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To understand the effect of attention on neuronal dynamics, we propose a multi-module network, with each module consisting of fully interconnected groups of excitatory and inhibitory neurons. This network shows transitive dynamics among quasi-attractors as its typical dynamics. When the release of acetylcholine onto the network is simulated by attention, the transitive dynamics change into stable dynamics in which the system converges to an attractor. We found that this network can reproduce three experimentally observed properties of attention-dependent response modulation, namely an increase in the firing rate, a decrease in the Fano factor of the firing rate, and a decrease in the correlation coefficients between the firing rates of pairs of neurons. Moreover, we also showed theoretically that the release of acetylcholine increases the sensitivity to bottom-up inputs by changing the response function. [ABSTRACT FROM AUTHOR]

Humans and other animals effortlessly identify natural sounds and categorize them into behaviorally relevant categories. Yet, the acoustic features and neural transformations that enable sound recognition and the formation of perceptual categories are largely unknown. Here, using multichannel neural recordings in the auditory midbrain of unanesthetized female rabbits, we first demonstrate that neural ensemble activity in the auditory midbrain displays highly structured correlations that vary with distinct natural sound stimuli. These stimulus-driven correlations can be used to accurately identify individual sounds using single-response trials, even when the sounds do not differ in their spectral content. Combining neural recordings and an auditory model, we then show how correlations between frequency-organized auditory channels can contribute to discrimination of not just individual sounds but sound categories. For both the model and neural data, spectral and temporal correlations achieved similar categorization performance and appear to contribute equally. Moreover, both the neural and model classifiers achieve their best task performance when they accumulate evidence over a time frame of approximately 1–2 seconds, mirroring human perceptual trends. These results together suggest that time-frequency correlations in sounds may be reflected in the correlations between auditory midbrain ensembles and that these correlations may play an important role in the identification and categorization of natural sounds. [ABSTRACT FROM AUTHOR]

Purpose: Diffusion magnetic resonance imaging and tractography has an important role in the visualization of brain white matter and assessment of tissue microstructure. There is a lack of correspondence between diffusion metrics of live tissue, ex vivo tissue, and histological findings. The objective of this study is to elucidate this connection by determining the specific diffusion alterations between live and ex vivo brain tissue. This may have an important role in the incorporation of diffusion imaging in ex vivo studies as a complement to histological sectioning as well as investigations of novel neurosurgical techniques. Methods: This study presents a method of high angular resolution diffusion imaging and tractography of intact and non-fixed ex vivo piglet brains. Most studies involving ex vivo brain specimens have been formalin-fixed or excised from their original biological environment, processes both of which are known to affect diffusion parameters. Thus, non-fixed ex vivo tissue is used. A region-of-interest based analysis of diffusion tensor metrics are compared to in vivo subjects in a selection of major white matter bundles in order to assess the translatability of ex vivo diffusion measurements. Results: Tractography was successfully achieved in both in vivo and ex vivo groups. No significant differences were found in tract connectivity, average streamline length, or apparent fiber density. Significantly decreased diffusivity (mean, axial, and radial; p<0.0005) in the non-fixed ex vivo group and unaltered fractional anisotropy (p>0.059) between groups were observed. Conclusion: This study validates the extrapolation of non-fixed fractional anisotropy measurements to live tissue and the potential use of ex vivo tissue for methodological development. [ABSTRACT FROM AUTHOR]

Transient receptor potential (TRP) proteins form Ca2+-permeable, nonselective cation channels, but their role in neuronal Ca2+ homeostasis is elusive. In the present paper, we show that TRPC channels potently regulate synaptic plasticity by changing the presynaptic Ca2+-homeostasis of hippocampal neurons. Specifically, loss of TRPC1/C4/C5 channels decreases basal-evoked secretion, decreases the pool size of readily releasable vesicles, and accelerates synaptic depression during high-frequency stimulation (HFS). In contrast, primary TRPC5 channel-expressing neurons, identified by a novel TRPC5–τ-green fluorescent protein (τGFP) knockin mouse line, show strong short-term enhancement (STE) of synaptic signaling during HFS, indicating a key role of TRPC5 in short-term plasticity. Lentiviral expression of either TRPC1 or TRPC5 turns classic synaptic depression of wild-type neurons into STE, demonstrating that TRPCs are instrumental in regulating synaptic plasticity. Presynaptic Ca2+ imaging shows that TRPC activity strongly boosts synaptic Ca2+ dynamics, showing that TRPC channels provide an additional presynaptic Ca2+ entry pathway, which efficiently regulates synaptic strength and plasticity. [ABSTRACT FROM AUTHOR]

At higher latitudes, vertebrates exhibit a seasonal cycle of reproduction in response to changes in day-length, referred to as photoperiodism. Extended day-length induces thyroid-stimulating hormone in the pars tuberalis of the pituitary gland. This hormone triggers the local activation of thyroid hormone in the mediobasal hypothalamus and eventually induces gonadal development. In avian species, light information associated with day-length is detected through photoreceptors located in deep-brain regions. Within these regions, the expressions of multiple photoreceptive molecules, opsins, have been observed. However, even though the Japanese quail is an excellent model for photoperiodism because of its robust and significant seasonal responses in reproduction, a comprehensive understanding of photoreceptors in the quail brain remains undeveloped. In this study, we initially analyzed an action spectrum using photoperiodically induced expression of the beta subunit genes of thyroid-stimulating hormone in quail. Among seven wavelengths examined, we detected maximum sensitivity of the action spectrum at 500 nm. The low value for goodness of fit in the alignment with a template of retinal1-based photopigment, assuming a spectrum associated with a single opsin, proposed the possible involvement of multiple opsins rather than a single opsin. Analysis of gene expression in the septal region and hypothalamus, regions hypothesized to be photosensitive in quail, revealed mRNA expression of a mammal-like melanopsin in the infundibular nucleus within the mediobasal hypothalamus. However, no significant diurnal changes were observed for genes in the infundibular nucleus. Xenopus-like melanopsin, a further isoform of melanopsin in birds, was detected in neither the septal region nor the infundibular nucleus. These results suggest that the mammal-like melanopsin expressed in the infundibular nucleus within the mediobasal hypothalamus could be candidate deep-brain photoreceptive molecule in Japanese quail. Investigation of the functional involvement of mammal-like melanopsin-expressing cells in photoperiodism will be required for further conclusions. [ABSTRACT FROM AUTHOR]

Congenital nystagmus, involuntary oscillating small eye movements, is commonly thought to originate from aberrant interactions between brainstem nuclei and foveal cortical pathways. Here, we investigated whether nystagmus associated with congenital stationary night blindness (CSNB) results from primary deficits in the retina. We found that CSNB patients as well as an animal model (nob mice), both of which lacked functional nyctalopin protein (NYX, nyx) in ON bipolar cells (BCs) at their synapse with photoreceptors, showed oscillating eye movements at a frequency of 4–7 Hz. nob ON direction-selective ganglion cells (DSGCs), which detect global motion and project to the accessory optic system (AOS), oscillated with the same frequency as their eyes. In the dark, individual ganglion cells (GCs) oscillated asynchronously, but their oscillations became synchronized by light stimulation. Likewise, both patient and nob mice oscillating eye movements were only present in the light when contrast was present. Retinal pharmacological and genetic manipulations that blocked nob GC oscillations also eliminated their oscillating eye movements, and retinal pharmacological manipulations that reduced the oscillation frequency of nob GCs also reduced the oscillation frequency of their eye movements. We conclude that, in nob mice, synchronized oscillations of retinal GCs, most likely the ON-DCGCs, cause nystagmus with properties similar to those associated with CSNB in humans. These results show that the nob mouse is the first animal model for a form of congenital nystagmus, paving the way for development of therapeutic strategies. [ABSTRACT FROM AUTHOR]

