Novel high-intensive cholesterol-lowering therapies do not ameliorate knee OA development in humanized dyslipidemic mice.

OBJECTIVE: High systemic cholesterol levels have been associated with osteoarthritis (OA) development. Therefore, cholesterol lowering by statins has been suggested as a potential treatment for OA. We investigated whether therapeutic high-intensive cholesterol-lowering attenuated OA development in dyslipidemic APOE∗3Leiden.CETP mice. METHODS: Female mice (n = 13-16 per group) were fed a Western-type diet (WTD) for 38 weeks. After 13 weeks, mice were divided into a baseline group and five groups receiving WTD alone or with treatment: atorvastatin alone, combined with PCSK9 inhibitor alirocumab and/or ANGPTL3 inhibitor evinacumab. Knee joints were analysed for cartilage degradation, synovial inflammation and ectopic bone formation using histology. Aggrecanase activity in articular cartilage and synovial S100A8 expression were determined as markers of cartilage degradation/regeneration and inflammation. RESULTS: Cartilage degradation and active repair were significantly increased in WTD-fed mice, but cholesterol-lowering strategies did not ameliorate cartilage destruction. This was supported by comparable aggrecanase activity and S100A8 expression in all treatment groups. Ectopic bone formation was comparable between groups and independent of cholesterol levels. CONCLUSIONS: Intensive therapeutic cholesterol lowering per se did not attenuate progression of cartilage degradation in dyslipidemic APOE∗3Leiden.CETP mice, with minor joint inflammation. We propose that inflammation is a key feature in the disease and therapeutic cholesterol-lowering strategies may still be promising for OA patients presenting both dyslipidemia and inflammation.

High-fat feeding primes the mouse knee joint to develop osteoarthritis and pathologic infrapatellar fat pad changes after surgically induced injury.

OBJECTIVE: Obesity is one of the greatest risk factors for osteoarthritis (OA) and evidence is accumulating that inflammatory mediators and innate immunity play an important role. The infrapatellar fat pad (IPFP) could be a potential local source of inflammatory mediators in the knee. Here, we combine surgical joint damage with high-fat feeding in mice to investigate inflammatory responses in the IPFP during OA development. DESIGN: Mice (n = 30) received either a low-fat diet (LFD), high-fat diet (HFD) for 18 weeks or switched diets (LFD > HFD) after 10 weeks. OA was induced by surgical destabilization of the medial meniscus (DMM), contralateral knees served as sham controls. An additional HFD-only group (n = 15) received no DMM. RESULTS: The most pronounced inflammation, characterized by macrophage crown-like structures (CLS), was found in HFD + DMM mice, CLS increased compared to HFD only (mean difference = 7.26, 95%CI [1.52-13.0]) and LFD + DMM (mean difference = 6.35, 95%CI [0.53-12.18). The M1 macrophage marker iNOS increased by DMM (ratio = 2.48, 95%CI [1.37-4.50]), while no change in M2 macrophage marker CD206 was observed. Fibrosis was minimal by HFD alone, but in combination with DMM it increased with 23.45% (95%CI [13.67-33.24]). CONCLUSIONS: These findings indicate that a high-fat diet alone does not trigger inflammation or fibrosis in the infrapatellar fat pad, but in combination with an extra damage trigger, like DMM, induces inflammation and fibrosis in the infrapatellar fat pad. These data suggest that HFD provides a priming effect on the infrapatellar fat pad and that combined actions bring the joint in a metabolic state of progressive OA.

Human C-reactive protein aggravates osteoarthritis development in mice on a high-fat diet.

