilia; it is an opening which is purely mechanical, depending on the special attachment of the different sized cilia. Because of its higher concentration in the endolymph, K+ flows into the cell and induces membrane depolarization / 2 / .
2.2
-
Neural transnlission at the IHC basal fsvnaotic) ooleThe morphology of synapses between the IHCs and the radial afferents, endings of the type I ganglion cells, clearly indicates that they belong to neurochemical type (see / I / and fig. 1). Within the IHC, on the presynaptic side, a ring of small and clear microvesicles is seen around a dense synaptic body. The best candidate for neurotransmission in this synapse is glutamate (see /3/): this has physiological as well as pathophysiological implications.
Actually, glutamate is considered to be an excellent neurotransmitter in the central nervous system when a fast excitation is needed, which, incidently, is the situation one would expect in the cochlea. On the other hand, glutamate is known to become neurotoxic when excessively released, as it can occur either after overstimulation or damage of the glutamatergic neuron, following ischemia or anoxia /4/. A glutamatergic synapse, to be safe, should be provided with an efficient mechanism of removal of the neurotransmitter from the synaptic cleft: as seems to be the case in the cochlea /3/, this is obtained by glial recycling of glutamate into glutamine. But when glutamate is released in excess, such a mechanism is not strong enough and neurotoxic processes affect the postsynaptic targets. This neurotoxicity is first characterized by a swelling of nerve endings, then a degeneration of glutamoceptive neurons / 5 / . Indeed, in the cochlea, the exposure to kainic acid, a glutamate analog, results in an acute swelling of radial afferent dendrites connected to IHCs /6/; later on, a loss of type I spiral ganglion neurons is observed. It is also striking to compare the acute damage that occurs in various conditions such as anoxia or acoustic trauma, with damage obtained in the kainic acid experiments. In all cases, the same type of immediate swelling probably linked to glutamate excitotoxicity is observed (see /7/).
The glutamate neurotoxicity is now taken into account in the CNS to explain some of the degenerative processes occuring in aging /8/. The increase with age of vascular problems such as local ischemia, could damage glutamatergic neurons, causing an excess release of glutamate and neurotoxicity in the surrounding (glutamoceptive) neurons.
This could also be a valuable working hypothesis in some forms of presbyacusis. In the aged cochlea, a loss of ganglion neurons has been observed to accompany IHC loss, particularly in the basal regions /9/. Similarly, in cochleas of the same age, a spiral vessel atrophy more severe in the basal area is observed / l o / Johnsson, 1973). Thus, basal IHCs are affected first by local anoxic conditions; this, in turn, may lead to a glutamate dependent toxicity and to the degeneration of corresponding type I spiral ganglion neurons.
2.3
-
Efferent modulation at the IHC levelBelow the IHCs, in the area called the inner spiral plexus, the auditory dendrites leaving the hair cell are synaptically connected (fig. 2) to the endings of the lateral efferent neurons (localized within the ipsilateral superior olive: see /]I/). The main characteristic of these efferent synapses is their chemical heterogeneity /1,3/. Evidence exists for at least six types of neurotransmitters in these synapses: acetylcholine, GABA, dopamine, and different neuropeptides such as enkephalins, CGRP, or dynorphins. Even if some co-localization is probable, this heterogeneity explains why the real function of the lateral efferents is not clear yet. In other words, one should not question what the lateral efferent system is doing, but what a subpopulation using this, or these, neuroactive substances is doing. Pharmacological experiments using separately different putative neurotransmitters may soon prove to be useful in this respect.
Indeed, this has recently been done with enkephalins, which seem to be used more in noisy conditions, probably to reduce the firing in the auditory nerve (see /3/).
