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Hanin, G, Yayon N, Tzur Y, Haviv R, Bennett ER, Udi S, Krishnamoorthy YR, Kotsiliti E, Zangen R, Efron B et al..  2017.  miRNA-132 induces hepatic steatosis and hyperlipidaemia by synergistic multitarget suppression. Gut. Abstract
OBJECTIVE: Both non-alcoholic fatty liver disease (NAFLD) and the multitarget complexity of microRNA (miR) suppression have recently raised much interest, but the in vivo impact and context-dependence of hepatic miR-target interactions are incompletely understood. Assessing the relative in vivo contributions of specific targets to miR-mediated phenotypes is pivotal for investigating metabolic processes. DESIGN: We quantified fatty liver parameters and the levels of miR-132 and its targets in novel transgenic mice overexpressing miR-132, in liver tissues from patients with NAFLD, and in diverse mouse models of hepatic steatosis. We tested the causal nature of miR-132 excess in these phenotypes by injecting diet-induced obese mice with antisense oligonucleotide suppressors of miR-132 or its target genes, and measured changes in metabolic parameters and transcripts. RESULTS: Transgenic mice overexpressing miR-132 showed a severe fatty liver phenotype and increased body weight, serum low-density lipoprotein/very low-density lipoprotein (LDL/VLDL) and liver triglycerides, accompanied by decreases in validated miR-132 targets and increases in lipogenesis and lipid accumulation-related transcripts. Likewise, liver samples from both patients with NAFLD and mouse models of hepatic steatosis or non-alcoholic steatohepatitis (NASH) displayed dramatic increases in miR-132 and varying decreases in miR-132 targets compared with controls. Furthermore, injecting diet-induced obese mice with anti-miR-132 oligonucleotides, but not suppressing its individual targets, reversed the hepatic miR-132 excess and hyperlipidemic phenotype. CONCLUSIONS: Our findings identify miR-132 as a key regulator of hepatic lipid homeostasis, functioning in a context-dependent fashion via suppression of multiple targets and with cumulative synergistic effects. This indicates reduction of miR-132 levels as a possible treatment of hepatic steatosis.
Jaffe-Dax, S, Raviv O, Loewenstein Y, Ahissar M.  2017.  A Computational Model of Dyslexics’ Perceptual Difficulties as Impaired Inference of Sound Statistics. Computational Models of Brain and Behavior. :3.
Daikhin, L, Raviv O, Ahissar M.  2017.  Auditory Stimulus Processing and Task Learning are adequate in Dyslexia, but Benefits From Regularities Are Reduced. Journal of Speech, Language, and Hearing Research. 60(2):471-479.
Banai, K, Ahissar M.  2017.  Poor sensitivity to sound statistics impairs the acquisition of speech categories in dyslexia. Language, Cognition and Neuroscience. :1-12.
Vinograd, A, Livneh Y, Mizrahi A.  2017.  History-dependent odor processing in the mouse olfactory bulb. The Journal of Neuroscience. 6;(37(49))::12018-12030.. Abstract
In nature, animals normally perceive sensory information on top of backgrounds. Thus, the neural substrate to perceive under background conditions is inherent in all sensory systems. Where and how sensory systems process backgrounds is not fully understood. In olfaction, only few studies addressed the issue of odor coding on top of continuous odorous backgrounds. Here, we tested how background odors are encoded by mitral cells (MCs) in the olfactory bulb (OB) of male mice. Using in vivo two-photon calcium imaging we studied how MCs responded to odors in isolation versus their responses to the same odors on top of continuous backgrounds. We show that MCs adapt to continuous odor presentation and that mixture responses are different when preceded by background. In a subset of odor combinations, this history dependent processing was useful to promote identification of target odors over background. Other odorous backgrounds were highly dominant, such that target odors were completely masked by their presence. Our data are consistent in both low and high odor concentrations and in anesthetized and awake mice. Thus, odor processing in the OB is strongly influenced by the recent history of activity, which could have strong impact on how odors are perceived.Significant statement: We examined a basic feature of sensory processing in the olfactory bulb. Specifically, we measured how mitral cells adapt to continuous background odors and how target odors are encoded on top of such background. Our results show clear differences in odor coding based on the immediate history of the stimulus. Our results support the argument that odor coding depends on the recent history of the sensory environment, already at the level of olfactory bulb output.
