Benjamin D. Auerbach

Correction of fragile X syndrome in mice

Fragile X syndrome (FXS) is the most common form of heritable mental retardation and the leading identified cause of autism. FXS is caused by transcriptional silencing of the FMR1 gene that encodes the fragile X mental retardation protein (FMRP), but the pathogenesis of the disease is unknown. According to one proposal, many psychiatric and neurological symptoms of FXS result from unchecked activation of mGluR5, a metabotropic glutamate receptor. To test this idea we generated Fmr1 mutant mice with a 50% reduction in mGluR5 expression and studied a range of phenotypes with relevance to the human disorder. Our results demonstrate that mGluR5 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for fragile X and related developmental disorders.

Mutations causing syndromic autism define an axis of synaptic pathophysiology

Tuberous sclerosis complex and fragile X syndrome are genetic diseases characterized by intellectual disability and autism. Because both syndromes are caused by mutations in genes that regulate protein synthesis in neurons, it has been hypothesized that excessive protein synthesis is one core pathophysiological mechanism of intellectual disability and autism. Using electrophysiological and biochemical assays of neuronal protein synthesis in the hippocampus of Tsc2+/− and Fmr1−/y mice, here we show that synaptic dysfunction caused by these mutations actually falls at opposite ends of a physiological spectrum. Synaptic, biochemical and cognitive defects in these mutants are corrected by treatments that modulate metabotropic glutamate receptor 5 in opposite directions, and deficits in the mutants disappear when the mice are bred to carry both mutations. Thus, normal synaptic plasticity and cognition occur within an optimal range of metabotropic glutamate-receptor-mediated protein synthesis, and deviations in either direction can lead to shared behavioural impairments.

Central Gain Control in Tinnitus and Hyperacusis

Sensorineural hearing loss induced by noise or ototoxic drug exposure reduces the neural activity transmitted from the cochlea to the central auditory system. Despite a reduced cochlear output, neural activity from more central auditory structures is paradoxically enhanced at suprathreshold intensities. This compensatory increase in the central auditory activity in response to the loss of sensory input is referred to as central gain enhancement. Enhanced central gain is hypothesized to be a potential mechanism that gives rise to hyperacusis and tinnitus, two debilitating auditory perceptual disorders that afflict millions of individuals. This review will examine the evidence for gain enhancement in the central auditory system in response to cochlear damage. Further, it will address the potential cellular and molecular mechanisms underlying this enhancement and discuss the contribution of central gain enhancement to tinnitus and hyperacusis. Current evidence suggests that multiple mechanisms with distinct temporal and spectral profiles are likely to contribute to central gain enhancement. Dissecting the contributions of these different mechanisms at different levels of the central auditory system is essential for elucidating the role of central gain enhancement in tinnitus and hyperacusis and, most importantly, the development of novel treatments for these disorders.

Loss of the Fragile X Mental Retardation Protein Decouples Metabotropic Glutamate Receptor Dependent Priming of Long-Term Potentiation From Protein Synthesis

Fragile X Syndrome (FXS), the most common inherited form of intellectual disability, is caused by loss of the fragile X mental retardation protein (FMRP). FMRP is a negative regulator of local mRNA translation downstream of group 1 metabotropic glutamate receptor (Gp1 mGluR) activation. In the absence of FMRP there is excessive mGluR-dependent protein synthesis, resulting in exaggerated mGluR-dependent long-term synaptic depression (LTD) in area CA1 of the hippocampus. Understanding disease pathophysiology is critical for development of therapies for FXS and the question arises of whether it is more appropriate to target excessive LTD or excessive mGluR-dependent protein synthesis. Priming of long-term potentiation (LTP) is a qualitatively different functional consequence of Gp1 mGluR-stimulated protein synthesis at the same population of CA1 synapses where LTD can be induced. Therefore we determined if LTP priming, like LTD, is also disrupted in the Fmr1 knockout (KO) mouse. We found that mGluR-dependent priming of LTP is of comparable magnitude in wild-type (WT) and Fmr1 KO mice. However, whereas LTP priming requires acute stimulation of protein synthesis in WT mice, it is no longer protein synthesis dependent in the Fmr1 KO. These experiments show that the dysregulation of mGluR-mediated protein synthesis seen in Fmr1 KO mice has multiple consequences on synaptic plasticity, even within the same population of synapses. Furthermore, it suggests that there is a bifurcation in the Gp1 mGluR signaling pathway, with one arm triggering synaptic modifications such as LTP priming and LTD and the other stimulating protein synthesis that is permissive for these modifications.