In the mouse spinal cord, V1 interneurons are a heterogeneous population of inhibitory spinal interneurons that have been implicated in regulating the frequency of the locomotor rhythm and in organizing flexor and extensor alternation. By introducing archaerhodopsin into engrailed-1-positive neurons, we demonstrate that the function of V1 neurons in locomotor-like activity is more complex than previously thought. In the whole cord, V1 hyperpolarization increased the rhythmic synaptic drive to flexor and extensor motoneurons, increased the spiking in each cycle, and slowed the locomotor-like rhythm. In the hemicord, V1 hyperpolarization accelerated the rhythm after an initial period of tonic activity, implying that a subset of V1 neurons are active in the hemicord, which was confirmed by calcium imaging. Hyperpolarizing V1 neurons resulted in an equalization of the duty cycle in flexor and extensors from an asymmetrical pattern in control recordings in which the extensor bursts were longer than the flexor bursts. Our results suggest that V1 interneurons are composed of several subsets with different functional roles. Furthermore, during V1 hyperpolarization, the default state of the locomotor central pattern generator (CPG) is symmetrical, with antagonist motoneurons each firing with an approximately 50% duty cycle. We hypothesize that one function of the V1 population is to set the burst durations of muscles to be appropriate to their biomechanical function and to adapt to the environmental demands, such as changes in locomotor speed. [ABSTRACT FROM AUTHOR]

Aims: Glucocorticoid (GC) stimulation has been shown to increase cardiac contractility by elevated intracellular [Ca] but the sources for Ca entry are unclear. This study aims to determine the role of store-operated Ca entry (SOCE) for GC-mediated inotropy. Methods and results: Dexamethasone (Dex) pretreatment significantly increased cardiac contractile force ex vivo in Langendorff-perfused Sprague-Dawley rat hearts (2 mg/kg BW i.p. Dex 24 h prior to experiment). Moreover, Ca transient amplitude as well as fractional shortening were significantly enhanced in Fura-2-loaded isolated rat ventricular myocytes exposed to Dex (1 mg/mL Dex, 24 h). Interestingly, these Dex-dependent effects could be abolished in the presence of SOCE-inhibitors SKF-96356 (SKF, 2 μM) and BTP2 (5 μM). Ca transient kinetics (time to peak, decay time) were not affected by SOCE stimulation. Direct SOCE measurements revealed a negligible magnitude in untreated myocytes but a dramatic increase in SOCE upon Dex-pretreatment. Importantly, the Dex-dependent stimulation of SOCE could be blocked by inhibition of serum and glucocorticoid-regulated kinase 1 (SGK1) using EMD638683 (EMD, 50 μM). Dex preincubation also resulted in increased mRNA expression of proteins involved in SOCE (stromal interaction molecule 2, STIM2, and transient receptor potential cation channels 3/6, TRPC 3/6), which were also prevented in the presence of EMD. Conclusion: Short-term GC-stimulation with Dex improves cardiac contractility by a SOCE-dependent mechanism, which appears to involve increased SGK1-dependent expression of the SOCE-related proteins. Since Ca transient kinetics were unaffected, SOCE appears to influence Ca cycling more by an integrated response across multiple cardiac cycles but not on a beat-to-beat basis. [ABSTRACT FROM AUTHOR]

We compared a published computational model of the action potential of a specific type of human induced pluripotent stem cell -derived cardiomyocytes (hiPSC-CM) with experimental field potential data with regard to their inter-beat interval and the duration of repolarization. In particular, concomitant changes in inter-beat interval and duration of repolarization were calculated after reduction and/or augmentation of specific ion channel conductances as a surrogate for pharmacological manipulation. The observed mismatches between calculations and experimental data indicate that there is information missing about the cellular test system. Based on our results we hypothesize that, among other currents, the actual If (“funny current”) may deviate from the prediction. We show that replacement of the If formulation by alternative equations causes the model predictions to change qualitatively, however, none of the available formulations is actually achieving a satisfactory match with experimental data. We suggest a strategy to clarify whether the mismatch can be completely resolved at all using single cell models and, if yes, how this goal could be reached. [ABSTRACT FROM AUTHOR]

Parvalbumin (PV)-positive interneurons modulate cortical activity through highly specialized connectivity patterns onto excitatory pyramidal neurons (PNs) and other inhibitory cells. PV cells are autoconnected through powerful autapses, but the contribution of this form of fast disinhibition to cortical function is unknown. We found that autaptic transmission represents the most powerful inhibitory input of PV cells in neocortical layer V. Autaptic strength was greater than synaptic strength onto PNs as a result of a larger quantal size, whereas autaptic and heterosynaptic PV-PV synapses differed in the number of release sites. Overall, single-axon autaptic transmission contributed to approximately 40% of the global inhibition (mostly perisomatic) that PV interneurons received. The strength of autaptic transmission modulated the coupling of PV-cell firing with optogenetically induced γ-oscillations, preventing high-frequency bursts of spikes. Autaptic self-inhibition represents an exceptionally large and fast disinhibitory mechanism, favoring synchronization of PV-cell firing during cognitive-relevant cortical network activity. [ABSTRACT FROM AUTHOR]

Rats are highly social creatures that produce ultrasonic vocalizations (USVs) during social interactions. Brattleboro rats, a Long-Evans derived rat that lacks vasopressin (AVP) due to a mutation in the Avp gene, exhibit atypical social behavior, including fewer USVs with altered spectrotemporal characteristics during social interactions. It is unclear why Brattleboro rats produce atypical USVs, but one factor could be differences in auditory acuity between them and wild-type Long Evans rats with functional vasopressin. Previous studies have suggested a link between increased levels of AVP and auditory processing. Additionally, few studies have investigated sex differences in auditory perception by Long-Evans rats. Sex differences in auditory acuity have been found throughout the animal kingdom, but have not yet been demonstrated in rat audiograms. This study aimed to measure auditory brainstem response (ABR) derived audiograms for frequencies ranging from 1 to 64 kHz in male and female homozygous Brattleboro (Hom), heterozygous Brattleboro (Het), and wild-type (WT) Long-Evans rats to better understand the role of AVP and sex differences in auditory processing by these rats. We failed to detect significant differences between the ABR audiograms of Hom, Het, and WT Long-Evans rats, suggesting that varying levels of AVP do not affect auditory processing. Interestingly, males and females of all genotypes did differ in their ABR thresholds, with males exhibiting higher thresholds than females. The sex differences in auditory acuity were significant at the lowest and highest frequencies, possibly affecting the perception of USVs. These are the first known sex differences in rat audiograms. [ABSTRACT FROM AUTHOR]

This study presents a modelling framework in which information on muscle fiber direction and orientation during contraction is derived from diffusion tensor imaging (DTI) and incorporated in a computational model of the surface electromyographic (EMG) signal. The proposed model makes use of the principle of reciprocity to simultaneously calculate the electric potentials produced at the recording electrode by charges distributed along an arbitrary number of muscle fibers within the muscle, allowing for a computationally efficient evaluation of extracellular motor unit action potentials. The approach is applied to the complex architecture of the first dorsal interosseous (FDI) muscle of the hand to simulate EMG during index finger flexion and abduction. Using diffusion tensor imaging methods, the results show how muscle fiber orientation and curvature in this intrinsic hand muscle change during flexion and abduction. Incorporation of anatomically accurate muscle architecture and other hand tissue morphologies enable the model to capture variations in extracellular action potential waveform shape across the motor unit population and to predict experimentally observed differences in EMG signal features when switching from index finger abduction to flexion. The simulation results illustrate how structural and electrical properties of the tissues comprising the volume conductor, in combination with fiber direction and curvature, shape the detected action potentials. Using the model, the relative contribution of motor units of different sizes located throughout the muscle under both conditions is examined, yielding a prediction of the detection profile of the surface EMG electrode array over the muscle cross-section. [ABSTRACT FROM AUTHOR]

