St. Jude's Discovers That Controlling Adenosine Induces Auditory Neuroplasticity

[NatureHiker]

https://www.eurekalert.org/pub_releases/2017-06/sjcr-cas062717.php

Previously, Jay Blundon at St Jude Children's Research Hospital in Memphis, Tennessee, and his colleagues discovered that levels of a chemical called adenosine in the thalamus – a part of the brain involved in sensory processing – rise as mice age. This activates a pathway that impairs learning in the brain's auditory cortex, so when old mice are played two tones that are close in pitch, they are unable to discriminate between them.

The team has now found that using genetic tools or drugs to reduce adenosine signalling makes the mice able to tell the difference.

Neuronal changes

To demonstrate this, the researchers exposed old mice to a continuous sound as background noise. Then, they played a slightly different tone in addition. The mice were startled by the new sound, showing they were able to hear it as being different from the background tone.

When the team blocked adenosine signalling, they observed an increase in the number of neurons in the auditory cortex that responded to sounds – a process called neuroplasticity. This may be why tone discrimination improved in the aged mice, says Blundon.

If neuroplasticity and tone discrimination could be enhanced in elderly people, it might be easier for them to learn new musical skills or languages, says Blundon. "Learning a second language later in life can often be more difficult because of your inability to accurately hear differences in phonemes," he says. Phonemes are the distinct units of sound that make up languages.

Improving auditory plasticity could also help in conditions like stroke and tinnitus, says Blundon. Different auditory neurons could potentially be trained to take over the role of those destroyed by stroke, or to replace those that become hyperactive in tinnitus, he says. "But we're far, far away from any human studies," he says.

https://www.newscientist.com/articl...ar-similar-sounds-but-a-drug-can-change-that/

http://science.sciencemag.org/content/356/6345/1352

 

[jer]

How would this discovery be able to help us?

 

[adagio]

Seems interesting to me. There was someone believing tinnitus could come from reorganizing neurons related to sounds after receiving a shock. Maybe we need some therapeutic measure (for example somehow stimulated by the sounds we hear), in addition to elevated neuroplacticity.

 

[NatureHiker]

How would this discovery be able to help us?

Basically this is just a better understanding of auditory neuroplasticity and how to possibly enhance it. Being able to enhance auditory neuroplasticity means that we could potentially "rewire" the brain to use different auditory neurons instead of the ones that are hyperactive as in tinnitus. As they said, it could possible to be able to control adenosine signaling in the brain and therefore auditory neuroplasticity through a gene or drug therapy.

Improving auditory plasticity could also help in conditions like stroke and tinnitus, says Blundon. Different auditory neurons could potentially be trained to take over the role of those destroyed by stroke, or to replace those that become hyperactive in tinnitus, he says. "But we're far, far away from any human studies," he says.

I'm sure there's a better explanation out there as neuroplasticity is a very detailed subject, but that's the gist of it.

I think we'll see inner ear hair cell and synapse regeneration and kv potassium channel drugs way way way before we see anything regarding adenosine, but it's still another potential weapon in the arsenal we have in the battle against tinnitus.

 

[Casper]

This activates a pathway that impairs learning in the brain's auditory cortex, so when old mice are played two tones that are close in pitch, they are unable to discriminate between them.

The team has now found that using genetic tools or drugs to reduce adenosine signalling makes the mice able to tell the difference.

I once came across a blog where someone made a simple app that would play two tones similar in pitch, and ask you to decide if they're the same or different. He claimed that it could encourage the brain to adapt and relieve tinnitus. Of course, there's no scientific evidence for this, but reading this article made me think about it again. Unfortunately, I can't find that blog now.

 

[ebbie]

I once came across a blog where someone made a simple app that would play two tones similar in pitch, and ask you to decide if they're the same or different. He claimed that it could encourage the brain to adapt and relieve tinnitus. Of course, there's no scientific evidence for this, but reading this article made me think about it again. Unfortunately, I can't find that blog now.

Hello, this one? http://plasticity.szynalski.com/

 

[Casper]

Hello, this one? http://plasticity.szynalski.com/

Yes!

 

[NatureHiker]

I once came across a blog where someone made a simple app that would play two tones similar in pitch, and ask you to decide if they're the same or different. He claimed that it could encourage the brain to adapt and relieve tinnitus. Of course, there's no scientific evidence for this, but reading this article made me think about it again. Unfortunately, I can't find that blog now.

WUSTL got millions in NIHL grants to fund research about using auditory training games to combat hearing loss. They're now actively helping seniors "train" their hearing and in trials to see if they can help kids with hearing loss.

http://www.stltoday.com/lifestyles/...cle_00c017e2-49aa-5132-acb2-6966c7c524d9.html

Neuroplasticity seems to be something more research is geared towards understanding and utilizing.