OBJECTIVE: C-reactive protein (CRP) levels can be elevated in osteoarthritis (OA) patients. In addition to indicating systemic inflammation, it is suggested that CRP itself can play a role in OA development. Obesity and metabolic syndrome are important risk factors for OA and also induce elevated CRP levels. Here we evaluated in a human CRP (hCRP)-transgenic mouse model whether CRP itself contributes to the development of 'metabolic' OA. DESIGN: Metabolic OA was induced by feeding 12-week-old hCRP-transgenic males (hCRP-tg, n = 30) and wild-type littermates (n = 15) a 45 kcal% high-fat diet (HFD) for 38 weeks. Cartilage degradation, osteophytes and synovitis were graded on Safranin O-stained histological knee joint sections. Inflammatory status was assessed by plasma lipid profiling, flow cytometric analyses of blood immune cell populations and immunohistochemical staining of synovial macrophage subsets. RESULTS: Male hCRP-tg mice showed aggravated OA severity and increased osteophytosis compared with their wild-type littermates. Both classical and non-classical monocytes showed increased expression of CCR2 and CD86 in hCRP-tg males. HFD-induced effects were evident for nearly all lipids measured and indicated a similar low-grade systemic inflammation for both genotypes. Synovitis scores and synovial macrophage subsets were similar in the two groups. CONCLUSIONS: Human CRP expression in a background of HFD-induced metabolic dysfunction resulted in the aggravation of OA through increased cartilage degeneration and osteophytosis. Increased recruitment of classical and non-classical monocytes might be a mechanism of action through which CRP is involved in aggravating this process. These findings suggest interventions selectively directed against CRP activity could ameliorate metabolic OA development.

Aging does not change the compressive stiffness of mandibular condylar cartilage in horses.

OBJECTIVE: Aging can cause an increase in the stiffness of hyaline cartilage as a consequence of increased protein crosslinks. By induction of crosslinking, a reduction in the diffusion of solutions into the hyaline cartilage has been observed. However, there is a lack of knowledge about the effects of aging on the biophysical and biochemical properties of the temporomandibular joint (TMJ) cartilage. Hence, the aim of this study was to examine the biophysical properties (thickness, stiffness, and diffusion) of the TMJ condylar cartilage of horses of different ages and their correlation with biochemical parameters. MATERIALS AND METHODS: We measured the compressive stiffness of the condyles, after which the diffusion of two contrast agents into cartilage was measured using Contrast Enhanced Computed Tomography technique. Furthermore, the content of water, collagen, GAG, and pentosidine was analyzed. RESULTS: Contrary to our expectations, the stiffness of the cartilage did not change with age (modulus remained around 0.7 MPa). The diffusion of the negatively charged contrast agent (Hexabrix) also did not alter. However, the diffusion of the uncharged contrast agent (Visipaque) decreased with aging. The flux was negatively correlated with the amount of collagen and crosslink level which increased with aging. Pentosidine, collagen, and GAG were positively correlated with age whereas thickness and water content showed negative correlations. CONCLUSION: Our data demonstrated that aging was not necessarily reflected in the biophysical properties of TMJ condylar cartilage. The combination of the changes happening due to aging resulted in different diffusive properties, depending on the nature of the solution.

Variable cartilage degradation in mice with diet-induced metabolic dysfunction: food for thought.

OBJECTIVE: Human cohort studies have demonstrated a role for systemic metabolic dysfunction in osteoarthritis (OA) pathogenesis in obese patients. To explore the mechanisms underlying this metabolic phenotype of OA, we examined cartilage degradation in the knees of mice from different genetic backgrounds in which a metabolic phenotype was established by various dietary approaches. DESIGN: Wild-type C57BL/6J mice and genetically modified mice (hCRP, LDLr-/-. Leiden and ApoE*3Leiden.CETP mice) based on C57BL/6J background were used to investigate the contribution of inflammation and altered lipoprotein handling on diet-induced cartilage degradation. High-caloric diets of different macronutrient composition (i.e., high-carbohydrate or high-fat) were given in regimens of varying duration to induce a metabolic phenotype with aggravated cartilage degradation relative to controls. RESULTS: Metabolic phenotypes were confirmed in all studies as mice developed obesity, hypercholesteremia, glucose intolerance and/or insulin resistance. Aggravated cartilage degradation was only observed in two out of the twelve experimental setups, specifically in long-term studies in male hCRP and female ApoE*3Leiden.CETP mice. C57BL/6J and LDLr-/-. Leiden mice did not develop HFD-induced OA under the conditions studied. Osteophyte formation and synovitis scores showed variable results between studies, but also between strains and gender. CONCLUSIONS: Long-term feeding of high-caloric diets consistently induced a metabolic phenotype in various C57BL/6J (-based) mouse strains. In contrast, the induction of articular cartilage degradation proved variable, which suggests that an additional trigger might be necessary to accelerate diet-induced OA progression. Gender and genetic modifications that result in a humanized pro-inflammatory state (human CRP) or lipoprotein metabolism (human-E3L.CETP) were identified as important contributing factors.

Cold-water or partial-body cryotherapy? Comparison of physiological responses and recovery following muscle damage.

