Gamma-aminobutyric acid and glutamic acid levels in the auditory pathway of rats with chronic tinnitus: a direct determination using high resolution point-resolved proton magnetic resonance spectroscopy (H-MRS)

Thomas Brozoski, Boris Odintsov, Carol Bauer, Thomas Brozoski, Boris Odintsov, Carol Bauer

Abstract

Damage to the auditory system following high-level sound exposure reduces afferent input. Homeostatic mechanisms appear to compensate for the loss. Overcompensation may produce the sensation of sound without an objective physical correlate, i.e., tinnitus. Several potential compensatory neural processes have been identified, such as increased spontaneous activity. The cellular mechanisms enabling such compensatory processes may involve down-regulation of inhibitory neurotransmission mediated by γ-amino butyric acid (GABA), and/or up-regulation of excitatory neurotransmission, mediated by glutamic acid (Glu). Because central processing systems are integrated and well-regulated, compensatory changes in one system may produce reactive changes in others. Some or all may be relevant to tinnitus. To examine the roles of GABA and Glu in tinnitus, high resolution point-resolved proton magnetic resonance spectroscopy ((1)H-MRS) was used to quantify their levels in the dorsal cochlear nucleus (DCN), inferior colliculus (IC), medial geniculate body (MGB), and primary auditory cortex (A1) of rats. Chronic tinnitus was produced by a single high-level unilateral exposure to noise, and was measured using a psychophysical procedure sensitive to tinnitus. Decreased GABA levels were evident only in the MGB, with the greatest decrease, relative to unexposed controls, obtained in the contralateral MGB. Small GABA increases may have been present bilaterally in A1 and in the contralateral DCN. Although Glu levels showed considerable variation, Glu was moderately and bilaterally elevated both in the DCN and in A1. In the MGB Glu was increased ipsilaterally but decreased contralaterally. These bidirectional and region-specific alterations in GABA and Glu may reflect large-scale changes in inhibitory and excitatory equilibrium accompanying chronic tinnitus. The present results also suggest that targeting both neurotransmitter systems may be optimal in developing more effective therapeutics.

Keywords: 1H-MRS; GABA; dorsal cochlear nucleus; glutamate; inferior colliculus; medial geniculate; primary auditory cortex; tinnitus animal model.

Figures

Figure 1
Figure 1
Calibration of GABA spectra using an array of phantoms, each containing 10 mM GABA in sterile normal saline, distributed across the imaging field of view. Using multiple phantoms arrayed throughout the field of view illustrates optimized field shimming and selection of the least-variant spectral peak, from among the multiplets at each location, used to quantify the compound of interest (in this example, GABA).
Figure 2
Figure 2
Calibration spectra of GABA and Glu, obtained using the same scanning parameters (see Methods for details) used to capture VOI spectra. The peak, from among the multiplets, used to quantify GABA and Glu is shown by the pointer.
Figure 3
Figure 3
Examples of tinnitus in individual rats. (A) A rat with focal narrow-band tinnitus in the vicinity of 20 kHz, and (B) A rat with rather broad-band tinnitus localized between 10 and 24 kHz. Error bars show the standard error of the mean of the unexposed group. Relative rate of lever pressing, as indicated by the suppression ratio (see Text), is shown on the y-axis, and test stimulus across stimulus levels (dB, SPL) is shown on the x-axis.
Figure 4
Figure 4
Frequency-specific group evidence of tinnitus. The statistics in each panel represent a comparison of exposed and unexposed groups for stimulus levels above the OFF setting. As in Figure 3, relative lever pressing is shown on the y-axis and test stimulus across levels is shown on the x-axis. Error bars show the standard error of the mean.
Figure 5
Figure 5
GABA and Glu levels (mM/ml) in the dorsal cochlear nucleus (DCN) of exposed and unexposed rats. Top panel: size and location of the VOI; Mid panel: a typical individual 1H-MRS; Lower panel: group average GABA and Glu levels. Error bars show the standard error of the mean. Asterisk next to the axis label indicates the direct pathway with respect to the trauma-exposed ear. Asterisk next to the data bar indicates statistical significance (p ≤ 0.05).
Figure 6
Figure 6
GABA and Glu levels (mM/ml) in the inferior colliculus (IC) of exposed and unexposed rats. No significant differences were obtained between exposed and unexposed animals in the IC. Graphic parameters as in Figure 5.
Figure 7
Figure 7
GABA and Glu levels (mM/ml) in the medial geniculate body (MGB) of exposed and unexposed rats. GABA and Glu concentrations were significantly lower in the contralateral MGB of exposed animals. Graphic parameters as in Figure 5.
Figure 8
Figure 8
GABA and Glu levels (mM/ml) in primary auditory cortex (A1) of exposed and unexposed rats. Although differences between exposed and unexposed animals were not statistically significant, significance levels may have been masked by measurement variability stemming from field anisotropy rather that neurochemical variability. Graphic parameters as in Figure 5.
Figure 9
Figure 9
Auditory brainstem response thresholds for exposed and unexposed rats. Top panel: thresholds before and immediately after acoustic exposure. Significant threshold elevation was evident only in the exposed ear. Bottom panel: thresholds prior to spectroscopy show normal levels in both groups. Error bars show the standard error of the mean.