Jaffe-Dax, S, Kimel E, Ahissar M.  2017.  Widespread shorter cortical adaptation in dyslexia. bioRxiv. :219923.
Raghavan, RT, Joshua M.  2017.  Dissecting patterns of preparatory activity in the frontal eye fields during pursuit target selection.. Journal of neurophysiology. 118(4):2216-2231. Abstract
We investigated the composition of preparatory activity of frontal eye field (FEF) neurons in monkeys performing a pursuit target selection task. In response to the orthogonal motion of a large and a small reward target, monkeys initiated pursuit biased toward the direction of large reward target motion. FEF neurons exhibited robust preparatory activity preceding movement initiation in this task. Preparatory activity consisted of two components, ramping activity that was constant across target selection conditions, and a flat offset in firing rates that signaled the target selection condition. Ramping activity accounted for 50% of the variance in the preparatory activity and was linked most strongly, on a trial-by-trial basis, to pursuit eye movement latency rather than to its direction or gain. The offset in firing rates that discriminated target selection conditions accounted for 25% of the variance in the preparatory activity and was commensurate with a winner-take-all representation, signaling the direction of large reward target motion rather than a representation that matched the parameters of the upcoming movement. These offer new insights into the role that the frontal eye fields play in target selection and pursuit control. They show that preparatory activity in the FEF signals more strongly when to move rather than where or how to move and suggest that structures outside the FEF augment its contributions to the target selection process. We used the smooth eye movement pursuit system to link between patterns of preparatory activity in the frontal eye fields and movement during a target selection task. The dominant pattern was a ramping signal that did not discriminate between selection conditions and was linked, on trial-by-trial basis, to movement latency. A weaker pattern was composed of a constant signal that discriminated between selection conditions but was only weakly linked to the movement parameters.
Yarden, TS, Nelken I.  2017.  Stimulus-specific adaptation in a recurrent network model of primary auditory cortex.. PLoS Comput Biol.. 13(3):e1005437. doi: 10.1371/journal.pcbi.1005437. Abstract
Stimulus-specific adaptation (SSA) occurs when neurons decrease their responses to frequently-presented (standard) stimuli but not, or not as much, to other, rare (deviant) stimuli. SSA is present in all mammalian species in which it has been tested as well as in birds. SSA confers short-term memory to neuronal responses, and may lie upstream of the generation of mismatch negativity (MMN), an important human event-related potential. Previously published models of SSA mostly rely on synaptic depression of the feedforward, thalamocortical input. Here we study SSA in a recurrent neural network model of primary auditory cortex. When the recurrent, intracortical synapses display synaptic depression, the network generates population spikes (PSs). SSA occurs in this network when deviants elicit a PS but standards do not, and we demarcate the regions in parameter space that allow SSA. While SSA based on PSs does not require feedforward depression, we identify feedforward depression as a mechanism for expanding the range of parameters that support SSA. We provide predictions for experiments that could help differentiate between SSA due to synaptic depression of feedforward connections and SSA due to synaptic depression of recurrent connections. Similar to experimental data, the magnitude of SSA in the model depends on the frequency difference between deviant and standard, probability of the deviant, inter-stimulus interval and input amplitude. In contrast to models based on feedforward depression, our model shows true deviance sensitivity as found in experiments.
