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A review of transneuronal changes of the auditory central nervous system as a consequence of auditory defects
International Journal of Pediatric Otorhinolaryngology, 0 ElsevierlNorth-Holland Biomedical Press
1 (1980)
269-277
269
Review Article A REVIEW OF TRANSNEURONAL CHANGES OF THE AUDITORY CENTRAL NERVOUS SYSTEM AS A CONSEQUENCE OF AUDITORY DEFECTS *
ROBERT J. RUBEN Department of Otorhinolaryngology, The Albert Einstein College of Medicine of Yeshiva University and Montefiore Hospital and Medical Center, Bronx, N. Y. (U.S.A.) (Received October 4th. 1979) (Accepted November llth, 1979)
INTRODUCTION
During the last three decades there have been numerous investigations revealing a consistent pattern of transneuronal changes of various portions of the central auditory nervous system which have been associated with either anatomical defects in the peripheral auditory apparatus (cochlear and/ or acoustic division of the VIII nerve), or with reduction of auditory stimulus to the cochlea (auditory deprivation). The changes are essentially consistent from species to species, and qualitatively similar regardless of the type of peripheral deficiency which was effected. These will be reviewed in this report. The physiological and behavioral consequences of these changes in other studies have also been reported, but will not be reviewed in this paper. The anatomical changes may or may not have implications in the care and habilitation of hearing deficits in man. As will be seen from the data, certain broad characteristics of the resultant central auditory nervous system changes are known in various species. Whether or not the same changes occur in man and how they might manifest themselves is unknown. It is hoped that one effect of this review will be to provide a basis to ask critical questions in the area of human audition and neuropathology.
* This paper was presented at the Sixth Annual Meeting of the Society for Ear, Nose and Throat Advances in Children (SENTAC), held December 7-8, 1978, at Santa Barbara, Calif., U.S.A.
270 SPECIES
Chicken The first controlled data which was reported was that of Levi-Montalcini in 1949 [7]. She ablated the otocyst in a 3-day-old chick embryo and allowed the embryo to mature for another 8 days. At the llth, 13th and 21st day of embryonic life the specimens were fixed and sectioned for microscopic study. She consistently observed two changes in the chick analogue of the mammalian cochlear nucleus complex. The complex in the chick is called the nucleus angularis, which is similar to the dorsal cochlear nucleus, and the nucleus magnocellularis, which could be considered the analogue of the ventral cochlear nucleus in the mammal. Ablation of the otocyst in these chicks resulted in a large decrease in the area of the nuclei of the nucleus angularis and changes in the nucleus magnocellularis. See Table I. Her work was re-examined and extended in a series of papers. Parks [ll] ablated the 2.5day-old chick otocyst and performed quantitative and qualitative studies of the nucleus angularis, the nucleus magnocellularis in which the cell volumes, number of cells and the cross-sectional area of the nuclei were determined. His findings were generally similar to those of LeviMontalcini. In addition, there were changes which were found to be associated with the various growth stages of the embryo. His findings were that at day 11 the nucleus angularis had decreased in cell volume and number of cells. This was approximately a 40% decrease in the normal expected size of the nucleus angular-is. Additional information was obtained which showed that the position of the nucleus angularis changed in the effected side. Nucleus magnocellularis had growth retardation evidence at 11 days of age. The mean size was greatly reduced at 15 days of age and there was a 30% loss of the neurons in nucleus magnocellularis after the 11th day. TABLE I SQUARE AREAS OF THE NUCLEI MAGNOCELLULARIS LOWING THE EXTIRPATION OF THE OTOCYST.
AND ANGULARIS
Figures in square inches on the camera lucida drawings Days of incubation
11 13 21
Nucleus angularis
Nucleus magnocellularis
Normal side
Operated side
Normal side
Operated side
13.00 32.00 120.50
11.50 13.00 13.50
21.00 29.02 60.50
21.00 19.50 28.70
FOL-
271
Jackson and Rubel [4], and Parks and Rubel [lo], carried out ablation of the inner ear of the chick at hatching and at various times up to 3 years after hatching. Their data showed a similar pattern of degeneration in the nucleus magnocellularis as that found when the ablation was done at 2.5 days of embryonic life. This latter study also examined the nucleus lamimu-is,which is a second order nucleus. This structure revealed a 15% decrease in its size. Whether this was due to intrinsic transneuronal degeneration of the nucleus laminaris, or the effect of a loss of dendrites from nucleus magnocellularis, is at this time not known. The chick experiments have demonstrated that ablation of the otocyst or the inner ear up to 8 days of age post-hatching will result in substantive changes in the two first order nuclei, nucleus angularis and nucleus magnocellularis, of the central auditory system of the chick. Whether or not there is further transneuronal degeneration in the second order nuclei is still an open question. Mouse
Trune [17,18] destroyed the cochlear and spiral ganglion cells of the Gday-old CBA-J mouse. The animals were sacrificed at 45 days of age. Both the central nervous system and the inner ear were examined. In the animals in which the inner ear was destroyed with the total destruction of the spiral ganglion cells in the modiolus, there was noted a large decrease in size in the entire cochlear nucleus complex. All major cell groups of the cochlear nucleus complex‘except the large spherical cells showed significant decreases in neuronal density on the ipsilateral side. Cell changes were found in both the dorsal and ventral cochlear nuclei. Webster and Webster [ 19,201 have carried out a series of studies using the newborn mouse. The studies have examined two groups of animals in which there is a reduction in auditory stimuli. One group was raised in a quiet environment and the other, one in which the external auditory meatus was closed so that there was a resultant loss of auditory input, similar to a moderate to severe conductive hearing loss. The most recent publication [19] demonstrated that after 45 days of sound deprivation there were significant decreases in the cross-sectional areas in 4 of the 5 cell types in the ventral cochlear nucleus, in the lateral superior olivary nucleus, the medial nucleus of the trapezoid body, and in the central nucleus of the inferior collicular superior. There was no significant change in the central nucleus of the dorsal cochlear nucleus. The Websters [19] examined a second group of animals which were raised in a sound-attenuated environment for 45 days, similar to those described in the first group, and then were placed in a normal sound environment for another 45 days. At the end of 90 days they were sacrificed. This second group showed similar changes in the ventral cochlear nucleus, except that the multipolar cells were significantly swollen at 90 days and there was