References

    1. Bauer C. A., Brozoski T. J. (2001). Assessing tinnitus and prospective tinnitus therapeutics using a psychophysical animal model. J. Assoc. Res. Otolaryngol. 2, 54–64.
    1. Bauer C. A., Turner J. G., Caspary D. M., Myers K. S., Brozoski T. J. (2008). Tinnitus and inferior colliculus activity in chinchillas related to three distinct patterns of cochlear trauma. J. Neurosci. Res. 86, 2564–2578. 10.1002/jnr.21699
    1. Brozoski T. J., Bauer C. A. (2008). Learning about tinnitus from an animal model. Semin. Hear. 29, 242–258.
    1. Brozoski T. J., Bauer C. A., Caspary D. M. (2002). Elevated fusiform cell activity in the dorsal cochlear nucleus of chinchillas with psychophysical evidence of tinnitus. J. Neurosci. 22, 2383–2390.
    1. Brozoski T. J., Caspary D. M., Bauer C. A., Richardson B. D. (2010). The effect of supplemental dietary taurine on tinnitus and auditory discrimination in an animal model. Hear. Res. 270, 71–80. 10.1016/j.heares.2010.09.006
    1. Brozoski T. J., Ciobanu L., Bauer C. A. (2007a). Central neural activity in rats with tinnitus evaluated with manganese-enhanced magnetic resonance imaging (MEMRI). Hear. Res. 228, 168–179. 10.1016/j.heares.2007.02.003
    1. Brozoski T. J., Spires T. J., Bauer C. A. (2007b). Vigabatrin, a GABA transaminase inhibitor, reversibly eliminates tinnitus in an animal model. J. Assoc. Res. Otolaryngol. 8, 105–118. 10.1007/s10162-006-0067-2
    1. Brozoski T. J., Wisner K. W., Sybert L. T., Bauer C. A. (2012). Bilateral dorsal cochlear nucleus lesions prevent acoustic-trauma induced tinnitus in an animal model. J. Assoc. Res. Otolaryngol. 13, 55–66. 10.1007/s10162-011-0290-3
    1. Dong S., Rodger J., Mulders W. H., Robertson D. (2010). Tonotopic changes in GABA receptor expression in guinea pig inferior colliculus after partial unilateral hearing loss. Brain Res. 1342, 24–32. 10.1016/j.brainres.2010.04.067
    1. Gu J. W., Halpin C. F., Nam E. C., Levine R. A., Melcher J. R. (2010). Tinnitus, diminished sound-level tolerance, and elevated auditory activity in humans with clinically normal hearing sensitivity. J. Neurophysiol. 104, 3361–3370. 10.1152/jn.00226.2010
    1. Guitton M. J., Dudai Y. (2007). Blockade of cochlear NMDA receptors prevents long-term tinnitus during a brief consolidation window after acoustic trauma. Neural Plast. 2007, 80904. 10.1155/2007/80904
    1. Halonen L. M., Sinkkonen S. T., Chandra D., Homanics G. E., Korpi E. R. (2009). Brain regional distribution of GABA(A) receptors exhibiting atypical GABA agonism: roles of receptor subunits. Neurochem. Int. 55, 389–396. 10.1016/j.neuint.2009.04.008
    1. Hogsden J. L., Rosen L. G., Dringenberg H. C. (2011). Pharmacological and deprivation-induced reinstatement of juvenile-like long-term potentiation in the primary auditory cortex of adult rats. Neuroscience 186, 208–219. 10.1016/j.neuroscience.2011.04.002
