Lijie Liu

Tinnitus and hyperacusis involve hyperactivity and enhanced connectivity in auditory-limbic-arousal-cerebellar network

Hearing loss often triggers an inescapable buzz (tinnitus) and causes everyday sounds to become intolerably loud (hyperacusis), but exactly where and how this occurs in the brain is unknown. To identify the neural substrate for these debilitating disorders, we induced both tinnitus and hyperacusis with an ototoxic drug (salicylate) and used behavioral, electrophysiological, and functional magnetic resonance imaging (fMRI) techniques to identify the tinnitus–hyperacusis network. Salicylate depressed the neural output of the cochlea, but vigorously amplified sound-evoked neural responses in the amygdala, medial geniculate, and auditory cortex. Resting-state fMRI revealed hyperactivity in an auditory network composed of inferior colliculus, medial geniculate, and auditory cortex with side branches to cerebellum, amygdala, and reticular formation. Functional connectivity revealed enhanced coupling within the auditory network and segments of the auditory network and cerebellum, reticular formation, amygdala, and hippocampus. A testable model accounting for distress, arousal, and gating of tinnitus and hyperacusis is proposed. DOI: http://dx.doi.org/10.7554/eLife.06576.001

Ribbon Synapse Plasticity in the Cochleae of Guinea Pigs after Noise-Induced Silent Damage

Noise exposure at low levels or low doses can damage hair cell afferent ribbon synapses without causing permanent threshold shifts. In contrast to reports in the mouse cochleae, initial damage to ribbon synapses in the cochleae of guinea pigs is largely repairable. In the present study, we further investigated the repair process in ribbon synapses in guinea pigs after similar noise exposure. In the control samples, a small portion of afferent synapses lacked synaptic ribbons, suggesting the co-existence of conventional no-ribbon and ribbon synapses. The loss and recovery of hair cell ribbons and post-synaptic densities (PSDs) occurred in parallel, but the recovery was not complete, resulting in a permanent loss of less than 10% synapses. During the repair process, ribbons were temporally separated from the PSDs. A plastic interaction between ribbons and postsynaptic terminals may be involved in the reestablishment of synaptic contact between ribbons and PSDs, as shown by location changes in both structures. Synapse repair was associated with a breakdown in temporal processing, as reflected by poorer responses in the compound action potential (CAP) of auditory nerves to time-stress signals. Thus, deterioration in temporal processing originated from the cochlea. This deterioration developed with the recovery in hearing threshold and ribbon synapse counts, suggesting that the repaired synapses had deficits in temporal processing.

Silent damage of noise on cochlear afferent innervation in guinea pigs and the impact on temporal processing

Noise-exposure at levels low enough to avoid a permanent threshold shift has been found to cause a massive, delayed degeneration of spiral ganglion neurons (SGNs) in mouse cochleae. Damage to the afferent innervation was initiated by a loss of synaptic ribbons, which is largely irreversible in mice. A similar delayed loss of SGNs has been found in guinea pig cochleae, but at a reduced level, suggesting a cross-species difference in SGN sensitivity to noise. Ribbon synapse damage occurs “silently” in that it does not affect hearing thresholds as conventionally measured, and the functional consequence of this damage is not clear. In the present study, we further explored the effect of noise on cochlear afferent innervation in guinea pigs by focusing on the dynamic changes in ribbon counts over time, and resultant changes in temporal processing. It was found that (1) contrary to reports in mice, the initial loss of ribbons largely recovered within a month after the noise exposure, although a significant amount of residual damage existed; (2) while the response threshold fully recovered in a month, the temporal processing continued to be deteriorated during this period.

Coding deficits in hidden hearing loss induced by noise: the nature and impacts

Hidden hearing refers to the functional deficits in hearing without deterioration in hearing sensitivity. This concept is proposed based upon recent finding of massive noise-induced damage on ribbon synapse between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) in the cochlea without significant permanent threshold shifts (PTS). Presumably, such damage may cause coding deficits in auditory nerve fibers (ANFs). However, such deficits had not been detailed except that a selective loss of ANFs with low spontaneous rate (SR) was reported. In the present study, we investigated the dynamic changes of ribbon synapses and the coding function of ANF single units in one month after a brief noise exposure that caused a massive damage of ribbon synapses but no PTS. The synapse count and functional response measures indicates a large portion of the disrupted synapses were re-connected. This is consistent with the fact that the change of SR distribution due to the initial loss of low SR units is recovered quickly. However, ANF coding deficits were developed later with the re-establishment of the synapses. The deficits were found in both intensity and temporal processing, revealing the nature of synaptopathy in hidden hearing loss.

