Little is known about the neural bases of the reduced auditory and cortical processing speeds that have been recorded in language-impaired, autistic, schizophrenic, and other disabled human ...populations. Although there is strong evidence for genetic contributions to etiologies, epigenetic factors such as perinatal anoxia (PA) have been argued to be contributors, or causal, in a significant proportion of cases. In this article, we explored the consequences of PA on this elementary aspect of auditory behavior and on auditory system function in rats that were briefly perinatally anoxic. PA rats had increased acoustic thresholds and reduced processing efficiencies recorded in an auditory behavioral task. These rats had modestly increased interpeak intervals in their auditory brainstem responses, and substantially longer latencies in poststimulus time histogram responses recorded in the primary auditory cortex. The latter were associated with degraded primary auditory cortex receptive fields and a disrupted tonotopy. These processing deficits are consistent with the parallel behavioral and physiological deficits recorded in children and adults with a history of language-learning impairment and autism.
The current study was conducted to extend our understanding of changes in spatial organization and response properties of cortical neurons in the developing mammalian forebrain. Extracellular ...multiunit responses to tones were recorded from a dense array of penetrations covering entire isofrequency contours in the primary auditory cortex (AI) of pentobarbital anesthetized kittens. Ages ranged from postnatal day 14 (P14), shortly after acquisition of normal auditory response thresholds, through postnatal day 111 (P111), when the kittens were largely mature. Spatial organization of the AI was tonotopically ordered by P14. The tonotopic gradient decreased with chronological maturation. At P14 the gradient was about 3.5 kHz/mm. By P111 it had declined to about 2.5 kHz/mm, so that the cortical region encompassing a fixed 3- to 15-kHz frequency range enlarged along its posterior-anterior dimension. Response properties of developing AI neurons changed in both frequency selectivity and intensity selectivity. The mean frequency tuning bandwidth increased with age. Initially, tuning bandwidths were narrow throughout the entire AI. With progressive maturation, broader bandwidths were observed in areas dorsal and ventral to a central region in which neurons remained narrowly tuned. The resulting spatial organization of tuning bandwidth was similar to that reported in adult cats. The majority of recording sites manifested nonmonotonic rate/level functions at all ages. However, the proportion of sites with monotonic rate/level functions increased with age. No spatial organization of rate/level functions (monotonic and nonmonotonic) was observed through P111. The relatively late development of bandwidth tuning in the AI compared with the early presence of tonotopic organization suggests that different developmental processes are responsible for structuring these two dimensions of acoustic selectivity.
The level of hearing rehabilitation enjoyed by cochlear implant (CI) recipients has increased dramatically since the introduction of these devices. This improvement is the result of continual ...development of these systems and the inclusion of subjects with less severe auditory pathology. Developments include advanced signal processing, higher stimulation rates, greater numbers of channels, and more efficient electrode arrays that are less likely to produce insertion damage. New directions in the application of CIs, particularly in combined acoustic and electrical stimulation, and increasing performance expectations will place greater demands on future electrode arrays. Specifically, the next generation of arrays must be reliably inserted without damage, must maintain residual acoustic function, and may need to be inserted more deeply. In this study, we measured the mechanical properties of eight clinical and prototype human CI electrode arrays and evaluated insertion trauma and insertion depth in 79 implanted cadaver temporal bones. We found that the size and shape of the array directly affect the incidence of observed trauma. Further, arrays with greater stiffness in the plane perpendicular to the plane of the cochlear spiral are less likely to cause severe trauma than arrays with similar vertical and horizontal stiffness.
A commonly accepted physiological model for lateralization of low-frequency sounds by interaural time delay (ITD) stipulates that binaural comparison neurons receive input from frequency-matched ...channels from each ear. Here, the effects of hypothetical interaural frequency mismatches on this model are reported. For this study, the cat's auditory system peripheral to the binaural comparison neurons was represented by a neurophysiologically derived model, and binaural comparison neurons were represented by cross-correlators. The results of the study indicate that, for binaural comparison neurons receiving input from one cochlear channel from each ear, interaural CF mismatches may serve to either augment or diminish the effective difference in ipsilateral and contralateral axonal time delays from the periphery to the binaural comparison neuron. The magnitude of this increase or decrease in the effective time delay difference can be up to 400 microseconds for CF mismatches of 0.2 octaves or less for binaural neurons with CFs between 250 Hz and 2.5 kHz. For binaural comparison neurons with nominal CFs near 500 Hz, the 25-microsecond effective time delay difference caused by a 0.012-octave CF mismatch is equal to the ITD previously shown to be behaviorally sufficient for the cat to lateralize a low-frequency sound source.
