Portuguese Version

Year:  2001  Vol. 67   Ed. 5 - (17º)

Artigo de Revisão

Pages: 716 to 720

Auditory system plasticity

Author(s): Maria Cristina L. C. Féres 1,
Norberto G. Cairasco 2

Keywords: auditory system, plasticity, regeneration, audiogenic seizures

The auditory system has been subject of studies that evaluated its capability to develop plastic responses to different kinds of lesions. Regeneration has been observed in the peripheral portions of the system, with neogenesis of the hair cells in avian, sometimes followed by functional rehabilitation as confirmed by electrophysiological testing. The occurrence of central auditory pathway disorders, secondary to peripheral damage, has been frequently noticed, probably due to a plastic reaction to the lack of afferent signal. A great example of these alterations is found in rodents that develop anomalous motor response to loud sounds, secondary to induced partial deafness, named audiogenic seizures. The authors presented a review about the theme.


Sixty years ago, the Spanish anatomist Santiago Ramon y Cajal, Nobel Prize awarded, stated that once you have completed your development, the chances of growth or regeneration of axons and dendrites were irrevocably lost and that the adult brain had fixed and immutable nervous pathways: everything could die and nothing could regenerate. Currently, research studies and findings in neurosciences lead to amore optimistic perspective after the advent of the neuroplasticity theory. According to this theory, nervous cells have a potential capacity to regenerate or differentiate and start performing activities once performed by the damaged cells (Stein et al., 1995).

As to sensorial systems, plasticity may be observed for sensorineural tissue both for peripheral and central pathways. A system that is currently being studied is the auditory system. Different animal species have been submitted to different studies about brain functioning, regeneration and plasticity capacity. Findings have proved that the system may react to situations that disturb its peripheral receptor and there are also regeneration attempts concerning the re-definition of the central nuclei.


Fish and amphibian have a sensorial epithelium that consists of hair and support cells similar to glia, and afferent and efferent nervous endings in the ear and on the "lateral line", which is the organ responsible for the perception of spatial position in animals. Hair cells may be produced throughout the whole life of the animal, repairing losses and increasing sensitivity. Cells produced as a result of regeneration are neo-innervated and have electrophysiological activity. In mammals and avian, this capacity is restricted to the short embryonic period. Anatomic pathological analysis have confirmed that loss of hair cells is present throughout the whole life of the animal, and they may be accelerated or aggravated by factors such as exposure to load noise, toxic drugs, chemotherapy agents, and viral infections (Corwin, 1992). Until recently, it was believed that the loss was irreversible. However, today some therapies are expected to be efficient to promote regeneration, even if partial.

Most of the studies on this hypothesis rely on sensorineural epithelium of chicken ears. Cellular regeneration was observed after acoustic trauma and systemic application of gentamicin (Adler and Raphael, 1996). Recovery may be resultant from mitosis, the onset of new cells, or differentiation of other cellular type into hair cells (Bhave et al., 1995; Adler and Raphael, 1996). Studies in chicken damaged with one single dose of 100mg/Kg gentamicin showed progressive recovery of the number of hair cells, reestablishing the regular cell count of control animals within a five week period (Janas et al., 1995).

It has been wondered if the regenerated cells of the auditory system contribute to the hearing function. Studies in avian have shown restoration of electrophysiological function, despite the temporal delay comparing to structural recovery. The origin of neoformed hair cells seems to be the support cells that involve them or cells that do not distinguish themselves from the support cells under microscopy. It is also believed that the new hair cells, once developed, are permanently specialized in the sensorial function and do not integrate the cell cycle (Corwin, 1992).

Although the largest part of the studies about plastic alterations that follow hearing system damage are conducted to involve the peripheral portion, it is known that the response to damage can also be found centrally. There is evidence that both absence of stimuli from the periphery and overstimulation may cause structural reorganization of the central nervous system (Szczepaniak and Moller, 1996).

At the brainstem, the nuclei of hearing systems depend on the afferent stimulation to maintain its structural and functional integrity. One of the mechanisms is the regulation of intracellular calcium concentration in neurons. The removal of auditory afferent path leads to increased concentration, which could result in neuronal death. Immunohistochemical studies of calcium-binding proteins, such as calbindin, parvalbumin and calretinin, showed that their coficentrations in the neurons of cochlear nuclei depend on the preservation of auditory afferent path (Caicedo et al., 1997).

