Power Dissipation in the Cochlea Can Enhance Frequency Selectivity

The cochlear cavity is filled with viscous fluids, and it is partitioned by a viscoelastic structure called the organ of Corti complex. Acoustic energy propagates toward the apex of the cochlea through vibrations of the organ of Corti complex. The dimensions of the vibrating structures range from a few hundred (e.g., the basilar membrane) to a few micrometers (e.g., the stereocilia bundle). Vibrations of microstructures in viscous fluid are subjected to energy dissipation. Because the viscous dissipation is considered to be detrimental to the function of hearing—sound amplification and frequency tuning—the cochlea uses cellular actuators to overcome the dissipation. Compared to extensive investigations on the cellular actuators, the dissipating mechanisms have not been given appropriate attention, and there is little consensus on damping models. For example, many theoretical studies use an inviscid fluid approximation and lump the viscous effect to viscous damping components. Others neglect viscous dissipation in the organ of Corti but consider fluid viscosity. We have developed a computational model of the cochlea that incorporates viscous fluid dynamics, organ of Corti microstructural mechanics, and electrophysiology of the outer hair cells. The model is validated by comparing with existing measurements, such as the viscoelastic response of the tectorial membrane, and the cochlear input impedance. Using the model, we investigated how dissipation components in the cochlea affect its function. We found that the majority of acoustic energy dissipation of the cochlea occurs within the organ of Corti complex, not in the scalar fluids. Our model suggests that an appropriate dissipation can enhance the tuning quality by reducing the spread of energy provided by the outer hair cells’ somatic motility.     

Shared genetic loci between depression and cardiometabolic traits

Epidemiological and clinical studies have found associations between depression and cardiovascular disease risk factors, and coronary artery disease patients with depression have worse prognosis. The genetic relationship between depression and these cardiovascular phenotypes is not known. We here investigated overlap at the genome-wide level and in individual loci between depression, coronary artery disease and cardiovascular risk factors. We used the bivariate causal mixture model (MiXeR) to quantify genome-wide polygenic overlap and the conditional/conjunctional false discovery rate (pleioFDR) method to identify shared loci, based on genome-wide association study summary statistics on depression (n = 450,619), coronary artery disease (n = 502,713) and nine cardiovascular risk factors (n = 204,402–776,078). Genetic loci were functionally annotated using FUnctional Mapping and Annotation (FUMA). Of 13.9K variants influencing depression, 9.5K (SD 1.0K) were shared with body-mass index. Of 4.4K variants influencing systolic blood pressure, 2K were shared with depression. ConjFDR identified 79 unique loci associated with depression and coronary artery disease or cardiovascular risk factors. Six genomic loci were associated jointly with depression and coronary artery disease, 69 with blood pressure, 49 with lipids, 9 with type 2 diabetes and 8 with c-reactive protein at conjFDR < 0.05. Loci associated with increased risk for depression were also associated with increased risk of coronary artery disease and higher total cholesterol, low-density lipoprotein and c-reactive protein levels, while there was a mixed pattern of effect direction for the other risk factors. Functional analyses of the shared loci implicated metabolism of alpha-linolenic acid pathway for type 2 diabetes. Our results showed polygenic overlap between depression, coronary artery disease and several cardiovascular risk factors and suggest molecular mechanisms underlying the association between depression and increased cardiovascular disease risk.     

NTPDase1 and NTPDase2 immunolocalization in mouse cochlea: implications for regulation of p2 receptor signaling.

Cellular, molecular, and physiological studies have demonstrated an important signaling role for ATP and related nucleotides acting via P2 receptors in the cochlea of the inner ear. Signal modulation is facilitated by ectonucleotidases, a heterologous family of surface-located enzymes involved in extracellular nucleotide hydrolysis. Our previous studies have implicated CD39/NTPDase1 and CD39L1/NTPDase2, members of the ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) family, as major ATP-hydrolyzing enzymes in the tissues lining the cochlear endolymphatic and perilymphatic compartments. NTPDase1 hydrolyzes both nucleoside triphosphates and diphosphates. In contrast, NTPDase2 is a preferential nucleoside triphosphatase. This study characterizes expression of these E-NTPDases in the mouse cochlea by immunohistochemistry. NTPDase1 can be immunolocalized to the cochlear vasculature and neural tissues (primary auditory neurons in the spiral ganglion). In contrast, NTPDase2 immunolabeling was principally localized to synaptic regions of the sensory inner and outer hair cells, stereocilia and cuticular plates of the outer hair cells, supporting cells of the organ of Corti (Deiters' cells and inner border cells), efferent nerve fibers located in the intraganglionic spiral bundle, and in the outer sulcus and root region of the spiral ligament. This differential expression of NTPDase1 and 2 in the cochlea suggests spatial regulation of P2 receptor signaling, potentially involving different nucleotide species and hydrolysis kinetics.     