272
no significant difference in the octopus cells of this nucleus. The lateral superior olive, and the medial nucleus of the trapezoid body showed a similar type of decrease in cell volume as those who had not had any experience in sound. There was also a significant difference in the cross-sectional area of the central nucleus of the inferior colliculus at 90 days which was not present at 45 days. These two studies show that a decrease in sound stimulation in the newborn mouse resulted in a concomitant change in both primary and secondary auditory nuclei in the brain stem. Furthermore that, except in one case, the octopus cells of the ventral cochlear nucleus, auditory stimulation from the 45th to the 90th day of life did not reverse the anatomical changes. Ross [15,16] examined the brains of 4 partially deaf, Waltzing mice. There is no information concerning the age of the mice nor quantitative information concerning their hearing loss. The specific genetic mutants which these animals represent are not given. Despite this lack of information her anatomical observations are of interest, although they still need to be confirmed and quantified. She found changes throughout the entire central auditory system. The dorsal cochlear nucleus showed a partial loss of fibers and a disappearance of lamination. The size of the ventral cochlear nucleus was reduced. The superior olivary nucleus was atrophied and not laminated. The inferior colliculus was noted to have all of its cells more closely grouped and there was also a deficiency in the uptake of Nissl substance. The medial geniculate nucleus was smaller and the dorsal portion showed the greatest amount of degeneration, with a marked loss of the spindle shaped cells of this nucleus. The auditory cortex showed a decrease in lamination which was attributed to the swelling of the neurons. These data suggest a widespread effect in the central auditory nervous system. Whether these effects were due to a primary abnormality of the peripheral auditory system or an associated and/or causal central nervous system anomaly is not known. Rat Gentschev and Sotelo [2] showed that there were both pre- and postsynaptic changes in the anterior ventral cochlear nucleus of the rat after primary deafferentation of the cochlea and the spiral ganglion cells of the adult rat. There were two types of postsynaptlc changes observed. The first was a reoccupation of the postsynaptic site by an intact axon terminal. The second, and most common, was the disappearance of the postsynaptic site by engulfment into the postsynaptic neuron. Killackey and Ryugo [6] studied unilateral and bilateral auditory deprivation in the rat by cauterizing the external auditory canals at birth. They found in the unilaterally deprived animals ipsilateral and contralateral changes of the inferior colliculus when sacrificed at 30 days of age. These changes consisted of a lack of central nuclear lamination, an absence of bitufted neurons, and a relative reduction of the size of the central nucleus
273
of the inferior colliculus. There were no changes found in the animals with bilateral auditory deprivation. The findings in the rat are similar to those in the other species in that the two nuclei examined showed that there was transneuronal degeneration after loss of the peripheral auditory end organ or with auditory deprivation. The data concerning the lack of changes in the inferior colliculus in the animals with bilateral conductive hearing loss have not been explained. Cat
Carpenter et al. [l] destroyed the right labyrinth of 6 cats and found degeneration in the ventral cochlear nucleus and, to a lesser extent, the dorsal cochlear nucleus. They also noted cell loss of the vestibular nuclei bilaterally. Typical retrograde cell changes were noticed in both sides of the vestibular nuclei. Powell and Erulkar [13] performed unilateral cochlear ablation in adult cats. They found transneuronal degeneration in the ipsilateral ventral cochlear nucleus, ipsilateral lateral superior olivary nucleus, ipsilateral preolivary nucleus, contralateral medial nucleus of the trapezoid body, and the contralateral lateral lemniscus. The authors attributed the transneuronal degeneration in secondary nuclei to a loss of neurons in the ventral cochlear nucleus. Powell and Cowan [12] performed experiments on 11 cats and 2 rabbits. Lesions were made in the cochlea of one side and the animals were sacrificed from 12 h to 15 days after the lesion was made. They also reported on animals from other experiments which survived for at least a year. They found that the nerve fibers from the cochlea did not pass beyond the dorsal and ventral cochlear nuclei. They found degeneration of both the dorsal and ventral cochlear nuclei. Furthermore, they presented evidence to show that the degeneration of the superior olivary complex and trapezoid nuclei were secondary to transneuronal atrophy of the cells of the cochlear nucleus. McGee and Olezewski [8] performed unilateral ablation of the cochlea in a number of adult cats which also underwent ototoxic labrinthectomy from streptomycin or dihydrostreptomycin. They found cochlear nucleus degeneration only on the side with the surgically destroyed ears. The ventral cochlear nucleus was reduced in size. This was attributed to smaller cell size with an increase in compactness of the cells. The changes in the dorsal cochlear nucleus were less apparent. They felt that the nucleus was narrowed and that the cells were also more compact. Rasmussen [ 141 destroyed the spiral ganglion cells in adult cats and found cell atrophy in the dorsal medial and ventral lateral areas of the anterior ventral cochlear nucleus. He observed cell atrophy in the interstitial nucleus of the ventral cochlear nucleus and, most strikingly, in the posterior ventral cochlear nucleus. There was also a decrease in the number of synaptic endings on the posterior ventral cochlear nucleus.
