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Neuronal hyperactivity has been associated with many brain diseases. In the auditory system, hyperactivity has been linked to hyperacusis and tinnitus. Previous research demonstrated the development of hyperactivity in inferior colliculus (IC) neurons after sound overexposure, but the underlying mechanism of this hyperactivity remains unclear. The main goal of this study was to determine the mechanism of this hyperactivity. Experiments were performed on CBA/CaJ mice in a restrained, unanesthetized condition using intracellular recordings with sharp microelectrodes. Recordings were obtained from control (unexposed) and unilaterally sound overexposed groups of mice. Our data suggest that sound exposure-induced hyperactivity was due to a depolarizing shift of the resting membrane potential (RMP) in the hyperactive neurons. The half width of action potentials in these neurons was also decreased after sound exposure. Surprisingly, we also found a RMP gradient in which neurons have more hyperpolarized RMPs with increasing depth in the IC. This gradient was altered in the overexposed animals.

The etiology of tinnitus is known to be diverse in the human population. An appropriate animal model of tinnitus should incorporate this pathological diversity. Previous studies evaluating the effect of acoustic over exposure (AOE) have found that animals typically display increased spontaneous firing rates and bursting activity of auditory neurons, which often has been linked to behavioral evidence of tinnitus. However, only a subset of studies directly associated these neural correlates to individual animals. Furthermore, the vast majority of tinnitus studies were conducted on anesthetized animals. The goal of this study was to test for a possible relationship between tinnitus, hearing loss, hyperactivity and bursting activity in the auditory system of individual unanesthetized animals following AOE. Sixteen mice were unilaterally exposed to 116 dB SPL narrowband noise (centered at 12.5 kHz) for 1 h under ketamine/xylazine anesthesia. Gap-induced prepulse inhibition of the acoustic startle reflex (GPIAS) was used to assess behavioral evidence of tinnitus whereas hearing performance was evaluated by measurements of auditory brainstem response (ABR) thresholds and prepulse inhibition PPI audiometry. Following behavioral assessments, single neuron firing activity was recorded from the inferior colliculus (IC) of four awake animals and compared to recordings from four unexposed controls. We found that AOE increased spontaneous activity in all mice tested, independently of tinnitus behavior or severity of threshold shifts. Bursting activity did not increase in two animals identified as tinnitus positive (T+), but did so in a tinnitus negative (T-) animal with severe hearing loss (SHL). Hyperactivity does not appear to be a reliable biomarker of tinnitus. Our data suggest that multidisciplinary assessments on individual animals following AOE could offer a powerful experimental tool to investigate mechanisms of tinnitus.

Exceptionally long-lived species, including many bats, rarely show overt signs of aging, making it difficult to determine why species differ in lifespan. Here, we use DNA methylation (DNAm) profiles from 712 known-age bats, representing 26 species, to identify epigenetic changes associated with age and longevity. We demonstrate that DNAm accurately predicts chronological age. Across species, longevity is negatively associated with the rate of DNAm change at age-associated sites. Furthermore, analysis of several bat genomes reveals that hypermethylated age- and longevity-associated sites are disproportionately located in promoter regions of key transcription factors (TF) and enriched for histone and chromatin features associated with transcriptional regulation. Predicted TF binding site motifs and enrichment analyses indicate that age-related methylation change is influenced by developmental processes, while longevity-related DNAm change is associated with innate immunity or tumorigenesis genes, suggesting that bat longevity results from augmented immune response and cancer suppression. DNA methylation profiles from 26 bat species accurately predicts chronological age, while longevity-related methylation patterns across the genome suggest that bat longevity results from augmented immune response and cancer suppression.

Tinnitus, the perception of a sound without an external acoustic source, is a complex perceptual phenomenon affecting the quality of life in 17% of the adult population. Despite its ubiquity and morbidity, the pathophysiology of tinnitus is a work in progress, and there is no generally accepted cure or treatment. Development of a reliable common animal model is crucial for tinnitus research and may advance this field. The goal of this study was to develop a tinnitus mouse model. Tinnitus was induced in an experimental group of mice by an exposure to a loud (116 dB sound pressure level (SPL)) narrow band noise (one octave, centered at 16 kHz) during 1 h under anesthesia. The tinnitus was then assessed behaviorally by measuring gap induced suppression of the acoustic startle reflex. We found that a vast majority of the sound-exposed mice (86%) developed behavioral signs of tinnitus. This was a complex, long lasting, and dynamic process. On the day following exposure, all mice demonstrated signs of acute tinnitus over the entire range of sound frequencies used for testing (10–31 kHz). However, 2–3 months later, a behavioral evidence of tinnitus was evident only at a narrow frequency range (20–31 kHz) representing a presumed chronic condition. Extracellular recordings confirmed a significantly higher rate of spontaneous activity in inferior colliculus neurons in sound-exposed compared to control mice. Surprisingly, unilateral sound exposure suppresses startle responses in mice and they remained suppressed even 3 months post-exposure, whereas auditory brainstem response thresholds were completely recovered during 2 months following exposure. In summary, behavioral evidence of tinnitus can be reliably developed in mice by sound exposure, and tinnitus induction can be assessed by quantifying prepulse inhibition of the acoustic startle reflex.