Alterations resultant from deafferention are also detected at the inferior colliculus (IC). In rats, cochlear lesion due to loud noise exposure resulted in disorganization of the electrophysiological activity of the external nucleus (Szczepaniak and Moller, 1990. In guinea pigs, deafening caused by use of ototoxic drugs resulted in decrease of IC metabolism, studied by the use of 2-dexoglucose. This fact would be reverted if the system were submitted to chronic electronic stimulation (Schwartz et al., 1993). Immunohistochemical studies of growth associated protein (GAP-43), which is a protein associated with neuronal growth and synaptic remodeling, showed very evident changes at the cochlear nucleus, olivary complex and IC, with unilateral increase of cochlear ablation. Illing et al., 1997 and Meleca et al., 1997, studied the cochlear nuclei of hamsters through electrophysiology after noise induced hearing loss. They showed alterations in tonotopy of cochlear dorsal nucleus, with loss of some frequencies and gain of others.

Plastic potential of neurons that comprise the sensorial system is essential during the earliest period of life, both for intra-uterine and neonatal period, acting as one of the factors that guarantee consolidation of its development. The knowledge of active processes that occur in the cochlea and culminate on transduction of mechanic into electrical signal and its interpretation will lead to the understanding that the whole group is not fully developed at the beginning of the activities. Conversely, maturation takes place slowly, during a couple of weeks and after the beginning of the operation of the inner ear, developing the contractile capacity of outer hair cells, arranging fine tune of neuron curves of spiral ganglia and cochlear nucleus, and incrementing otoacoustic emissions (Weaver et al., 1994).

The moment in which the cochlear functions begins is variable, depending on the species, and it may take place early in uterine life, or later, after birth (Romand, 1971; Dum, 1984; Henley and Ribak, 1995). The normal process of brain maturation in mammals depends on the appropriate input of two types of information: one internal, from molecular origin, and another external, resultant from the regular stimulation of sensorial organs. Both are essential to form inter-neural connections and to conduct the stimuli via efficient pathways. This fact is known for sight, somatic sensitivity and hearing, which is more evident during the so-called critical period of development, when regular stimulation guarantees appropriate maturation of the respective neural system (Henley and Ribak, 1995; Illing et al., 1997). Interference upon the capacity of the system to receive the stimulus in the critical period may lead to flaws in its development, disturbing the synaptic consolidation and modifying the neuronal architecture of central structures. We would like to emphasize the high potential of plastic rearrangements in sensorial systems during the earliest phases of development. In the visual system, this fact is known since the moment it was demonstrated that deprivation of unilateral sight in neonate cats led to atrophy of neurons of lateral' geniculate body and rearrangements of functional connections of striated cortex (Moore et al.,1989).

As to auditory pathways, manipulation of rodents conducted during the critical period of hearing development and causing partial hearing loss may lead to marked alteration of the central nervous system, manifested by symptoms of motor response to sound, known as audiogenic epilepsy (Pierson and Snyder-Keller, 1992). In this kind of reflexive epilepsy, the exposure to loud noise results in tonic-clonic generalized seizure.

Different types of manipulation may be employed to produce this alteration, aiming at partial loss of hearing capacity in the animal. Henry (1967) described the sensitization of mice to audiogenic seizures (AS) through exposure to loud noise, and the method is efficient only if applied after the 14th day of post-natal life, when the external auditory canal is opened. The author stated that sensitization takes place even if the sound is applied under anesthesia, showing that the process does not depend on the reticular formation of the brainstem, nor on conscious mechanisms. Pierson and Liebmann (1992) described the same period as optimal for sensitization through exposure to a 125dB noise. Pierson and Swann (1988) described the application of a 10-mg/Kg dose of intraperitoneal kanamicin as an efficient method to develop AS in rats. Kanamicin is a drug known for its cochlear toxicity, leading to irreversible cellular damage. The optimal period for the application of this protocol is four days, from the 9th to the 12th post-natal day. Other possibilities of sensitization to AS includes development of congenital hypothyroidism in rats by administering propylthiouracil to pregnant females (Middlesworth and Norris, 1980), occlusion of one ear in rats as soon as the external ear canal is opened, (Pierson and Snyder-Keller, 1992), mice treatment with anticonvulsant drugs and their sudden withdrawal (Voiculescu et al., 1985), and mice exposure to loud noise on the 21st day of life (Saunders et al., 1972).