Noise induced hearing loss impairs spatial learning/memory and hippocampal neurogenesis in mice.

Hearing loss has been associated with cognitive decline in the elderly and is considered to be an independent risk factor for dementia. One of the most common causes for acquired sensorineural hearing loss is exposure to excessive noise, which has been found to impair learning ability and cognitive performance in human subjects and animal models. Noise exposure has also been found to depress neurogenesis in the hippocampus. However, the effect is mainly attributed to the oxidant stress of noise on the cognitive brain. In the present study, young adult CBA/CAJ mice (between 1.5 and 2 months of age) were briefly exposed a high sound level to produce moderate-to-severe hearing loss. In both the blood and hippocampus, only transient oxidative stress was observed after noise exposure. However, a deficit in spatial learning/memory was revealed 3 months after noise exposure. Moreover, the deficit was correlated with the degree of hearing loss and was associated with a decrease in neurogenesis in the hippocampus. We believe that the observed effects were likely due to hearing loss rather than the initial oxidant stress, which only lasted for a short period of time.

Coding Deficits in Noise-Induced Hidden Hearing Loss May Stem from Incomplete Repair of Ribbon Synapses in the Cochlea

Recent evidence has shown that noise-induced damage to the synapse between inner hair cells (IHCs) and type I afferent auditory nerve fibers (ANFs) may occur in the absence of permanent threshold shift (PTS), and that synapses connecting IHCs with low spontaneous rate (SR) ANFs are disproportionately affected. Due to the functional importance of low-SR ANF units for temporal processing and signal coding in noisy backgrounds, deficits in cochlear coding associated with noise-induced damage may result in significant difficulties with temporal processing and hearing in noise (i.e., “hidden hearing loss”). However, significant noise-induced coding deficits have not been reported at the single unit level following the loss of low-SR units. We have found evidence to suggest that some aspects of neural coding are not significantly changed with the initial loss of low-SR ANFs, and that further coding deficits arise in association with the subsequent reestablishment of the synapses. This suggests that synaptopathy in hidden hearing loss may be the result of insufficient repair of disrupted synapses, and not simply due to the loss of low-SR units. These coding deficits include decreases in driven spike rate for intensity coding as well as several aspects of temporal coding: spike latency, peak-to-sustained spike ratio and the recovery of spike rate as a function of click-interval.

Changes in the default mode networks of individuals with long-term unilateral sensorineural hearing loss

Hearing impairment contributes to cognitive dysfunction. Previous studies have found changes of functional connectivity in the default mode network (DMN) associated with cognitive processing in individuals with sensorineural hearing loss (SNHL). Whereas the changes in the DMN in patients with long-term unilateral SNHL (USNHL) is still not entirely clear. In this work, we analyzed resting-state functional magnetic resonance imaging (fMRI) data and neuropsychological test scores from normal hearing subjects (n = 11) and patients (n = 21) with long-term USNHL. Functional connectivity and nodal topological properties were computed for every brain region in the DMN. Analysis of covariance (ANCOVA) and post hoc analyses were conducted to identify differences between normal controls and patients for each measure. Results indicated that the left USNHL presented enhanced connectivity (p < 0.05, false discovery rate (FDR) corrected), and significant changes (p < 0.05, Bonferroni corrected) of the nodal topological properties in the DMN compared with the control. More changes in the DMN have been found in the left than right long-term USNHL (RUSNHL). However, the neuropsychological tests did not show significant differences between the USNHL and the control. These findings suggest that long-term USNHL contributes to changes in the DMN, and these changes might affect cognitive abilities in patients with long-term USNHL. Left hearing loss affects the DMN more than the right hearing loss does. The fMRI measures might be more sensitive for observing cognitive changes in patients with hearing loss than clinical neuropsychological tests. This study provides some insights into the mechanisms of the association between hearing loss and cognitive function.

Noise-induced damage to ribbon synapses without permanent threshold shifts in neonatal mice.