Although it is well established that the vertebrate retina contains endogenous circadian clocks that regulate retinal physiology and function during day and night, the processes that the clocks affect and the means by which the clocks control these processes remain unresolved. We previously demonstrated that a circadian clock in the goldfish retina regulates rod-cone electrical coupling so that coupling is weak during the day and robust at night. The increase in rod-cone coupling at night introduces rod signals into cones so that the light responses of both cones and cone horizontal cells, which are post-synaptic to cones, become dominated by rod input. By comparing the light responses of cones, cone horizontal cells and rod horizontal cells, which are post-synaptic to rods, under dark-adapted conditions during day and night, we determined whether the daily changes in the strength of rod-cone coupling could account entirely for rhythmic changes in the light response properties of cones and cone horizontal cells. We report that although some aspects of the day/night changes in cone and cone horizontal cell light responses, such as response threshold and spectral tuning, are consistent with modulation of rod-cone coupling, other properties cannot be solely explained by this phenomenon. Specifically, we found that at night compared to the day the time course of spectrally-isolated cone photoresponses was slower, cone-to-cone horizontal cell synaptic transfer was highly non-linear and of lower gain, and the delay in cone-to-cone horizontal cell synaptic transmission was longer. However, under bright light-adapted conditions in both day and night, cone-to-cone horizontal cell synaptic transfer was linear and of high gain, and no additional delay was observed at the cone-to-cone horizontal cell synapse. These findings suggest that in addition to controlling rod-cone coupling, retinal clocks shape the light responses of cone horizontal cells by modulating cone-to-cone horizontal cell synaptic transmission. [ABSTRACT FROM AUTHOR]

Motion is an essential component of everyday tactile experience: most manual interactions involve relative movement between the skin and objects. Much of the research on the neural basis of tactile motion perception has focused on how direction is encoded, but less is known about how speed is. Perceived speed has been shown to be dependent on surface texture, but previous studies used only coarse textures, which span a restricted range of tangible spatial scales and provide a limited window into tactile coding. To fill this gap, we measured the ability of human observers to report the speed of natural textures—which span the range of tactile experience and engage all the known mechanisms of texture coding—scanned across the skin. In parallel experiments, we recorded the responses of single units in the nerve and in the somatosensory cortex of primates to the same textures scanned at different speeds. We found that the perception of speed is heavily influenced by texture: some textures are systematically perceived as moving faster than are others, and some textures provide a more informative signal about speed than do others. Similarly, the responses of neurons in the nerve and in cortex are strongly dependent on texture. In the nerve, although all fibers exhibit speed-dependent responses, the responses of Pacinian corpuscle–associated (PC) fibers are most strongly modulated by speed and can best account for human judgments. In cortex, approximately half of the neurons exhibit speed-dependent responses, and this subpopulation receives strong input from PC fibers. However, speed judgments seem to reflect an integration of speed-dependent and speed-independent responses such that the latter help to partially compensate for the strong texture dependence of the former. [ABSTRACT FROM AUTHOR]

Pituitary endocrine cells fire action potentials (APs) to regulate their cytosolic Ca2+ concentration and hormone secretion rate. Depending on animal species, cell type, and biological conditions, pituitary APs are generated either by TTX-sensitive Na+ currents (INa), high-voltage activated Ca2+ currents (ICa), or by a combination of the two. Previous computational models of pituitary cells have mainly been based on data from rats, where INa is largely inactivated at the resting potential, and spontaneous APs are predominantly mediated by ICa. Unlike in rats, spontaneous INa-mediated APs are consistently seen in pituitary cells of several other animal species, including several species of fish. In the current work we develop a computational model of gonadotropin releasing cells in the teleost fish medaka (Oryzias latipes). The model stands out from previous modeling efforts by being (1) the first model of a pituitary cell in teleosts, (2) the first pituitary cell model that fires sponateous APs that are predominantly mediated by INa, and (3) the first pituitary cell model where the kinetics of the depolarizing currents, INa and ICa, are directly fitted to voltage-clamp data. We explore the firing properties of the model, and compare it to the properties of previous models that fire ICa-based APs. We put a particular focus on how the big conductance K+ current (IBK) modulates the AP shape. Interestingly, we find that IBK can prolong AP duration in models that fire ICa-based APs, while it consistently shortens the duration of the predominantly INa-mediated APs in the medaka gonadotroph model. Although the model is constrained to experimental data from gonadotroph cells in medaka, it may likely provide insights also into other pituitary cell types that fire INa-mediated APs. [ABSTRACT FROM AUTHOR]

Neuronal physiology is particularly sensitive to acute stressors that affect excitability, many of which can trigger seizures and epilepsies. Although intrinsic neuronal homeostasis plays an important role in maintaining overall nervous system robustness and its resistance to stressors, the specific genetic and molecular mechanisms that underlie these processes are not well understood. Here we used a reverse genetic approach in Drosophila to test the hypothesis that specific voltage-gated ion channels contribute to neuronal homeostasis, robustness, and stress resistance. We found that the activity of the voltage-gated potassium channel seizure (sei), an ortholog of the mammalian ERG channel family, is essential for protecting flies from acute heat-induced seizures. Although sei is broadly expressed in the nervous system, our data indicate that its impact on the organismal robustness to acute environmental stress is primarily mediated via its action in excitatory neurons, the octopaminergic system, as well as neuropile ensheathing and perineurial glia. Furthermore, our studies suggest that human mutations in the human ERG channel (hERG), which have been primarily implicated in the cardiac Long QT Syndrome (LQTS), may also contribute to the high incidence of seizures in LQTS patients via a cardiovascular-independent neurogenic pathway. [ABSTRACT FROM AUTHOR]

We have previously shown that the physiological size of postsynaptic currents maximises energy efficiency rather than information transfer across the retinothalamic relay synapse. Here, we investigate information transmission and postsynaptic energy use at the next synapse along the visual pathway: from relay neurons in the thalamus to spiny stellate cells in layer 4 of the primary visual cortex (L4SS). Using both multicompartment Hodgkin-Huxley-type simulations and electrophysiological recordings in rodent brain slices, we find that increasing or decreasing the postsynaptic conductance of the set of thalamocortical inputs to one L4SS cell decreases the energy efficiency of information transmission from a single thalamocortical input. This result is obtained in the presence of random background input to the L4SS cell from excitatory and inhibitory corticocortical connections, which were simulated (both excitatory and inhibitory) or injected experimentally using dynamic-clamp (excitatory only). Thus, energy efficiency is not a unique property of strong relay synapses: even at the relatively weak thalamocortical synapse, each of which contributes minimally to the output firing of the L4SS cell, evolutionarily-selected postsynaptic properties appear to maximise the information transmitted per energy used. [ABSTRACT FROM AUTHOR]

The stereo correspondence problem exists because false matches between the images from multiple sensors camouflage the true (veridical) matches. True matches are correspondences between image points that have the same generative source; false matches are correspondences between similar image points that have different sources. This problem of selecting true matches among false ones must be overcome by both biological and artificial stereo systems in order for them to be useful depth sensors. The proposed re-examination of this fundamental issue shows that false matches form a symmetrical pattern in the array of all possible matches, with true matches forming the axis of symmetry. The patterning of false matches can therefore be used to locate true matches and derive the depth profile of the surface that gave rise to them. This reverses the traditional strategy, which treats false matches as noise. The new approach is particularly well-suited to extract the 3-D locations and shapes of camouflaged surfaces and to work in scenes characterized by high degrees of clutter. We demonstrate that the symmetry of false-match signals can be exploited to identify surfaces in random-dot stereograms. This strategy permits novel depth computations for target detection, localization, and identification by machine-vision systems, accounts for physiological and psychophysical findings that are otherwise puzzling and makes possible new ways for combining stereo and motion signals. [ABSTRACT FROM AUTHOR]

The human retina contains three classes of cone photoreceptors each sensitive to different portions of the visual spectrum: long (L), medium (M) and short (S) wavelengths. Color information is computed by downstream neurons that compare relative activity across the three cone types. How cone signals are combined at a cellular scale has been more difficult to resolve. This is especially true near the fovea, where spectrally-opponent neurons in the parvocellular pathway draw excitatory input from a single cone and thus even the smallest stimulus projected through natural optics will engage multiple color-signaling neurons. We used an adaptive optics microstimulator to target individual and pairs of cones with light. Consistent with prior work, we found that color percepts elicited from individual cones were predicted by their spectral sensitivity, although there was considerable variability even between cones within the same spectral class. The appearance of spots targeted at two cones were predicted by an average of their individual activations. However, two cones of the same subclass elicited percepts that were systematically more saturated than predicted by an average. Together, these observations suggest both spectral opponency and prior experience influence the appearance of small spots. [ABSTRACT FROM AUTHOR]