    1. Holt A. G., Bissig D., Mirza N., Rajah G., Berkowitz B. (2010). Evidence of key tinnitus-related brain regions documented by a unique combination of manganese-enhanced MRI and acoustic startle reflex testing. PLoS One 5, e14260. 10.1371/journal.pone.0014260
    1. Kaltenbach J. A., Godfrey D. A. (2008). Dorsal cochlear nucleus hyperactivity and tinnitus: are they related? Am. J. Audiol. 17, S148–S161. 10.1044/1059-0889(2008/08-0004)
    1. Kaltenbach J. A., Zacharek M. A., Zhang J., Frederick S. (2004). Activity in the dorsal cochlear nucleus of hamsters previously tested for tinnitus following intense tone exposure. Neurosci. Lett. 355, 121–125. 10.1016/j.neulet.2003.10.038
    1. Kullmann D. M., Lamsa K. P. (2011). LTP and LTD in cortical GABAergic interneurons: emerging rules and roles. Neuropharmacology 60, 712–719. 10.1016/j.neuropharm.2010.12.020
    1. Llinas R., Urbano F. J., Leznik E., Ramirez R. R., van Marle H. J. (2005). Rhythmic and dysrhythmic thalamocortical dynamics: GABA systems and the edge effect. Trends Neurosci. 28, 325–333. 10.1016/j.tins.2005.04.006
    1. Lovinger D. M. (2010). Neurotransmitter roles in synaptic modulation, plasticity and learning in the dorsal striatum. Neuropharmacology 58, 951–961. 10.1016/j.neuropharm.2010.01.008
    1. Middleton J. W., Kiritani T., Pedersen C., Turner J. G., Shepherd G. M., Tzounopoulos T. (2011). Mice with behavioral evidence of tinnitus exhibit dorsal cochlear nucleus hyperactivity because of decreased GABAergic inhibition. Proc. Natl. Acad. Sci. U.S.A. 108, 7601–7606. 10.1073/pnas.1100223108
    1. Mlynarik V., Cudalbu C., Xin L., Gruetter R. (2008). 1H NMR spectroscopy of rat brain in vivo at 14.1Tesla: improvements in quantification of the neurochemical profile. J. Magn. Reson. 194, 163–168. 10.1016/j.jmr.2008.06.019
    1. Muhr P., Rosenhall U. (2011). The influence of military service on auditory health and the efficacy of a Hearing Conservation Program. Noise Health 13, 320–327. 10.4103/1463-1741.82965
    1. Nondahl D. M., Cruickshanks K. J., Wiley T. L., Klein R., Klein B. E., Tweed T. S. (2002). Prevalence and 5-year incidence of tinnitus among older adults: the epidemiology of hearing loss study. J. Am. Acad. Audiol. 13, 323–331.
    1. Norena A. J. (2011). An integrative model of tinnitus based on a central gain controlling neural sensitivity. Neurosci. Biobehav. Rev. 35, 1089–1109. 10.1016/j.neubiorev.2010.11.003
    1. Odintsov B. (2011). Tunable Radio-Frequency Coil. USA patent application 61081954. November 1, 2011.
    1. Olah S., Fule M., Komlosi G., Varga C., Baldi R., Barzo P., Tamas G. (2009). Regulation of cortical microcircuits by unitary GABA-mediated volume transmission. Nature 461, 1278–1281. 10.1038/nature08503