 

[Casper]

Neuroplasticity seems to be something more research is geared towards understanding and utilizing.

That makes sense, I suppose --- to eliminate tinnitus, either repair the damaged hair cells, or rewire the brain not to use those cells. That's a very simplified understanding, but I haven't yet had the time to do enough reading to get a thorough understanding of the different research directions. Regardless, I hope they see significant results.

 

[NatureHiker]

Interestingly it seems adenosine and hearing/tinnitus has been researched by MIT back in 2007. https://www.sciencedaily.com/releases/2007/10/071031152922.htm

Apparently they discovered in mice that supporting cells in the cochlea released adenosine and haircells have receptors for adenosine. When the supporting cells released adenosine it caused the haircells to react the same as if sound was present.

Although there is no ATP floating around at that point, the hair cells continue to be able to respond to it, and exposure to loud sounds can trigger ATP release in the ear. Bergles suspects that "if ATP were released by the remaining support cells, it may cause the sensation of sound when there is none," a condition known as tinnitus or ringing in the ears. Alternatively, he notes that bursts of activity might trigger changes in the connectivity of neurons in the brain, just like it does during development, eventually leading to abnormal activity that is perceived as sound.

That's interesting and a new theory i just learned about. Supporting cells releasing adenosine and causing haircells to react and cause tinnitus. Maybe that's why in this study 67% of the people who had their auditory nerve severed saw relief from their tinnitus. https://www.ncbi.nlm.nih.gov/pubmed/7671835

I'm just happy more research is being done in this area and someday we'll be able to understand how tinnitus works exactly.

 

[Neuro]

The articles from most of the science reporters (Scientific American, New Scientist, MedicalXpress) have gotten the Blundon et al. paper incorrect in several ways, so it's better to go to the primary article (and even the perspective written in the same Science issue) for a better understanding. But the theory behind using an adenosine blockers plus sound therapy is very similar to that published by Mike Kilgard of UT Dallas using vagus nerve stimulation plus sound therapy. Vagus nerve stimulation releases acetylcholine in the auditory cortex. Blundon et al (2011, 2013 and now 2017) have shown that acetylcholine reduces adenosine signaling which enables neuroplasticity in the adult brain (juvenile brains have much less adenosine so their brains are much more plastic naturally). By combining an adenosine blocker (very specific to the A1 receptor) with sound training as is done with vagus nerve stimulation (supply a wide range of sound frequencies EXCLUDING the tinnitus frequency), it is thought that the area of the brain receiving the hyperactive signalling with be re-tuned with neural pathways that are not hyperactive. At least that's the idea. Taking a pill along with the sound training is certainly a much less invasive procedure than VNS. But the new study has only been done in mice. Whether it will work in humans remains to be seen... much less the fact that all kinds of side effects have to be monitored in human clinical trials first.
JAB

 

[HomeoHebbian]

The articles from most of the science reporters (Scientific American, New Scientist, MedicalXpress) have gotten the Blundon et al. paper incorrect in several ways, so it's better to go to the primary article (and even the perspective written in the same Science issue) for a better understanding. But the theory behind using an adenosine blockers plus sound therapy is very similar to that published by Mike Kilgard of UT Dallas using vagus nerve stimulation plus sound therapy. Vagus nerve stimulation releases acetylcholine in the auditory cortex. Blundon et al (2011, 2013 and now 2017) have shown that acetylcholine reduces adenosine signaling which enables neuroplasticity in the adult brain (juvenile brains have much less adenosine so their brains are much more plastic naturally). By combining an adenosine blocker (very specific to the A1 receptor) with sound training as is done with vagus nerve stimulation (supply a wide range of sound frequencies EXCLUDING the tinnitus frequency), it is thought that the area of the brain receiving the hyperactive signalling with be re-tuned with neural pathways that are not hyperactive. At least that's the idea. Taking a pill along with the sound training is certainly a much less invasive procedure than VNS. But the new study has only been done in mice. Whether it will work in humans remains to be seen... much less the fact that all kinds of side effects have to be monitored in human clinical trials first.
JAB

Just wanted to point out that the Blundon paper is describing a totally different mechanism for brain plasticity than the changes that are thought to underlie tinnitus or the changes that underlie brain reorganization following vagus nerve stimulation. Put simply, there are three fairly independent sets of mechanisms (i.e. cellular pathways) that drive long-lasting plasticity in sensory areas of the cerebral cortex and thalamus (where these studies were done). 1) Homeostatic plasticity, which describes processes that allows cells and circuits to regulate their own excitability. 2) Hebbian plasticity, or associative plasticity, wherein properly timed release of neuromodulators and reliably patterns of spiking between one cell and another can lead to long-term changes in connection strength. 3) critical period plasticity, or exposure-based plasticity, when the passively experienced statistical properties of the sensory world can sculpt the patterns of connections. This paper really addresses a mechanism for this third form of plasticity. There is not a strong connection to tinnitus, which draws more heavily on the first two. Not to say that this paper isn't interesting or might someday be important for tinnitus.

