Noise-Induced Hearing Loss Restored in Mice Through Increased NT3 Production

There's gotta be much more to it than just spontaneously firing neurons. I'm one of the few users on this site I've spoken to that have lost the ability to feel. Truly feel. No connections to people anymore. No connections to my family. I would feel so much happiness from my hearing not even 2 years ago. Music is what truly moved me. It made me who I was. It's what built up the memories I had from the past years. Now life is just all logic in my brain. I struggle to even feel comfortable resting and struggle to wake up every morning.

https://www.sciencedaily.com/releases/2015/12/151214145956.htm
This change in emotional processing. There has got be more than just using something like "GABA" to calm down neuronal firings. I can't be the only one noticing a gigantic loss in my ability to emotionally understand this world and myself. Who I was before. Am I just crazy or are there mechanisms involved in our auditory system that allow "feel good" chemicals to take place? What the heck was I feeling from music so much before? My understanding of the past has already started to become distorted because of what's been going on.

 

You're not alone. I had the same 15 years ago and I'm barely ok now, but it need to be fixed, it is vital for well-being again. I'm sure there are many other people who suffer from it but unable to explain that, like the older persons almost brain dead because of hearing loss or those for whom sound was not that important in their life. It is like a pianist who would loose a huge amount of sensitivity in his hands. I'm sure once lost sensitivity is recovered in any body part the emotions come back more or less in their former state and our patience may reward if we are fixed one day, whatever advanced or poor proof between hearing and emotions since for now medicine is unfortunately still done through near impervious specialities and not enough through different specialities working together (i.e in this case hearing / brain)

 

You are right, I didn't read the paper carefully enough. The assumption is 1) more intense noise exposure = 2) more extensive cochlear damage = 3) more central gain = 4) higher spontaneous rate. This paper confirms that long-standing observation that noise exposure increasing spontaneous firing rate in the central auditory pathway but then presents data that challenge the assumption that more noise exposure induces a greater increase in spontaneous firing rate.

Two points to consider here: 1) Tinnitus is highly variable between individuals. Two people exposed to the same noise trauma can have very different outcomes. This study treats all mice within an exposure group as belonging to the same condition when, in fact, the brains of individual mice, like humans, can respond differently. (Yes, even though mice are inbred; identical DNA does not mean identical brain function) They have a reasonable number of neuron recordings in their study but they don't have a lot of individual mice and they don't subdivide their mice based on behavioral indications of tinnitus (at least not that I read). 2) The pathology that drives tinnitus waxes and wanes over time. They took one 'snapshot' of the the brain but the spontaneous firing rates may rise and fall as the brain wanders back and forth in adjusting its central gain.

There is always the chance of reaching an erroneous conclusion when you 1) don't take individual differences into account and 2) take one snapshot of a dynamic system and assume that it represents it stable operating point.

Maybe they are right, maybe they are wrong. In my estimation, this is an above-average research paper on tinnitus but there are still many caveats that have to be considered.

 

Yes, so true. SO true. There are (at least) two 'kernels' of neurological impairment underlying tinnitus: 1) the whole thing about pathology in the auditory processing centers of the brain (brain gain, GABA, nerve fibers, spontaneous rate increases etc. etc.) 2) how the rest of one's brain reacts to this invasive, unwanted phantom sound. One's ability to control a key sense and this introduces a major psychological stressor.

Regarding the second 'kernel', there is a deep and ancient connection in our brain between sound and emotion, particularly as it relates to music. This is disrupted when external sounds are distorted (thanks to a banged-up cochlea) and internally generated (thanks to a pathologically over-powered internal amplifier). The limbic centers and frontal cortex of your brain react to this disruption, which can manifest as anxiety, depression and anhedonia (limbic centers process emotional content and engender emotionally driven). When you read the work of Rauschecker on limbic system changes or the work of people like Gander and Howard, you really appreciate how widespread the effects of tinnitus are.

Call me an optimist, but my hope is that if we can turn down the central auditory amplifier (either by reconnecting the nerve to their hair cell or by directly manipulating the volume knob on the brain's amplifier) that the limbic system will fall into line.

Sorry this post was a little rushed. I have to finish writing a grant (on tinnitus). Such an important point that I couldn't resist responding.

 

http://hearinghealthfoundation.org/blog?blogid=253

"Recently, it became clear that loud signals can also damage the connecting interface between the hair cell and the auditory nerve. This interface is the synapse. When the synapse is disrupted, hearing is impaired even without the loss of hair cells, leading to a condition called synaptopathy.

Experiments using transgenic mice showed that elevating levels of a specific molecule called NT3 in the area of the synapse can heal synaptopathy caused by exposure to loud noise. Since transgenic technology is a research tool not applicable for clinical use on humans, it is now necessary to design methods for elevating NT3 in human ears, leading to repair of synaptopathy. This is an important task, because if left untreated, synaptopathy progresses to include nerve cell death and permanent hearing deficits.