    1. Puts N. A., Edden R. A., Evans C. J., Mcglone F., Mcgonigle D. J. (2011). Regionally specific human GABA concentration correlates with tactile discrimination thresholds. J. Neurosci. 31, 16556–16560. 10.1523/JNEUROSCI.4489-11.2011
    1. Rauschecker J. P., Leaver A. M., Muhlau M. (2010). Tuning out the noise: limbic-auditory interactions in tinnitus. Neuron 66, 819–826. 10.1016/j.neuron.2010.04.032
    1. Richardson B. D., Ling L. L., Uteshev V. V., Caspary D. M. (2011). Extrasynaptic GABA(A) receptors and tonic inhibition in rat auditory thalamus. PLoS One 6, e16508. 10.1371/journal.pone.0016508
    1. Roberts L. E., Eggermont J. J., Caspary D. M., Shore S. E., Melcher J. R., Kaltenbach J. A. (2010). Ringing ears: the neuroscience of tinnitus. J. Neurosci. 30, 14972–14979. 10.1523/JNEUROSCI.4028-10.2010
    1. Stagg C. J., Bachtiar V., Johansen-Berg H. (2011a). The role of GABA in human motor learning. Curr. Biol. 21, 480–484. 10.1016/j.cub.2011.01.069
    1. Stagg C. J., Bachtiar V., Johansen-Berg H. (2011b). What are we measuring with GABA magnetic resonance spectroscopy? Commun. Integr. Biol. 4, 573–575. 10.4161/cib.4.5.16213
    1. Tzounopoulos T., Rubio M. E., Keen J. E., Trussell L. O. (2007). Coactivation of pre- and postsynaptic signaling mechanisms determines cell-specific spike-timing-dependent plasticity. Neuron 54, 291–301. 10.1016/j.neuron.2007.03.026
    1. van der Heyden J. A., Korf J. (1978). Regional levels of GABA in the brain: rapid semiautomated assay and prevention of postmortem increase by 3-mercapto-propionic acid. J. Neurochem. 31, 197–203.
    1. Wang H., Brozoski T. J., Caspary D. M. (2011). Inhibitory neurotransmission in animal models of tinnitus: maladaptive plasticity. Hear. Res. 279, 111–117. 10.1016/j.heares.2011.04.004
    1. Winer J. A., Larue D. T. (1996). Evolution of GABAergic circuitry in the mammalian medial geniculate body. Proc. Natl. Acad. Sci. U.S.A. 93, 3083–3087.
    1. Yang S., Weiner B. D., Zhang L. S., Cho S. J., Bao S. (2011). Homeostatic plasticity drives tinnitus perception in an animal model. Proc. Natl. Acad. Sci. U.S.A. 108, 14974–14979. 10.1073/pnas.1107998108
    1. Zeng C., Nannapaneni N., Zhou J., Hughes L. F., Shore S. (2009). Cochlear damage changes the distribution of vesicular glutamate transporters associated with auditory and nonauditory inputs to the cochlear nucleus. J. Neurosci. 29, 4210–4217. 10.1523/JNEUROSCI.0208-09.2009
    1. Zhu K. Y., Fu Q., Leung K. W., Wong Z. C., Choi R. C., Tsim K. W. (2011). The establishment of a sensitive method in determining different neurotransmitters simultaneously in rat brains by using liquid chromatography-electrospray tandem mass spectrometry. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 879, 737–742. 10.1016/j.jchromb.2011.02.011
    1. Zhuo M. (2009). Plasticity of NMDA receptor NR2B subunit in memory and chronic pain. Mol. Brain 2, 4. 10.1186/1756-6606-2-4

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