The aim of this study is to compare (a) the physiological responses following cold-water immersion (CWI) and partial-body cryotherapy (PBC) and (b) the effects on recovery following a muscle-damaging protocol (5 × 20 drop jumps). Nineteen healthy males were randomly allocated into either a CWI (10°C for 10 minutes; n = 9) or a PBC (-60°C for 30 seconds, -135°C for 2 minutes; n = 10) group. The physiological variables (thigh muscle oxygen saturation [SmO2 ], cutaneous vascular conductance [CVC], mean arterial pressure [MAP], and local skin temperature) were assessed immediately prior and up to 60 minutes post-treatment (10-minutes intervals). The recovery variables (thigh muscle swelling, maximum voluntary contraction [MVC] of the right knee extensors, vertical jump performance [VJP], and delayed onset of muscle soreness [DOMS]) were measured immediately prior and up to 72 hours post-treatment (24-hours intervals). Compared to PBC values, CVC (at 30 minutes), SmO2 (at 40 minutes), and lower extremity skin temperature (thigh/shin at 60 minutes) were significantly reduced in the CWI group after the treatment (all P < .05). Only lower extremity skin temperature was significantly reduced in the PBC group directly post-treatment (all P < .05). MAP significantly increased in both groups after the treatments (both P < .05). DOMS did not differ between groups. MVC and VJP returned to baseline in both groups after 24 hours (P > .05). CWI had a greater impact on the physiological response compared to PBC. However, both treatments resulted in similar recovery profiles during a 72-hours follow-up period.

Translational neuroscience of basolateral amygdala lesions: Studies of Urbach-Wiethe disease.

Urbach-Wiethe disease (UWD) is an extremely rare autosomal recessive disorder characterized by mutations in the extracellular matrix protein 1 gene on chromosome 1. Typical clinical manifestations include voice hoarseness in early infancy and neuropsychiatric, laryngeal, and dermatological pathologies later in life. Neuroimaging studies have revealed a pattern of brain calcification often but not exclusively leading to selective bilateral amygdala damage. A large body of work on amygdala lesions in rodents exists, generally employing a subregion model focused on the basolateral amygdala (BLA) and the central-medial amygdala. However, human work usually considers the amygdala as a unified structure, not only complicating the translation of animal findings to humans but also providing a unique opportunity for further research. To compare data from rodent models with human cases and to complement existing data from Europe and North America, a series of investigations was undertaken on UWD subjects with selective BLA damage in the Namaqualand region, South Africa. This review presents key findings from this work, including fear processing, social-economic behavior, and emotional conflict processing. Our findings are broadly consistent with and support rodent models of selective BLA lesions and show that the BLA is integral to processing sensory stimuli and exhibits inhibitory regulation of responses to unconditioned innate fear stimuli. Furthermore, our findings suggest that the human BLA mediates calculative-instrumental economic behaviors and may compromise working memory via competition for attentional resources between the BLA salience detection system and the dorsolateral prefrontal cortex working memory system.

Osteoarthritis-related fibrosis is associated with both elevated pyridinoline cross-link formation and lysyl hydroxylase 2b expression.

OBJECTIVE: Fibrosis is a major contributor to joint stiffness in osteoarthritis (OA). We investigated several factors associated with the persistence of transforming growth factor beta (TGF-ß)-induced fibrosis and whether these factors also play a role in OA-related fibrosis. DESIGN: Mice were injected intra-articularly (i.a.) with an adenovirus encoding either TGF-ß or connective tissue growth factor (CTGF). In addition, we induced OA by i.a. injection of bacterial collagenase into the right knee joint of C57BL/6 mice. mRNA was isolated from the synovium for Q-PCR analysis of the gene expression of various extracellular matrix (ECM) components, ECM degraders, growth factors and collagen cross-linking-related enzymes. Sections of murine knee joints injected with Ad-TGF-ß or Ad-CTGF or from experimental OA were stained for lysyl hydroxylase 2 (LH2). The number of pyridinoline cross-links per triple helix collagen in synovium biopsies was determined with high-performance liquid chromatography (HPLC). RESULTS: Expression of collagen alpha-1(I) chain precursor (Col1a1), tissue inhibitor of metalloproteinases 1 (TIMP1) and especially procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2b (Plod2b) were highly upregulated by TGF-ß but not by CTGF. Elevated expression of Plod2b mRNA was associated with high lysyl hydroxylase 2 (LH2) protein staining after TGF-ß overexpression and in experimental OA. Furthermore, in experimental OA the number of hydroxypyridinoline cross-links was significant increased compared to control knee joints. CONCLUSIONS: Our data show that elevated LH2b expression is associated with the persistent nature of TGF-ß-induced fibrosis. Also in experimental OA, LH2b expression as well as the number of hydroxypyridinoline cross-link were significantly upregulated. We propose that LH2b, and the subsequent increase in pyridinoline cross-links, is responsible for the persistent fibrosis in experimental OA.

