Translation of sensory input into behavioral output via an olfactory system

We investigate the logic by which sensory input is translated into behavioral output. First we provide a functional analysis of the entire odor receptor repertoire of an olfactory system. We construct tuning curves for the 21 functional odor receptors of the Drosophila larva and show that they sharpen at lower odor doses. We construct a 21-dimensional odor space from the responses of the receptors and find that the distance between two odors correlates with the extent to which one odor masks the other. Mutational analysis shows that different receptors mediate the responses to different concentrations of an odorant. The summed response of the entire receptor repertoire correlates with the strength of the behavioral response. The activity of a small number of receptors is a surprisingly powerful predictor of behavior. Odors that inhibit more receptors are more likely to be repellents. Odor space is largely conserved between two dissimilar olfactory systems.     

NMDA receptors in sensory information processing.

During the past year electrophysiological studies, particularly in the visual and somatosensory systems, have begun to uncover the specific roles played by NMDA receptors in the processing of sensory information. Many of the features of NMDA-receptor-mediated sensory responses reflect known properties of the receptor.     

Warm body temperature facilitates energy efficient cortical action potentials

The energy efficiency of neural signal transmission is important not only as a limiting factor in brain architecture, but it also influences the interpretation of functional brain imaging signals. Action potential generation in mammalian, versus invertebrate, axons is remarkably energy efficient. Here we demonstrate that this increase in energy efficiency is due largely to a warmer body temperature. Increases in temperature result in an exponential increase in energy efficiency for single action potentials by increasing the rate of Na(+) channel inactivation, resulting in a marked reduction in overlap of the inward Na(+), and outward K(+), currents and a shortening of action potential duration. This increase in single spike efficiency is, however, counterbalanced by a temperature-dependent decrease in the amplitude and duration of the spike afterhyperpolarization, resulting in a nonlinear increase in the spike firing rate, particularly at temperatures above approximately 35°C. Interestingly, the total energy cost, as measured by the multiplication of total Na(+) entry per spike and average firing rate in response to a constant input, reaches a global minimum between 37-42°C. Our results indicate that increases in temperature result in an unexpected increase in energy efficiency, especially near normal body temperature, thus allowing the brain to utilize an energy efficient neural code.     

Mechanism of action of capsaicin-like molecules on sensory neurons.

Capsaicin produces pain by selectively activating polymodal nociceptive neurons. This involves a membrane depolarization and the opening of a unique, cation-selective, ion channel which can be blocked by ruthenium red. The capsaicin-induced activation is mediated by a specific membrane receptor which can be selectively and competitively antagonised by capsazepine. Repetitive administrations of capsaicin produces a desensitization and an inactivation of sensory neurons. Several mechanisms are involved. These include receptor inactivation, block of voltage activated calcium channels, intracellular accumulation of ions leading to osmotic changes and activation of proteolytic enzyme processes. Systemic and topical capsaicin produces a reversible antinociceptive and antiinflammatory action after an initial undesirable algesic effect. Capsaicin analogues, such as olvanil, have similar properties with minimal initial pungency. Systemic capsaicin produces antinociception by activating capsaicin receptors on afferent nerve terminals in the spinal cord. Spinal neurotransmission is subsequently blocked by a prolonged inactivation of sensory neurotransmitter release. Local or topical application of capsaicin blocks C-fibre conduction and inactivates neuropeptide release from peripheral nerve endings. These mechanisms account for localized antinociception and the reduction of neurogenic inflammation respectively.     

A nonlinear cascade model for action potential encoding in an insect sensory neuron.