Recently, ribbon synapses to the hair cells (HCs) in the cochlea have become a novel site of interest in the investigation of noise-induced cochlear lesions in adult rodents (Kujawa and Liberman, 2009; Lin et al., 2011; Liu et al., 2012; Shi et al., 2013). Permanent noise-induced damage to this type of synapse can result in subsequent degeneration of spiral ganglion neurons (SGNs) in the absence of permanent changes to hearing sensitivity. To verify whether noise exposure during an early developmental period produces a similar impact on ribbon synapses, the present study examined the damaging effects of noise exposure in neonatal Kunming mice. The animals received exposure to broadband noise at 105-decibel (dB) sound pressure level (SPL) for 2h on either postnatal day 10 (P10d) or postnatal day 14 (P14d), and then hearing function (based on the auditory brainstem response (ABR)) and cochlear morphology were evaluated during either postnatal weeks 3-4 (P4w) or postnatal weeks 7-8 (P8w). There were no significant differences in the hearing threshold between noise-exposed and control animals, which suggests that noise did not cause permanent loss of hearing sensitivity. However, noise exposure did produce a significant loss of ribbon synapses, particularly in P14d mice, which continued to increase from P4w to P8w. Additionally, a corresponding reduction in the amplitude of compound action potential (CAP) was observed in the noise-exposed groups at P4w and P8w, and the CAP latency was elongated, indicating a change in synaptic function.

Effects of Noise Exposure on Systemic and Tissue-Level Markers of Glucose Homeostasis and Insulin Resistance in Male Mice.

Background: Epidemiological studies have indicated that noise exposure is associated with an increased risk of type 2 diabetes mellitus (T2DM). However, the nature of the connection between noise exposure and T2DM remains to be explored. Objectives: We explored whether and how noise exposure affects glucose homeostasis in mice as the initial step toward T2DM development. Methods: Male ICR mice were randomly assigned to one of four groups: the control group and three noise groups (N20D, N10D, and N1D), in which the animals were exposed to white noise at 95 decibel sound pressure level (dB SPL) for 4 hr per day for 20 successive days, 10 successive days, or 1 day, respectively. Glucose tolerance and insulin sensitivity were evaluated 1 day, 1 week, and 1 month after the final noise exposure (1DPN, 1WPN, and 1MPN). Standard immunoblots, immunohistochemical methods, and enzyme-linked immunosorbent assays (ELISA) were performed to assess insulin signaling in skeletal muscle, the morphology of β cells, and plasma corticosterone levels. Results: Noise exposure for 1 day caused transient glucose intolerance and insulin resistance, whereas noise exposure for 10 and 20 days had no effect on glucose tolerance but did cause prolonged insulin resistance and an increased insulin response to glucose challenge. Akt phosphorylation and GLUT4 translocation in response to exogenous insulin were decreased in the skeletal muscle of noise-exposed animals. Conclusions: Noise exposure at 95 dB SPL caused insulin resistance in male ICR mice, which was prolonged with longer noise exposure and was likely related to the observed blunted insulin signaling in skeletal muscle. Citation: Liu L, Wang F, Lu H, Cao S, Du Z, Wang Y, Feng X, Gao Y, Zha M, Guo M, Sun Z, Wang J. 2016. Effects of noise exposure on systemic and tissue-level markers of glucose homeostasis and insulin resistance in male mice. Environ Health Perspect 124:1390–1398; http://dx.doi.org/10.1289/EHP162

Changes of the directional brain networks related with brain plasticity in patients with long-term unilateral sensorineural hearing loss.

Previous studies often report that early auditory deprivation or congenital deafness contributes to cross-modal reorganization in the auditory-deprived cortex, and this cross-modal reorganization limits clinical benefit from cochlear prosthetics. However, there are inconsistencies among study results on cortical reorganization in those subjects with long-term unilateral sensorineural hearing loss (USNHL). It is also unclear whether there exists a similar cross-modal plasticity of the auditory cortex for acquired monaural deafness and early or congenital deafness. To address this issue, we constructed the directional brain functional networks based on entropy connectivity of resting-state functional MRI and researched changes of the networks. Thirty-four long-term USNHL individuals and seventeen normally hearing individuals participated in the test, and all USNHL patients had acquired deafness. We found that certain brain regions of the sensorimotor and visual networks presented enhanced synchronous output entropy connectivity with the left primary auditory cortex in the left long-term USNHL individuals as compared with normally hearing individuals. Especially, the left USNHL showed more significant changes of entropy connectivity than the right USNHL. No significant plastic changes were observed in the right USNHL. Our results indicate that the left primary auditory cortex (non-auditory-deprived cortex) in patients with left USNHL has been reorganized by visual and sensorimotor modalities through cross-modal plasticity. Furthermore, the cross-modal reorganization also alters the directional brain functional networks. The auditory deprivation from the left or right side generates different influences on the human brain.