 

[Neuro]

Apologies to the lay readers who may not understand the nitty gritty details of the following. Skip to the bottom 3 paragraphs for the summary:

Actually HomeoHebbian, you're mistaken. Our paper does indeed relate directly to vagus nerve stimulation and both critical period plasticity as well as homeostatic plasticity and Hebbian. There are aspects of all three that come together in this case, and keeping them in distinct categories is an oversimplification. Mike Kilgard's research showed that vagus nerve stimulation timed with sound stimuli was able to induce a passive auditory cortex plasticity in adult rats similar to the plasticity in juveniles (given sound stimulation alone, no VNS) before the end of the critical period. But our papers, first in 2011 and 2013 in brain slices and now in 2017 in vivo, showed the mechanism whereby this may work. During the critical period for auditory plasticity, passive sound triggers synaptic plasticities in the synapses between thalamus and cortex. So this would be homosynaptic plasticity. But with age (after the critical period) these synapses show a presynaptic autoinhibition of glutamate release due to increased synaptic levels of adenosine (the adenosine producing enzyme CD73 is found in higher levels in adult thalamus). We showed that adenosine actually reduced glutamate release from the thalamus, making synaptic plasticity more difficult to achieve. These adult brains can still show auditory cortex plasticity, but you have to time the sound stimulus with a reward or punishment. What does reward or punishment do? It activates the nucleus basalis to release acetylcholine throughout the brain and including the synapses between thalamus and auditory cortex. Kilgard actually bypassed the reward or punishment and went straight to VNS, which similarly releases ACh throughout the brain. In the case where you have sound stimuli timed with VNS or timed with reward or punishment, that's more your description of Hebbian (or heterosynaptic) plasticity. What our 2011 and 2013 papers showed was the mechanism whereby ACh allowed or enabled the plasticity in the adult brain. ACh activates presynaptic receptors that turn off the presynaptic adenosine signaling, allowing the adult thalamus to release "juvenile" levels of glutamate, unfettered by adenosine autoinhibition. Our Science paper this June 30 just recently backed this up in live animals, where we genetically modified the adult mice to have little or no adenosine signaling, and we showed passive auditory cortex plasticity in adults similar to that in juveniles (still within the critical period).

How does this relate to tinnitus? (sorry it took so long to get here). Similar to VNS, if you provide a variety of sound frequencies (but NOT the tinnitus frequency) to the patient (repeated sound pulses for an hour or two, daily, for a couple of weeks) either during simultaneous VNS (or perhaps now with an adenosine A1 receptor blocker), the synaptic connections of these sound delivering (thalamic) neurons may become tuned to these new frequencies (by strengthing the synaptic connections specific to those sound frequencies. And the hyperactive neurons that had previously produced the perception of constant ringing will be trained at a new frequency. Alternatively, it could also be that the cortical neurons responsible for the ringing will receive strengthened input from thalamic neurons of adjacent frequency and/or the hyperactive thalamic neurons themselves through retraining will lose the hyperactivity). All of this relates to excitatory pathways... we have reason to believe that inhibitory connections are involved to.

This could also relate to stroke patients. Following a lesion to the brain that produces difficulty perhaps in speech production (whether that lesion is in the auditory cortex or another sensory (perhaps even motor?) cortex... rehab training to restore normal speech may be slow to progress or may fail entirely because the remaining healthy neuronal pathways can't be retrained. But with VNS or perhaps an adenosine A1 blocker, synaptic plasticity may once again be possible and training the remaining connections may be more successful.

And by the way, even though caffeine is an adenosine blocker, we tried it in our mice (100% Columbian, not Starbucks...I kid, I kid).. no we really tried caffeine and it didn't work. We think that's because caffeine is a sloppy drug, meaning that not only does it block adenosine A1 receptors, at also blocks A2a and A2b receptors. Some of these receptor actions are excitatory and some are inhibitory, so blocking all of the above may send mixed signals as far as synaptic plasticity is concerned. We only had success with a very specific adenosine A1 receptor blocker. So are we ready to start trying out A1 blockers to cure tinnitus? Not hardly.... our research was done only in mice. There are many other physiological processes that could be altered by an A1 antagonist, leading to who knows what kind of side effects... so the mechanism whereby we turn off adenosine autoinhibition with as few side effects as possible is something that has to be dealt with for certain.
JAB