274
West and Harrison [21] studied the cat. The data was obtained from congenitally deaf white cats, one animal which had its cochlea destroyed 8 years previous to sacrifice and another animal which was deafened with kanamycin at 3 weeks of age. The deaf white cats were found to have reduced cell size in the ventral cochlear nucleus and in the superior olivary complex. The cell areas for all of the medullary nuclei, with the exception of the spherical cells of the dorsal cochlear nucleus, were reduced. Their findings were similar in part to Rasmussen’s in that there was a decrease in size in the cross-sectional area of the cochlear nucleus. A decrease in size was also noted in the anterior ventral cochlear nucleus, especially in the “C type cells”. The “K type cells” of the posterior ventral cochlear nucleus in all of the lateral and medial superior olive were also decreased. There was a decrease in the size of the medial nucleus of the trapezoid body. There was no difference noted in the spindle cells of the dorsal cochlear nucleus and, as a control, there were no differences in size or anatomical characteristics of the Purkinje’s cells of the cerebellum. Jean-Baptiste and Morest [5] found that after unilateral destruction of the cochlea in the adult cat there were structural changes in the medial trapezoid nucleus, which consisted of a decrease in the bulbs of Helad and also a decrease in the cell size of those cells contacted by presynaptic elements of the cells of the medial trapezoid nucleus. The work in the cat has shown that there is transneuronal degeneration in the ventral cochlear nucleus (Powell, West, Rasmussen and McGee), lateral superior olivary nucleus (Powell and West) and the nucleus of the trapezoid body (Powell, Jean-Baptiste and West). The dorsal cochlear nucleus appears to be less affected (West and McGee) than others. TIME OF LOSS OF AUDITORY
INPUT
The experiments which have been reported here were performed either during embryonic life, postnatal life when the animal was still immature, or in the mature animal. It is apparent from the embryonic experiments that the effect on the primary central auditory nuclei shows the greatest changes. When the peripheral auditory deficit occurs after birth in the mouse, rat or cat there are always changes present, predominantly in the ventral cochlear nucleus, but these are not as great as seen when the deficit occurs in the embryo chick. The exception to this is possibly the 4 animals reported by Ross. The effect on the second order nuclei from the available information is less than that on the first order central order nucl,ei. However, the second order nuclei have not been that extensively studied. The effects in the mouse, on the superior olivary complex, inferior colliculus and geniculate, appear to be consistent, but still need further description and quantification. It is evident that the loss of the auditory portion of the VIII nerve with spiral ganglion cells in the adult mammals examined will result in transneuronal
275
degeneration of the first order nuclei, and in some cases of second order central nuclei as well. TYPE OF PERIPHERAL
DEFICIT
There are three reports [6,19,20] which assess the effect of reduction of sound stimulation on still developing, postpartum auditory central nervous systems of the rodent. All of these reports show changes in the primary and second order auditory nuclei of the brain stem. These changes are not as marked as those which result from the ablation of the peripheral auditory nervous system, which includes the spiral ganglion cells. These changes, although subtle, may have significant physiological and behavioral correlates. Unfortunately, the peripheral and behavioral changes secondary to auditory deprivation after birth which have been reported have not been correlated with anatomical changes. Unfortunately, the anatomical changes secondary to auditory deprivation which have been noted have not been correlated with the physiological and behavioral characteristics of the deprived animals. It is expected that these critical studies are now being carried out in various laboratories throughout the world. The data now available suggest certain hypotheses. These are: (1) The earlier in the develop_ment of an animal that there is an anatomical loss of the inner ear and its nerve, the greater the anatomical effect will be on the central auditory pathways. (2) Anatomical loss of the inner ear and its nerve or auditory deprivation during the immediate postnatal period in the rodent and the cat will result in changes in the primary and second order auditory nuclei of the brain stem. (3) The anatomical effects of auditory deprivation in the newborn mouse are, in the main, irreversible. There are still a large number of open questions concerning the physiological and behavioral effects of these changes. Furthermore, there is almost no data concerning the effects on the thalamus and the cortex in either the chick, the rodent, or the cat. Another area in which there is a need for more