Chronic tinnitus and unipolar brush cell alterations in the cerebellum and dorsal cochlear nucleus

Abstract

Animal model research has shown that the central features of tinnitus, the perception of sound without an acoustic correlate, include elevated spontaneous and stimulus-driven activity, enhanced burst-mode firing, decreased variance of inter-spike intervals, and distortion of tonotopic frequency representation. Less well documented are cell-specific correlates of tinnitus. Unipolar brush cell (UBC) alterations in animals with psychophysical evidence of tinnitus has recently been reported. UBCs are glutamatergic interneurons that appear to function as local-circuit signal amplifiers. UBCs are abundant in the dorsal cochlear nucleus (DCN) and very abundant in the flocculus (FL) and paraflocculus (PFL) of the cerebellum. In the present research, two indicators of UBC structure and function were examined: Doublecortin (DCX) and epidermal growth factor receptor substrate 8 (Eps8). DCX is a protein that binds to microtubules where it can modify their assembly and growth. Eps8 is a cell-surface tyrosine kinase receptor mediating the response to epidermal growth factor; it appears to have a role in actin polymerization as well as cytoskeletal protein interactions. Both functions could contribute to synaptic remodeling. In the present research UBC Eps8 and DCX immunoreactivity (IR) were determined in 4 groups of rats distinguished by their exposure to high-level sound and psychophysical performance: Unexposed, exposed to high-level sound with behavioral evidence of tinnitus, and two exposed groups without behavioral evidence of tinnitus. Compared to unexposed controls, exposed animals with tinnitus had Eps8 IR elevated in their PFL; other structures were not affected, nor was DCX IR affected. This was interpreted as UBC upregulation in animals with tinnitus. Exposure that failed to produce tinnitus did not increase either Eps8 or DCX IR. Rather Eps8 IR was decreased in the FL and DCN of one subgroup (Least-Tinnitus), while DCX IR decreased in the FL of the other subgroup (No-Tinnitus). Neuron degeneration was also documented in the cochlear nucleus and PFL of exposed animals, both with and without tinnitus. Degeneration was not found in unexposed animals. Implications for tinnitus neuropathy are discussed in the context of synaptic remodeling and cerebellar sensory modulation.

Dissociation between Cerebellar and Cerebral Neural Activities in Humans with Long-Term Bilateral Sensorineural Hearing Loss

“…Of note, these neural abnormalities in FC were correlated with the severity of HL and SAS scores, suggesting that cerebellum-related connectivity might be a candidate imaging marker for SNHL. Along with previous studies [15, 54], our findings provide support for the cerebellum as a crucial node in auditory and emotional processing.…”

Increased Resting-State Cerebellar-Cerebral Functional Connectivity Underlying Chronic Tinnitus

“…After auditory nerve transection, the phantom experience of tinnitus still does not disappear (Jackler and Whinney, 2001 ). It has been demonstrated that tinnitus involves aberrant neural activity in not only auditory regions but also non-auditory structures such as the prefrontal cortex, parahippocampal gyrus (PHG), amygdala, and cerebellum, which have been confirmed to be important in the development or progression of tinnitus (Rauschecker et al, 2010 ; Leaver et al, 2011 ; Langguth et al, 2013 ; Chen et al, 2015a , 2017a , b , c ; Brozoski et al, 2017 ).…”

“…This suggests that the cerebellum could impact the signal from the peripheral hearing organs or modulate the activity of the acoustic center. Previous studies demonstrated that the unipolar brush cells upregulate and enhance glutamatergic transmission in the cerebellum and contribute to the pathophysiology of tinnitus (Bauer et al, 2013b ; Brozoski et al, 2017 ). Moreover, the paraflocculus lobe of the cerebellum, which integrates the information from the vestibular and auditory centers, has been confirmed to be involved in the modulation of tinnitus by examination of electrophysiological changes (Chen et al, 2017a ).…”

Early Onset Region and Cell Specific Alterations of Doublecortin Expression in the CNS of Animals with Sound Damage Induced Hearing Loss

“…UBCs reside in the granular layer of discrete regions in the cerebellar cortex (vermis and flocculonodular node [PFL]) and the granule cell domain of the DCN (Mugnaini, Sekerkova et al 2011, Manohar, Paolone et al 2012). Due to their distinct morphology and corresponding cellular properties, UBCs have been described as having a role in automatic gain circuitry in which they aid in modulating sensory afferents (Brozoski et al, 2017).…”

“…At what time point does remodeling or neuroplasticity take place following a single auditory insult? DCX expression has been investigated 10 weeks post damage in the hippocampus (Kraus, Mitra et al 2010) and 9-11 months post damage in the DCN and PFL (Bauer et al, 2013b, Brozoski et al, 2017), while changes at earlier time points have not been investigated using DCX expression as an index of change. Altered spontaneous firing rate (SFR) is evident in the auditory cortex just a few hours after acoustic trauma (Norena and Eggermont 2003) while the timeline of changes to SFR in the DCN is variable.…”