Douglas B. Webster and Molly Webster- Contributions to Auditory Neural Plasticity

1. Douglas B. Webster and Molly Webster-Contributions to Auditory Neural Plasticity -Robert Dietz, M.B.A.

2. Douglas B. Webster – Molly Webster • Molly Webster - a highly literate writer and editor as well as an accomplished histology associate • Douglas Webster - a broadly trained zoologist who had done a post-doc at Cal Tech with Konishi* in the early ‘60s.” • Joined Kresge Lab (Louisiana State University ) in 1973 coming from NYU • Retired from Kresge Lab in 1998 (1973 -1998) • Was a teacher for LSU’s neuroscience courses • Cadaver anatomy teacher -audiology and speech graduates of LSU’s Communication Disorders Program • Researched and wrote prolifically about the auditory system. • Work on the kangaroo rat was cited in the classic McGraw-Hill Encyclopedia of Science and Technology (Webster, 1971). -Charles Berlin 1998 *Masakazu Konishi, Ph.D., 1963, University of California - Berkeley

3. Where it all began

4. Earliest Research • The ear apparatus of the kangaroo rat, Dipodomys. (Am J Anat. 1961 Mar;108:123-47 ) • Ear structure and function in modern mammals. (Am Zool. 1966 Aug;6(3):451-66.) • Central auditory system of the kangaroo rat, Dipodomys merriami. J Comp Neurol. 1968 Aug;133(4):477-93. • Adaptive value of hearing and vision in kangaroo rat predator avoidance.Webster DB, Webster M.Brain Behav Evol. 1971;4(4):310-22.

5. Adaptive Value • The predatory strikes of a rattlesnake (Crotalus cerastes) can be avoided by kangaroo rats (Dipodomys merriami) in the normal condition – using both auditory and visual peripheral systems. • But, avoidance is also possible after: (1) removal of the eyes, or (2) reduction of middle ear volume. • When both these operations are performed, however, the kangaroo rat is struck by the rattlesnake with relative ease. • Exception: Reduction of middle ear volume alone in a natural population of kangaroo rats resulted in a high loss; most of them disappeared from the population during the dark phase of the moon. • It is concluded that both vision and audition play significant adaptive roles in predator avoidance.

6. Observations from this study • Removal of a peripheral structure resulted in behavioral adaptation changes • Deprivation adaptation overcame limitations of a peripheral deficit. • Adaptation could not entirely replace a normally functioning peripheral structure under certain conditions.

7. Plasticity significance from this study • “Stimulation of various systems other than auditory supports the concept that neuronal change is likely.” • “Results from animal studies on the visual and cerebellar systems show that sensory/motor stimulation influences neuronal morphology and function.” -Central Auditory Processing Disorders – p.68

8. Auditory Research • Many studies conducted during the 1970’s were conducted using the CBA/J mouse.

9. A Comment on the CBA/J Mouse

10. A Comment on the CBA/J Mouse • A laboratory mouse is useful for medical research because it has specific characteristics that resemble a human disease or disorder. • Strains of mice having natural mutations similar to human ones may serve as models of such conditions. • Scientists can also create mouse models by transferring new genes into mice or by inactivating certain existing genes in them.

11. CBA/J Mouse • CBA/J inbred mice are widely used as a general purpose strain. • CBA/J strain is the only CBA substrain that carries the Pde6brd1 mutation, which causes blindness by wean age. • The CBA/J inbred mouse strain is used to study granulomatous experimental autoimmune thyroiditis (G-EAT) • Are relatively resistant to diet-induced atherosclerosis (Paigen et al. 1990), • Develop a mild hearing loss late in life, with most of the hearing loss occurring in the higher frequencies (Sweet et al. 1988).

12. CBA/J Mouse

14. CBA/J Mouse – Commonly used in research.

15. WD MM-1 Mouse - not commonly usedin research Usually found in Orlando, FL

16. CBA/J Mouse – Commonly used in research.

17. Auditory Research

18. Neonatal sound deprivation affects brain stem auditory nuclei. Arch Otolaryngol. 1977 Jul;103(7):392-6. Webster DB, Webster M. • CBA/J mice deprived of airborne sound stimulation during postnatal development have smaller globular cells in the ventral cochlear nucleus and smaller neurons in the medial nucleus of the trapezoid body than do normal control mice. • The sound deprivation in these mice is similar to that experienced by persons with pure congenital conductive hearing losses. • Even more profound central neural changes were found in auditory nuclei in the brain stem of a congenitally sensorineural deaf human.

19. Cochlear nerve projections following organ of corti destruction. Otolaryngology. 1978 Mar-Apr;86(2):ORL342-53 Webster DB, Webster M. Experimental organ of Corti destruction results in: • Secondary loss of all type I spiral ganglion neurons. • Development of type III spiral ganglion neurons. (rapid onset, sensitive, very slow off). • Degeneration of most cochlear nerve myelinated fibers. • Terminal degeneration in the ventral and dorsal cochlear nuclei. • The first signs of degenerative changes occur by eight days after organ of Corti destruction and degeneration debris remains until 28 weeks after destruction.