One potential way to increase NT3 concentration in the cochlea is by the use of gene transfer technology, which is based on infecting cochlear cells with viruses that are engineered to secrete NT3 and not cause infections. A potential risk of this method is that the site of NT3 is not restricted to the area of the synapses affected by the synaptopathy; NT3 can influence other types of cells.

In my lab at the University of Michigan, we tested the outcome of injecting such viruses on the structure and function of normal (intact) ears. We determined that the procedure resulted in the deterioration of hearing thresholds, and the auditory nerve and its connectivity to the hair cells were also negatively affected.

This negative outcome indicates that treatment of synaptopathy should be based on a more specific way to provide NT3 in an area restricted to the synaptic region. My work with the Hearing Restoration Project is dedicated to optimization of gene transfer technology in the cochlea, and may assist in finding more detailed methods for NT3 gene transfer that better target affected cells."

 

Did the people with the Astaxanthin high dosing happen to develop orange palms or skin overall? Liver problems?

 

Not really, but it did grow me a beak and made me automatically retract my left leg when standing.

On a more serious note; no, astaxanthin didnt have such effects on me when I took it. I took 20mg daily without any effects (no side effects, but did nothing for the ears too). I was planning to increase the dosage, but I changed my mind as I read we need a more localized/targeted approach for NT3 provisioning, like @lapidus wrote above.

 

To be fair, the mice that they give tinnitus are probably begging for death at some point -.-

 

I volunteer to be the next mouse. For science.

 

Well, an extremely reliable source once told me they (mice) generally tell eachother that there are "far worse diseases to get in the lab" (like cancer) and hence "to be glad and just live with it".

If they are still overly concerned, they can however inquire at an Ear- Nose and Throat Mouse, who will tell them pretty much the same with the added advice to "run a hamster wheel in the background".

It is henceforth clear to me why scientists test new potential drugs on mice; both mice and men are very much alike indeed!

 

I think I just died. Thank you for this.

 

Does anyone know if the nt-3 research only applies to people with recent hearing loss?

I keep feeling like that if they master the ribbon synapse structure stuff, and it applies to people who had damage in distant past, then treatments will be much closer than anyone would ever think. The rest would involve growing new haircells/stereocilia, or giving old ones a fresh new breath of life.

I have been getting the impression that the nt-3 treatments will be available to all levels of hearing degeneration, while the haircell growth, atoh1, will be a little farther off unless they create a less invasive method of implementation sooner.

 

I asked the same question to Charles Liberman, precisely what is the therapeutic window for NT3 to be effective. His answer was: we really don't know yet. It can be months as well as years. This is a subject of current research.

 

As someone who is still within the first year, is there any way to contact anybody to try this? It sounds like it would just be a supplement, not even an injection or topical gel? Surely there should be some way to try it. If you are into Traditional Chinese Medicine, you know all kinds of "unscientific", and potentially dangerous supplements can be sold over the counter, and online (some Traditional Chinese Medicine uses asbestos to treat some illnesses).

EDIT: I see now that the major study is working on INJECTIONS to the middle ear.

If not, are there any proven natural/over the counter/dietary ways of increasing NT3 in the body?

EDIT: OK after reading the whole thread it sounds like 20mg of astaxanthin is my best bet

 

Holy cow dude, I'm sure you're aware that according to many dietary guidelines this dosage of D3 is considered dangerous right?

I tested somewhat deficient and pharmacists still question me when I say I take 4000IU a day.

 

Protection from noise-induced cochlear synaptopathy by virally mediated overexpression of NT3

Abstract
Noise exposures causing only transient threshold shifts can destroy auditory-nerve synapses without damaging hair cells. Here, we asked whether virally mediated neurotrophin3 (NT3) overexpression can repair this damage. CBA/CaJ mice at 6 wks were injected unilaterally with adeno-associated virus (AAV) containing either NT3 or GFP genes, via the posterior semicircular canal, 3 wks prior to, or 5 hrs after, noise exposure. Controls included exposed animals receiving vehicle only, and unexposed animals receiving virus. Thresholds were measured 2 wks post-exposure, just before cochleas were harvested for histological analysis. In separate virus-injected animals, unexposed cochleas were extracted for qRT-PCR. The GFP reporter showed that inner hair cells (IHCs) were transfected throughout the cochlea, and outer hair cells mainly in the apex. qRT-PCR showed 4- to 10-fold overexpression of NT3 from 1–21 days post-injection, and 1.7-fold overexpression at 40 days. AAV-NT3 delivered prior to noise exposure produced a dose-dependent reduction of synaptopathy, with nearly complete rescue at some cochlear locations. In unexposed ears, NT3 overexpression did not affect thresholds, however GFP overexpression caused IHC loss. In exposed ears, NT3 overexpression increased permanent threshold shifts. Thus, although NT3 overexpression can minimize noise-induced synaptic damage, the forced overexpression may be harmful to hair cells themselves during cochlear overstimulation.

Full article: https://www.nature.com/articles/s41598-019-51724-6