information is to correlate the developmental stage of the inner ear and the time when the auditory deficit is made with the developmental stage of the central nervous system. The mouse, for which there is a large body of data, does not develop a mature inner ear in regard to anatomy and physiology until about the second week of postnatal life [9]. The mouse brain is likewise immature until about the 20th day of postnatal life. The inner ear in the chick, rat and the cat also mature before the central nervous system. There is a similar pattern of development in man, in that the inner ear appears to be mature, anatomically and physiologically, at birth and perhaps as early as the 7th or 8th month of gestation, whereas the central nervous system may not be mature until after the first decade of life. Yet it is known that in man the physiological responses of the brain stem to sound appear to reach maturity between the 12th and 18th months of age [3]. The character-
276
istics of different rates of maturation for both the inner ear and the central nervous system between species must be considered in any generalization of the information which has been reported. It would not be correct to make generalizations from one species to another without understanding the effects of these different rates of maturation and their effect on the consequence of the various auditory deficits, either due to anatomical lesions or deprivations, on the central nervous system in terms of anatomy, and ultimately, physiology and behavior. ACKNOWLEDGEMENTS
This work was supported by NIH Grant 5ROlNS0835-11, the Deafness Research Foundation and the National Foundation Grant l-372. REFERENCES 1 Carpenter, M.B., Bard, D.S. and Alling, F.A., Anatomical connections between the fastigial nuclei, the labyrinth and the vestibular nuclei in the cat, J. camp. Neurol., 3 (1959) l-23. 2 Gentschev, T. and Sotelo, C., Degenerative patterns in the ventral cochlear nucleus of the rat after primary deafferentation. An ultrastructural study, Brain Research, 62 (1973) 37-60. 3 Hecox, K. and Galambos, R., Brain stem auditory evoked potentials in human infants and adults, Arch. Otolaryng., 99 (1974) 30-33. 4 Jackson, J.H. and Rubel, E.W., Rapid transneuronal degeneration following cochlea removal in chickens, Anat. Rec., 84 (1976) 434-435. 5 Jean-Baptiste, J. and Morest, D.K., Transneuronal changes of synaptic endings and nuclear chromatin in the trapezoid body following cochlear ablation in cats, J. camp. Neurol., 162 (1975) 111-133. 6 Killackey, H.P. and Ryugo, D.K., Effects of neonatal peripheral auditory system damage on the structure of the inferior colliculus of the rat, Anat. Rec., 187 (1977) 624. 7 Levi-Montalcini, R., The development of the acoustico-vestibular centers in the chick embryo in the absence of the afferent root fibers and of descending fiber tracts, J. camp. Neurol., 91 (1949) 209-242. 8 McGee, T.M. and Olzewski, J., Streptomycin sulfate and dihydrostreptomycin ototoxicity: behavioral and histopathological studies, Arch. Otolaryng., 75 (1962) 295311. 9 Mikaelian, D.O. and Ruben, R.J., Hearing degeneration in the Shaker-l mouse: correlation of physiological observations with behavioral responses and with cochlear anatomy, Arch. Otolaryng., 80 (1964) 418-430. 10 Parks, T.N. and Rubel, E.W., Organization and development of the brain stem auditory nuclei of the chicken: primary afferent projection, J. camp. Neurol., 180 (1978) 439-448. 11 Parks, T.N., Afferent influences on the development of the brain stem auditory nuclei of the chicken: otocyst ablation, J. camp. Neurol., in press. 12 Powell, T.S. and Cowan, W.M., An experimental study of the projection of the cochlea, J. Anat. (Lond.), 96 (1962) 269-284. 13 Powell, T.S. and Erulkar, S.D., Transneuronal cell degeneration in the auditory relay nuclei of the cat, J. Anat. (Lond.), 96 (1962) 249-268.
277 14 Rasmussen, G.L., Efferent connections of the cochlear nucleus. In A.B. Graham (Ed.), Sensorineural Hearing Processes and Disorders, Little, Brown, Boston, 1967, pp. 61-75. 15 Ross, M.D., The auditory pathways of the epileptic Waltzing mouse. II. Partially deaf mice, J. camp. Neurol., 125 (1965) 141-164. 16 Ross, M.D., The auditory pathways of the epileptic Waltzing mouse. I. A comparison of the acoustic pathways of the normal mouse with those of the totally deaf epileptic Waltzer, J. camp. Neurol., 119 (1962) 317-339. 17 Trune, D.R., Influence of neonatal cochlear removal on size and density of cochlear nuclear neurons, Anat. Rec., 190 (1978) 566. 18 Trune, D.R., Dependence of cochlear nuclei development upon peripheral auditory structure, Anat. Rec., 187 (1977) 733. 19 Webster, D.B. and Webster, M., Auditory brain stem: sound deprivation and critical period, Arch. Otolaryng., in press. 20 Webster, D.B. and Webster, M., Neonatal sound deprivation affects brain stem auditory nuclei, Arch. Otolaryng., 103 (1977) 392-396. 21 West, C.D. and Harrison, J.M., Transneuronal cell atrophy in the congenitally deaf white cat, J. camp. Neurol., 151 (1973) 377-398.