20. Effects of neonatal conductive hearing loss on brain stem auditory nuclei. Ann Otol Rhinol Laryngol. 1979 Sep-Oct;88(5 Pt 1):684-8 Webster DB, Webster M. • Both postnatal auditory deprivation and experimentally produced conductive hearing losses in mice result in incomplete maturation of most brain stem auditory neurons. • The affected groups are: octopus cell, globular cell, small spherical cell, and large spherical cell groups in ventral cochlear nuclei; and the lateral superior olive and medial nucleus of the trapezoid body of the superior olivary complex.

21. (2) Effects of neonatal conductive hearing loss on brain stem auditory nuclei. Ann Otol Rhinol Laryngol. 1979 Sep-Oct;88(5 Pt 1):684-8 Webster DB, Webster M. • When 45 days of auditory deprivation are followed by 45 days of normal acoustic stimulation, there is incomplete maturation of neurons in: multipolar cell, globular cell, small spherical cell, and large spherical cell groups in ventral cochlear nuclei; lateral superior olive and medial nucleus of trapezoid body in superior olivary complex; and central nucleus of inferior colliculus. • A critical period exists when adequate sound stimulation is needed for full development of these neurons.

22. A critical period during postnatal auditory development of mice.Int J Pediatr Otorhinolaryngol. 1983 Nov;6(2):107-18.Webster DB • CBA/J mice were given a 50 dB unilateral conductive hearing loss by removal of the left cartilaginous external auditory meatus. • When the conductive loss extended from 12 to 24 days after birth, the left globular cells and left large spherical cells of the ventral cochlear nucleus were significantly smaller (P less than 0.01) than comparable cells on the right side. • Right medial nucleus of the trapezoid body cells and right inferior colliculus cells were significantly smaller (P less than 0.01) than comparable left side cells. • These same effects were found with conductive losses of 4-24, 4-45, and 4-90 days after birth.

23. (2) A critical period during postnatal auditory development of mice. • There were no significant differences (P greater than 0.05) between right and left cell sizes with conductive losses of 4-12 or 24-45 days after birth. • There were significant right/left cell size differences (P less than 0.01) when the conductive loss was present in the 4-18, 12-18, or 18-24 day period. These differences were of lesser magnitude than when the conductive loss included the full 12-24 day period. • Since normally all these neurons have adult soma size by postnatal day 12, it is evident that adequate acoustic stimulation is necessary between 12 and 24 days postnatally in order to maintain normal brainstem auditory neuronal size in CBA/J mice.

24. Sound amplification negates central effects of a neonatal conductive hearing loss.Hear Res. 1988 Feb-Mar;32(2-3):193-5.Webster DB • Neonatal CBA/J mice, with external auditory meati removed, were raised in a sound-amplified environment. • If amplification continued until sacrifice at 24 or 45 days of age, both cochlear nuclear volumes and cross-sectional areas of VCN globular cells were of normal size. • Without amplification both measurements were significantly reduced .

25. Plasticiy significance from these studies • Plasticity is related to maturation • There are critical time periods for normal neural development

26. Does electrical stimulation of deaf cochleae prevent spiral ganglion degeneration?Hear Res. 1999 Jul;133(1-2):27-39. Li L, Parkins CW, Webster DB.Department of Otorhinolaryngology and Biocommunication, Louisiana State University Medical Center, New Orleans 70112-2234, USA. • Thirty-six drug deafened guinea pigs were studied to determine how electrical stimulation of the cochlea affects spiral ganglion cell (SGC) survival. • Animals were divided into two groups, extracochlear and intracochlear stimulation, and each group was further divided into four stimulus subgroups: no stimulation (implanted controls), the inferior colliculus electrically evoked potential (ICEEP) threshold-2 dB, ICEEP threshold+2 dB, and ICEEP threshold+6 dB. • Stimuli consisted of 200 micros/phase charge balanced biphasic current pulses presented at 100 pulses per second using monopolar stimulation.

27. (2) Does electrical stimulation of deaf cochleae prevent spiral ganglion degeneration?Hear Res. 1999 Jul;133(1-2):27-39. Li L, Parkins CW, Webster DB.Department of Otorhinolaryngology and Biocommunication, Louisiana State University Medical Center, New Orleans 70112-2234, USA. • Animals were stimulated 5 h/day, 5 days per week, for 8 weeks. • The animals were then perfused and the cochleae serially sectioned at 4 microm saving every 8th section. • We counted the number of intact SGCs and also measured SGC densities (number of neurons per mm2 of Rosenthal's canal). • The number of surviving spiral ganglion neurons was not significantly different (P > 0.05) between the implanted and the unimplanted ears in any of the experimental groups.

28. (3) Does electrical stimulation of deaf cochleae prevent spiral ganglion degeneration?Hear Res. 1999 Jul;133(1-2):27-39. Li L, Parkins CW, Webster DB.Department of Otorhinolaryngology and Biocommunication, Louisiana State University Medical Center, New Orleans 70112-2234, USA. • However, the spiral ganglion neuron densities were significantly elevated in the electrically stimulated ears (P < 0.001) but not in the implanted but not chronically stimulated ears (P > 0.05).