Zylbertal, A, Yarom Y, Wagner S.  2017.  Synchronous Infra-Slow Bursting in the Mouse Accessory Olfactory Bulb Emerge from Interplay between Intrinsic Neuronal Dynamics and Network Connectivity.. The Journal of neuroscience : the official journal of the Society for Neuroscience. 37(10):2656-2672. Abstract
Rhythmic neuronal activity of multiple frequency bands has been described in many brain areas and attributed to numerous brain functions. Among these, little is known about the mechanism and role of infra-slow oscillations, which have been demonstrated recently in the mouse accessory olfactory bulb (AOB). Along with prolonged responses to stimuli and distinct network connectivity, they inexplicably affect the AOB processing of social relevant stimuli. Here, we show that assemblies of AOB mitral cells are synchronized by lateral interactions through chemical and electrical synapses. Using a network model, we demonstrate that the synchronous oscillations in these assemblies emerge from interplay between intrinsic membrane properties and network connectivity. As a consequence, the AOB network topology, in which each mitral cell receives input from multiple glomeruli, enables integration of chemosensory stimuli over extended time scales by interglomerular synchrony of infra-slow bursting. These results provide a possible functional significance for the distinct AOB physiology and topology. Beyond the AOB, this study presents a general model for synchronous infra-slow bursting in neuronal networks.SIGNIFICANCE STATEMENT Infra-slow rhythmic neuronal activity with a very long (>10 s) duration has been described in many brain areas, but little is known about the role of this activity and the mechanisms that produce it. Here, we combine experimental and computational methods to show that synchronous infra-slow bursting activity in mitral cells of the mouse accessory olfactory bulb (AOB) emerges from interplay between intracellular dynamics and network connectivity. In this novel mechanism, slow intracellular Na(+) dynamics endow AOB mitral cells with a weak tendency to burst, which is further enhanced and stabilized by chemical and electrical synapses between them. Combined with the unique topology of the AOB network, infra-slow bursting enables integration and binding of multiple chemosensory stimuli over a prolonged time scale.
Berman, S, West KL, Does MD, Yeatman JD, Mezer AA.  2017.  Evaluating g-ratio weighted changes in the corpus callosum as a function of age and sex.. NeuroImage. Abstract
Recent years have seen a growing interest in relating MRI measurements to the structural-biophysical properties of white matter fibers. The fiber g-ratio, defined as the ratio between the inner and outer radii of the axon myelin sheath, is an important structural property of white matter, affecting signal conduction. Recently proposed modeling methods that use a combination of quantitative-MRI signals, enable a measurement of the fiber g-ratio in vivo. Here we use an MRI-based g-ratio estimation to observe the variance of the g-ratio within the corpus callosum, and evaluate sex and age related differences. To estimate the g-ratio we used a model (Stikov et al., 2011; Duval et al., 2017) based on two different WM microstructure parameters: the relative amounts of myelin (myelin volume fraction, MVF) and fibers (fiber volume fraction, FVF) in a voxel. We derived the FVF from the fractional anisotropy (FA), and estimated the MVF by using the lipid and macromolecular tissue volume (MTV), calculated from the proton density (Mezer et al., 2013). In comparison to other methods of estimating the MVF, MTV represents a stable parameter with a straightforward route of acquisition. To establish our model, we first compared histological MVF measurements (West et al., 2016) with the MRI derived MTV. We then implemented our model on a large database of 92 subjects (44 males), aged 7 to 81, in order to evaluate age and sex related changes within the corpus callosum. Our results show that the MTV provides a good estimation of MVF for calculating g-ratio, and produced values from the corpus callosum that correspond to those found in animals ex vivo and are close to the theoretical optimum, as well as to published in vivo data. Our results demonstrate that the MTV derived g-ratio provides a simple and reliable in vivo g-ratio-weighted (GR*) measurement in humans. In agreement with theoretical predictions, and unlike other tissue parameters measured with MRI, the g-ratio estimations were found to be relatively stable with age, and we found no support for a significant sexual dimorphism with age.
Goldstein, RH, Katz B, Lev S, Binshtok AM.  2017.  Ultrafast optical recording reveals distinct capsaicin-induced ion dynamics along single nociceptive neurite terminals in vitro.. Journal of Biomedical Optics. 22(7):76010.
Jaffe-Dax, S, Frenkel O, Ahissar M.  2017.  Dyslexics' faster decay of implicit memory for sounds and words is manifested in their shorter neural adaptation.. eLife. 6 Abstract
Dyslexia is a prevalent reading disability whose underlying mechanisms are still disputed. We studied the neural mechanisms underlying dyslexia using a simple frequency-discrimination task. Though participants were asked to compare the two tones in each trial, implicit memory of previous trials affected their responses. We hypothesized that implicit memory decays faster among dyslexics. We tested this by increasing the temporal intervals between consecutive trials, and by measuring the behavioral impact and ERP responses from the auditory cortex. Dyslexics showed a faster decay of implicit memory effects on both measures, with similar time constants. Finally, faster decay of implicit memory also characterized the impact of sound regularities in benefitting dyslexics' oral reading rate. Their benefit decreased faster as a function of the time interval from the previous reading of the same non-word. We propose that dyslexics' shorter neural adaptation paradoxically accounts for their longer reading times, since it reduces their temporal window of integration of past stimuli, resulting in noisier and less reliable predictions for both simple and complex stimuli. Less reliable predictions limit their acquisition of reading expertise.