Posturographic signals were recorded for 384 subjects of different ages and with old persons with gait disturbances. Four conditions were used: Eyes Open/Closed vs. Head Normal/Bent Back. ‘Center of Pressure’ (CoP) signals were decomposed into ‘Center of Mass’ (CoM) and the remaining difference between Center of Pressure and Center of Mass (CoPM). The Zero-Crossing points in which the Center of Mass and Center of Pressure paths cross each other have been extracted. Velocity of CoM, velocity of CoPM and acceleration of CoPM in Zero-Crossing points were analyzed to be potential markers of balance efficiency. Three factors causing the deterioration of balance quality were analyzed: closing eyes, bending the head back and patient age. The influence of the given factors was measured using the significance p of the t-Student test and Cohen's d effect size and applied to differences for the logarithms of three of the mentioned above variables measured without and with the given deteriorating factor. In the majority of comparisons, the proposed new parameters of balance quality possessed higher statistical power to detect deteriorated balance quality than the standard parameters: standard deviation of the signal and ellipse area covering 90% of the signal envelope. Most valuable are the velocity and acceleration of CoPM for the medio-lateral direction. Logarithms of the analyzed parameters are proposed to be used in analyses because they possess normal or close to normal distribution and they are less sensitive to single high values occurring often in measurements. [ABSTRACT FROM AUTHOR]

Although algae have been the focal point of biofuel research, studies on their biological activities have been limited. In recent years, however, the importance of algae as sources of functional ingredients has been recognized due to their health beneficial effects. In this study, we evaluated the antidepressant-like activities of ethanol extract of Aurantiochytrium sp. (EEA) in the forced swimming test (FST)-induced depression in ICR mice. Imipramine, a commercially available tricyclic antidepressant drug, was used as positive control. Animals were administered EEA orally for 14 consecutive days and were subjected to the locomotor activity testing. Additionally, changes in gene expression in mice brain were assessed by real-time PCR and microarray assays to understand the molecular mechanisms underlying the effect of EEA. We found that the immobility time in FST was significantly reduced in the EEA-treated mice compared to that of in the control mice. Microarray and real-time PCR results revealed that EEA treatment induced changes in several genes in mice brain associated with pro-inflammation and dopaminergic, cholinergic, glutamatergic, and serotonergic synapses. It has previously been reported that several cytokines, such as IL-6 and TNF-α, which mediate neuroinflammation, are also responsible for indirectly altering brain neurotransmitter levels in neuropsychiatric disorders. Therefore, the regulation of the expression of pro-inflammatory genes in EEA-administered mice brain is considered to contribute to the enhancement of neurotransmitter systems-related gene expression in our study. Moreover, our in vitro study suggested that squalene, a component produced by Aurantiochytrium, was one of the active substances in EEA. In conclusion, our study provides the first evidence that Aurantiochytrium sp. can reduce neuroinflammation that may contribute to the modulation of the neurotransmitter systems, which could underlie its antistress and antidepressant effects. [ABSTRACT FROM AUTHOR]

We address the question of color-space interactions in the brain, by proposing a neural field model of color perception with spatial context for the visual area V1 of the cortex. Our framework reconciles two opposing perceptual phenomena, known as simultaneous contrast and chromatic assimilation. They have been previously shown to act synergistically, so that at some point in an image, the color seems perceptually more similar to that of adjacent neighbors, while being more dissimilar from that of remote ones. Thus, their combined effects are enhanced in the presence of a spatial pattern, and can be measured as larger shifts in color matching experiments. Our model supposes a hypercolumnar structure coding for colors in V1, and relies on the notion of color opponency introduced by Hering. The connectivity kernel of the neural field exploits the balance between attraction and repulsion in color and physical spaces, so as to reproduce the sign reversal in the influence of neighboring points. The color sensation at a point, defined from a steady state of the neural activities, is then extracted as a nonlinear percept conveyed by an assembly of neurons. It connects the cortical and perceptual levels, because we describe the search for a color match in asymmetric matching experiments as a mathematical projection on color sensations. We validate our color neural field alongside this color matching framework, by performing a multi-parameter regression to data produced by psychophysicists and ourselves. All the results show that we are able to explain the nonlinear behavior of shifts observed along one or two dimensions in color space, which cannot be done using a simple linear model. [ABSTRACT FROM AUTHOR]

Many computational theories have been developed to improve artificial phonetic classification performance from linguistic auditory streams. However, less attention has been given to psycholinguistic data and neurophysiological features recently found in cortical tissue. We focus on a context in which basic linguistic units–such as phonemes–are extracted and robustly classified by humans and other animals from complex acoustic streams in speech data. We are especially motivated by the fact that 8-month-old human infants can accomplish segmentation of words from fluent audio streams based exclusively on the statistical relationships between neighboring speech sounds without any kind of supervision. In this paper, we introduce a biologically inspired and fully unsupervised neurocomputational approach that incorporates key neurophysiological and anatomical cortical properties, including columnar organization, spontaneous micro-columnar formation, adaptation to contextual activations and Sparse Distributed Representations (SDRs) produced by means of partial N-Methyl-D-aspartic acid (NMDA) depolarization. Its feature abstraction capabilities show promising phonetic invariance and generalization attributes. Our model improves the performance of a Support Vector Machine (SVM) classifier for monosyllabic, disyllabic and trisyllabic word classification tasks in the presence of environmental disturbances such as white noise, reverberation, and pitch and voice variations. Furthermore, our approach emphasizes potential self-organizing cortical principles achieving improvement without any kind of optimization guidance which could minimize hypothetical loss functions by means of–for example–backpropagation. Thus, our computational model outperforms multiresolution spectro-temporal auditory feature representations using only the statistical sequential structure immerse in the phonotactic rules of the input stream. [ABSTRACT FROM AUTHOR]

Inflorescence patterns of ultraviolet (UV) absorption and UV-reflection are attractive to many insect pollinators. To understand whether UV inflorescence cues affect the attraction of nectar-foraging mosquitoes, we worked with the common house mosquito, Culex pipiens and with two plant species exhibiting floral UV cues: the tansy, Tanacetum vulgare, and the common hawkweed Hieraciumm lachenalii. Electroretinograms revealed that Cx. pipiens eyes can sense UV wavelengths, with peak sensitivity at 335 nm. Behavioural bioassays divulged that UV inflorescence cues enhance the attractiveness of inflorescence odour. In the presence of natural floral odour, female Cx. pipiens were attracted to floral patterns of UV-absorption and UV-reflection but preferred uniformly UV-dark inflorescences. Moreover, Cx. pipiens females preferred UV-dark and black inflorescence models to UV-dark and yellow inflorescence models. With feathers and pelts of many avian and mammalian hosts also being UV-dark and dark-coloured, foraging Cx. pipiens females may respond to analogous visual cues when they seek nectar and vertebrate blood resources. [ABSTRACT FROM AUTHOR]

We extend the existing ordinary differential equations modeling neural electrical activity to include the memory effect of electromagnetic induction through magnetic flux, used to describe time varying electromagnetic field. Through the multi-scale expansion in the semi-discrete approximation, we show that the neural network dynamical equations can be governed by the complex Ginzburg-Landau equation. The analytical and numerical envelop soliton of this equation are reported. The results obtained suggest the possibility of collective information processing and sharing in the nervous system, operating in both the spatial and temporal domains in the form of localized modulated waves. The effects of memristive synaptic electromagnetic induction coupling and perturbation on the modulated action potential dynamics examined. Large electromagnetic induction coupling strength may contribute to signal block as the amplitude of modulated waves are observed to decrease. This could help in the development of a chemical brain anaesthesia for some brain pathologies. [ABSTRACT FROM AUTHOR]

The conduction of electrical signals through cardiac tissue is essential for maintaining the function of the heart, and conduction abnormalities are known to potentially lead to life-threatening arrhythmias. The properties of cardiac conduction have therefore been the topic of intense study for decades, but a number of questions related to the mechanisms of conduction still remain unresolved. In this paper, we demonstrate how the so-called EMI model may be used to study some of these open questions. In the EMI model, the extracellular space, the cell membrane, the intracellular space and the cell connections are all represented as separate parts of the computational domain, and the model therefore allows for study of local properties that are hard to represent in the classical homogenized bidomain or monodomain models commonly used to study cardiac conduction. We conclude that a non-uniform sodium channel distribution increases the conduction velocity and decreases the time delays over gap junctions of reduced coupling in the EMI model simulations. We also present a theoretical optimal cell length with respect to conduction velocity and consider the possibility of ephaptic coupling (i.e. cell-to-cell coupling through the extracellular potential) acting as an alternative or supporting mechanism to gap junction coupling. We conclude that for a non-uniform distribution of sodium channels and a sufficiently small intercellular distance, ephaptic coupling can influence the dynamics of the sodium channels and potentially provide cell-to-cell coupling when the gap junction connection is absent. [ABSTRACT FROM AUTHOR]