Hyperbaric oxygen therapy (HBOT) serves as “primary” or “adjunctive” therapy in a wide range of pathologies. It is considered the mainstay of management for potentially life-threatening conditions ...such as carbon monoxide poisoning, decompression illness, and gas embolisms. Moreover, HBOT has been utilized for decades as an adjunctive therapy in a variety of medical disciplines, including chronic wounds, which affect approximately 6.5 million Americans annually. In general, chronic wounds are characterized by hypoxia, impaired angiogenesis, and prolonged inflammation, all of which may theoretically be ameliorated by HBOT. Nonetheless, the cellular, biochemical, and physiological mechanisms by which HBOT achieves beneficial results in chronic wounds are not fully understood, and there remains significant skepticism regarding its efficacy. This review article provides a comprehensive overview of HBOT, and discusses its history, mechanisms of action, and its implications in management of chronic wounds. In particular, we discuss the current evidence regarding the use of HBOT in diabetic foot ulcers, while digging deeply into the roots of controversy surrounding its efficacy. We discuss how the paucity of high-quality research is a tremendous challenge, and offer future direction to address existing obstacles.
Purpose:
Scarring in the mouse dorsal dermis is mediated by pro-fibrotic,
Engrailed-1
lineage-positive fibroblasts (EPFs). We recently showed that mechanotransduction blockade (YAP inhibition, using ...the drug verteporfin), results in complete wound regeneration, with full recovery of normal dermal appendages (hair follicles, glands), extracellular matrix (ECM) architecture, and tensile strength. This regenerative outcome following verteporfin treatment is mediated by
Engrailed-1
lineage-negative fibroblasts (ENFs). The complex milieu of cell types and molecular signals involved in wound repair makes it difficult to study using any single data modality. Thus, we sought to use a holistic approach, incorporating multiple high-throughput, high-dimensional analyses, to define the divergent molecular events distinguishing typical scarring healing from verteporfin-induced wound regeneration.
Methods:
C57BL/6J mice underwent dorsal splinted excisional wounding per standard protocol. Wounds were treated with local injection of either verteporfin or vehicle control (PBS) on POD 0. We harvested unwounded skin and wounds at POD 2, 7, 14, and 30 (
n
=5 mice/timepoint and treatment) and subjected wound cells to three analyses: single-cell RNA-sequencing (scRNA-seq, using 10X Genomics Chromium); timsTOF, a recently-developed, high-throughput proteomic sequencing platform; and a novel machine learning algorithm for quantitatively comparing ECM ultrastructure.
Results:
Pseudotime analysis (Monocle3) of pooled scRNA-seq data revealed that fibroblasts followed two distinct transcriptional trajectories, one characterized by mechanical activation (
En-1
lineage-positive, “fibrotic” trajectory) and the other characterized by developmental and regenerative pathways (
En-1
lineage-negative; Rspo1, Dkk2/3, Trps1). Cross-platform data integration confirmed that fibroblasts in the fibrotic trajectory correlated with myofibroblast proteomic signatures (Col1a1/2, Fn1, etc.) and fibrotic/scar ECM features. In contrast, fibroblasts in the regenerative trajectory negatively correlated with myofibroblast markers and were associated with a “basket-weave” ECM pattern quantitatively indistinguishable from that of unwounded skin. Our integrated dataset suggested an important role for Wnt pathway proteins in ENF-mediated skin regeneration, so we compared POD 14 scars and regenerated wounds by multiplexed
in situ
hybridization (RNAScope) for
Rspo1
(Wnt agonist),
Trps1
(master hair follicle regulator),
Ank1
(YAP target gene), and
Dpp4
(EPF marker). Quantification of RNA granules across thousands of cells using a custom image analysis pipeline revealed that ENF-mediated healing (low
Dpp4
) in YAP-inhibited (low
Ank1
) wounds yielded regeneration of functional hair follicles through Wnt-mediated pathway activation (high
Rpos1
,
Trps1
). These data suggest that YAP inhibition unlocks wound regeneration via Wnt-active,
En-1
lineage-negative fibroblasts.
Conclusion:
By studying regenerating (verteporfin-treated) versus scarring wounds across multiple healing timepoints and high-dimensional data modalities, we were able to profile fibrotic versus regenerative healing at unprecedented depth. Our integrated analysis revealed that dermal fibroblasts in these two wound settings exhibit distinct molecular trajectories defined by divergent transcriptomic, proteomic, and ultrastructural properties. Further, we found that wound regeneration in the context of verteporfin treatment is associated with suppression of mechanical signaling and activation of key Wnt pathway members including
Trps1
(a gene with known hair follicle developmental roles). These results could have important implications for both the fundamental study of wound healing and potential anti-scarring therapeutic avenues
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