Keskin, AD, Kekuš M, Adelsberger H, Neumann U, Shimshek DR, Song B, Zott B, Peng T, Förstl H, Staufenbiel M et al..  2017.  BACE inhibition-dependent repair of Alzheimer's pathophysiology.. Proceedings of the National Academy of Sciences of the United States of America. 114(32):8631-8636. Abstract
Amyloid-β (Aβ) is thought to play an essential pathogenic role in Alzheimer´s disease (AD). A key enzyme involved in the generation of Aβ is the β-secretase BACE, for which powerful inhibitors have been developed and are currently in use in human clinical trials. However, although BACE inhibition can reduce cerebral Aβ levels, whether it also can ameliorate neural circuit and memory impairments remains unclear. Using histochemistry, in vivo Ca imaging, and behavioral analyses in a mouse model of AD, we demonstrate that along with reducing prefibrillary Aβ surrounding plaques, the inhibition of BACE activity can rescue neuronal hyperactivity, impaired long-range circuit function, and memory defects. The functional neuronal impairments reappeared after infusion of soluble Aβ, mechanistically linking Aβ pathology to neuronal and cognitive dysfunction. These data highlight the potential benefits of BACE inhibition for the effective treatment of a wide range of AD-like pathophysiological and cognitive impairments.
Li, J, Liao X, Zhang J, Wang M, Yang N, Zhang J, Lv G, Li H, Lu J, Ding R et al..  2017.  Primary Auditory Cortex is Required for Anticipatory Motor Response.. Cerebral cortex (New York, N.Y. : 1991). 27(6):3254-3271. Abstract
The ability of the brain to predict future events based on the pattern of recent sensory experience is critical for guiding animal's behavior. Neocortical circuits for ongoing processing of sensory stimuli are extensively studied, but their contributions to the anticipation of upcoming sensory stimuli remain less understood. We, therefore, used in vivo cellular imaging and fiber photometry to record mouse primary auditory cortex to elucidate its role in processing anticipated stimulation. We found neuronal ensembles in layers 2/3, 4, and 5 which were activated in relationship to anticipated sound events following rhythmic stimulation. These neuronal activities correlated with the occurrence of anticipatory motor responses in an auditory learning task. Optogenetic manipulation experiments revealed an essential role of such neuronal activities in producing the anticipatory behavior. These results strongly suggest that the neural circuits of primary sensory cortex are critical for coding predictive information and transforming it into anticipatory motor behavior.
Barkai, O, Goldstein RH, Caspi Y, Katz B, Lev S, Binshtok AM.  2017.  The Role of Kv7/M Potassium Channels in Controlling Ectopic Firing in Nociceptors.. Frontiers in Molecular Neuroscience. 10:181. Abstract
Peripheral nociceptive neurons encode and convey injury-inducing stimuli toward the central nervous system. In normal conditions, tight control of nociceptive resting potential prevents their spontaneous activation. However, in many pathological conditions the control of membrane potential is disrupted, leading to ectopic, stimulus-unrelated firing of nociceptive neurons, which is correlated to spontaneous pain. We have investigated the role of KV7/M channels in stabilizing membrane potential and impeding spontaneous firing of nociceptive neurons. These channels generate low voltage-activating, noninactivating M-type K(+) currents (M-current, IM ), which control neuronal excitability. Using perforated-patch recordings from cultured, rat nociceptor-like dorsal root ganglion neurons, we show that inhibition of M-current leads to depolarization of nociceptive neurons and generation of repetitive firing. To assess to what extent the M-current, acting at the nociceptive terminals, is able to stabilize terminals' membrane potential, thus preventing their ectopic activation, in normal and pathological conditions, we built a multi-compartment computational model of a pseudo-unipolar unmyelinated nociceptive neuron with a realistic terminal tree. The modeled terminal tree was based on the in vivo structure of nociceptive peripheral terminal, which we assessed by in vivo multiphoton imaging of GFP-expressing nociceptive neuronal terminals innervating mice hind paw. By modifying the conductance of the KV7/M channels at the modeled terminal tree (terminal gKV7/M) we have found that 40% of the terminal gKV7/M conductance is sufficient to prevent spontaneous firing, while ~75% of terminal gKV7/M is sufficient to inhibit stimulus induced activation of nociceptive neurons. Moreover, we showed that terminal M-current reduces susceptibility of nociceptive neurons to a small fluctuations of membrane potentials. Furthermore, we simulated how the interaction between terminal persistent sodium current and M-current affects the excitability of the neurons. We demonstrated that terminal M-current in nociceptive neurons impeded spontaneous firing even when terminal Na(V)1.9 channels conductance was substantially increased. On the other hand, when terminal gKV7/M was decreased, nociceptive neurons fire spontaneously after slight increase in terminal Na(V)1.9 conductance. Our results emphasize the pivotal role of M-current in stabilizing membrane potential and hereby in controlling nociceptive spontaneous firing, in normal and pathological conditions.