Purpose: To link optic nerve (ON) structural properties to clinical markers of glaucoma using advanced, semi-automated diffusion magnetic resonance imaging (dMRI) tractography in human glaucoma patients. Methods: We characterized optic neuropathy in patients with unilateral advanced-stage glaucoma (n = 6) using probabilistic dMRI tractography and compared their results to those in healthy controls (n = 6). Results: We successfully identified the ONs of glaucoma patients based on dMRI in all patients and confirmed that dMRI measures of the ONs correlated with clinical markers of glaucoma severity. Specifically, we found reduced fractional anisotropy (FA) in the ONs of eyes with advanced, as compared to mild, glaucoma (F(1,10) = 55.474, p < 0.0001, FDR < 0.0005). Furthermore, by comparing the ratios of ON FA in glaucoma patients to those of healthy controls (n = 6), we determined that this difference was beyond that expected from normal anatomical variation (F(1,9) = 20.276, p < 0. 005). Finally, we linked the dMRI measures of ON FA to standard clinical glaucoma measures. ON vertical cup-to-disc ratio (vCD) predicted ON FA (F(1,10) = 11.061, p < 0.01, R2 = 0.66), retinal nerve fiber layer thickness (RNFL) predicted ON FA (F(1,10) = 11.477, p < 0.01, R2 = 0.63) and ON FA predicted perceptual deficits (visual field index [VFI]) (F(1,10) = 15.308, p < 0.005, R2 = 0.52). Conclusion: We describe semi-automated methods to detect glaucoma-related structural changes using dMRI and confirm that they correlate with clinical measures of glaucoma. [ABSTRACT FROM AUTHOR]

Visual performance depends on polar angle, even when eccentricity is held constant; on many psychophysical tasks observers perform best when stimuli are presented on the horizontal meridian, worst on the upper vertical, and intermediate on the lower vertical meridian. This variation in performance ‘around’ the visual field can be as pronounced as that of doubling the stimulus eccentricity. The causes of these asymmetries in performance are largely unknown. Some factors in the eye, e.g. cone density, are positively correlated with the reported variations in visual performance with polar angle. However, the question remains whether these correlations can quantitatively explain the perceptual differences observed ‘around’ the visual field. To investigate the extent to which the earliest stages of vision–optical quality and cone density–contribute to performance differences with polar angle, we created a computational observer model. The model uses the open-source software package ISETBIO to simulate an orientation discrimination task for which visual performance differs with polar angle. The model starts from the photons emitted by a display, which pass through simulated human optics with fixational eye movements, followed by cone isomerizations in the retina. Finally, we classify stimulus orientation using a support vector machine to learn a linear classifier on the photon absorptions. To account for the 30% increase in contrast thresholds for upper vertical compared to horizontal meridian, as observed psychophysically on the same task, our computational observer model would require either an increase of ~7 diopters of defocus or a reduction of 500% in cone density. These values far exceed the actual variations as a function of polar angle observed in human eyes. Therefore, we conclude that these factors in the eye only account for a small fraction of differences in visual performance with polar angle. Substantial additional asymmetries must arise in later retinal and/or cortical processing. [ABSTRACT FROM AUTHOR]

Organ level simulation of bioelectric behavior in the body benefits from flexible and efficient models of cellular membrane potential. These computational organ and cell models can be used to study the impact of pharmaceutical drugs, test hypotheses, assess risk and for closed-loop validation of medical devices. To move closer to the real-time requirements of this modeling a new flexible Fourier based general membrane potential model, called as a Resonant model, is developed that is computationally inexpensive. The new model accurately reproduces non-linear potential morphologies for a variety of cell types. Specifically, the method is used to model human and rabbit sinoatrial node, human ventricular myocyte and squid giant axon electrophysiology. The Resonant models are validated with experimental data and with other published models. Dynamic changes in biological conditions are modeled with changing model coefficients and this approach enables ionic channel alterations to be captured. The Resonant model is used to simulate entrainment between competing sinoatrial node cells. These models can be easily implemented in low-cost digital hardware and an alternative, resource-efficient implementations of sine and cosine functions are presented and it is shown that a Fourier term is produced with two additions and a binary shift. [ABSTRACT FROM AUTHOR]

When one views a square-wave grating and dichoptically changes the average luminance or contrast of the monocular images, at least three perceptual phenomena might occur. These are the Venetian blind effect, or a perceived rotation of the bars around individual vertical axes; binocular luster, or a perceived shimmering; and binocular rivalry, or an alternating perception between the views of the two eyes. Perception of luster and rivalry occur when the "light bars" in the grating dichoptically straddle the background luminance (one eye’s image has a higher luminance than the background and the other eye’s image has a lower luminance than the background), with little impact from the "dark bars." Perception of rotation, on the other hand, is related to average luminance or contrast disparity, independent of whether or not the "light bars" straddle the background luminance. The patterns for perceived rotation versus binocular luster and binocular rivalry suggest at least two separate mechanisms in the visual system for processing luminance and contrast information over and above their differing physiological states suggested by their different appearances. While luster and rivalry depend directly on the relation between stimuli and the background, perceived rotation depends on the magnitude of the luminance or contrast disparity, as described by the generalized difference model. [ABSTRACT FROM AUTHOR]

Rapamycin (Rap) and its derivatives, called rapalogs, are being explored in clinical trials targeting cancer and neurodegeneration. The underlying mechanisms of Rap actions, however, are not well understood. Mechanistic target of rapamycin (mTOR), a lysosome-localized protein kinase that acts as a critical regulator of cellular growth, is believed to mediate most Rap actions. Here, we identified mucolipin 1 (transient receptor potential channel mucolipin 1 [TRPML1], also known as MCOLN1), the principle Ca2+ release channel in the lysosome, as another direct target of Rap. Patch-clamping of isolated lysosomal membranes showed that micromolar concentrations of Rap and some rapalogs activated lysosomal TRPML1 directly and specifically. Pharmacological inhibition or genetic inactivation of mTOR failed to mimic the Rap effect. In vitro binding assays revealed that Rap bound directly to purified TRPML1 proteins with a micromolar affinity. In both healthy and disease human fibroblasts, Rap and rapalogs induced autophagic flux via nuclear translocation of transcription factor EB (TFEB). However, such effects were abolished in TRPML1-deficient cells or by TRPML1 inhibitors. Hence, Rap and rapalogs promote autophagy via a TRPML1-dependent mechanism. Given the demonstrated roles of TRPML1 and TFEB in cellular clearance, we propose that lysosomal TRPML1 may contribute a significant portion to the in vivo neuroprotective and anti-aging effects of Rap via an augmentation of autophagy and lysosomal biogenesis. [ABSTRACT FROM AUTHOR]

Somatosensory thalamocortical (TC) neurons from the ventrobasal (VB) thalamus are central components in the flow of sensory information between the periphery and the cerebral cortex, and participate in the dynamic regulation of thalamocortical states including wakefulness and sleep. This property is reflected at the cellular level by the ability to generate action potentials in two distinct firing modes, called tonic firing and low-threshold bursting. Although the general properties of TC neurons are known, we still lack a detailed characterization of their morphological and electrical properties in the VB thalamus. The aim of this study was to build biophysically-detailed models of VB TC neurons explicitly constrained with experimental data from rats. We recorded the electrical activity of VB neurons (N = 49) and reconstructed morphologies in 3D (N = 50) by applying standardized protocols. After identifying distinct electrical types, we used a multi-objective optimization to fit single neuron electrical models (e-models), which yielded multiple solutions consistent with the experimental data. The models were tested for generalization using electrical stimuli and neuron morphologies not used during fitting. A local sensitivity analysis revealed that the e-models are robust to small parameter changes and that all the parameters were constrained by one or more features. The e-models, when tested in combination with different morphologies, showed that the electrical behavior is substantially preserved when changing dendritic structure and that the e-models were not overfit to a specific morphology. The models and their analysis show that automatic parameter search can be applied to capture complex firing behavior, such as co-existence of tonic firing and low-threshold bursting over a wide range of parameter sets and in combination with different neuron morphologies. [ABSTRACT FROM AUTHOR]