Tinnitus is a maladaptive neuropathic condition that develops in humans and laboratory animals following auditory insult. In our previous study we demonstrated that sound exposure leads to development of behavioral evidence of tinnitus in a sample of exposed mice. However, this tinnitus mouse model did not account for long-term maladaptive plasticity or aging, factors that are commonly linked to the human tinnitus population. Therefore the same group of mice was monitored for tinnitus for 360 days post exposure. Tinnitus was assessed behaviorally by measuring gap-induced pre-pulse suppression of the acoustic startle (GPIAS). Cochlear histology was performed on both control (unexposed) and experimental mice to determine whether sound exposure caused any evident cochlear damage. We found that 360 days after exposure the vast majority of exposed mice exhibited similar gap detection deficits as detected at 84 days post exposure. These mice did not demonstrate significant loss of inner/outer hair cells or spiral ganglion neurons compared to the control sample. Lastly, we demonstrated that GPIAS deficits observed in exposed animals were unlikely exclusively caused by cochlear damage, but could be a result of central auditory maladaptive plasticity. We conclude that CBA/CaJ mice can be considered a good animal model to study the possible contribution of age effects on tinnitus development following auditory insult.

Previous studies in echolocating bats, Myotis lucifugus, showed that paradoxical latency shift (PLS) is essential for neural computation of target range and that a number of neurons in the inferior colliculus (IC) exhibit unit-specific PLS (characterized by longer first-spike latency at higher sound levels) in response to tone pulses at the unit's best frequency. The present study investigated whether or not frequency-modulated (FM) pulses that mimic the bat's echolocation sonar signals were equally effective in eliciting PLS. For two-thirds of PLS neurons in the IC, both FM and tone pulses could elicit PLS, but only FM pulses consistently produced unit-specific PLS. For the remainder of PLS neurons, only FM pulses effectively elicited PLS; these cells showed either no PLS or no response, to tone pulses. PLS neurons generally showed more pronounced PLS in response to narrow-band FM (each sweeping 20 kHz in 2 ms) pulse that contained the unit's best frequency. In addition, almost all PLS neurons showed duration-independent PLS to FM pulses, but the same units exhibited duration-dependent PLS to tone pulses. Taken together, when compared to tone pulses, FM stimuli can provide more reliable estimates of target range.

Abstract Exceptionally long-lived species, including many bats, rarely show overt signs of aging, making it difficult to determine why species differ in lifespan. Here, we use DNA methylation (DNAm) profiles from 712 known-age bats, representing 26 species, to identify epigenetic changes associated with age and longevity. We demonstrate that DNAm accurately predicts chronological age. Across species, longevity is negatively associated with the rate of DNAm change at age-associated sites. Furthermore, analysis of several bat genomes reveals that hypermethylated age- and longevity-associated sites are disproportionately located in promoter regions of key transcription factors (TF) and enriched for histone and chromatin features associated with transcriptional regulation. Predicted TF binding site motifs and enrichment analyses indicate that age-related methylation change is influenced by developmental processes, while longevity-related DNAm change is associated with innate immunity or tumorigenesis genes, suggesting that bat longevity results from augmented immune response and cancer suppression. Competing Interest Statement SH is a founder of the non-profit Epigenetic Clock Development Foundation which plans to license several patents from his employer UC Regents. These patents list SH as inventor. The other authors declare no conflicts of interest. Footnotes * ↵† These authors jointly supervised this work: G.S. Wilkinson, S. Horvath * This version now contains a separate Abstract, Introduction, Results and Discussion sections. Additional data were added for one species, an error in the genome annotation pipeline was corrected, and all results were recomputed, which resulted in small changes to all figures. Author order was changed to reflect relative contributions. Additional information on data and code availability are provided. * http://hdl.handle.net/1903/26373 * https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GPL28271