1 (1980)
269-277
269
Review Article A REVIEW OF TRANSNEURONAL CHANGES OF THE AUDITORY CENTRAL NERVOUS SYSTEM AS A CONSEQUENCE OF AUDITORY DEFECTS *
ROBERT J. RUBEN Department of Otorhinolaryngology, The Albert Einstein College of Medicine of Yeshiva University and Montefiore Hospital and Medical Center, Bronx, N. Y. (U.S.A.) (Received October 4th. 1979) (Accepted November llth, 1979)
INTRODUCTION
During the last three decades there have been numerous investigations revealing a consistent pattern of transneuronal changes of various portions of the central auditory nervous system which have been associated with either anatomical defects in the peripheral auditory apparatus (cochlear and/ or acoustic division of the VIII nerve), or with reduction of auditory stimulus to the cochlea (auditory deprivation). The changes are essentially consistent from species to species, and qualitatively similar regardless of the type of peripheral deficiency which was effected. These will be reviewed in this report. The physiological and behavioral consequences of these changes in other studies have also been reported, but will not be reviewed in this paper. The anatomical changes may or may not have implications in the care and habilitation of hearing deficits in man. As will be seen from the data, certain broad characteristics of the resultant central auditory nervous system changes are known in various species. Whether or not the same changes occur in man and how they might manifest themselves is unknown. It is hoped that one effect of this review will be to provide a basis to ask critical questions in the area of human audition and neuropathology.
* This paper was presented at the Sixth Annual Meeting of the Society for Ear, Nose and Throat Advances in Children (SENTAC), held December 7-8, 1978, at Santa Barbara, Calif., U.S.A.
270 SPECIES
Chicken The first controlled data which was reported was that of Levi-Montalcini in 1949 [7]. She ablated the otocyst in a 3-day-old chick embryo and allowed the embryo to mature for another 8 days. At the llth, 13th and 21st day of embryonic life the specimens were fixed and sectioned for microscopic study. She consistently observed two changes in the chick analogue of the mammalian cochlear nucleus complex. The complex in the chick is called the nucleus angularis, which is similar to the dorsal cochlear nucleus, and the nucleus magnocellularis, which could be considered the analogue of the ventral cochlear nucleus in the mammal. Ablation of the otocyst in these chicks resulted in a large decrease in the area of the nuclei of the nucleus angularis and changes in the nucleus magnocellularis. See Table I. Her work was re-examined and extended in a series of papers. Parks [ll] ablated the 2.5day-old chick otocyst and performed quantitative and qualitative studies of the nucleus angularis, the nucleus magnocellularis in which the cell volumes, number of cells and the cross-sectional area of the nuclei were determined. His findings were generally similar to those of LeviMontalcini. In addition, there were changes which were found to be associated with the various growth stages of the embryo. His findings were that at day 11 the nucleus angularis had decreased in cell volume and number of cells. This was approximately a 40% decrease in the normal expected size of the nucleus angular-is. Additional information was obtained which showed that the position of the nucleus angularis changed in the effected side. Nucleus magnocellularis had growth retardation evidence at 11 days of age. The mean size was greatly reduced at 15 days of age and there was a 30% loss of the neurons in nucleus magnocellularis after the 11th day. TABLE I SQUARE AREAS OF THE NUCLEI MAGNOCELLULARIS LOWING THE EXTIRPATION OF THE OTOCYST.
AND ANGULARIS
Figures in square inches on the camera lucida drawings Days of incubation
11 13 21
Nucleus angularis
Nucleus magnocellularis
Normal side
Operated side
Normal side
Operated side
13.00 32.00 120.50
11.50 13.00 13.50
21.00 29.02 60.50
21.00 19.50 28.70
FOL-
271
Jackson and Rubel [4], and Parks and Rubel [lo], carried out ablation of the inner ear of the chick at hatching and at various times up to 3 years after hatching. Their data showed a similar pattern of degeneration in the nucleus magnocellularis as that found when the ablation was done at 2.5 days of embryonic life. This latter study also examined the nucleus lamimu-is,which is a second order nucleus. This structure revealed a 15% decrease in its size. Whether this was due to intrinsic transneuronal degeneration of the nucleus laminaris, or the effect of a loss of dendrites from nucleus magnocellularis, is at this time not known. The chick experiments have demonstrated that ablation of the otocyst or the inner ear up to 8 days of age post-hatching will result in substantive changes in the two first order nuclei, nucleus angularis and nucleus magnocellularis, of the central auditory system of the chick. Whether or not there is further transneuronal degeneration in the second order nuclei is still an open question. Mouse
Trune [17,18] destroyed the cochlear and spiral ganglion cells of the Gday-old CBA-J mouse. The animals were sacrificed at 45 days of age. Both the central nervous system and the inner ear were examined. In the animals in which the inner ear was destroyed with the total destruction of the spiral ganglion cells in the modiolus, there was noted a large decrease in size in the entire cochlear nucleus complex. All major cell groups of the cochlear nucleus complex‘except the large spherical cells showed significant decreases in neuronal density on the ipsilateral side. Cell changes were found in both the dorsal and ventral cochlear nuclei. Webster and Webster [ 19,201 have carried out a series of studies using the newborn mouse. The studies have examined two groups of animals in which there is a reduction in auditory stimuli. One group was raised in a quiet environment and the other, one in which the external auditory meatus was closed so that there was a resultant loss of auditory input, similar to a moderate to severe conductive hearing loss. The most recent publication [19] demonstrated that after 45 days of sound deprivation there were significant decreases in the cross-sectional areas in 4 of the 5 cell types in the ventral cochlear nucleus, in the lateral superior olivary nucleus, the medial nucleus of the trapezoid body, and in the central nucleus of the inferior collicular superior. There was no significant change in the central nucleus of the dorsal cochlear nucleus. The Websters [19] examined a second group of animals which were raised in a sound-attenuated environment for 45 days, similar to those described in the first group, and then were placed in a normal sound environment for another 45 days. At the end of 90 days they were sacrificed. This second group showed similar changes in the ventral cochlear nucleus, except that the multipolar cells were significantly swollen at 90 days and there was
