Time Course Of Activation Research Articles

The hERG PAS domain: A major regulator of IKr and a promising anti-arrhythmic drug target.

The hERG1 potassium channel conducts the critical cardiac repolarizing current IKr. Given its role in mediating electrical excitability, several groups have investigated the antiarrhythmic capacity of hERG1 activators in cardiac diseases marked by prolonged action potential duration (APD), such as long QT Syndrome. hERG1 activators have had limited success due to their off-target effects. We recently generated a single chain variable fragment (scFv) antibody, scFv2.10, that selectively binds the hERG1 Per-Arnt-Sim (PAS) domain. The PAS domain binds to the C-terminal cyclic nucleotide binding homology domain (CNBHD) and slows channel activation and promotes inactivation. scFv2.10 disrupts the PAS-CNBHD interaction, which in turn causes a two-fold increase in the time course of hERG1 activation and inactivation recovery, thereby increasing hERG1 current in HEK293 cells. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), disrupting the PAS-CNBHD interaction with scFv2.10 increases IKr and shortens APD. We hypothesized that the hERG1 PAS domain could represent a novel therapeutic target for diseases of impaired cardiac repolarization. To test this, we measured the antiarrhythmic capacity of scFv2.10 on a novel hiPSC-CM line derived from a patient with Jervell and Lange Nielsen syndrome (JLN). JLN syndrome is a severe form of long QT Syndrome Type 1 characterized by increased APD and incidence of sudden cardiac death. Compared to hiPSC-CMs derived from a healthy genetic background, JLN hiPSC-CMs display hallmarks of pro-arrhythmia including prolonged APD, increased action potential variability, and early afterdepolarizations. scFv2.10 reduced APD, action potential variability, and the incidence of early afterdepolarizations in JLN hiPSC-CMs, compared to GFP controls. These data demonstrate that the hERG1 PAS domain is a potential therapeutic target to treat disorders of electrical excitability.

Patterns and predictors of inter-litter differences in rabbit pup locomotor activity, based on an automatized quantification method

Individual-level sibling interactions in the litter huddle have been studied extensively, especially in the domestic rabbit (Oryctolagus cuniculus). However, little is known about inter-litter differences in pup activity patterns during early postnatal life, in particular regarding the drivers of such variation. In our study on 2–3-day-old rabbit pups, we predicted lower locomotor activity in litters with lower mean body masses on the day of birth (starting body mass) and with lower daily milk intake per pup, possibly constituting a behavioral strategy of pups to cope with associated energetic constraints. For an automatized assessment of pup locomotor activity in the litter huddle, we successfully developed and validated a method based on the quantification of dissimilarities between consecutive frames of video footage. Using this method, we could confirm a U-shaped time course of litter-level locomotor activity, with maximum values shortly before and after the once-daily nursing typical for the rabbit. As predicted, between-litter variation in mean starting body mass and in daily milk intake affected the degree of locomotor activity in the litter huddle, in an interactive way. That is, in litters with heavier starting body masses, pup locomotor activity was greater in pups with an initially higher milk intake, suggesting that only pups with better body condition and a higher energy intake could afford higher levels of activity. This interaction was exclusively apparent during the middle phase of the 24 h inter-nursing interval, when litter activity was low. Shortly before nursing, when pups show higher levels of locomotor behavior in anticipation of the mother's arrival, and shortly after nursing when the pups were more active possibly due to adjustments of their positions in the huddle, activity levels were decoupled from pups’ starting body mass and previous milk intake. Our findings highlight the importance of pup body mass and daily energy intake, two parameters known to be related to maternal characteristics, in shaping inter-litter differences in pup locomotor activity.

Sleep-inducing effect of Rhynchophylline in EphA4 knockout mice.

We have recently demonstrated that the alkaloid rhynchophylline (RHY; purified from Uncaria plants) induces sleep and modifies electrocorticographic (ECoG) activity throughout the 24-h day in a vigilance state-dependent manner in wild-type mice. We here asked whether this alkaloid impacts wake/sleep variables in the absence of the cell adhesion protein EPHA4, via ECoG recording in EphA4 knockout (KO) mice submitted to the same RHY treatment contemporaneously to the wild-type mice (littermates). We uncover that RHY decreases time spent awake and increases time spent in slow wave sleep in EphA4 KO mice and alters the 24-h time course of ECoG activity during wakefulness and sleep states. These observations are similar to the reported effects of RHY in wild-type littermate animals, which strongly supports that RHY-driven sleep alterations are not dependent on the presence of EPHA4.

