Icon for: Gabriel Ocker

GABRIEL OCKER

University of Pittsburgh
Years in Grad School: 3
Judges’ Queries and Presenter’s Replies
  • Icon for: Eileen Kowler

    Eileen Kowler

    Judge
    Faculty: Project PI
    May 20, 2013 | 04:54 p.m.

    What means are typically used to produce tinnitus in mice and how do these compare to those found in clinical populations?

  • Icon for: Gabriel Ocker

    Gabriel Ocker

    Lead Presenter
    May 21, 2013 | 09:30 a.m.

    Hi! Thanks for your question. Most people develop tinnitus via prolonged exposure to very loud sounds. Researchers used to induce tinnitus in lab rodents by injecting certain drugs (for example, salicylate) into the inner ear to cause damage to the hair cells. Now, they use a more directly comparable method; researchers induce tinnitus in lab animals by loud noise exposure. While the animal is anesthetized, narrow band-pass noise at (usually) 16kHz is played to one ear at ~100 dB (around the loudness of a rock concert). Afterwards, the mice are behaviorally tested to determine which ones develop tinnitus without hearing loss.

  • Icon for: Kristopher Irizarry

    Kristopher Irizarry

    Judge
    Faculty: Project Co-PI
    May 21, 2013 | 06:20 p.m.

    You describe how tinnitus can emerge from altered AHP currents via an increase in firing rate and covariability of spike train responses. Based on your current understanding of the biophysics underlying aberrant neuronal activity in this disease, if you could ask a pharmaceutical company to manufacture a perfect treatment for this disorder, what would you ask that the drug accomplish at the neuronal and biophysical level?

  • Icon for: Gabriel Ocker

    Gabriel Ocker

    Lead Presenter
    May 22, 2013 | 03:44 p.m.

    Thanks for the question! Our understanding of the biophysics underlying tinnitus-related activity is really limited to the dorsal cochlear nucleus (DCN), which is involved in the development of the disorder but is not necessary for maintaining it. (Removing the cochlear nucleus a few weeks after tinnitus induction does not affect behavioral evidence of the disorder in lab animals.) Our collaborators have determined which potassium channel is altered in DCN neurons and have a drug which, by activating that channel during acoustic overexposure, can prevent development of the disorder in mice (Li, Choi & Tzounopoulos, coming out in Proc. Natl. Acad. Sci. sometime soon).

    In order to treat the disorder after it has been allowed to develop, we would probably need to target neurons higher in the auditory system, in auditory cortex (and maybe also the inferior colliculus or the thalamus). It’s known that neurons in those areas are hyperactive in tinnitus, and also that neurons in primary auditory cortex are hyper-synchronous. The biophysical changes underlying hyperactivity in those areas, however, aren’t known for sure. One of the drugs currently used to treat tinnitus, Alprazolam, targets inhibitory neurotranmission. There isn’t any data that I know of about tinnitus-related changes in the intrinsic properties (like the AHP) of neurons outside the DCN; most previous work has focussed on the hypotheses that tinnitus involves changes in the balance between excitatory and inhibitory neurotransmission, and in the structure of connections between neurons in auditory cortex. At the neural level, a drug to treat tinnitus should restore the average spontaneous firing rates and the healthy (low) correlation between neurons’ spontaneous activity in auditory cortex. At the biophysical level, a drug that would allow the healthy reorganization of connections in auditory cortex might be able to eliminate the phantom sound.

  • Icon for: Mary Gauvain

    Mary Gauvain

    Judge
    Faculty: Project Co-PI
    May 21, 2013 | 07:36 p.m.

    You introduce tinnitus as involving a phantom sound, however, your results suggest that it may be a confused signal, or am I misinterpreting what you found?

  • Icon for: Gabriel Ocker

    Gabriel Ocker

    Lead Presenter
    May 22, 2013 | 02:09 p.m.

    The defining feature of tinnitus is the phantom sound – the ‘ringing in the ears’, which is due to some long-term change in neural activity in the auditory system. Somehow, spontaneous (non-sound-driven) activity comes to represent a sound, causing tinnitus patients to hear it although no external stimulus is driving the perception. Our work links a biophysical change in particular neurons to changes in their spontaneous activity that make it more like a sound-driven signal.

  • Icon for: Timothy Waring

    Timothy Waring

    Judge
    Faculty
    May 21, 2013 | 10:08 p.m.

    Interesting work here. Is it possible that any of the perceived sound is not generated in the cochlear region, but elsewhere during perception processing? Or if it did, would that still be tinnitus?

  • Icon for: Gabriel Ocker

    Gabriel Ocker

    Lead Presenter
    May 22, 2013 | 01:40 p.m.

    Thanks for the question. Tinnitus takes some time to develop and stabilize, after which it is generated by activity in the central nervous system.