Background: Alternans have been associated with the development of ventricular fibrillation and its control has been proposed as antiarrhythmic strategy. However, cardiac arrhythmias are a spatiotemporal phenomenon in which multiple factors are involved (e.g. calcium and voltage spatial alternans or heterogeneous conduction velocity) and how an antiarrhythmic drug modifies these factors is poorly understood. Objective: The objective of the present study is to evaluate the relation between spatial electrophysiological properties (i.e. spatial discordant alternans and conduction velocity) and the induction of ventricular fibrillation (VF) when a calcium blocker is applied. Methods: The mechanisms of initiation of VF were studied by simultaneous epicardial voltage and calcium optical mapping in isolated rabbit hearts using an incremental fast pacing protocol. The additional value of analyzing spatial phenomena in the generation of unidirectional blocks and reentries as precursors of VF was depicted. Specifically, the role of action potential duration (APD), calcium transients (CaT), spatial alternans and conduction velocity in the initiation of VF was evaluated during basal conditions and after the administration of verapamil. Results: Our results enhance the relation between (1) calcium spatial alternans and (2) slow conduction velocities with the dynamic creation of unidirectional blocks that allowed the induction of VF. In fact, the administration of verapamil demonstrated that calcium and not voltage spatial alternans were the main responsible for VF induction. Conclusions: VF induction at high activation rates was linked with the concurrence of a low conduction velocity and high magnitude of calcium alternans, but not necessarily related with increases of APD. Verapamil can postpone the development of cardiac alternans and the apparition of ventricular arrhythmias. [ABSTRACT FROM AUTHOR]

Macroscopic oscillations of different brain regions show multiple phase relationships that are persistent across time and have been implicated in routing information. While multiple cellular mechanisms influence the network oscillatory dynamics and structure the macroscopic firing motifs, one of the key questions is to identify the biophysical neuronal and synaptic properties that permit such motifs to arise. A second important issue is how the different neural activity coherence states determine the communication between the neural circuits. Here we analyse the emergence of phase-locking within bidirectionally delayed-coupled spiking circuits in which global gamma band oscillations arise from synaptic coupling among largely excitable neurons. We consider both the interneuronal (ING) and the pyramidal-interneuronal (PING) population gamma rhythms and the inter coupling targeting the pyramidal or the inhibitory neurons. Using a mean-field approach together with an exact reduction method, we reduce each spiking network to a low dimensional nonlinear system and derive the macroscopic phase resetting-curves (mPRCs) that determine how the phase of the global oscillation responds to incoming perturbations. This is made possible by the use of the quadratic integrate-and-fire model together with a Lorentzian distribution of the bias current. Depending on the type of gamma (PING vs. ING), we show that incoming excitatory inputs can either speed up the macroscopic oscillation (phase advance; type I PRC) or induce both a phase advance and a delay (type II PRC). From there we determine the structure of macroscopic coherence states (phase-locking) of two weakly synaptically-coupled networks. To do so we derive a phase equation for the coupled system which links the synaptic mechanisms to the coherence states of the system. We show that a synaptic transmission delay is a necessary condition for symmetry breaking, i.e. a non-symmetric phase lag between the macroscopic oscillations. This potentially provides an explanation to the experimentally observed variety of gamma phase-locking modes. Our analysis further shows that symmetry-broken coherence states can lead to a preferred direction of signal transfer between the oscillatory networks where this directionality also depends on the timing of the signal. Hence we suggest a causal theory for oscillatory modulation of functional connectivity between cortical circuits. [ABSTRACT FROM AUTHOR]

Microstructural asymmetry of the brain can provide more direct causal explanations of functional lateralization than can macrostructural asymmetry. We performed a cross-sectional diffusion imaging study of 314 patients treated for childhood acute lymphoblastic leukemia (ALL) at a single institution and 92 healthy controls. An asymmetry index based on diffusion metrics was computed to quantify brain microstructural asymmetry. The effects of age and the asymmetry metrics of the two cohorts were examined with t-tests and linear models. We discovered two new types of microstructural asymmetry. Myelin-related asymmetry in controls was prominent in the back brain (89% right), whereas axon-related asymmetry occurred in the front brain (67% left) and back brain (88% right). These asymmetries indicate that white matter is more mature and more myelinated in the left back brain, potentially explaining the leftward lateralization of language and visual functions. The asymmetries increase throughout childhood and adolescence (P = 0.04) but were significantly less in patients treated for ALL (P<0.01), especially in younger patients. Our results indicate that atypical brain development may appear long before patients treated with chemotherapy become symptomatic. [ABSTRACT FROM AUTHOR]

Under typical daytime light levels, the human pupillary light response (PLR) is driven by the activity of the L, M, and S cones, and melanopsin expressed in the so-called intrinsically photosensitive retinal ganglion cells (ipRGCs). However, the importance of each of these photoreceptive mechanisms in defining pupil size under real-world viewing conditions remains to be established. To address this question, we embedded photoreceptor-specific modulations in a movie displayed using a novel projector-based five-primary spatial stimulation system, which allowed for the precise control of photoreceptor activations in time and space. We measured the pupillary light response in eleven observers, who viewed short cartoon movies which contained hidden low-frequency (0.25 Hz) silent-substitution modulations of the L, M and S cones (no stimulation of melanopsin), melanopsin (no stimulation of L, M and S cones), both L, M, and S cones and melanopsin or no modulation at all. We find that all photoreceptors active at photopic light levels regulate pupil size under this condition. Our data imply that embedding modulations in photoreceptor contrast could provide a method to manipulate key adaptive aspects of the human visual system in everyday, real-world activities such as watching a movie. [ABSTRACT FROM AUTHOR]

Spontaneous waves in the developing retina are essential in the formation of the retinotopic mapping in the visual system. From experiments in rabbits, it is known that the earliest type of retinal waves (stage I) is nucleated spontaneously, propagates at a speed of 451±91 μm/sec and relies on gap junction coupling between ganglion cells. Because gap junctions (electrical synapses) have short integration times, it has been argued that they cannot set the low speed of stage I retinal waves. Here, we present a theoretical study of a two-dimensional neural network of the ganglion cell layer with gap junction coupling and intrinsic noise. We demonstrate that this model can explain observed nucleation rates as well as the comparatively slow propagation speed of the waves. From the interaction between two coupled neurons, we estimate the wave speed in the model network. Furthermore, using simulations of small networks of neurons (N≤260), we estimate the nucleation rate in the form of an Arrhenius escape rate. These results allow for informed simulations of a realistically sized network, yielding values of the gap junction coupling and the intrinsic noise level that are in a physiologically plausible range. [ABSTRACT FROM AUTHOR]

In this paper we set the previously reported pressure-dependent, ordinary differential equation outflow model by Smith and Gardiner for the human eye, into a new three-dimensional (3D) porous media outflow model of the eye, and calibrate model parameters using data reported in the literature. Assuming normal outflow through anterior pathways, we test the ability of 3D flow model to predict the pressure elevation with a silicone oil tamponade. Then assuming outflow across the retinal pigment epithelium is normal, we test the ability of the 3D model to predict the pressure elevation in Schwartz-Matsuo syndrome. For the first time we find the flow model can successfully model both conditions, which helps to build confidence in the validity and accuracy of the 3D pressure-dependent outflow model proposed here. We employ this flow model to estimate the translaminar pressure gradient within the optic nerve head of a normal eye in both the upright and supine postures, and during the day and at night. Based on a ratio of estimated and measured pressure gradients, we define a factor of safety against acute interruption of axonal transport at the laminar cribrosa. Using a completely independent method, based on the behaviour of dynein molecular motors, we compute the factor of safety against stalling the dynein molecule motors, and so compromising retrograde axonal transport. We show these two independent methods for estimating factors of safety agree reasonably well and appear to be consistent. Taken together, the new 3D pressure-dependent outflow model proves itself to capable of providing a useful modeling platform for analyzing eye behaviour in a variety of physiological and clinically useful contexts, including IOP elevation in Schwartz-Matsuo syndrome and with silicone oil tamponade, and potentially for risk assessment for optic glaucomatous neuropathy. [ABSTRACT FROM AUTHOR]