Dimensionality reduction of calcium-imaged neuronal population activity.

Calcium imaging has been widely adopted for its ability to record from large neuronal populations. To summarize the time course of neural activity, dimensionality reduction methods, which have been applied extensively to population spiking activity, may be particularly useful. However, it is unclear if the dimensionality reduction methods applied to spiking activity are appropriate for calcium imaging. We thus carried out a systematic study of design choices based on standard dimensionality reduction methods. We also developed a method to perform deconvolution and dimensionality reduction simultaneously (Calcium Imaging Linear Dynamical System, CILDS). CILDS most accurately recovered the single-trial, low-dimensional time courses from simulated calcium imaging data. CILDS also outperformed the other methods on calcium imaging recordings from larval zebrafish and mice. More broadly, this study represents a foundation for summarizing calcium imaging recordings of large neuronal populations using dimensionality reduction in diverse experimental settings.

Sedative Properties of Dexmedetomidine Are Mediated Independently from Native Thalamic Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Function at Clinically Relevant Concentrations.

Dexmedetomidine is a selective α2-adrenoceptor agonist and appears to disinhibit endogenous sleep-promoting pathways, as well as to attenuate noradrenergic excitation. Recent evidence suggests that dexmedetomidine might also directly inhibit hyperpolarization-activated cyclic-nucleotide gated (HCN) channels. We analyzed the effects of dexmedetomidine on native HCN channel function in thalamocortical relay neurons of the ventrobasal complex of the thalamus from mice, performing whole-cell patch-clamp recordings. Over a clinically relevant range of concentrations (1-10 µM), the effects of dexmedetomidine were modest. At a concentration of 10 µM, dexmedetomidine significantly reduced maximal Ih amplitude (relative reduction: 0.86 [0.78-0.91], n = 10, and p = 0.021), yet changes to the half-maximal activation potential V1/2 occurred exclusively in the presence of the very high concentration of 100 µM (-4,7 [-7.5--4.0] mV, n = 10, and p = 0.009). Coincidentally, only the very high concentration of 100 µM induced a significant deceleration of the fast component of the HCN activation time course (τfast: +135.1 [+64.7-+151.3] ms, n = 10, and p = 0.002). With the exception of significantly increasing the membrane input resistance (starting at 10 µM), dexmedetomidine did not affect biophysical membrane properties and HCN channel-mediated parameters of neuronal excitability. Hence, the sedative qualities of dexmedetomidine and its effect on the thalamocortical network are not decisively shaped by direct inhibition of HCN channel function.

Up close and emotional: Electrophysiological dynamics of approaching angry faces

Recent evidence suggests that looming emotional faces are processed rapidly by the neural system, and that this apparent approach further interacts with emotion, causing an enhanced neural response for angry expressions. However, previous research has not demonstrated unequivocally if these effects are due to low-level visual features, or if they are indeed due to the emotional content of the stimuli. To address this question, the current study presented upright and inverted angry and neutral faces, which either expanded or contracted in size on a constant depth-cued background, such that they appeared to approach or retreat from the viewer. EEG/ERP measures were used to identify the time course of brain activity for these stimuli. The results showed that when faces were upright, both the P1 and N170 were enhanced for angry expressions, with the P1 being further increased with looming angry faces. The inversion of the faces caused an increase in both the P1 and N170 amplitudes, but no modulation was found for emotions. These findings show an early modulation of brain activity for upright looming angry faces and rule out the influence of low-level visual features as a contributing factor.

Autohrf-an R package for generating data-informed event models for general linear modeling of task-based fMRI data.