    Removing the cochlea itself (the inner ear) a few weeks after tinnitus induction does not stop the behavior evidence of the disorder in lab animals. The same is true for removal of the cochlear nucleus (the earliest auditory center in the central nervous system – this study is about the neurons in the dorsal part of that area that project onwards to the next auditory center).

    So in fully-developed tinnitus, the perceived sound is generated higher in the auditory system – probably involving activity in auditory cortex.

  • Icon for: Timothy Waring

    Timothy Waring

    Judge
    Faculty
    May 22, 2013 | 09:42 p.m.

    Oh, thanks for the explanation. So then how does your research lead toward solutions?

  • Icon for: Gabriel Ocker

    Gabriel Ocker

    Lead Presenter
    May 22, 2013 | 11:17 p.m.

    My research suggests that a drug that activates AHP currents (reversing the loss associated with tinnitus) in the projection neurons of the dorsal cochlear nucleus during the period immediately after exposure to traumatically loud sounds could prevent development of tinnitus. Our experimental collaborators have tested this idea in mice and seen that it is, indeed, the case (Li, Choi & Tzounopoulos, to appear in Proc. Natl. Acad. Sci.). The work presented here is an example of how understanding the particular biophysical mechanism responsible for changes in the activity of individual neurons can have specific implications for population-level activity and, ultimately, sensory perception.

  • Icon for: Ayelet Gneezy

    Ayelet Gneezy

    Judge
    Faculty
    May 22, 2013 | 01:03 a.m.

    I am not familiar with tinnitus at all, so thanks for that.
    Could you please tell me to what extent tinnitus and phantom limb syndrome are (dis)similar, and whether you think your findings could provide insights that would be useful for understanding/treating other disorders?

  • Icon for: Gabriel Ocker

    Gabriel Ocker

    Lead Presenter
    May 22, 2013 | 07:35 p.m.

    Hi! Thanks for your question! Both tinnitus and phantom limb syndrome are defined by a phantom percept – spontaneous neural activity representing a stimulus that doesn’t exist. It’s hard to say how similar or disimilar tinnitus and phantom limb syndrome are from a biophysical perspective, because we don’t know the biophysical causes for the changes responsible for the long-term phantom percept in either case. Both involve changes in the structure of sensory cortex. In tinnitus, the area of primary auditory cortex representing the frequency of the tinnitus percept is enlarged, while in phantom limb after amputation it’s been shown that the area of primary somatosensory cortex responsible for representing the amputated limb starts to represent other body parts instead.

    Tinnitus is characterized by neural hyperactivity and it shares this with a number of other disorders, like (for example) neuropathic pain and epilepsy. A lot of research is aimed at isolating biophysical changes associated with those disorders. As far as I know, more work in neuropathic pain has been done on isolating changes in intrinsic properties of neurons, while research in epilepsy has been more focussed on the idea that it is caused by an imbalance between excitatory and inhibitory neurotransmission in the cortex. In both of those cases and in general, using mathematical modeling to link biophysical changes to effects on pairwise- and population-level activity could help reveal which molecular changes are the most important and the best targets for drug therapies.

Presentation Discussion
  • Icon for: Joni Falk

    Joni Falk

    Faculty: Project PI
    May 23, 2013 | 04:23 p.m.

    Thanks for this. Having a relative with tinnitus, I was particularly interested in this. Can you see any implications from your work for possible treatments for this disorder?

    Also, and unrelated, you may be interested in the following presentation
    http://posterhall.org/igert2013/posters/340 as you seem to have some overlapping areas of expertise.

    Thanks for this presentation.

  • Icon for: Gabriel Ocker

    Gabriel Ocker

    Lead Presenter
    May 23, 2013 | 06:31 p.m.

    Hi, Joni! Thanks for the question. Our collaborators have actually isolated that particular membrane channel responsible for the change I modelled here, and found a drug that activates it (reversing the loss of function seen in tinnitus). In mice, administering that drug immediately following noise exposure blocks development of tinnitus (Li, Choi & Tzounopoulos, to appear in Proc. Natl. Acad. Sci.)

    Unfortunately, however, this work doesn’t suggest any treatments for tinnitus after it has developed – when it is maintained by dysfunctional spontaneous activity in higher auditory areas.

  • Icon for: Joni Falk

    Joni Falk

    Faculty: Project PI
    May 23, 2013 | 07:50 p.m.

    Thanks for your reply!

  • Icon for: Joni Falk

    Joni Falk

    Faculty: Project PI
    May 24, 2013 | 12:00 p.m.

    Gabriel, wanted to tell you (if you have not already found it) that there is another poster on tinnitus. You can still comment on that poster and converse with the presenter. Look at: http://posterhall.org/igert2013/posters/359

  • Further posting is closed as the event has ended.