Metabolic stress-induced inflammation plays a major role in the development of osteoarthritis in mice.

OBJECTIVE: Obesity is associated with systemic inflammation and is a risk factor for osteoarthritis (OA) development. We undertook this study to test the hypothesis that metabolic stress-induced inflammation, and not mechanical overload, is responsible for the development of high-fat diet-induced OA in mice. METHODS: Human C-reactive protein (CRP)-transgenic mice received a high-fat diet without or with 0.005% (weight/weight) rosuvastatin or 0.018% (w/w) rosiglitazone, 2 different drugs with antiinflammatory properties. Mice fed chow were included as controls. After 42 weeks, mice were killed and histologic OA grading of the knees was performed. To monitor the overall inflammation state, systemic human CRP levels were determined. RESULTS: Male mice on a high-fat diet had significantly higher OA grades than mice on chow and showed no correlation between OA severity and body weight. In male mice, high-fat diet-induced OA was significantly inhibited by rosuvastatin or rosiglitazone to OA grades observed in control mice. Both treatments resulted in reduced human CRP levels. Furthermore, a positive correlation was found between the relative individual induction of human CRP evoked by a high-fat diet on day 3 and OA grade at end point. CONCLUSION: High-fat diet-induced OA in mice is due to low-grade inflammation and not to mechanical overload, since no relationship between body weight and OA grade was observed. Moreover, the OA process was inhibited to a great extent by treatment with 2 drugs with antiinflammatory properties. The inflammatory response to a metabolic high-fat challenge may predict individual susceptibility to developing OA later in life. The use of statins or peroxisome proliferator-activated receptor γ agonists (e.g., rosiglitazone) could be a strategy for interfering with the progression of OA.

True reference nanosensor realized with silicon nanowires.

Conventional gate oxide layers (e.g., SiO(2), Al(2)O(3), or HfO(2)) in silicon field-effect transistors (FETs) provide highly active surfaces, which can be exploited for electronic pH sensing. Recently, great progress has been achieved in pH sensing using compact integrateable nanowire FETs. However, it has turned out to be much harder to realize a true reference electrode, which--while sensing the electrostatic potential--does not respond to the proton concentration. In this work, we demonstrate a highly effective reference sensor, a so-called reference FET, whose proton sensitivity is suppressed by as much as 2 orders of magnitude. To do so, the Al(2)O(3) surface of a nanowire FET was passivated with a self-assembled monolayer of silanes with a long alkyl chain. We have found that a full passivation can be achieved only after an extended period of self-assembling lasting several days at 80 °C. We use this slow process to measure the number of active proton binding sites as a function of time by a quantitative comparison of the measured nonlinear pH-sensitivities to a theoretical model (site-binding model). Furthermore, we have found that a partially passivated surface can sense small changes in the number of active binding sites reaching a detection limit of δN(s) ≈ 170 µm(-2) Hz(-1/2) at 10 Hz and pH 3.

Mesocopic comparison of complex networks based on periodic orbits.

Complex noiseless dynamical systems can be represented in a compressed manner by unstable periodic orbits. It is unknown, however, how to use this technique to obtain a suitable notion of similarity among them, how to extend such an approach to more general complex networks, and how to apply such a method in the important case of noisy systems. Our approach provides a solution to these questions. For a proof-of-concept, we consider Drosophila's precopulatory courtship, where our method reveals the existence of a complex grammar (similar to those found in complex physical systems and in language), leading to the conclusion that the observed grammar is very unlikely the product of chance.

Potentiation of transmitter release by ciliary neurotrophic factor requires somatic signaling.