The sarcolemmal membrane associated proteins (SLMAPs) belong to the super family of tail anchored membrane proteins which serve diverse roles in biology including cell growth, protein trafficking and ion channel regulation. Mutations in human SLMAP have been linked to Brugada syndrome with putative deficits in trafficking of the sodium channel (Nav1.5) to the cell membrane resulting in aberrant electrical activity and heart function. Three main SLMAP isoforms (SLMAP1 (35 kDa), SLMAP2 (45 kDa), and SLMAP3 (91 kDa)) are expressed in myocardium but their precise role remains to be defined. Here we generated transgenic (Tg) mice with cardiac-specific expression of the SLMAP3 isoform during postnatal development which present with a significant decrease (20%) in fractional shortening and (11%) in cardiac output at 5 weeks of age. There was a lack of any notable cardiac remodeling (hypertrophy, fibrosis or fetal gene activation) in Tg hearts but the electrocardiogram indicated a significant increase (14%) in the PR interval and a decrease (43%) in the R amplitude. Western blot analysis indicated a selective and significant decrease (55%) in protein levels of Nav1.5 while 45% drop in its transcript levels were detectable by qRT-PCR. Significant decreases in the protein and transcript levels of the calcium transport system of the sarcoplasmic reticulum (SERCA2a/PLN) were also evident in Tg hearts. These data reveal a novel role for SLMAP3 in the selective regulation of important ion transport proteins at the level of gene expression and suggest that it may be a unique target in cardiovascular function and disease. [ABSTRACT FROM AUTHOR]

Purpose: The circadian clock is entrained to light by the intrinsically photosensitive retinal ganglion cells. Loss of these cells in glaucoma, an eye disease with loss of retinal ganglion cells as its key feature, might thus result in a change in chronotype. We aimed to compare the chronotype between glaucoma patients and healthy subjects. Methods: We sent the Munich ChronoType Questionnaire to 221 glaucoma patients (response rate 81%); controls (primary control group) were primarily their spouses. After exclusion of shift workers and participants who woke-up due to an alarm clock on days off, 159 glaucoma patients (88 early, 21 moderate, 23 severe) and 163 controls remained. We calculated chronotype as the mid-sleep on days off, corrected for workweek accumulated sleep debt (MSFsc). We compared means and variances between groups using Welch’s tests and F-tests, respectively. A secondary control group was recruited from participants in a citizen-science project (n = 17073) who completed an online questionnaire. A resampling method was applied to enable an age- and gender- matched comparison with the glaucoma patients. Results: Compared to the primary control group, glaucoma did not affect the mean MSFsc (controls 3:47; early, moderate, and severe glaucoma 3:40, 3:45, and 3:33, respectively [P = 0.62]). Chronotype variability seemed to increase with increasing disease severity (severe glaucoma versus controls: P = 0.023). The mean MSFsc of the secondary control group was 3:50 (95% confidence interval 3:48 to 3:52); significantly later than that of the glaucoma patients (3:40; P = 0.024). Mean MSFsc did not differ significantly between the control groups (P = 0.42). Conclusions: No clear changes were found in the chronotype as determined by sleep phase in patients with glaucoma, especially not in early and moderate glaucoma. In severe glaucoma, chronotype variability seems to increase, possibly alongside a small advancement. [ABSTRACT FROM AUTHOR]

Optogenetics enables the selective activation of genetically-targeted neuronal populations using light-sensitive ion channels. Genetic strategies using Cre-dependent mouse strains, especially the Ai32 line expressing Channelrhodopsin (ChR2)-EYFP fusion protein, have been a popular means to drive opsin expression in a cell-type specific manner. Here we report a low level of leaky ‘off-target’ (Cre-independent) ChR2-EYFP expression in Ai32/Ai32 homozygous mice throughout the nervous system. This leaky off-target expression was characterized in multiple prevalent nervous system regions using anti-EYFP immunostaining. Expression of full-length ChR2-EYFP protein was confirmed using immunoprecipitation followed by Western blotting. Notably, light stimulation of these ChR2-EYFP expressing neurons in the spinal cord dorsal horn did not induce detectable photocurrents in juvenile 4-week old mice. Given the wide use of the Ai32 line by many labs, our results suggest researchers should be vigilant of possible off-target ChR2-EYFP expression in their region of interest, especially when generating Ai32/Ai32 homozygotes to drive high levels of ChR2-EYFP expression in adult mice. [ABSTRACT FROM AUTHOR]

Primary cilia of renal epithelial cells express several members of the transient receptor potential (TRP) class of cation-conducting channel, including TRPC1, TRPM3, TRPM4, TRPP2, and TRPV4. Some cases of autosomal dominant polycystic kidney disease (ADPKD) are caused by defects in TRPP2 (also called polycystin-2, PC2, or PKD2). A large-conductance, TRPP2-dependent channel in renal cilia has been well described, but it is not known whether this channel includes any other protein subunits. To study this question, we investigated the pharmacology of the TRPP2-dependent channel through electrical recordings from the cilia of mIMCD-3 cells, a murine cell line of renal epithelial origin. The pharmacology was found to match that of TRPM3 channels. The ciliary TRPP2-dependent channel is known to be activated by depolarization and by increasing cytoplasmic Ca2+. This activation was greatly enhanced by external pregnenolone sulfate, an agonist of TRPM3 channels. Pregnenolone sulfate did not change the single-channel current-voltage relation. The channels were effectively blocked by isosakuranetin, a specific inhibitor of TRPM3 channels. Both pregnenolone sulfate and isosakuranetin were effective at concentrations as low as 1 μM. Knocking out TRPM3 by CRISPR/Cas9 genome editing eliminated the ciliary channel. Thus the channel is both TRPM3-dependent and TRPP2-dependent, suggesting that it may include both types of subunit. Knocking out TRPM3 did not change the level of TRPP2 protein in the cilia, so it is unlikely that the absence of functional ciliary channels results from a failure of trafficking. [ABSTRACT FROM AUTHOR]

While rods, cones, and intrinsically photosensitive melanopsin-containing ganglion cells (ipRGCs) all drive light entrainment of the master circadian pacemaker of the suprachiasmatic nucleus, recent studies have proposed that entrainment of the mouse retinal clock is exclusively mediated by a UV-sensitive photopigment, neuropsin (OPN5). Here, we report that the retinal circadian clock can be phase shifted by short duration and relatively low-irradiance monochromatic light in the visible part of the spectrum, up to 520 nm. Phase shifts exhibit a classical photon dose-response curve. Comparing the response of mouse models that specifically lack middle-wavelength (MW) cones, melanopsin, and/or rods, we found that only the absence of rods prevented light-induced phase shifts of the retinal clock, whereas light-induced phase shifts of locomotor activity are normal. In a “rod-only” mouse model, phase shifting response of the retinal clock to light is conserved. At shorter UV wavelengths, our results also reveal additional recruitment of short-wavelength (SW) cones and/or OPN5. These findings suggest a primary role of rod photoreceptors in the light response of the retinal clock in mammals. [ABSTRACT FROM AUTHOR]

Whole-brain recordings give us a global perspective of the brain in action. In this study, we describe a method using light field microscopy to record near-whole brain calcium and voltage activity at high speed in behaving adult flies. We first obtained global activity maps for various stimuli and behaviors. Notably, we found that brain activity increased on a global scale when the fly walked but not when it groomed. This global increase with walking was particularly strong in dopamine neurons, which showed little activity otherwise. Second, we extracted maps of spatially distinct sources of activity as well as their time series using principal component analysis and independent component analysis. The characteristic shapes in the maps matched the anatomy of subneuropil regions and, in some cases, a specific neuron type. Brain structures that responded to light and odor were consistent with previous reports, confirming the new technique’s validity. We also observed previously uncharacterized behavior-related activity as well as patterns of spontaneous voltage activity. [ABSTRACT FROM AUTHOR]