29. What do these studies tell us? –C. Berlin • Webster discovered that the brainstem of mice deprived of sound was mal-developed compared to mice properly stimulated. • Their studies demonstrate the same phenomenon on the side of the brain opposite a unilateral atresia. • His work suggested that conductive hearing loss in human infants would lead to mal-development of both the auditory and speech systems. * • Subsequent studies by many authors continue to support the notion that middle ear disease, as well as congenital hearing loss, have significant effects on the organization and efficiency of the central auditory system. • Today, in children who show evidence of auditory deprivation, we often recommend Fast ForWord™ as a tool to use neuroplasticity to mitigate the language, speech, and reading deficits that often accompany such histories. *(Since mice are altricial and develop hearing 21 days after birth, they are quite different from humans and other precocial species whose peripheral hearing organs are usually fully developed at birth. Doug often protested the use of his work as a premature proof that conductive hearing losses caused clinically significant central auditory problems in humans.)

30. Neural Plasticity 101 – (or PNB 300 Revisited) • An illustration of synapse enhancement

31. Long Term Potentiation • LTP is defined as the condition when the strength of tramsmission at many synapses increases with repetitive use. • Appears to take place in the amygdala* and hippocampal areas of brain • -see page 70 of CAPD text for reference • *the one of the four basal ganglia in each cerebral hemisphere that is part of the limbic system and consists of an almond-shaped mass of gray matter in the anterior extremity of the temporal lobe —called also amygdaloid nucleus

33. Plasticity 101 • The N-methyl D-aspartate receptor (NMDAR) is an ionotropic receptor for glutamate. Activation of NMDA receptors results in the opening of an ion channel that allows flow of Na+ and small amounts of Ca2+ ions into the cell and K+ out of the cell. • The AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor is a non-NMDA-type ionotropic receptor for glutamate that mediates fast synaptic transmission in the central nervous system (CNS). Its name is derived from its ability to be activated by the artificial glutamate analog, AMPA. AMPARs are found in many parts of the brain and are the most commonly found receptor in the nervous system.

34. NMDA AMPA

35. CA1 Hippocampus

38. Neurotransmitters that affect the membrane bring about an excitatory postsynaptic potential (EPSP). AMPA Receptor

43. Their Contribution • Their animal research demonstrates that neural plasticity can occur from manipulation of peripheral function (removal of vision and/or some peripheral hearing mechanism). • Much of their work illustrates the contribution of peripheral system function on neural plasticity – (e.g. increased plasticity for the vision deprived kangaroo rat..... and atrophy within ventral cochlear nucleus and spiral ganglion for animals whose peripheral systems have been compromised). • Their studies suggest that a degree of peripheral dysfunction can be overcome by changes in plasticity, and that neural degradation can occur when the peripheral system is damaged and there is no alternative stimulation modality.

44. Their Contribution • These observations form the basis of modern-day auditory rehabilitation strategies and the need for continued acoustic stimulation to preserve central function. • Neural stimulation strategies based upon their research are employed every day for both the young and the old. • The effects of their research form the basis of early childhood intervention programs - including early auditory stimulation with both cochlear implants and remedial amplification devices. • Their research provided the foundation for audiotory rehabilitation programs such as FastForward, EarRobics, and L.A.C.E. .

45. Take Home Message • I want to say just three words to you…. • Just three words • Are you listening? • Auditory Neural Plasticity

46. Thanks to the work of Douglas and Molly Webster

47. Bibliography • Cochlear nerve projections following organ of corti destruction. Webster DB, Webster M., Otolaryngology. 1978 Mar-Apr;86(2):ORL342-53. • The ear apparatus of the kangaroo rat, Dipodomys. Webster, D.B., Am J Anat. 1961 Mar;108:123-47. • Effects of neonatal conductive hearing loss on brain stem auditory nuclei. Webster DB, Webster M., Ann Otol Rhinol Laryngol. 1979 Sep-Oct;88(5 Pt 1):684-8 • Mouse brainstem auditory nuclei development. Webster DB, Webster M., Ann Otol Rhinol Laryngol Suppl. 1980 May-Jun;89(3 Pt 2):254-6 • Neonatal sound deprivation affects brain stem auditory nuclei. Webster DB, Webster M. Arch Otolaryngol. 1977 Jul;103(7):392-6.

48. Bibliography • A critical period during postnatal auditory development of mice.Webster DB. , Int J Pediatr Otorhinolaryngol. 1983 Nov;6(2):107-18. • Does electrical stimulation of deaf cochleae prevent spiral ganglion degeneration? Li L, Parkins CW, Webster DB., Hear Res. 1999 Jul;133(1-2):27-39. • Ear Structure and Function in Modern Mammals Webster DB. , American Zoologist 1966 6(3):451-466; doi:10.1093/icb/6.3.451 (Biology Department, New York University Bronx, New York)

49. The End questions? comments? observations?