- Jan 16, 2018
- 209
- Tinnitus Since
- 12/2017
- Cause of Tinnitus
- acustic trauma, neuro-lyme/rx co-op toxins
https://www.nature.com/articles/srep24907
In acquired sensorineural hearing loss, such as that produced by noise or aging, there can be massive loss of the synaptic connections between cochlear sensory cells and primary sensory neurons, without loss of the sensory cells themselves. Because the cell bodies and central projections of these cochlear neurons survive for months to years, there is a long therapeutic window in which to re-establish functional connections and improve hearing ability. Here we show in noise-exposed mice that local delivery of neurotrophin-3 (NT-3) to the round window niche, 24 hours after an exposure that causes an immediate loss of up to 50% loss of synapses in the cochlear basal region, can regenerate pre- and post-synaptic elements at the hair cell / cochlear nerve interface. This synaptic regeneration, as documented by confocal microscopy of immunostained cochlear sensory epithelia, was coupled with a corresponding functional recovery.
Recent work on noise-induced and age-related hearing loss shows that the most vulnerable elements in the inner ear are not the sensory cells, but their synapses with cochlear nerve terminals1. A noise exposure causing a large, but ultimately reversible, elevation of cochlear thresholds, can immediately, and permanently, destroy these synapses, thereby silencing up to 50% of the fibers in the cochlear nerve, despite no immediate or delayed loss of hair cells1,3. Although this cochlear synaptopathy does not elevate thresholds, the loss of neural channels likely causes difficulties understanding speech in noisy or reverberant environments2 and may also cause tinnitus3,4, the phantom sounds commonly brought on by acoustic overexposure. This type of cochlear synaptopathy has been called "hidden hearing loss"5, because the auditory deficits can hide behind a normal threshold audiogram.
In the adult ear, cochlear nerve fibers often degenerate after cochlear insult, including noise damage and ototoxic antibiotics6. This degeneration occurs with a variable time course, depending on the nature and severity of the insult; however, the unmyelinated terminal dendrites within the organ of Corti disappear first (within hours to days), followed more slowly by the peripheral axons in the osseous spiral lamina (within days to weeks), and, only on a much slower time course, the cell bodies in the spiral ganglion and their central axons that compose the cochlear nerve (over weeks to months and longer)7,8,9. Given that cochlear implants can continue to provide useful hearing for years after hair cell loss, these long-surviving neurons must remain electrically excitable and appropriately connected to their central targets10. Thus, in many types of sensorineural hearing loss, there is a long therapeutic window wherein a treatment to elicit neurite outgrowth could reconnect silenced cochlear ganglion cells with hair cells, and thereby potentially improve speech in noise performance and reduce tinnitus.
Neurotrophin-3 (NT-3) is a member of the neurotrophic factor family that contributes to neuronal differentiation, survival and axonal outgrowth via its interactions with TrkC receptors11,12. Neurotrophins are necessary for normal development of cochlear innervation13,14,15,16, and NT-3 is necessary for the formation and maintenance of hair cell ribbon synapses in the postnatal cochlea17. In the early postnatal ear, NT-3 is broadly expressed in the organ of Corti, but becomes restricted to the inner hair cells (IHCs) with a longitudinal gradient (apex > base) in the adult18,19.
Prior studies have shown that exogenous neurotrophins, delivered directly to the cochlear fluids, can prolong the survival of cochlear neurons after hair cell destruction by ototoxic drugs20. Furthermore, using transgenic overexpression of NT-3 by supporting cells in mice, we have shown partial synapse regeneration and partial recovery of cochlear neural responses after noise damage17. However, a more clinically relevant question is whether exogenous NT-3 can be locally delivered to the inner ear to reverse cochlear synapthopathy. Here, we show that NT-3, delivered at the round window, can regenerate hair cell synapses and restore sound-evoked neural function after a synaptopathic noise exposure. We also describe techniques for surgically accessing, and delivering drugs with a thermoreversible hydrogel to the round window in mice, without jeopardizing cochlear function. Considering that round-window drug delivery in humans could be accomplished via injection through the eardrum21, our results suggest a promising therapeutic approach for the treatment of cochlear synaptopathy, and for the tinnitus and auditory processing deficits it likely causes.