3 - NEUROBIOLOGY O F OUTER HAIR CELLS
As seen i n the introduction, the OHCs are not considered any more as conventional mechanoreceptors. Apart from the fact that they are excited in the same way as the IHCs, they react to auditory stimulation in a completely different manner. Before describing the different steps of this physiology, one should recall what was some years ago the most intriguing feature of the neurosensory organization of the cochlea: OHCs are connected to the brain by means of the spiral afferents (see /I/), which are the dendrites of the type I1 spiral ganglion neurons. Nobody has ever recorded an auditory message in these fibers!
3.1 - Mechano-electro transduction at the OHC aoical ole
Similarly, as occurs in the IHCs, the bio-electrical stimulation of the OHCs is driven by a mechanical opening of ion channels at the top of cilia, with K+ (playing the role of a charge carrier) depolarizing the cell. The only diference in this mechano- electrotransduction process depends on the specific attachment of the tallest OHC cilia to the tectorial membrane, which increases the relative sensitivity of these receptors.
Because of the shearing motion of the tectorial membrane, OHCs can be excited at a level of vibration which is, by itself, unable to move IHC cilia.
3.2
-
Fast motilitv of OHCs felectro-mechano transduction)The demonstration, in in vitro preparations, that OHCs could contract or elongate depending on changes in their membrane potential represents one of the major steps in the understanding of modern cochlear physiology /12/ Brownell, 1984). In fact, an active mechanism enhancing and filtering the vibration, already modelled in 1948 /13/ became obvious when oto-acoustic emissions were discovered /14/.
Moreover, this active mechanism had to take place before the sensory-neural transduction at the IHC level, since in normal conditions the basilar membrane /15,16/,
COLLOQUE DE PHYSIQUE
as well as the IHCs /17/ are perfectly tuned.
The exact mechanism of the fast motility of the OHCs is still not completely understood. However, this type of contraction, Caz+- and ATP-independent, which can follow the stimulus frequency is supposed to be electro-osmotic /12/ or electro- restrictive /IS/. In either case, the transfer of charges through the plasma membrane of the excited OHC results in longitudinal forces, because of a very special arrangment of internal membranes: the laminated cisternae. As the OHC is firmly coupled to the basilar membrane, by means of supporting cells, and with the tectorial membrane, by means of its tallest cilia, its contraction may change the vibration of the cochlear partition. Incidently, the fast OHC motility is also responsible for the oto-acoustic emissions; thus by recording evoked oto-acoustic emissions /14/ one gets a direct idea of the OHC function.
3.3
-
Efferent confrol o f OHCs ( s l o w motilifvlThe motile properties of the OHCs are not limited to the fast intrinsic process just described above. A "muscular" type, linked to Caz+ and contractile proteins /19/, has also been evidenced in vitro /20/. In vivo this slow motility is probably dependent on the activity of the medial efferent system: formed by neurons from the controlateral medial trapezoid body /11/, whose endings synapse directly with the OHCs. The neurotransmission there is cholinergic although a neuropeptide, CGRP, has also been found in these synapses. Acetylcholine, possibly through second messengers like inositol trisphosphate, mediates a slow OHC motility which results in a modification of the fast response and consequently in a reduction of the active mechanism. Among data supporting this idea let us recall that oto-acoustic emissions are reduced by activating the medial efferents /21,22/.
4 - CONCLUSIONS
After having briefly rewieved the main events which have drastically affected our knowledge of the cochlear neurobiology, it is possible in conclusion to predict the trends in this field for the near future.
First, different obscure explanations or even "black boxes" have been already pointed out. Thus, it would be of great value to know the role of the spiral system: i.e., to know about what type of message the OHC is sending to the brain. Two hypotheses are curently worked on: either the spiral afferents inform the CNS about the OHC motility, or they only play a (protective?) role in conditions of intense loud stimulation.