Toward a More General Understanding of Bohr’s Complementarity: Insights from Modeling of Ion Channels

Acta Biotheoretica - Some contemporary theorists such as Mazzocchi, Theise and Kafatos are convinced that the reformed complementarity may redefine how we might exploit the complexity theory in...     

Development of c‐kit immunopositive interstitial cells of Cajal in the human stomach

Interstitial cells of Cajal (ICC) include several types of specialized cells within the musculature of the gastrointestinal tract (GIT). Some types of ICC act as pacemakers in the GIT musculature, whereas others are implicated in the modulation of enteric neurotransmission. Kit immunohistochemistry reliably identifies the location of these cells and provides information on changes in ICC distribution and density. Human stomach specimens were obtained from 7 embryos and 28 foetuses without gastrointestinal disorders. The specimens were 7–27 weeks of gestational age, and both sexes are represented in the sample. The specimens were exposed to anti‐c‐kit antibodies to investigate ICC differentiation. Enteric plexuses were immunohistochemically examined by using anti‐neuron specific enolase and the differentiation of smooth muscle cells (SMC) was studied with anti‐α smooth muscle actin and anti‐desmin antibodies. By week 7, c‐kit‐immunopositive precursors formed a layer in the outer stomach wall around myenteric plexus elements. Between 9 and 11 weeks some of these precursors differentiated into ICC. ICC at the myenteric plexus level differentiated first, followed by those within the muscle layer: between SMC, at the circular and longitudinal layers, and within connective tissue septa enveloping muscle bundles. In the fourth month, all subtypes of c‐kit‐immunoreactivity ICC which are necessary for the generation of slow waves and their transfer to SMC have been developed. These results may help elucidate the origin of ICC and the aetiology and pathogenesis of stomach motility disorders in neonates and young children that are associated with absence or decreased number of these cells.     

Differential expression of P2Y receptors in the rat cochlea during development

Purinergic signaling has broad physiological significance to the hearing organ, involving signal transduction via ionotropic P2X receptors and metabotropic G-protein-coupled P2Y and P1 (adenosine), alongside conversion of nucleotides and nucleosides by ecto-nucleotidases and ecto-nucleoside diphosphokinase. In addition, ATP release is modulated by acoustic overstimulation or stress and involves feedback regulation. Many of these principal elements of the purinergic signaling complex have been well characterized in the cochlea, while the characterization of P2Y receptor expression is emerging. The present study used immunohistochemistry to evaluate the expression of five P2Y receptors, P2Y₁, P2Y₂, P2Y₄, P2Y₆, and P2Y₁₂, during development of the rat cochlea. Commencing in the late embryonic period, the P2Y receptors studied were found in the cells lining the cochlear partition, associated with establishment of the electrochemical environment which provides the driving force for sound transduction. In addition, early postnatal P2Y₂ and P2Y₄ protein expression in the greater epithelial ridge, part of the developing hearing organ, supports the view that initiation and regulation of spontaneous activity in the hair cells prior to hearing onset is mediated by purinergic signaling. Sub-cellular compartmentalization of P2Y receptor expression in sensory hair cells, and diversity of receptor expression in the spiral ganglion neurons and their satellite cells, indicates roles for P2Y receptor-mediated Ca²⁺-signaling in sound transduction and auditory neuron excitability. Overall, the dynamics of P2Y receptor expression during development of the cochlea complement the other elements of the purinergic signaling complex and reinforce the significance of extracellular nucleotide and nucleoside signaling to hearing.     