272
no significant difference in the octopus cells of this nucleus. The lateral superior olive, and the medial nucleus of the trapezoid body showed a similar type of decrease in cell volume as those who had not had any experience in sound. There was also a significant difference in the cross-sectional area of the central nucleus of the inferior colliculus at 90 days which was not present at 45 days. These two studies show that a decrease in sound stimulation in the newborn mouse resulted in a concomitant change in both primary and secondary auditory nuclei in the brain stem. Furthermore that, except in one case, the octopus cells of the ventral cochlear nucleus, auditory stimulation from the 45th to the 90th day of life did not reverse the anatomical changes. Ross [15,16] examined the brains of 4 partially deaf, Waltzing mice. There is no information concerning the age of the mice nor quantitative information concerning their hearing loss. The specific genetic mutants which these animals represent are not given. Despite this lack of information her anatomical observations are of interest, although they still need to be confirmed and quantified. She found changes throughout the entire central auditory system. The dorsal cochlear nucleus showed a partial loss of fibers and a disappearance of lamination. The size of the ventral cochlear nucleus was reduced. The superior olivary nucleus was atrophied and not laminated. The inferior colliculus was noted to have all of its cells more closely grouped and there was also a deficiency in the uptake of Nissl substance. The medial geniculate nucleus was smaller and the dorsal portion showed the greatest amount of degeneration, with a marked loss of the spindle shaped cells of this nucleus. The auditory cortex showed a decrease in lamination which was attributed to the swelling of the neurons. These data suggest a widespread effect in the central auditory nervous system. Whether these effects were due to a primary abnormality of the peripheral auditory system or an associated and/or causal central nervous system anomaly is not known. Rat Gentschev and Sotelo [2] showed that there were both pre- and postsynaptic changes in the anterior ventral cochlear nucleus of the rat after primary deafferentation of the cochlea and the spiral ganglion cells of the adult rat. There were two types of postsynaptlc changes observed. The first was a reoccupation of the postsynaptic site by an intact axon terminal. The second, and most common, was the disappearance of the postsynaptic site by engulfment into the postsynaptic neuron. Killackey and Ryugo [6] studied unilateral and bilateral auditory deprivation in the rat by cauterizing the external auditory canals at birth. They found in the unilaterally deprived animals ipsilateral and contralateral changes of the inferior colliculus when sacrificed at 30 days of age. These changes consisted of a lack of central nuclear lamination, an absence of bitufted neurons, and a relative reduction of the size of the central nucleus
273
of the inferior colliculus. There were no changes found in the animals with bilateral auditory deprivation. The findings in the rat are similar to those in the other species in that the two nuclei examined showed that there was transneuronal degeneration after loss of the peripheral auditory end organ or with auditory deprivation. The data concerning the lack of changes in the inferior colliculus in the animals with bilateral conductive hearing loss have not been explained. Cat
Carpenter et al. [l] destroyed the right labyrinth of 6 cats and found degeneration in the ventral cochlear nucleus and, to a lesser extent, the dorsal cochlear nucleus. They also noted cell loss of the vestibular nuclei bilaterally. Typical retrograde cell changes were noticed in both sides of the vestibular nuclei. Powell and Erulkar [13] performed unilateral cochlear ablation in adult cats. They found transneuronal degeneration in the ipsilateral ventral cochlear nucleus, ipsilateral lateral superior olivary nucleus, ipsilateral preolivary nucleus, contralateral medial nucleus of the trapezoid body, and the contralateral lateral lemniscus. The authors attributed the transneuronal degeneration in secondary nuclei to a loss of neurons in the ventral cochlear nucleus. Powell and Cowan [12] performed experiments on 11 cats and 2 rabbits. Lesions were made in the cochlea of one side and the animals were sacrificed from 12 h to 15 days after the lesion was made. They also reported on animals from other experiments which survived for at least a year. They found that the nerve fibers from the cochlea did not pass beyond the dorsal and ventral cochlear nuclei. They found degeneration of both the dorsal and ventral cochlear nuclei. Furthermore, they presented evidence to show that the degeneration of the superior olivary complex and trapezoid nuclei were secondary to transneuronal atrophy of the cells of the cochlear nucleus. McGee and Olezewski [8] performed unilateral ablation of the cochlea in a number of adult cats which also underwent ototoxic labrinthectomy from streptomycin or dihydrostreptomycin. They found cochlear nucleus degeneration only on the side with the surgically destroyed ears. The ventral cochlear nucleus was reduced in size. This was attributed to smaller cell size with an increase in compactness of the cells. The changes in the dorsal cochlear nucleus were less apparent. They felt that the nucleus was narrowed and that the cells were also more compact. Rasmussen [ 141 destroyed the spiral ganglion cells in adult cats and found cell atrophy in the dorsal medial and ventral lateral areas of the anterior ventral cochlear nucleus. He observed cell atrophy in the interstitial nucleus of the ventral cochlear nucleus and, most strikingly, in the posterior ventral cochlear nucleus. There was also a decrease in the number of synaptic endings on the posterior ventral cochlear nucleus.