Action potential encoding in the cockroach tactile spine neuron can be represented as a single-input single-output nonlinear dynamic process. We have used a new functional expansion method to characterize the nonlinear behavior of the neural encoder. This method, which yields similar kernels to the Wiener method, is more accurate than the latter and is efficient enough to obtain reasonable kernels in less than 15 min using a personal computer. The input stimulus was band-limited white Gaussian noise and the output consisted of the resulting train of action potentials, which were unitized to give binary values. The kernels and the system input-output signals were used to identify a model for encoding comprising a cascade of dynamic linear, static nonlinear, and dynamic linear components. The two dynamic linear components had repeatable and distinctive forms with the first being low-pass and the second being high-pass. The static nonlinearity was fitted with a fifth-order polynomial function over several input amplitude ranges and had the form of a half-wave rectifier. The complete model gave a good approximation to the output of the neuron when both were subjected to the same novel white noise input signal.     

MXR7 facilitates liver cancer metastasis via epithelial-mesenchymal transition

MXR7 is a cell-surface protein and highly expressed in hepatocellular carcinoma(HCC). The aim of this study is to determine the expression profile of MXR7 in HCC and investigate the influence of MXR7 on invasion and metastasis of HCC cells. For this purpose, immunohistochemical assay was used to identify the differential expression of MXR7 in 94 HCC specimens. Expression of MXR7 in 4 pairs of HCC and portal vein tumor thrombus(PVTT) was also tested. The motility of HCC cells were characterized by transwell migration and matrigel invasion assays. In vivo metastasis potential was determined via tail vein injection assay.Moreover, compared with noninvasive HCC tumors or human HCC cell lines with low metastatic potential, invasive HCC samples and HCC cell lines with high metastatic potential exhibited higher MXR7 expression. Furthermore, forced expression of MXR7 in SMMC-7721 promoted cell proliferation, migration and invasion in vitro and accelerated tumor growth and metastasis in vivo. Conversely, knockdown of MXR7 expression in HuH7 cells inhibited proliferation and motility of cells. Mechanically,overexpression of MXR7 promoted epithelial-mesenchymal transition(EMT) progress, and MXR7 depletion repressed the EMT phenotype. In conclusion, MXR7 is a mediator of EMT and metastasis in HCC and may serve as a novel therapeutic target.     

Central processing of sensory information in electric fish

Summary Comparative studies of neural mechanisms underlying the perception of natural stimulus patterns and the control of adaptive behavioral responses have revealed organizational principles that are shared by a wide spectrum of animals. Mechanisms of perception and motor control are commonly executed in a distributed network of neurons that lack pontifical elements. Individual neurons even at an organizational level as high as the optic tectum may still have very general response characteristics, and the recruitment of individual neurons reveals little about the nature of the stimulus situation outside. Only the joint evaluation of messages from large populations of such neurons yields unambiguous pictures of the outside world. Stimulus variables are commonly mapped continuously within a stratum of neurons so that their variation over time can be monitored by mechanisms similar to motion detection in a retina. The ordered representation of a stimulus variable within an array of broadly tuned elements allows for a degree of stimulus resolution that by far exceeds that of individual elements in the array. Neural systems are burdened by their evolutionary history and suffer from imperfections that are overcome by a patchwork of compensations. The existence of multiple neuronal representations of sensory information and multiple circuits for the control of behavioral responses should provide the necessary freedom for evolutionary tinkering and the invention of new designs.     

Brain states: top-down influences in sensory processing

All cortical and thalamic levels of sensory processing are subject to powerful top-down influences, the shaping of lower-level processes by more complex information. New findings on the diversity of top-down interactions show that cortical areas function as adaptive processors, being subject to attention, expectation, and perceptual task. Brain states are determined by the interactions between multiple cortical areas and the modulation of intrinsic circuits by feedback connections. In perceptual learning, both the encoding and recall of learned information involves a selection of the appropriate inputs that convey information about the stimulus being discriminated. Disruption of this interaction may lead to behavioral disorders, including schizophrenia.     