Essential Oil Variability in Natural Populations of Picea omorika,a Rare European Conifer

This study is the first report on the composition and variability of essential oil in the relic, endemic, and vulnerable tree species Serbian spruce, Picea omorika, in its natural populations. In the needles of 108 trees of four natural populations, 49 components of essential oils were identified. The main compounds were bornyl acetate (29.2%), camphene (18.7%), and α‐pinene (12.9%). Fourteen additional components had the contents of up to 0.5%: α‐cadinol (6.1%), limonene (5.8%), santene (3.5%), (E)‐hex‐2‐enal (2.9%), T‐cadinol (2.9%), δ‐cadinene (2.3%), tricyclene (2.1%), myrcene (1.6%), β‐pinene (1.2%), borneol (0.9%), germacrene D (0.9%), α‐muurolene (0.6%), and two unidentified compounds. Population IV from Mile?evka Canyon had a much higher content of bornyl acetate (42.9%). Populations I–III from Mt. Tara were more abundant in sesquiterpenes (up to 18.2%). The content of bornyl acetate, the multi‐variation analyses according to seven selected components, especially the cluster analysis and genetic analysis of α‐cadinol, which suggested the monogenic type of heredity, showed a clear differentiation of the two geographic areas, the similarity of populations I–III from the area of Mt. Tara, and the separation of the population IV from Mile?evka Canyon.     

The impact of sparsity in low-rank recurrent neural networks

Neural population dynamics are often highly coordinated, allowing task-related computations to be understood as neural trajectories through low-dimensional subspaces. How the network connectivity and input structure give rise to such activity can be investigated with the aid of low-rank recurrent neural networks, a recently-developed class of computational models which offer a rich theoretical framework linking the underlying connectivity structure to emergent low-dimensional dynamics. This framework has so far relied on the assumption of all-to-all connectivity, yet cortical networks are known to be highly sparse. Here we investigate the dynamics of low-rank recurrent networks in which the connections are randomly sparsified, which makes the network connectivity formally full-rank. We first analyse the impact of sparsity on the eigenvalue spectrum of low-rank connectivity matrices, and use this to examine the implications for the dynamics. We find that in the presence of sparsity, the eigenspectra in the complex plane consist of a continuous bulk and isolated outliers, a form analogous to the eigenspectra of connectivity matrices composed of a low-rank and a full-rank random component. This analogy allows us to characterise distinct dynamical regimes of the sparsified low-rank network as a function of key network parameters. Altogether, we find that the low-dimensional dynamics induced by low-rank connectivity structure are preserved even at high levels of sparsity, and can therefore support rich and robust computations even in networks sparsified to a biologically-realistic extent.     

A Genetic Deconstruction of Neurocognitive Traits in Schizophrenia and Bipolar Disorder

Background

Impairments in cognitive functions are common in patients suffering from psychiatric disorders, such as schizophrenia and bipolar disorder. Cognitive traits have been proposed as useful for understanding the biological and genetic mechanisms implicated in cognitive function in healthy individuals and in the dysfunction observed in psychiatric disorders.

Methods

Sets of genes associated with a range of cognitive functions often impaired in schizophrenia and bipolar disorder were generated from a genome-wide association study (GWAS) on a sample comprising 670 healthy Norwegian adults who were phenotyped for a broad battery of cognitive tests. These gene sets were then tested for enrichment of association in GWASs of schizophrenia and bipolar disorder. The GWAS data was derived from three independent single-centre schizophrenia samples, three independent single-centre bipolar disorder samples, and the multi-centre schizophrenia and bipolar disorder samples from the Psychiatric Genomics Consortium.

Results

The strongest enrichments were observed for visuospatial attention and verbal abilities sets in bipolar disorder. Delayed verbal memory was also enriched in one sample of bipolar disorder. For schizophrenia, the strongest evidence of enrichment was observed for the sets of genes associated with performance in a colour-word interference test and for sets associated with memory learning slope.

Conclusions

Our results are consistent with the increasing evidence that cognitive functions share genetic factors with schizophrenia and bipolar disorder. Our data provides evidence that genetic studies using polygenic and pleiotropic models can be used to link specific cognitive functions with psychiatric disorders.