Neurotrophic factors participate in the development and maintenance of the nervous system. Application of ciliary neurotrophic factor (CNTF), a protein that promotes survival of motor neurons, resulted in an immediate potentiation of spontaneous and impulse-evoked transmitter release at developing neuromuscular synapses in Xenopus cell cultures. When CNTF was applied at the synapse, the onset of the potentiation was slower than that produced by application at the cell body of the presynaptic neuron. The potentiation effect was abolished when the neurite shaft was severed from the cell body. Thus, transmitter secretion from the nerve terminals is under immediate somatic control and can be regulated by CNTF.

Biophysical parameters modification could overcome essential hearing gaps.

A majority of hearing defects are due to malfunction of the outer hair cells (OHCs), those cells within the mammalian hearing sensor (the cochlea) that provide an active amplification of the incoming signal. Malformation of the hearing sensor, ototoxic drugs, acoustical trauma, infections, or the effect of aging affect often a whole frequency interval, which leads to a substantial loss of speech intelligibility. Using an energy-based biophysical model of the passive cochlea, we obtain an explicit description of the dependence of the tonotopic map on the biophysical parameters of the cochlea. Our findings indicate the possibility that by suitable local modifications of the biophysical parameters by microsurgery, even very salient gaps of the tonotopic map could be bridged.

Evaluation and review of body fluids saliva, sweat and tear compared to biochemical hydration assessment markers within blood and urine.

Evaluating and testing hydration status is increasingly requested by rehabilitation, sport, military and performance-related activities. Besides commonly used biochemical hydration assessment markers within blood and urine, which have their advantages and limitations in collection and evaluating hydration status, there are other potential markers present within saliva, sweat or tear. This literature review focuses on body fluids saliva, sweat and tear compared to blood and urine regarding practicality and hydration status influenced by fluid restriction and/or physical activity. The selected articles included healthy subjects, biochemical hydration assessment markers and a well-described (de)hydration procedure. The included studies (n=16) revealed that the setting and the method of collecting respectively accessing body fluids are particularly important aspects to choose the optimal hydration marker. To obtain a sample of saliva is one of the simplest ways to collect body fluids. During exercise and heat exposures, saliva composition might be an effective index but seems to be highly variable. The collection of sweat is a more extensive and time-consuming technique making it more difficult to evaluate dehydration and to make a statement about the hydration status at a particular time. The collection procedure of tear fluid is easy to access and causes very little discomfort to the subject. Tear osmolarity increases with dehydration in parallel to alterations in plasma osmolality and urine-specific gravity. But at the individual level, its sensitivity has to be further determined.

Gamma oscillatory activity in vitro: a model system to assess pathophysiological mechanisms of comorbidity between autism and epilepsy.

Autism spectrum disorder (ASD) and temporal lobe epilepsy exhibit remarkable comorbidity, but for reasons not clearly understood. To reveal a common pathophysiological mechanism, we here describe and characterize an in vitro epileptiform activity in the rat hippocampus that exhibits common features with in vivo activity in rodent ASD models. We discovered the development of this activity in the CA1 region of horizontal slices after prolonged interictal-like epileptiform activity in the CA3 region that was provoked by incubation in high potassium artificial cerebrospinal fluid. The CA1 epileptiform bursts were insensitive to blockers of glutamatergic transmission, and were carried by synaptic as well as extrasynaptic, tonically activated gamma-aminobutyric acid type A (GABA(A)) receptors. The bursts bear resemblance to in vivo gamma-oscillatory activity found in rat ASD models with respect to their gamma frequency spectrum, their origin (in the CA1), and their sensitivity to blockers of cation-chloride pumps (NKCC1 and KCC2), as well as to oxytocin. Considering this bursting activity as an in vitro model for studying comorbidity between epilepsy and ASD may help to disentangle the intricate interactions that underlie the comorbidity between both diseases and suggests that extrasynaptic tonic GABAergic transmission could represent a potential target for ASD.

Phase synchronization of coupled bursting neurons and the generalized Kuramoto model.

Bursting neurons fire rapid sequences of action potential spikes followed by a quiescent period. The basic dynamical mechanism of bursting is the slow currents that modulate a fast spiking activity caused by rapid ionic currents. Minimal models of bursting neurons must include both effects. We considered one of these models and its relation with a generalized Kuramoto model, thanks to the definition of a geometrical phase for bursting and a corresponding frequency. We considered neuronal networks with different connection topologies and investigated the transition from a non-synchronized to a partially phase-synchronized state as the coupling strength is varied. The numerically determined critical coupling strength value for this transition to occur is compared with theoretical results valid for the generalized Kuramoto model.

