Noise Exposure Alters Glutamatergic and GABAergic Synaptic Connectivity in the Hippocampus and Its Relevance to Tinnitus.

Accumulating evidence implicates a role for brain structures outside the ascending auditory pathway in tinnitus, the phantom perception of sound. In addition to other factors such as age-dependent hearing loss, high-level sound exposure is a prominent cause of tinnitus. Here, we examined how noise exposure altered the distribution of excitatory and inhibitory synaptic inputs in the guinea pig hippocampus and determined whether these changes were associated with tinnitus. In experiment one, guinea pigs were overexposed to unilateral narrow-band noise (98 dB SPL, 2 h). Two weeks later, the density of excitatory (VGLUT-1/2) and inhibitory (VGAT) synaptic terminals in CA1, CA3, and dentate gyrus hippocampal subregions was assessed by immunohistochemistry. Overall, VGLUT-1 density primarily increased, while VGAT density decreased significantly in many regions. Then, to assess whether the noise-induced alterations were persistent and related to tinnitus, experiment two utilized a noise-exposure paradigm shown to induce tinnitus and assessed tinnitus development which was assessed using gap-prepulse inhibition of the acoustic startle (GPIAS). Twelve weeks after sound overexposure, changes in excitatory synaptic terminal density had largely recovered regardless of tinnitus status, but the recovery of GABAergic terminal density was dramatically different in animals expressing tinnitus relative to animals resistant to tinnitus. In resistant animals, inhibitory synapse density recovered to preexposure levels, but in animals expressing tinnitus, inhibitory synapse density remained chronically diminished. Taken together, our results suggest that noise exposure induces striking changes in the balance of excitatory and inhibitory synaptic inputs throughout the hippocampus and reveal a potential role for rebounding inhibition in the hippocampus as a protective factor leading to tinnitus resilience.

Zhang L ，Wu C ，Martel DT ，West M ，Sutton MA ，Shore SE ... -  《-》

Remodeling of cholinergic input to the hippocampus after noise exposure and tinnitus induction in Guinea pigs.

Here, we investigate remodeling of hippocampal cholinergic inputs after noise exposure and determine the relevance of these changes to tinnitus. To assess the effects of noise exposure on the hippocampus, guinea pigs were exposed to unilateral noise for 2 hr and 2 weeks later, immunohistochemistry was performed on hippocampal sections to examine vesicular acetylcholine transporter (VAChT) expression. To evaluate whether the changes in VAChT were relevant to tinnitus, another group of animals was exposed to the same noise band twice to induce tinnitus, which was assessed using gap-prepulse Inhibition of the acoustic startle (GPIAS) 12 weeks after the first noise exposure, followed by immunohistochemistry. Acoustic Brainstem Response (ABR) thresholds were elevated immediately after noise exposure for all experimental animals but returned to baseline levels several days after noise exposure. ABR wave I amplitude-intensity functions did not show any changes after 2 or 12 weeks of recovery compared to baseline levels. In animals assessed 2-weeks following noise-exposure, hippocampal VAChT puncta density decreased on both sides of the brain by 20-60% in exposed animals. By 12 weeks following the initial noise exposure, changes in VAChT puncta density largely recovered to baseline levels in exposed animals that did not develop tinnitus, but remained diminished in animals that developed tinnitus. These tinnitus-specific changes were particularly prominent in hippocampal synapse-rich layers of the dentate gyrus and areas CA3 and CA1, and VAChT density in these regions negatively correlated with tinnitus severity. The robust changes in VAChT labeling in the hippocampus 2 weeks after noise exposure suggest involvement of this circuitry in auditory processing. After chronic tinnitus induction, tinnitus-specific changes occurred in synapse-rich layers of the hippocampus, suggesting that synaptic processing in the hippocampus may play an important role in the pathophysiology of tinnitus.

Zhang L ，Wu C ，Martel DT ，West M ，Sutton MA ，Shore SE ... -  《-》

Synaptic and vesicular coexistence of VGLUT and VGAT in selected excitatory and inhibitory synapses.

Zander JF ，Münster-Wandowski A ，Brunk I ，Pahner I ，Gómez-Lira G ，Heinemann U ，Gutiérrez R ，Laube G ，Ahnert-Hilger G ... -  《-》

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 《-》

Noise Trauma-Induced Behavioral Gap Detection Deficits Correlate with Reorganization of Excitatory and Inhibitory Local Circuits in the Inferior Colliculus and Are Prevented by Acoustic Enrichment.

Hearing loss leads to a host of cellular and synaptic changes in auditory brain areas that are thought to give rise to auditory perception deficits such as temporal processing impairments, hyperacusis, and tinnitus. However, little is known about possible changes in synaptic circuit connectivity that may underlie these hearing deficits. Here, we show that mild hearing loss as a result of brief noise exposure leads to a pronounced reorganization of local excitatory and inhibitory circuits in the mouse inferior colliculus. The exact nature of these reorganizations correlated with the presence or absence of the animals' impairments in detecting brief sound gaps, a commonly used behavioral sign for tinnitus in animal models. Mice with gap detection deficits (GDDs) showed a shift in the balance of synaptic excitation and inhibition that was present in both glutamatergic and GABAergic neurons, whereas mice without GDDs showed stable excitation-inhibition balances. Acoustic enrichment (AE) with moderate intensity, pulsed white noise immediately after noise trauma prevented both circuit reorganization and GDDs, raising the possibility of using AE immediately after cochlear damage to prevent or alleviate the emergence of central auditory processing deficits.SIGNIFICANCE STATEMENT Noise overexposure is a major cause of central auditory processing disorders, including tinnitus, yet the changes in synaptic connectivity underlying these disorders remain poorly understood. Here, we find that brief noise overexposure leads to distinct reorganizations of excitatory and inhibitory synaptic inputs onto glutamatergic and GABAergic neurons and that the nature of these reorganizations correlates with animals' impairments in detecting brief sound gaps, which is often considered a sign of tinnitus. Acoustic enrichment immediately after noise trauma prevents circuit reorganizations and gap detection deficits, highlighting the potential for using sound therapy soon after cochlear damage to prevent the development of central processing deficits.

Sturm JJ ，Zhang-Hooks YX ，Roos H ，Nguyen T ，Kandler K ... -  《-》