In acquired sensorineural hearing loss, such as that produced by noise or aging, there can be massive loss of the synaptic connections between cochlear sensory cells and primary sensory neurons, without loss of the sensory cells themselves. Because the cell bodies and central projections of these cochlear neurons survive for months to years, there is a long therapeutic window in which to re-establish functional connections and improve hearing ability. Here we show in noise-exposed mice that local delivery of neurotrophin-3 (NT-3) to the round window niche, 24 hours after an exposure that causes an immediate loss of up to 50% loss of synapses in the cochlear basal region, can regenerate pre- and post-synaptic elements at the hair cell / cochlear nerve interface. This synaptic regeneration, as documented by confocal microscopy of immunostained cochlear sensory epithelia, was coupled with a corresponding functional recovery.
Recent work on noise-induced and age-related hearing loss shows that the most vulnerable elements in the inner ear are not the sensory cells, but their synapses with cochlear nerve terminals1. A noise exposure causing a large, but ultimately reversible, elevation of cochlear thresholds, can immediately, and permanently, destroy these synapses, thereby silencing up to 50% of the fibers in the cochlear nerve, despite no immediate or delayed loss of hair cells1,3. Although this cochlear synaptopathy does not elevate thresholds, the loss of neural channels likely causes difficulties understanding speech in noisy or reverberant environments2 and may also cause tinnitus3,4, the phantom sounds commonly brought on by acoustic overexposure. This type of cochlear synaptopathy has been called "hidden hearing loss"5, because the auditory deficits can hide behind a normal threshold audiogram.
In the adult ear, cochlear nerve fibers often degenerate after cochlear insult, including noise damage and ototoxic antibiotics6. This degeneration occurs with a variable time course, depending on the nature and severity of the insult; however, the unmyelinated terminal dendrites within the organ of Corti disappear first (within hours to days), followed more slowly by the peripheral axons in the osseous spiral lamina (within days to weeks), and, only on a much slower time course, the cell bodies in the spiral ganglion and their central axons that compose the cochlear nerve (over weeks to months and longer)7,8,9. Given that cochlear implants can continue to provide useful hearing for years after hair cell loss, these long-surviving neurons must remain electrically excitable and appropriately connected to their central targets10. Thus, in many types of sensorineural hearing loss, there is a long therapeutic window wherein a treatment to elicit neurite outgrowth could reconnect silenced cochlear ganglion cells with hair cells, and thereby potentially improve speech in noise performance and reduce tinnitus.
Neurotrophin-3 (NT-3) is a member of the neurotrophic factor family that contributes to neuronal differentiation, survival and axonal outgrowth via its interactions with TrkC receptors11,12. Neurotrophins are necessary for normal development of cochlear innervation13,14,15,16, and NT-3 is necessary for the formation and maintenance of hair cell ribbon synapses in the postnatal cochlea17. In the early postnatal ear, NT-3 is broadly expressed in the organ of Corti, but becomes restricted to the inner hair cells (IHCs) with a longitudinal gradient (apex > base) in the adult18,19.
Prior studies have shown that exogenous neurotrophins, delivered directly to the cochlear fluids, can prolong the survival of cochlear neurons after hair cell destruction by ototoxic drugs20. Furthermore, using transgenic overexpression of NT-3 by supporting cells in mice, we have shown partial synapse regeneration and partial recovery of cochlear neural responses after noise damage17. However, a more clinically relevant question is whether exogenous NT-3 can be locally delivered to the inner ear to reverse cochlear synapthopathy. Here, we show that NT-3, delivered at the round window, can regenerate hair cell synapses and restore sound-evoked neural function after a synaptopathic noise exposure. We also describe techniques for surgically accessing, and delivering drugs with a thermoreversible hydrogel to the round window in mice, without jeopardizing cochlear function. Considering that round-window drug delivery in humans could be accomplished via injection through the eardrum21, our results suggest a promising therapeutic approach for the treatment of cochlear synaptopathy, and for the tinnitus and auditory processing deficits it likely causes.
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Read the rest in the full article:
https://www.nature.com/articles/srep24907
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