274
West and Harrison [21] studied the cat. The data was obtained from congenitally deaf white cats, one animal which had its cochlea destroyed 8 years previous to sacrifice and another animal which was deafened with kanamycin at 3 weeks of age. The deaf white cats were found to have reduced cell size in the ventral cochlear nucleus and in the superior olivary complex. The cell areas for all of the medullary nuclei, with the exception of the spherical cells of the dorsal cochlear nucleus, were reduced. Their findings were similar in part to Rasmussen’s in that there was a decrease in size in the cross-sectional area of the cochlear nucleus. A decrease in size was also noted in the anterior ventral cochlear nucleus, especially in the “C type cells”. The “K type cells” of the posterior ventral cochlear nucleus in all of the lateral and medial superior olive were also decreased. There was a decrease in the size of the medial nucleus of the trapezoid body. There was no difference noted in the spindle cells of the dorsal cochlear nucleus and, as a control, there were no differences in size or anatomical characteristics of the Purkinje’s cells of the cerebellum. Jean-Baptiste and Morest [5] found that after unilateral destruction of the cochlea in the adult cat there were structural changes in the medial trapezoid nucleus, which consisted of a decrease in the bulbs of Helad and also a decrease in the cell size of those cells contacted by presynaptic elements of the cells of the medial trapezoid nucleus. The work in the cat has shown that there is transneuronal degeneration in the ventral cochlear nucleus (Powell, West, Rasmussen and McGee), lateral superior olivary nucleus (Powell and West) and the nucleus of the trapezoid body (Powell, Jean-Baptiste and West). The dorsal cochlear nucleus appears to be less affected (West and McGee) than others. TIME OF LOSS OF AUDITORY
INPUT
The experiments which have been reported here were performed either during embryonic life, postnatal life when the animal was still immature, or in the mature animal. It is apparent from the embryonic experiments that the effect on the primary central auditory nuclei shows the greatest changes. When the peripheral auditory deficit occurs after birth in the mouse, rat or cat there are always changes present, predominantly in the ventral cochlear nucleus, but these are not as great as seen when the deficit occurs in the embryo chick. The exception to this is possibly the 4 animals reported by Ross. The effect on the second order nuclei from the available information is less than that on the first order central order nucl,ei. However, the second order nuclei have not been that extensively studied. The effects in the mouse, on the superior olivary complex, inferior colliculus and geniculate, appear to be consistent, but still need further description and quantification. It is evident that the loss of the auditory portion of the VIII nerve with spiral ganglion cells in the adult mammals examined will result in transneuronal
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degeneration of the first order nuclei, and in some cases of second order central nuclei as well. TYPE OF PERIPHERAL
DEFICIT
There are three reports [6,19,20] which assess the effect of reduction of sound stimulation on still developing, postpartum auditory central nervous systems of the rodent. All of these reports show changes in the primary and second order auditory nuclei of the brain stem. These changes are not as marked as those which result from the ablation of the peripheral auditory nervous system, which includes the spiral ganglion cells. These changes, although subtle, may have significant physiological and behavioral correlates. Unfortunately, the peripheral and behavioral changes secondary to auditory deprivation after birth which have been reported have not been correlated with anatomical changes. Unfortunately, the anatomical changes secondary to auditory deprivation which have been noted have not been correlated with the physiological and behavioral characteristics of the deprived animals. It is expected that these critical studies are now being carried out in various laboratories throughout the world. The data now available suggest certain hypotheses. These are: (1) The earlier in the develop_ment of an animal that there is an anatomical loss of the inner ear and its nerve, the greater the anatomical effect will be on the central auditory pathways. (2) Anatomical loss of the inner ear and its nerve or auditory deprivation during the immediate postnatal period in the rodent and the cat will result in changes in the primary and second order auditory nuclei of the brain stem. (3) The anatomical effects of auditory deprivation in the newborn mouse are, in the main, irreversible. There are still a large number of open questions concerning the physiological and behavioral effects of these changes. Furthermore, there is almost no data concerning the effects on the thalamus and the cortex in either the chick, the rodent, or the cat. Another area in which there is a need for more