Animal studies suggest that cochlear nerve degeneration precedes sensory cell degeneration in both noise-induced hearing loss (NIHL) and age-related hearing loss (ARHL), producing a hearing impairment that is not reflected in audiometric thresholds. Here, we investigated the histopathology of human ARHL and NIHL by comparing loss of auditory nerve fibers (ANFs), cochlear hair cells and the stria vascularis in a group of 52 cases with noise-exposure history against an age-matched control group. Although strial atrophy increased with age, there was no effect of noise history. Outer hair cell (OHC) loss also increased with age throughout the cochlea but was unaffected by noise history in the low-frequency region (<2 kHz), while greatly exacerbated at high frequencies (≥2 kHz). Inner hair cell (IHC) loss was primarily seen at high frequencies but was unaffected by noise at either low or high frequencies. ANF loss was substantial at all cochlear frequencies and was exacerbated by noise throughout. According to ...

Schwann cells produce a considerable amount of lipids and proteins to form myelin in the PNS. For this reason, the quality control of myelin proteins is crucial to ensure proper myelin synthesis. Deletion of serine 63 from P0 (P0S63del) protein in myelin forming Schwann cells causes Charcot-Marie-Tooth type 1B neuropathy in humans and mice. Misfolded P0S63del accumulates in the ER of Schwann cells where it elicits the unfolded protein response (UPR). PERK is the UPR transducer that attenuates global translation and reduces ER stress by phosphorylating the translation initiation factor eIF2alpha. Paradoxically, Perk ablation in P0S63del Schwann cells (S63del/ PerkSCKO ) reduced the level of P-eIF2alpha, leaving UPR markers upregulated, yet unexpectedly improved S63del myelin defects in vivo . We therefore investigated the hypothesis that PERK may interfere with signals outside of the UPR and specifically with calcineurin/NFATc4 pro-myelinating pathway. Using mouse genetics including females and males in our...

Transmembrane channel-like protein isoform 1 (TMC1) is a major component of the mechano-electrical transducer (MET) channel in cochlear hair cells and is subject to numerous mutations causing deafness. We report a new dominant human deafness mutation, TMC1 p.T422K, and have characterized the homologous mouse mutant, Tmc1 p.T416K, which caused deafness and outer hair cell (OHC) loss by the fourth postnatal week. MET channels showed decreased Ca2+ permeability and resting open probability, but no change in single-channel conductance or expression. Three adjacent deafness mutations are TMC1 p.L416R, p.G417R, and p.M418K, the last homologous to the mouse Beethoven that exhibits similar channel effects. All substitute a positive for a neutral residue, which could produce charge screening in the channel pore or influence binding of an accessory subunit. Channel properties were compared in mice of both sexes between dominant ( Tmc1 p.T416K, Tmc1 p.D569N) and recessive ( Tmc1 p.W554L, Tmc1 p.D528N) mutations of re...

Adam J. Dourson, Zachary K. Ford, Kathryn J. Green, Carolyn E. McCrossan, Megan C. Hofmann, et al. (see pages [4410–4427][1]) The development of human somatosensory circuits occurs perinatally and can be influenced by early sensory experience. This can be problematic, especially for preterm

Voices are arguably among the most relevant sounds in humans’ everyday life, and several studies have suggested the existence of voice-selective regions in the human brain. Despite two decades of research, defining the human brain regions supporting voice recognition remains challenging. Moreover, whether neural selectivity to voices is merely driven by acoustic properties specific to human voices (e.g., spectrogram, harmonicity), or whether it also reflects a higher-level categorization response is still under debate. Here, we objectively measured rapid automatic categorization responses to human voices with fast periodic auditory stimulation (FPAS) combined with electroencephalography (EEG). Participants were tested with stimulation sequences containing heterogeneous non-vocal sounds from different categories presented at 4 Hz (i.e., four stimuli/s), with vocal sounds appearing every three stimuli (1.333 Hz). A few minutes of stimulation are sufficient to elicit robust 1.333-Hz voice-selective focal brai...

Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by a trinucleotide expansion in exon 1 of the huntingtin ( HTT ) gene. Cell death in HD occurs primarily in striatal medium spiny neurons (MSNs), but the involvement of specific MSN subtypes and of other striatal cell types remains poorly understood. To gain insight into cell type-specific disease processes, we studied the nuclear transcriptomes of 4524 cells from the striatum of a genetically precise knock-in mouse model of the HD mutation, HttQ175/+ , and from wild-type controls. We used 14- to 15-month-old male mice, a time point at which multiple behavioral, neuroanatomical, and neurophysical changes are present but at which there is no known cell death. Thousands of differentially expressed genes (DEGs) were distributed across most striatal cell types, including transcriptional changes in glial populations that are not apparent from RNA-seq of bulk tissue. Reconstruction of cell type-specific transcriptional networks...

Early-life inflammatory stress increases seizure susceptibility later in life. However, possible sex- and age-specific differences and the associated mechanisms are largely unknown. C57BL/6 mice were bred in house, and female and male pups were injected with lipopolysaccharide (LPS; 100 μg/kg, i.p.) or vehicle control (saline solution) at postnatal day 14 (P14). Seizure threshold was assessed in response to pentylenetetrazol (1% solution, i.v.) in adolescence (∼P40) and adulthood (∼P60). We found that adult, but not adolescent, mice treated with LPS displayed ∼34% lower seizure threshold compared with controls. Females and males showed similar increased seizure susceptibility, suggesting that altered brain excitability was age dependent, but not sex dependent. Whole-cell recordings revealed no differences in excitatory synaptic activity onto CA1 pyramidal neurons from control or neonatally inflamed adolescent mice of either sex. However, adult mice of both sexes previously exposed to LPS displayed spontane...

Our subjective perception of time is optimized to temporal regularities in the environment. This is illustrated by the central tendency effect: When estimating a range of intervals, short intervals are overestimated, whereas long intervals are underestimated to reduce the overall estimation error. Most models of interval timing ascribe this effect to the weighting of the current interval with previous memory traces after the interval has been perceived. Alternatively, the perception of the duration could already be flexibly tuned to its temporal context. We investigated this hypothesis using an interval reproduction task in which human participants (both sexes) reproduced a shorter and longer interval range. As expected, reproductions were biased toward the subjective mean of each presented range. EEG analyses showed that temporal context indeed affected neural dynamics during the perception phase. Specifically, longer previous durations decreased contingent negative variation and P2 amplitude and increase...

The fact that the transmission and processing of visual information in the brain takes time presents a problem for the accurate real-time localization of a moving object. One way this problem might be solved is extrapolation: using an object's past trajectory to predict its location in the present moment. Here, we investigate how a simulated in silico layered neural network might implement such extrapolation mechanisms, and how the necessary neural circuits might develop. We allowed an unsupervised hierarchical network of velocity-tuned neurons to learn its connectivity through spike-timing-dependent plasticity (STDP). We show that the temporal contingencies between the different neural populations that are activated by an object as it moves causes the receptive fields of higher-level neurons to shift in the direction opposite to their preferred direction of motion. The result is that neural populations spontaneously start to represent moving objects as being further along their trajectory than where they ...