Design principles of sensory processing in cerebellum-like structures

Cerebellum-like structures are compared for two sensory systems: electrosensory and auditory. The electrosensory lateral line lobe of mormyrid electric fish is reviewed and the neural representation of electrosensory objects in this structure is modeled and discussed. The dorsal cochlear nucleus in the auditory brainstem of mammals is reviewed and new data are presented that characterize the responses of neurons in this structure in the mouse. Similarities between the electrosensory and auditory cerebellum-like structures are shown, in particular adaptive processes that may reduce responses to predictable stimuli. We suggest that the differences in the types of sensory objects may drive the differences in the anatomical and physiological characteristics of these two cerebellum-like structures.     

Potencies of Cocaine Methiodide on Major Cocaine Targets in Mice

Cocaine methiodide (CM), a charged cocaine analog, cannot pass the blood brain barrier. It has been assumed the effects of systemic CM represent cocaine actions in peripheral tissues. However, the IC₅₀ values of CM have not been clearly determined for the major cocaine targets: dopamine, norepinephrine, and serotonin transporters, and sodium channels. Using cells transfected with individual transporters from mice and synaptosomes from mouse striatum tissues, we observed that the inhibition IC₅₀ values for monoamine uptake by CM were 31-fold to 184-fold higher compared to cocaine at each of the transporters. In dorsal root ganglion neurons, cocaine inhibited sodium channels with an apparent IC₅₀ of 75 µM, while CM showed no observable effect at concentrations up to 3 mM. These results indicate that an equal dose of CM will not produce an equivalent peripheral effect of cocaine.     

Fast pacing facilitates discontinuous action potential propagation between rabbit atrial cells

We examined the critical coupling conductance (G(C)) for propagation at different pacing cycle lengths (CLs) (1,000 and 400 ms). As G(C) was progressively reduced, propagation failed at a CL of 1,000 ms, whereas propagation succeeded at a CL of 400 ms over a range of G(C) values before failing at a CL of 400 ms at a lower G(C), showing facilitation of propagation at the shorter CL. Critical G(C) was (means +/- SE) 0.8 +/- 0.1 nS for a CL of 400 ms and 1.3 +/- 0.1 nS for a CL of 1,000 ms (a 63% increase, P < 0.002, n = 9 cell pairs). In 14 uncoupled cells, action potential duration at 30% repolarization (APD(30)) increased from 19.9 +/- 2.5 to 41.8 +/- 2.6 ms (P < 0.001) as CL decreased from 1,000 to 400 ms. In five cell pairs, critical G(C) with 4-aminopyridine (4-AP) was reduced to 0.4 +/- 0.1 nS at a CL of 1,000 ms (P < 0.05 compared with control solution), and critical G(C) in 4-AP was unchanged by decreasing CL to 400 ms. It is possible that the "remodeling" of atrial cells due to atrial fibrillation or tachycardia, which has been shown to produce a decrease in the transient outward current, may result in an enhanced ability to propagate, possibly facilitating further development of fibrillation under conditions of decreased cellular coupling.     

Information processing in noisy burster models of sensory neurons

Processing of external stimuli by sensory neurons often involves bursting, when epochs of fast firing alternate with intervals of quiescence. In particular, sensory neurons of electroreceptors in paddlefish (Polyodon spathula) undergo bursting when stimulated externally with broad-band noise, but otherwise fire spontaneously in a quasiperiodic tonic manner. We use a simple phenomenological model for noise-induced bursting to quantify analytically, by means of the Kullback entropy and Fisher information, the gain in information transfer and electroreceptor sensitivity for external noisy stimuli. A good agreement between theoretical predictions, numerical simulations and experimental data is shown.     