Audiogenic epilepsy was initially described by Studentsov, in 1924. In addition to being induced by peripheral auditory system manipulations, it may also be a genetically inherited characteristic; there are well known lines of audiogenic animals, especially rats and mice. The main strains of rats genetically sensitive to audiogenic seizures is the Russian strain Krushinski-Molodkina, derived from Wistar rats, and the GEPRs (Genetically Epilepsy-Prone Rats) lines, derived from Sprague-Dawley rats. In addition to these two, new ones are being developed, one of them at Centre de Neurochimie, in Strasbourg, France, and another one at the Laboratory of Neurophysiology and Experimental Neuroetology, Department of Physiology, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo. The latter is derived from Wistar rats and it is called WAR - Wistar Audiogenic Rats (Garcia-Cairasco et al., 1990; Doretto, 1992). It is known that genetically audiogenic prone animals present poor hearing acuity. Anatomical studies showed structural alterations of Corti's organ, such as stereocilia aberrations and abnormal number of inner and outer hair cells (Penny et al., 1983).


In the past, the interest in studying the hearing system physiology was left behind that of studying sight and balance. The only Nobel Prize awarded to a study dedicated to auditory pathways was received by Georg von Bekesy, more than 30 years ago. In the 1980's, the interest in hearing functioning was stimulated after the findings that there were active mechanisms in the system. Even so, most of the studies aimed at learning about the peripheral portion, and the central portion had been limited to poor findings, usually directed to morphology rather than physiology. However, this trend has currently changed, and there are more studies focused on central auditory system (Erminy et al., 1995).

Adaptation is a basic property of the central nervous system as a whole and it has been clearly demonstrated in the hearing system as well. Understanding the functioning and the plastic potential of the central auditory pathway is essential for the knowledge about how the brain integrates and discriminates complex stimuli, such as speech sounds.

It is also important to understand how the sensorineural hearing loss affects central functioning. The development of new methods to promote hearing communication in patients with total deafness, such as cochlear implants, requires detailed knowledge about neural signs received from the brainstem and their processing (Merchan et al., 1993; Ruben, 1996). The concept of auditory plasticity refers to the possibility of having anatomical and/or functional modifications in the system responsible for the transmission of auditory information. Therefore, behavioral alterations observed after a cochlear implant procedure are empirical evidence of the occurrence of the plastic phenomenon, demonstrating the capacity the system has to adapt to new auditory sensations, after variable periods of deprivation. Conversely, the study of auditory plasticity is highly relevant for the treatment of deaf subjects of all ages who are implanted, because it is correlated with the nervous system capacity to adapt to artificial stimuli. It is particularly important in the discussion about implanting congenital, pre-lingual or long-lasting deafness in adults and children (Mecklenburg and Babighian, 1996).


In the current context, cases of profound sensorineural loss are treated with hearing aids or multi-channel cochlear implants. Regardless of the high technology, they do not restore normal hearing. The future might bring us biological restoration for damaged cochlea. The knowledge about how mechanisms are used by the central structures of the hearing system to react to loss of regular afferent input, and later to new incoming information, may help the development of new methods that would ensure better communication performance. The systematic study of hearing system regeneration is recent and it is mainly focused on hair cells, especially in avian. The long believed concept that hair cells in mammals are permanent has been challenged, since the occurrence of regeneration was shown under specific conditions. The onset of a response, such as audiogenic epilepsy as a reaction to the peripheral hearing organ damage, highlights the structural richness of the system and the long and winding road to be taken up to satisfactory understanding of it all.


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1 Ph.D., Professor, Discipline of Otorhinolaryngology, Department of Ophthalmology, Otorhinolaryngology and Head and Neck Surgery, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo.
2 Ph.D., Professor, Department of Physiology, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Head of the Laboratory of Neurophysiology and Experimental Neuroetology.

Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo.
Address correspondence to: Profa. Dra. Maria Cristina Lancia Cury Féres. Departamento de Oftalmologia, Otorrinolaringologia a Cirurgia de Cabeça a Pescoço. Hospital das Clínicas de Ribeirão Preto - Campus USP - Avenida Bandeirantes, 3900. 14900-090 - Ribeirão Preto /SP.
Tel: (55 16) 602-2863 / 602-2526 / 633-0186 - Fax: (55 16) 602-2860
E-mail: ramancio@fmtp.usp.br
The present paper is part of the Doctorate Dissertation of the author, submitted to Faculdade de Medicina de Ribeirão Preto, USP, on Aug 10/1998.
Financial support: CAPES.
Article submitted on February 16, 2001. Article accepted on March 27, 2001.





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