information is to correlate the developmental stage of the inner ear and the time when the auditory deficit is made with the developmental stage of the central nervous system. The mouse, for which there is a large body of data, does not develop a mature inner ear in regard to anatomy and physiology until about the second week of postnatal life [9]. The mouse brain is likewise immature until about the 20th day of postnatal life. The inner ear in the chick, rat and the cat also mature before the central nervous system. There is a similar pattern of development in man, in that the inner ear appears to be mature, anatomically and physiologically, at birth and perhaps as early as the 7th or 8th month of gestation, whereas the central nervous system may not be mature until after the first decade of life. Yet it is known that in man the physiological responses of the brain stem to sound appear to reach maturity between the 12th and 18th months of age [3]. The character-
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istics of different rates of maturation for both the inner ear and the central nervous system between species must be considered in any generalization of the information which has been reported. It would not be correct to make generalizations from one species to another without understanding the effects of these different rates of maturation and their effect on the consequence of the various auditory deficits, either due to anatomical lesions or deprivations, on the central nervous system in terms of anatomy, and ultimately, physiology and behavior. ACKNOWLEDGEMENTS
This work was supported by NIH Grant 5ROlNS0835-11, the Deafness Research Foundation and the National Foundation Grant l-372. REFERENCES 1 Carpenter, M.B., Bard, D.S. and Alling, F.A., Anatomical connections between the fastigial nuclei, the labyrinth and the vestibular nuclei in the cat, J. camp. Neurol., 3 (1959) l-23. 2 Gentschev, T. and Sotelo, C., Degenerative patterns in the ventral cochlear nucleus of the rat after primary deafferentation. An ultrastructural study, Brain Research, 62 (1973) 37-60. 3 Hecox, K. and Galambos, R., Brain stem auditory evoked potentials in human infants and adults, Arch. Otolaryng., 99 (1974) 30-33. 4 Jackson, J.H. and Rubel, E.W., Rapid transneuronal degeneration following cochlea removal in chickens, Anat. Rec., 84 (1976) 434-435. 5 Jean-Baptiste, J. and Morest, D.K., Transneuronal changes of synaptic endings and nuclear chromatin in the trapezoid body following cochlear ablation in cats, J. camp. Neurol., 162 (1975) 111-133. 6 Killackey, H.P. and Ryugo, D.K., Effects of neonatal peripheral auditory system damage on the structure of the inferior colliculus of the rat, Anat. Rec., 187 (1977) 624. 7 Levi-Montalcini, R., The development of the acoustico-vestibular centers in the chick embryo in the absence of the afferent root fibers and of descending fiber tracts, J. camp. Neurol., 91 (1949) 209-242. 8 McGee, T.M. and Olzewski, J., Streptomycin sulfate and dihydrostreptomycin ototoxicity: behavioral and histopathological studies, Arch. Otolaryng., 75 (1962) 295311. 9 Mikaelian, D.O. and Ruben, R.J., Hearing degeneration in the Shaker-l mouse: correlation of physiological observations with behavioral responses and with cochlear anatomy, Arch. Otolaryng., 80 (1964) 418-430. 10 Parks, T.N. and Rubel, E.W., Organization and development of the brain stem auditory nuclei of the chicken: primary afferent projection, J. camp. Neurol., 180 (1978) 439-448. 11 Parks, T.N., Afferent influences on the development of the brain stem auditory nuclei of the chicken: otocyst ablation, J. camp. Neurol., in press. 12 Powell, T.S. and Cowan, W.M., An experimental study of the projection of the cochlea, J. Anat. (Lond.), 96 (1962) 269-284. 13 Powell, T.S. and Erulkar, S.D., Transneuronal cell degeneration in the auditory relay nuclei of the cat, J. Anat. (Lond.), 96 (1962) 249-268.
277 14 Rasmussen, G.L., Efferent connections of the cochlear nucleus. In A.B. Graham (Ed.), Sensorineural Hearing Processes and Disorders, Little, Brown, Boston, 1967, pp. 61-75. 15 Ross, M.D., The auditory pathways of the epileptic Waltzing mouse. II. Partially deaf mice, J. camp. Neurol., 125 (1965) 141-164. 16 Ross, M.D., The auditory pathways of the epileptic Waltzing mouse. I. A comparison of the acoustic pathways of the normal mouse with those of the totally deaf epileptic Waltzer, J. camp. Neurol., 119 (1962) 317-339. 17 Trune, D.R., Influence of neonatal cochlear removal on size and density of cochlear nuclear neurons, Anat. Rec., 190 (1978) 566. 18 Trune, D.R., Dependence of cochlear nuclei development upon peripheral auditory structure, Anat. Rec., 187 (1977) 733. 19 Webster, D.B. and Webster, M., Auditory brain stem: sound deprivation and critical period, Arch. Otolaryng., in press. 20 Webster, D.B. and Webster, M., Neonatal sound deprivation affects brain stem auditory nuclei, Arch. Otolaryng., 103 (1977) 392-396. 21 West, C.D. and Harrison, J.M., Transneuronal cell atrophy in the congenitally deaf white cat, J. camp. Neurol., 151 (1973) 377-398.