Keap1 facilitates p62-mediated ubiquitin aggregate clearance via autophagy

The accumulation of ubiquitin-positive protein aggregates has been implicated in the pathogenesis of neurodegenerative diseases, heart disease and diabetes. Emerging evidence indicates that the autophagy lysosomal pathway plays a critical role in the clearance of ubiquitin aggregates, a process that is mediated by the ubiquitin binding protein p62. In addition to binding ubiquitin, p62 also interacts with LC3 and transports ubiquitin conjugates to autophagosomes for degradation. The exact regulatory mechanism of this process is still largely unknown. Here we report the identification of Keap1 as a binding partner for p62 and LC3. Keap1 inhibits Nrf2 by sequestering it in the cytosol and preventing its translocation to the nucleus and activation of genes involved in the oxidative stress response. In this study, we found that Keap1 interacts with p62 and LC3 in a stress-inducible manner, and that Keap1 colocalizes with LC3 and p62 in puromycin-induced ubiquitin aggregates. Moreover, p62 serves as a bridge between Keap1 and ubiquitin aggregates and autophagosomes. Finally, genetic ablation of Keap1 leads to the accumulation of ubiquitin aggregates, increased cytotoxicity of misfolded protein aggregates, and defective activation of autophagy. Therefore, this study assigns a novel positive role of Keap1 in upregulating p62-mediated autophagic clearance of ubiquitin aggregates.     

G protein-coupled receptor 183 facilitates endothelial-to-hematopoietic transition via Notch1 inhibition

In vertebrates, embryonic hematopoietic stem and progenitor cells (HSPCs) are derived from a subset of endothelial cells, the hemogenic endothelium (HE), through the endothelial-to-hematopoietic transition (EHT). Notch signaling is essential for HSPC development during embryogenesis across vertebrates. However, whether and how it regulates EHT remains unclear. Here, we show that G protein-coupled receptor 183 (Gpr183) signaling serves as an indispensable switch for HSPC emergence by repressing Notch signaling before the onset of EHT. Inhibition of Gpr183 significantly upregulates Notch signaling and abolishes HSPC emergence. Upon activation by its ligand 7α-25-OHC, Gpr183 recruits β-arrestin1 and the E3 ligase Nedd4 to degrade Notch1 in specified HE cells and then facilitates the subsequent EHT. Importantly, 7α-25-OHC stimulation promotes HSPC emergence in vivo and in vitro, providing an attractive strategy for enhancing the in vitro generation of functional HSPCs.     

Ellagic acid facilitates indomethacin-induced gastric ulcer healing via COX-2 up-regulation

The mechanism of indomethacin-induced gastric ulcer healing by ellagic acid (EA) in experimental mice model is described in our study. Ulcer index (UI) and myeloperoxidase (MPO) activity of the stomach tissues showed maximum ulceration on the third day after indomethacin (18 mg/kg, single dose) administration. Preliminary observation of UI and MPO activity suggests that EA possesses ulcer-healing activity. Other anti-ulcer parameters such as the levels of prostaglandin E(2), cyclooxygenase (COX) 1 and 2 enzymes, anti-inflammatory cytokines [interleukin (IL)-4 and -5], pro-angiogenic factors, e.g. vascular endothelial growth factor, hepatocyte growth factor (HGF), and endothelial growth factor (EGF) were down-regulated by indomethacin. EA (7 mg/kg/day) treatment for 3 days shifted the indomethacin-induced pro-inflammatory biochemical parameters to the healing side. These activities were correlated with the ability of EA to alter the COX-2-dependent healing pathways. The ulcer-healing activity of EA was, however, compromised by pre-administration of the specific COX-2 inhibitor, celecoxib, and NS-398. Taken together, these results suggested that the EA treatment accelerates ulcer healing by inducing IL-4, EGF/HGF levels and enhances COX-2 expression.     

The role of inhibition and adaptation in sensory information processing

Some common features of neural transformations along sensory pathways are discussed. The emphasis is on spatial mapping in the visual system, but close parallels exist in temporal visual mapping as well as other sensory systems. The role played by lateral inhibition in sequential transformations is investigated by direct computation and by mathematical analysis.     

Invertebrate neurobiology: sensory processing in reverse for backward walking

Humans and many other animals can readily walk forward or backward. In insects, the nervous system changes the effects of sense organs that signal forces on a leg when the direction of walking is reversed.