Effects of restricted basilar papillar lesions and hair cell regeneration on auditory forebrain frequency organization in adult European Starlings

The frequency organization of neurons in the forebrain Field L complex (FLC) of adult starlings was investigated to determine the effects of hair cell (HC) destruction in the basal portion of the basilar papilla (BP) and of subsequent HC regeneration. Conventional microelectrode mapping techniques were used in normal starlings and in lesioned starlings either 2 d or 6-10 weeks after aminoglycoside treatment. Histological examination of the BP and recordings of auditory brainstem evoked responses confirmed massive loss of HCs in the basal portion of the BP and hearing losses at frequencies >2 kHz in starlings tested 2 d after aminoglycoside treatment. In these birds, all neurons in the region of the FLC in which characteristic frequencies (CFs) normally increase from 2 to 6 kHz had CF in the range of 2-4 kHz. The significantly elevated thresholds of responses in this region of altered tonotopic organization indicated that they were the residue of prelesion responses and did not reflect CNS plasticity. In the long-term recovery birds, there was histological evidence of substantial HC regeneration. The tonotopic organization of the high-frequency region of the FLC did not differ from that in normal starlings, but the mean threshold at CF in this frequency range was intermediate between the values in the normal and lesioned short-recovery groups. The recovery of normal tonotopicity indicates considerable stability of the topography of neuronal connections in the avian auditory system, but the residual loss of sensitivity suggests deficiencies in high-frequency HC function

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Plasticity of frequency organization in auditory cortex of guinea pigs with partial unilateral deafness.

ABSTRACT We have examined the effect of restricted unilateral cochlear lesions on the orderly topographic mapping of sound frequency in the auditory cortex of adult guinea pigs. These lesions, although restricted in spatial extent, resulted in a variety of patterns of histological damage to receptor cells and nerve fibres within the cochlea. Nevertheless, all lesions resulted in permanent losses of sensitivity of the cochlear neural output across a limited frequency range. Thirty-five to 81 days after such damage to the organ of Corti, the area of contralateral auditory cortex in which the lesioned frequency range would normally have been represented was partly occupied by an expanded representation of sound frequencies adjacent to the frequency range damaged by the lesion. The thresholds at their new characteristic frequencies (CFs) of clusters of cortical neurones in these regions were close to normal thresholds at those frequencies (mean difference across all animals was 3.8 dB). In a second series of experiments, the responses of neurone clusters were examined within hours of making similar cochlear lesions. It was found that shifts in CF toward frequencies spared by the lesions could occur, but thresholds were greatly elevated compared to normal (mean difference was 31.7 dB in five animals). The emergence of sensitive drive in such regions after prolonged recovery periods in lesioned animals thus suggests that the auditory cortical frequency map undergoes reorganization in cases of partial deafness. Some features of this reorganization are similar to changes reported in somatosensory cortex after peripheral nerve injury, and this form of plasticity may therefore be a feature of all adult sensory systems

Plasticity in the tonotopic organization of the medial geniculate body in adult cats following restricted unilateral cochlear lesions

To investigate subcortical contributions to cortical reorganization, the frequency organization of the ventral nucleus of the medial geniculate body (MGv) in six normal adult cats and in eight cats with restricted unilateral cochlear lesions was investigated using multiunit electrophysiological recording techniques. The tonotopic organization of MGv in the lesioned animals, with severe mid-to-high frequency hearing losses, was investigated 40-186 days following the lesioning procedure. Frequency maps were generated from neural responses to pure tone bursts presented separately to each ear under barbiturate anesthesia. Consideration of the frequency organization in normal animals, and of the apparently normal representation of the ipsilateral (unlesioned) cochlea in lesioned animals, allowed for a detailed specification of the extent of changes observed in MGv. In the lesioned animals it was found that, in the region of MGv in which mid-to-high frequencies are normally represented, there was an expanded representation of lesion-edge frequencies. Neuron clusters within these regions of enlarged representation that had new characteristic frequencies displayed response properties (latency, bandwidth) very similar to those in normal animals. Thresholds of these neurons were not consistent with the argument that the changes merely reflect the residue of prelesion responses, suggesting a dynamic process of reorganization. The tonotopic reorganization observed in MGv is similar to that seen in the primary auditory cortex and is more extensive than the reorganization found in the auditory midbrain, suggesting that the auditory thalamus plays an important role in cortical plasticity. J. Comp. Neurol. 459:355-367, 2003. © 2003 Wiley-Liss, Inc

Plasticity in the adult central auditory system

The central auditory system retains into adulthood a remarkable capacity for plastic changes in the response characteristics of single neurons and the functional organization of groups of neurons. The most dramatic examples of this plasticity are provided by changes in frequency selectivity and organization as a consequence of either partial hearing loss or procedures that alter the significance of particular frequencies for the organism. Changes in temporal resolution are also seen as a consequence of altered experience. These forms of plasticity are likely to contribute to the improvements exhibited by cochlear implant users in the post-implantation period

Effects of prismatic adaptation on spatial gradients in unilateral neglect: A comparison of visual and auditory target detection with central attentional load

Prismatic adaptation is increasingly recognised as an effective procedure for rehabilitating symptoms of unilateral spatial neglect - producing relatively long-lasting improvements on a variety of spatial attention tasks. The mechanisms by which the aftereffects of adaptation change neglect patients' performance on these tasks remain controversial. It is not clear, for example, whether adaptation directly influences the pathological ipsilesional attention bias that underlies neglect, or whether it simply changes exploratory motor behaviour. Here we used visual and auditory versions of a target detection task with a secondary task at fixation. Under these conditions, patients with neglect demonstrated a spatial gradient in their ability to orient to the brief, peripheral visual or auditory targets. Following prism adaptation, we found that overall performance on both the auditory and visual task improved, however, most patients in our sample did not show changes in their visual or auditory spatial gradient of attention, despite adequate aftereffects of adaptation and significant improvement in neglect on visual cancellation. Although there were individual cases that suggested prism-induced changes in visual target detection, and even reversal of the visual spatial gradient, such cases were not evident for the auditory modality. The findings indicate that spatial gradients in stimulus-driven attention may be less responsive to the effects of prism adaptation than neglect symptoms in voluntary orienting and exploratory behaviour. Individual factors such as lesion site and symptom severity may also determine the expression of prism effects on spatial neglect