Reshef, R, Kudryavitskaya E, Shani-Narkiss H, Isaacson B, Rimmerman N, Mizrahi A, Yirmiya R.  2017.  The role of microglia and their CX3CR1 signaling in adult neurogenesis in the olfactory bulb. eLife. 6:e30809. Abstract
Microglia play important roles in perinatal neuro- and synapto-genesis. To test the role of microglia in these processes during adulthood, we examined the effects of microglia depletion, via treatment of mice with the CSF-1 receptor antagonist PLX5622, and abrogated neuronal-microglial communication in CX3C receptor-1 deficient (Cx3cr1−/−) mice. Microglia depletion significantly lowered spine density in young (developing) but not mature adult-born-granule-cells (abGCs) in the olfactory bulb. Two-photon time-lapse imaging indicated that microglia depletion reduced spine formation and elimination. Functionally, odor-evoked responses of mitral cells, which are normally inhibited by abGCs, were increased in microglia-depleted mice. In Cx3cr1−/− mice, abGCs exhibited reduced spine density, dynamics and size, concomitantly with reduced contacts between Cx3cr1-deficient microglia and abGCs' dendritic shafts, along with increased proportion of microglia-contacted spines. Thus, during adult neurogenesis, microglia regulate the elimination (pruning), formation, and maintenance of synapses on newborn neurons, contributing to the functional integrity of the olfactory bulb circuitry.
Ravid Tannenbaum, N, Burak Y.  2017.  Theory of nonstationary Hawkes processes. Physical Review E. 96(6):0623141-10.
Habib, N, Davidi AI, Basu A, Burks T, Shekhar K, Hofree M, Choudhury SR, Aguet F, Gelfand E, Ardlie K et al..  2017.  Massively parallel single-nucleus RNA-seq with DroNc-seq. Nat Methods. Abstract
Single-nucleus RNA sequencing (sNuc-seq) profiles RNA from tissues that are preserved or cannot be dissociated, but it does not provide high throughput. Here, we develop DroNc-seq: massively parallel sNuc-seq with droplet technology. We profile 39,111 nuclei from mouse and human archived brain samples to demonstrate sensitive, efficient, and unbiased classification of cell types, paving the way for systematic charting of cell atlases.
Jaffe-Dax, S, Raviv O, Loewenstein Y, Ahissar M.  2017.  A Computational Model of Dyslexics’ Perceptual Difficulties as Impaired Inference of Sound Statistics. Computational Models of Brain and Behavior. 3PDF
Mongillo, G, Rumpel S, Loewenstein Y.  2017.  Intrinsic volatility of synaptic connections — a challenge to the synaptic trace theory of memory. Current Opinion in Neurobiology. 46:7-13. Abstractpdf
According to the synaptic trace theory of memory, activity-induced changes in the pattern of synaptic connections underlie the storage of information for long periods. In this framework, the stability of memory critically depends on the stability of the underlying synaptic connections. Surprisingly however, synaptic connections in the living brain are highly volatile, which poses a fundamental challenge to the synaptic trace theory. Here we review recent experimental evidence that link the initial formation of a memory with changes in the pattern of connectivity, but also evidence that synaptic connections are considerably volatile even in the absence of learning. Then we consider different theoretical models that have been put forward to explain how memory can be maintained with such volatile building blocks.