Inner Hair Cell Loss Disrupts Hearing and Cochlear Function Leading to Sensory Deprivation and Enhanced Central Auditory Gain

There are three times as many outer hair cells (OHC) as inner hair cells (IHC), yet IHC transmit virtually all acoustic information to the brain as they synapse with 90–95% of type I auditory nerve fibers. Here we review a comprehensive series of experiments aimed at determining how loss of the IHC/type I system affects hearing by selectively destroying these cells in chinchillas using the ototoxic anti-cancer agent carboplatin. Eliminating IHC/type I neurons has no effect on distortion product otoacoustic emission or the cochlear microphonic potential generated by OHC; however, it greatly reduces the summating potential produced by IHC and the compound action potential (CAP) generated by type I neurons. Remarkably, responses from remaining auditory nerve fibers maintain sharp tuning and low thresholds despite innervating regions of the cochlea with ~80% IHC loss. Moreover, chinchillas with large IHC lesions have surprisingly normal thresholds in quiet until IHC losses exceeded 80%, suggesting that only a few IHC are needed to detect sounds in quiet. However, behavioral thresholds in broadband noise are elevated significantly and tone-in-narrow band noise masking patterns exhibit greater remote masking. These results suggest the auditory system is able to compensate for considerable loss of IHC/type I neurons in quiet but not in difficult listening conditions. How does the auditory brain deal with the drastic loss of cochlear input? Recordings from the inferior colliculus found a relatively small decline in sound-evoked activity despite a large decrease in CAP amplitude after IHC lesion. Paradoxically, sound-evoked responses are generally larger than normal in the auditory cortex, indicative of increased central gain. This gain enhancement in the auditory cortex is associated with decreased GABA-mediated inhibition. These results suggest that when the neural output of the cochlea is reduced, the central auditory system compensates by turning up its gain so that weak signals once again become comfortably loud. While this gain enhancement is able to restore normal hearing under quiet conditions, it may not adequately compensate for peripheral dysfunction in more complex sound environments. In addition, excessive gain increases may convert recruitment into the debilitating condition known as hyperacusis.

Tinnitus and Hyperacusis: Contributions of Paraflocculus, Reticular Formation and Stress

ABSTRACT Tinnitus and hyperacusis are common and potentially serious hearing disorders associated with noise‐, age‐ or drug‐induced hearing loss. Accumulating evidence suggests that tinnitus and hyperacusis are linked to excessive neural activity in a distributed brain network that not only includes the central auditory pathway, but also brain regions involved in arousal, emotion, stress and motor control. Here we examine electrophysiological changes in two novel non‐auditory areas implicated in tinnitus and hyperacusis: the caudal pontine reticular nucleus (PnC), involved in arousal, and the paraflocculus lobe of the cerebellum (PFL), implicated in head‐eye coordination and gating tinnitus and we measure the changes in corticosterone stress hormone levels. Using the salicylate‐induced model of tinnitus and hyperacusis, we found that long‐latency (>10 ms) sound‐evoked response components in both the brain regions were significantly enhanced after salicylate administration, while the short‐latency responses were reduced, likely reflecting cochlear hearing loss. These results are consistent with the central gain model of tinnitus and hyperacusis, which proposes that these disorders arise from the amplification of neural activity in central auditory pathway plus other regions linked to arousal, emotion, tinnitus gating and motor control. Finally, we demonstrate that salicylate results in an increase in corticosterone level in a dose‐dependent manner consistent with the notion that stress may interact with hearing loss in tinnitus and hyperacusis development. This increased stress response has the potential to have wide‐ranging effects on the central nervous system and may therefore contribute to brain‐wide changes in neural activity. Graphical abstract Figure. No Caption available. HighlightsSalicylate enhanced auditory response of the cerebellar paraflocculus.Salicylate enhanced auditory response of the reticular formation.While the late response component was enhanced the early response was reduced.Salicylate enhanced serum corticosterone level.The physiological changes and the stress hormone increase may be involved in tinnitus and hyperacusis.