Although the developmental principles of sensory and cognitive processing have been extensively investigated, their synergy has been largely neglected. During early life, most sensory systems are still largely immature. As a notable exception, the olfactory system is functional at birth, controlling mother–offspring interactions and neonatal survival. Here, we elucidate the structural and functional principles underlying the communication between olfactory bulb (OB) and lateral entorhinal cortex (LEC)—the gatekeeper of limbic circuitry—during neonatal development. Combining optogenetics, pharmacology, and electrophysiology in vivo with axonal tracing, we show that mitral cell–dependent discontinuous theta bursts in OB drive network oscillations and time the firing in LEC of anesthetized mice via axonal projections confined to upper cortical layers. Acute pharmacological silencing of OB activity diminishes entorhinal oscillations, whereas odor exposure boosts OB–entorhinal coupling at fast frequencies. Chronic impairment of olfactory sensory neurons disrupts OB–entorhinal activity. Thus, OB activity shapes the maturation of entorhinal circuits. [ABSTRACT FROM AUTHOR]

During spatial navigation, the frequency and timing of spikes from spatial neurons including place cells in hippocampus and grid cells in medial entorhinal cortex are temporally organized by continuous theta oscillations (6–11 Hz). The theta rhythm is regulated by subcortical structures including the medial septum, but it is unclear how spatial information from place cells may reciprocally organize subcortical theta-rhythmic activity. Here we recorded single-unit spiking from a constellation of subcortical and hippocampal sites to study spatial modulation of rhythmic spike timing in rats freely exploring an open environment. Our analysis revealed a novel class of neurons that we termed ‘phaser cells,’ characterized by a symmetric coupling between firing rate and spike theta-phase. Phaser cells encoded space by assigning distinct phases to allocentric isocontour levels of each cell’s spatial firing pattern. In our dataset, phaser cells were predominantly located in the lateral septum, but also the hippocampus, anteroventral thalamus, lateral hypothalamus, and nucleus accumbens. Unlike the unidirectional late-to-early phase precession of place cells, bidirectional phase modulation acted to return phaser cells to the same theta-phase along a given spatial isocontour, including cells that characteristically shifted to later phases at higher firing rates. Our dynamical models of intrinsic theta-bursting neurons demonstrated that experience-independent temporal coding mechanisms can qualitatively explain (1) the spatial rate-phase relationships of phaser cells and (2) the observed temporal segregation of phaser cells according to phase-shift direction. In open-field phaser cell simulations, competitive learning embedded phase-code entrainment maps into the weights of downstream targets, including path integration networks. Bayesian phase decoding revealed error correction capable of resetting path integration at subsecond timescales. Our findings suggest that phaser cells may instantiate a subcortical theta-rhythmic loop of spatial feedback. We outline a framework in which location-dependent synchrony reconciles internal idiothetic processes with the allothetic reference points of sensory experience. [ABSTRACT FROM AUTHOR]

Color deficiency is a common inherited disorder affecting 8% of Caucasian males with anomalous trichromacy (AT); it is the most common type of inherited color vision deficiency. Anomalous trichromacy is caused by alteration of one of the three cone-opsins’ spectral sensitivity; it is usually considered to impose marked limitations for daily life as well as for choice of occupation. Nevertheless, we show here that anomalous trichromat subjects have superior basic visual functions such as visual acuity (VA), contrast sensitivity (CS), and stereo acuity, compared with participants with normal color vision. Both contrast sensitivity and stereo acuity performance were correlated with the severity of color deficiency. We further show that subjects with anomalous trichromacy exhibit a better ability to detect objects camouflaged in natural gray scale figures. The advantages of color-deficient subjects in spatial vision performance could explain the relatively high prevalence of color-vision polymorphism in humans. [ABSTRACT FROM AUTHOR]

We investigate how the neural processing in auditory cortex is shaped by the statistics of natural sounds. Hypothesising that auditory cortex (A1) represents the structural primitives out of which sounds are composed, we employ a statistical model to extract such components. The input to the model are cochleagrams which approximate the non-linear transformations a sound undergoes from the outer ear, through the cochlea to the auditory nerve. Cochleagram components do not superimpose linearly, but rather according to a rule which can be approximated using the max function. This is a consequence of the compression inherent in the cochleagram and the sparsity of natural sounds. Furthermore, cochleagrams do not have negative values. Cochleagrams are therefore not matched well by the assumptions of standard linear approaches such as sparse coding or ICA. We therefore consider a new encoding approach for natural sounds, which combines a model of early auditory processing with maximal causes analysis (MCA), a sparse coding model which captures both the non-linear combination rule and non-negativity of the data. An efficient truncated EM algorithm is used to fit the MCA model to cochleagram data. We characterize the generative fields (GFs) inferred by MCA with respect to in vivo neural responses in A1 by applying reverse correlation to estimate spectro-temporal receptive fields (STRFs) implied by the learned GFs. Despite the GFs being non-negative, the STRF estimates are found to contain both positive and negative subfields, where the negative subfields can be attributed to explaining away effects as captured by the applied inference method. A direct comparison with ferret A1 shows many similar forms, and the spectral and temporal modulation tuning of both ferret and model STRFs show similar ranges over the population. In summary, our model represents an alternative to linear approaches for biological auditory encoding while it captures salient data properties and links inhibitory subfields to explaining away effects. [ABSTRACT FROM AUTHOR]

β-alanine is the rate-limiting point for the endogenous synthesis of carnosine in skeletal muscle. Carnosine has a wide range of implications for health, normal function and exercise performance. Whilst the physiological relevance of carnosine to different tissues remains enigmatic, β-alanine administration is a useful strategy to investigate the physiological roles of carnosine in humans. Intravenous administration of β-alanine is an interesting approach to study carnosine metabolism. However, sterilisation is mandatory due to the nature of the administration route. We evaluated whether sterilising doses of gamma radiation damages the molecular structure and leads to the loss of functional characteristics of β-alanine. Pure β-alanine was sterilised by gamma radiation in sealed glass vials using a 60Co multipurpose irradiator at a dose rate of 8.5 kGy.hour-1 totalising 10, 20, 25 30 and 40 kGy. The molecular integrity was assessed by X-ray Diffraction and changes in content were determined by High Performance Liquid Chromatography (UV-HPLC) and Triple Quadrupole Mass Spectrometer (HPLC/MS-MS). Sterility assurance was evaluated by inoculation assay. To examine whether functional properties were preserved, β-alanine was infused in one participant, who rated the level of paraesthesia on the skin using a 0–3 scale. Urinary β-alanine was quantified before and 24-h following β-alanine infusion using HPLC-ESI+-MS/MS. Irradiation resulted in no change in the crystal structure of β-alanine, no degradation, and no new peaks were identified in the dose range assayed. The inoculation assay showed the absence of viable microorganisms in all β-alanine samples, including those that did not undergo irradiation. Intravenous infusion of β-alanine resulted in paraesthesia and it detected in the urine as per normal. We conclude that gamma radiation is a suitable technique for the sterilisation of β-alanine. It does not lead to degradation, damage to the β-alanine structure, content or loss of function within the evaluated irradiation conditions. [ABSTRACT FROM AUTHOR]

Brain coding strategies are enabled by the balance of synaptic inputs that individual neurons receive as determined by the networks in which they reside. Inhibitory cell types contribute to brain function in distinct ways but recording from specific, inhibitory cell types during behaviour to determine their contributions is highly challenging. In particular, the in vivo activities of vasoactive intestinal peptide-expressing interneuron specific 3 (IS3) cells in the hippocampus that only target other inhibitory cells are unknown at present. We perform a massive, computational exploration of possible synaptic inputs to IS3 cells using multi-compartment models and optimized synaptic parameters. We find that asynchronous, in vivo-like states that are sensitive to additional theta-timed inputs (8 Hz) exist when excitatory and inhibitory synaptic conductances are approximately equally balanced and with low numbers of activated synapses receiving correlated inputs. Specifically, under these balanced conditions, the input resistance is larger with higher mean spike firing rates relative to other activated synaptic conditions investigated. Incoming theta-timed inputs result in strongly increased spectral power relative to baseline. Thus, using a generally applicable computational approach we predict the existence and features of background, balanced states in hippocampal circuits. [ABSTRACT FROM AUTHOR]