Gal, E, London M, Globerson A, Ramaswamy S, Reimann MW, Muller E, Markram H, Segev I.  2017.  Rich cell-type-specific network topology in neocortical microcircuitry. Nature Neuroscience. 20(7) Abstract
Uncovering structural regularities and architectural topologies of cortical circuitry is vital for understanding neural computations. Recently, an experimentally constrained algorithm generated a dense network reconstruction of a ~0.3-mm 3 volume from juvenile rat somatosensory neocortex, comprising ~31,000 cells and ~36 million synapses. Using this reconstruction, we found a small-world topology with an average of 2.5 synapses separating any two cells and multiple cell-type-specific wiring features. Amounts of excitatory and inhibitory innervations varied across cells, yet pyramidal neurons maintained relatively constant excitation/inhibition ratios. The circuit contained highly connected hub neurons belonging to a small subset of cell types and forming an interconnected cell-type-specific rich club. Certain three-neuron motifs were overrepresented, matching recent experimental results. Cell-type-specific network properties were even more striking when synaptic strength and sign were considered in generating a functional topology. Our systematic approach enables interpretation of microconnectomics ‘big data’ and provides several experimentally testable predictions.
Mosheiff, N, Agmon H, Moriel A, Burak Y.  2017.  An efficient coding theory for a dynamic trajectory predicts non-uniform allocation of entorhinal grid cells to modules. PLoS Computational Biology. 13(6):e1005597.
Yarden-Rabinowitz, Y, Yarom Y.  2017.  In vivo analysis of synaptic activity in cerebellar nucleineurons unravels the efficacy of excitatory inputs. Journal of Physiology. 595(17) Abstract
It is commonly agreed that the main function of the cerebellar system is to providewell-timed signals used for the execution of motor commands or prediction of sensory inputs.This function is manifested as a temporal sequence of spiking that should be expressed in thecerebellar nuclei (CN) projection neurons. Whether spiking activity is generated by excitationor release from inhibition is still a hotly debated issue. In an attempt to resolve this debate,we recorded intracellularly from CN neurons in anaesthetized mice and performed an analysisof synaptic activity that yielded a number of important observations. First, we demonstratethat CN neurons can be classified into four groups. Second, shape-index plots of the excitatoryevents suggest that they are distributed over the entire dendritic tree. Third, the rise time ofexcitatory events is linearly related to amplitude, suggesting that all excitatory events contributeequally to the generation of action potentials (APs). Fourth, we identified a temporal patternof spontaneous excitatory events that represent climbing fibre inputs and confirm the resultsby direct stimulation and analysis on harmaline-evoked activity. Finally, we demonstrate thatthe probability of excitatory inputs generating an AP is 0.1 yet half of the APs are generated byexcitatory events. Moreover, the probability of a presumably spontaneous climbing fibre inputgenerating an AP is higher, reaching a mean population value of 0.15. In view of these results, themode of synaptic integration at the level of the CN should be re-considered.
Mongillo, G, Loewenstein Y.  2017.  Neuroscience: Formation of a Percept in the Rat Cortex. Current Biology. 27(11):1585-1596.e6. Abstractpdf
It has long been known that we subjectively experience longer stimuli as being more intense. A recent study sheds light on the neural mechanisms underlying this bias by tracking the formation of a percept of intensity in the rat brain.
Murakami, M, Shteingart H, Loewenstein Y, Mainen ZF.  2017.  Distinct Sources of Deterministic and Stochastic Components of Action Timing Decisions in Rodent Frontal Cortex. Neuron. 94(4):908–919. Abstractmmc2.pdf
The selection and timing of actions are subject to determinate influences such as sensory cues and internal state as well as to effectively stochastic variability. Although stochastic choice mechanisms are assumed by many theoretical models, their origin and mechanisms remain poorly understood. Here we investigated this issue by studying how neural circuits in the frontal cortex determine action timing in rats performing a waiting task. Electrophysiological recordings from two regions necessary for this behavior, medial prefrontal cortex (mPFC) and secondary motor cortex (M2), revealed an unexpected functional dissociation. Both areas encoded deterministic biases in action timing, but only M2 neurons reflected stochastic trial-by-trial fluctuations. This differential coding was reflected in distinct timescales of neural dynamics in the two frontal cortical areas. These results suggest a two-stage model in which stochastic components of action timing decisions are injected by circuits downstream of those carrying deterministic bias signals.