Testing the Central Gain Model: Loudness Growth Correlates with Central Auditory Gain Enhancement in a Rodent Model of Hyperacusis

The central gain model of hyperacusis proposes that loss of auditory input can result in maladaptive neuronal gain increases in the central auditory system, leading to the over-amplification of sound-evoked activity and excessive loudness perception. Despite the attractiveness of this model, and supporting evidence for it, a critical test of the central gain theory requires that changes in sound-evoked activity be explicitly linked to perceptual alterations of loudness. Here we combined an operant conditioning task that uses a subjects reaction time to auditory stimuli to produce reliable measures of loudness growth with chronic electrophysiological recordings from the auditory cortex and inferior colliculus of awake, behaviorally-phenotyped animals. In this manner, we could directly correlate daily assessments of loudness perception with neurophysiological measures of sound encoding within the same animal. We validated this novel psychophysical-electrophysiological paradigm with a salicylate-induced model of hearing loss and hyperacusis, as high doses of sodium salicylate reliably induce temporary hearing loss, neural hyperactivity, and auditory perceptual disruptions like tinnitus and hyperacusis. Salicylate induced parallel changes to loudness growth and evoked response-intensity functions consistent with temporary hearing loss and hyperacusis. Most importantly, we found that salicylate-mediated changes in loudness growth and sound-evoked activity were correlated within individual animals. These results provide strong support for the central gain model of hyperacusis and demonstrate the utility of using an experimental design that allows for within-subject comparison of behavioral and electrophysiological measures, thereby making inter-subject variability a strength rather than a limitation.

Noise-induced hearing loss induces loudness intolerance in a rat Active Sound Avoidance Paradigm (ASAP)

ABSTRACT Hyperacusis is a loudness hypersensitivity disorder in which moderate‐intensity sounds are perceived as extremely loud, aversive and/or painful. To assess the aversive nature of sounds, we developed an Active Sound Avoidance Paradigm (ASAP) in which rats altered their place preference in a Light/Dark shuttle box in response to sound. When no sound (NS) was present, rats spent more than 95% of the time in the Dark Box versus the transparent Light Box. However, when a 60 or 90 dB SPL noise (2–20 kHz, 2–8 kHz, or 16–20 kHz bandwidth) was presented in the Dark Box, the rats” preference for the Dark Box significantly decreased. Percent time in the dark decreased as sound intensity in the Dark Box increased from 60 dB to 90 dB SPL. Interestingly, the magnitude of the decrease was not a monotonic function of intensity for the 16–20 kHz noise and not related to the bandwidth of the 2–20 kHz and 2–8 kHz noise bands, suggesting that sound avoidance is not solely dependent on loudness but the aversive quality of the noise as well. Afterwards, we exposed the rats for 28 days to a 16–20 kHz noise at 102 dB SPL; this exposure produced a 30–40 dB permanent threshold shift at 16 and 32 kHz. Following the noise exposure, the rats were then retested on the ASAP paradigm. High‐frequency hearing loss did not alter Dark Box preference in the no‐sound condition. However, when the 2–20 kHz or 2–8 kHz noise was presented at 60 or 90 dB SPL, the rats avoided the Dark Box significantly more than they did before the exposure, indicating these two noise bands with energy below the region of hearing loss were perceived as more aversive. In contrast, when the 16–20 kHz noise was presented at 60 or 90 dB SPL, the rats remained in the Dark Box presumably because the high‐frequency hearing loss made 16–20 kHz noise less audible and less aversive. These results indicate that when rats develop a high‐frequency hearing loss, they become less tolerant of low frequency noise, i.e., high intensity sounds are perceived as more aversive and should be avoided. HIGHLIGHTSThe Active Sound Avoidance Paradigm is a useful model of sound aversion in rats.Rats typically prefer a dark, enclosed environment to a bright, open one.This preference is lost when an aversive sound is presented in the dark enclosure.High‐frequency hearing loss induced stronger aversion to low‐frequency noise.