Similarly, the demonstration of what exactly occurs in vivo at the level of OHC would be very important to exactly understand what is called the active mechanism: i.e., how an OHC contraction, or elongation, may change so profoundly and so sharply the vibration of the cochlear partition. Other major steps will probably be made by means of research into the biochemistry and pharmacology of the neurotransmitters. We have already mentioned that the understanding of the lateral efferents would benefit from specific neuropharmacological approaches. There, some clinical applications could also follow, especially in the domain of preventing neuronal loss particularly if the neurotoxic glutamate hypothesis proves to be true; or in curing some types of peripheral tinnitus: those possibly due to a deregulation of the glutamatergic synapses, or to an imbalance of the efferent inhibition of the auditory fibers.
A second type of prediction can be proposed. It is based on the fact that what has been described in this rewiev does not correspond to the function of the whole cochlea, but to the function of the cochlea for high- or mid-frequency coding. The concept of a
"basal" cochlea, working as described above, and of an "apical" cochlea, working for low frequencies, is more and more taken into account (see 3). During the past decade most of the efforts have been concentrated on the former. The apical cochlea with much less, if any, active mechanisms has now to be investigated seriously. A way to solve this problem is a comparative approach: for example the bat cochlea on the one hand, and the mole cochlea on the other hand could be valuable and natural models of
"basal" and "apical" cochleas respectively.
REFERENCES
Only some key references have been given in the text. A complete list may be found in a recent rewiev by the author: PUJOL, R., Arch. Int. Physiol. Bioch. 97-4 (1989) A51.
/1/ PUJOL, R. and LENOIR, M., In: Neurobiology of Hearing: The Cochlea, Raven Press (1986) pp. 161-172.
/2/ HUDSPETH, A.J., Hear. Res. 2 (1986) 21.
/3/ EYBALIN, M. and PUJOL, R., Arch. Oto-Rhino-Laryngol. 246 (1989) 228 /4/ MAYER, M.L. and WESTBROOK, G.L. TINS
10
(1987) 59/5/ CHOI, D.W., TINS
11
(1988) 465/6/ PUJOL, R., LENOIR, M., ROBERTSON, D., EYBALIN, M. and JOHNSTONE, B.M., Hear: Res.
18
(1985) 145/7/ PUJOL, R., REBILLARD, G., LENOIR, M., EYBALIN, M. and RECASENS, M., Acta Otolaryngol. (Stockh.) in press (1990)
/8/ MARAGOS, W.F., GREENAMYRE, J.T., PENNEY, J.B. Jr. and YOUNG, A.B., TINS JQ (1987) 65
/9/ SPOENDLIN, H. and SCHROTT, A., Acta Otolaryngol. (Stockh.)
105
(1988) 403 / l o / JOHNSSON, L.-G., Adv. Oto-Rhino-Laryngol. 20 (1973) 197/11/ WARR, W.B., GUINAN, J.J. Jr. and WHITE, J.S., In: Neurobiology of Hearing:
The Cochlea, Raven Press (1986) pp. 333-348
/12/ BROWNELL, W.E., Scan. Electr. Microsc.
I11
(1984) 1401 /13/ GOLD, T., Proc. R. Soc. London B135
(1948) 492 /14/ KEMP, D.T., J. Acoust. Soc. Am.64
(1978) 1386/15/ SELLICK, P.M., PATUZZI, R. and JOHNSTONE, B.M., J. Acoust. Soc. Am.
2
(1982) 131
/16/ KHANNA, S.M. and LEONARD, D.G.B., Science 215 (1982) 305 /17/ RUSSELL, I.J. and SELLICK, P.M., J. Physiol. London 284 (1978) 261 /IS/ ASHMORE,J.F., J. Physiol. London
388
(1987) 323/19/ FLOCK, A., FLOCK, B. and ULFENDAHL, M., Arch. Otorhinolaryngol. 243 (1986) 83
/20/ ZENNER, H.-P., ZIMMERMANN, U. and SCHMITT, U., Hear. Res.
18
(1985) 127/21/-MOUNTAIN, D.C., Science 210 (1980) 71
/22/ PUEL, J.-L., REBILLARD, G. and PUJOL, R., Advances in Audiology, (1990) in press
