Tinnitus Correlates with Downregulation of Cortical Glutamate Decarboxylase 65 Expression But Not Auditory Cortical Map Reorganization.

Hearing loss is the biggest risk factor for tinnitus, and hearing-loss-related pathological changes in the auditory pathway have been hypothesized as the mechanism underlying tinnitus. However, due to the comorbidity of tinnitus and hearing loss, it has been difficult to differentiate between neural correlates of tinnitus and consequences of hearing loss. In this study, we dissociated tinnitus and hearing loss in FVB mice, which exhibit robust resistance to tinnitus following monaural noise-induced hearing loss. Furthermore, knock-down of glutamate decarboxylase 65 (GAD65) expression in auditory cortex (AI) by RNA interference gave rise to tinnitus in normal-hearing FVB mice. We found that tinnitus was significantly correlated with downregulation of GAD65 in the AI. By contrast, cortical map distortions, which have been hypothesized as a mechanism underlying tinnitus, were correlated with hearing loss but not tinnitus. Our findings suggest new strategies for the rehabilitation of tinnitus and other phantom sensation, such as phantom pain.SIGNIFICANCE STATEMENT Hearing loss is the biggest risk factor for tinnitus in humans. Most animal models of tinnitus also exhibit comorbid hearing loss, making it difficult to dissociate the mechanisms underlying tinnitus from mere consequences of hearing loss. Here we show that, although both C57BL/6 and FVB mice exhibited similar noise-induced hearing threshold increase, only C57BL/6, but not FVB, mice developed tinnitus following noise exposure. Although both strains showed frequency map reorganization following noise-induced hearing loss, only C57BL/6 mice had reduced glutamate decarboxylase 65 (GAD65) expression in the auditory cortex (AI). Knocking down GAD65 expression in the AI resulted in tinnitus in normal-hearing FVB mice. Our results suggest that reduced inhibitory neuronal function, but not sensory map reorganization, underlies noise-induced tinnitus.

Miyakawa A ，Wang W ，Cho SJ ，Li D ，Yang S ，Bao S ... -  《-》

Acute high-intensity noise induces rapid Arc protein expression but fails to rapidly change GAD expression in amygdala and hippocampus of rats: Effects of treatment with D-cycloserine.

Tinnitus is a devastating auditory disorder impacting a growing number of people each year. The aims of the current experiment were to assess neuronal mechanisms involved in the initial plasticity after traumatic noise exposure that could contribute to the emergence of tinnitus and to test a potential pharmacological treatment to alter this early neural plasticity. Specifically, this study addressed rapid effects of acute noise trauma on amygdalo-hippocampal circuitry, characterizing biomarkers of both excitation and inhibition in these limbic regions, and compared them to expression of these same markers in primary auditory cortex shortly after acute noise trauma. To assess excitatory plasticity, activity-regulated cytoskeleton-associated (Arc) protein expression was evaluated in male rats 45 min after bilateral exposure to acute high-intensity noise (16 kHz, 115 dB SPL, for 1 h), sufficient to cause acute cochlear trauma, a common cause of tinnitus in humans and previously shown sufficient to induce tinnitus in rat models of this auditory neuropathology. Western blot analyses confirmed that up-regulation of amygdalo-hippocampal Arc expression occurred rapidly post-noise trauma, corroborating several lines of evidence from our own and other laboratories indicating that limbic brain structures, i.e. outside of the classical auditory pathways, exhibit plasticity early in the initiation of tinnitus. Western blot analyses revealed no noise-induced changes in amygdalo-hippocampal expression of glutamate decarboxylase (GAD), the biosynthetic enzyme required for GABAergic inhibition. No changes in either Arc or GAD protein expression were observed in primary auditory cortex in this immediate post-noise exposure period, confirming other reports that auditory cortical plasticity may not occur until later in the development of tinnitus. As a further control, our experiments compared Arc protein expression between groups exposed to the quiet background of a sound-proof chamber to those exposed not only to the traumatic noise described above, but also to an intermediate, non-traumatic noise level (70 dB SPL) for the same duration in each of these three brain regions. We found that non-traumatic noise did not up-regulate Arc protein expression in these brain regions. To see if changes in Arc expression due to acute traumatic noise exposure were stress-related, we compared circulating serum corticosterone in controls and rats exposed to traumatic noise at the time when changes in Arc were observed, and found no significant differences in this stress hormone in our experimental conditions. Finally, the ability of D-cycloserine (DCS; an NMDA-receptor NR1 partial agonist) to reduce or prevent the noise trauma-related plastic changes in the biomarker, Arc, was tested. D-cycloserine prevented traumatic noise-induced up-regulation of Arc protein expression in amygdala but not in hippocampus, suggesting that DCS alone is not fully effective in eliminating regionally-specific early plastic changes after traumatic noise exposure.

Kapolowicz MR ，Thompson LT 《-》

Tinnitus behavior and hearing function correlate with the reciprocal expression patterns of BDNF and Arg3.1/arc in auditory neurons following acoustic trauma.

Tan J ，Rüttiger L ，Panford-Walsh R ，Singer W ，Schulze H ，Kilian SB ，Hadjab S ，Zimmermann U ，Köpschall I ，Rohbock K ，Knipper M ... -  《NEUROSCIENCE》

Neurophysiological, structural, and molecular alterations in the prefrontal and auditory cortices following noise-induced hearing loss.

It is well established that hearing loss can lead to widespread plasticity within the central auditory pathway, which is thought to contribute to the pathophysiology of audiological conditions such as tinnitus and hyperacusis. Emerging evidence suggests that hearing loss can also result in plasticity within brain regions involved in higher-level cognitive functioning like the prefrontal cortex; findings which may underlie the association between hearing loss and cognitive impairment documented in epidemiological studies. Using the 40-Hz auditory steady state response to assess sound-evoked gamma oscillations, we previously showed that noise-induced hearing loss results in impaired gamma phase coherence within the prefrontal but not the auditory cortex. To determine whether region-specific structural or molecular changes accompany this differential plasticity following hearing loss, in the present study we utilized Golgi-Cox staining to assess dendritic organization and synaptic density, as well as Western blotting to measure changes in synaptic signaling proteins in these cortical regions. We show that following noise exposure, impaired gamma phase coherence within the prefrontal cortex is accompanied by alterations in pyramidal cell dendritic morphology and decreased expression of proteins involved in GABAergic (GAD65) and glutamatergic (NR2B) neurotransmission; findings that were not observed in the auditory cortex, where gamma phase coherence remained unchanged post-noise exposure. In contrast to the noise-induced effects we observed in the prefrontal cortex, plasticity in the auditory cortex was characterized by an increase in NR2B suggesting increased excitability, as well as increases in the synaptic proteins PSD95 and synaptophysin within the auditory cortex. Overall, our results highlight the disparate effect of noise-induced hearing loss on auditory and higher-level brain regions as well as potential structural and molecular mechanisms by which hearing loss may contribute to impaired cognitive and sensory functions mediated by the prefrontal and auditory cortices.

Hayes SH ，Patel SV ，Arora P ，Zhao L ，Schormans AL ，Whitehead SN ，Allman BL ... -  《-》

Neuroinflammation mediates noise-induced synaptic imbalance and tinnitus in rodent models.

Wang W ，Zhang LS ，Zinsmaier AK ，Patterson G ，Leptich EJ ，Shoemaker SL ，Yatskievych TA ，Gibboni R ，Pace E ，Luo H ，Zhang J ，Yang S ，Bao S ... -  《-》