A simplified measurement of degraded collagen in tissues: application in healthy, fibrillated and osteoarthritic cartilage.

Intact triple helical collagen molecules are highly resistant to proteolytic enzymes, whereas degraded (unwound) collagen is easily digested. This fact was exploited to develop a simplified method for the quantification of the amount of degraded collagen in the collagen network of connective tissues. Essentially, the method involves extraction of proteoglycans with 4 M guanidinium chloride, selective digestion of degraded collagen by alpha-chymotrypsin, hydrolysis in 6 M HCl of the released fragments as well as the residual tissue, and then measurement of the amount of hydroxyproline in both pools. Since the digestion of degraded collagen by alpha-chymotrypsin and measurement of hydroxyproline is not restricted to a specific collagen type, this technique can be applied to a wide variety of connective tissues. The method was validated with articular cartilage. Levels of in situ degraded collagen were about four-fold higher in degenerated (fibrillated) cartilage than in its healthy counterpart derived from the same donor. More detailed investigations revealed that the collagen damage in degenerated cartilage is more extensive at the cartilage surface than in the region adjacent to bone. This was not the case in healthy cartilage; identical low values were obtained at the surface and close to the bone. An impaired collagen network has been hypothesized to be the reason for the swelling of cartilage in osteoarthritis (OA). The present paper presents the first experimental evidence to support this hypothesis: more damage to the collagen network (i.e., more degraded collagen molecules within fibrils) is linearly related to more extensive swelling of the OA tissue in hypotonic saline.

Determination of group I metabotropic glutamate receptor subtypes involved in the frequency of epileptiform activity in vitro using mGluR1 and mGluR5 mutant mice.

In mouse hippocampal slices, bicuculline elicited spontaneous epileptiform bursts with a duration of 200-300 ms and with a frequency of five to six events per minute. Application of group I metabotropic glutamate receptor agonist (RS)-3,5-dihydroxyphenylglycine ((RS)-DHPG) increased the burst frequency up to 300% at concentrations of 50 to 100 microM, while it decreased the burst duration below 100 ms. In slices of subtype I mGluR1 or subtype I mGluR5 knockout mice, bicuculline elicited spontaneous epileptiform bursts with similar duration and frequency as those measured in wild-type mice but without the previous effects seen following application of DHPG at concentrations up to 100 microM. Likewise, in slices of wild-type mice, preincubation with mGluR1 antagonist, 1-aminoindan-1,5-dicarboxylic acid (AIDA) or mGluR5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP) blocked in both cases completely the increase in frequency following DHPG application. These findings suggest an interactive mechanism between mGluR1 and mGluR5 receptors in the modulation of epileptiform bursting activity by DHPG that could indicate a common intracellular signaling mechanism or possibly direct interaction between these two receptors.

Fading and rebound of P2X2 currents at millimolar ATP concentrations caused by low pH.

When ATP is applied at high concentrations (above 1 mM) to PC12 cells, it produces a rapidly desensitizing peak current followed by a rebound of the current after termination of the ATP application. We expressed P2X2 receptors, which are thought to mediate the ATP currents of PC12 cells, in HEK293 cells and studied the effects of acidification on this 'fading and rebound' phenomenon. We found that the desensitization disappeared after adjusting the low pH (<5.0) of the millimolar ATP concentrations to a more physiological value (pH 7.3). Furthermore, the fading and rebound could also be induced at much lower ATP concentrations by decreasing the pH of the ATP containing application solutions. Thus, it appears this phenomenon is not caused directly by high concentrations of ATP, but is due to a concomitant acidification that occurs when high concentrations of ATP are dissolved in only moderately buffered application solutions.

Limit cycles, noise, and chaos in hearing.

Based on insight obtained from a newly developed cochlea model, we argue that noise-driven limit cycles are the basic ingredient in the mammalian cochlea hearing process. For insect audition, we provide evidence in favor of the persistence of this principle. We emphasize the role of bifurcations for the emergence of broad-range sound perception, both in the frequency and amplitude domain, and indicate that this crucially depends on the correct coupling between limit cycles. We review the limit-cycle coupling universality, and outline how it can be used to encode information. Cortical noise is the microscopic basis for this encoding, whereas chaos emerges as the macroscopic expression of computation being done in the network. Large neuron firing variability is one possible consequence of the proposed mechanism that may apply to both vertebrate and insect hearing.