The analysis of task-related fMRI data at the level of individual participants is commonly based on general linear modeling (GLM), which allows us to estimate the extent to which the BOLD signal can be explained by the task response predictors specified in the event model. The predictors are constructed by convolving the hypothesized time course of neural activity with an assumed hemodynamic response function (HRF). However, our assumptions about the components of brain activity, including their onset and duration, may be incorrect. Their timing may also differ across brain regions or from person to person, leading to inappropriate or suboptimal models, poor fit of the model to actual data, and invalid estimates of brain activity. Here, we present an approach that uses theoretically driven models of task response to define constraints on which the final model is computationally derived using actual fMRI data. Specifically, we developed autohrf-an R package that enables the evaluation and data-driven estimation of event models for GLM analysis. The highlight of the package is the automated parameter search that uses genetic algorithms to find the onset and duration of task predictors that result in the highest fitness of GLM based on the fMRI signal under predefined constraints. We evaluated the usefulness of the autohrf package on two original datasets of task-related fMRI activity, a slow event-related spatial working memory study and a mixed state-item study using the flanker task, and on a simulated slow event-related working memory data. Our results suggest that autohrf can be used to efficiently construct and evaluate better task-related brain activity models to gain a deeper understanding of BOLD task response and improve the validity of model estimates. Our study also highlights the sensitivity of fMRI analysis with GLM to precise event model specification and the need for model evaluation, especially in complex and overlapping event designs.

Attentional capture mediates the emergence and suppression of intrusive memories.

Intrusive memories hijack consciousness and their control may lead to forgetting. However, the contribution of reflexive attention to qualifying a memory signal as interfering is unknown. We used machine learning to decode the brain's electrical activity and pinpoint the otherwise hidden emergence of intrusive memories reported during a memory suppression task. Importantly, the algorithm was trained on an independent attentional model of visual activity, mimicking either the abrupt and interfering appearance of visual scenes into conscious awareness or their deliberate exploration. Intrusion of memories into conscious awareness were decoded above chance. The decoding accuracy increased when the algorithm was trained using a model of reflexive attention. Conscious detection of intrusive activity decoded from the brain signal was central to the future silencing of suppressed memories and laterforgetting. Unwanted memories require the reflexive orienting of attention and access to consciousness to be suppressed effectively by inhibitory control.

Characterization in Potent Modulation on Voltage-Gated Na+ Current Exerted by Deltamethrin, a Pyrethroid Insecticide

Deltamethrin (DLT) is a type-II pyrethroid ester insecticide used in agricultural and domestic applications as well as in public health. However, transmembrane ionic channels perturbed by this compound remain largely unclear, although the agent is thought to alter the gating characteristics of voltage-gated Na+ (NaV) channel current. In this study, we reappraised whether and how it and other related compounds can make any further modifications on voltage-gated Na+ current (INa) in pituitary tumor (GH3) cells. Cell exposure to DLT produced a differential and dose-dependent stimulation of peak (transient, INa(T)) or sustained (late, INa(L)) INa; consequently, the EC50 value required for DLT-stimulated INa(T) or INa(L) was determined to be 11.2 or 2.5 μM, respectively. However, neither the fast nor slow component in the inactivation time constant of INa(T) activated by short depolarizing pulse was changed with the DLT presence; conversely, tefluthrin (Tef), a type-I pyrethroid insecticide, can accentuate INa with a slowing in inactivation time course of the current. The INa(L) augmented by DLT was attenuated by further application of either dapagliflozin (Dapa) or amiloride, but not by chlorotoxin. During pulse train (PT) stimulation, with the Tef or DLT presence, the cumulative inhibition of INa(T) became slowed; moreover, following PT stimuli, a large tail current with a slowly recovering process was observed. Alternatively, during rapid depolarizing pulse, the amplitude of INa(L) and tail INa (INa(Tail)) for each depolarizing pulse became progressively increased by adding DLT, not by Tef. The recovery time constant following PT stimulation with continued presence of Tef or DLT was shortened by further addition of Dapa. The voltage-dependent hysteresis (Hys(V)) of persistent INa was differentially augmented by Tef or DLT. Taken together, the magnitude, gating, frequency dependence, as well as Hys(V) behavior of INa exerted by the presence of DLT or Tef might exert a synergistic impact on varying functional activities of excitable cells in culture or in vivo.

Anatomical location of injected microglia in different activation states and time course of injury determines survival of retinal ganglion cells after optic nerve crush

Background: Activated microglia release harmful substances to retinal ganglion cells (RGCs), but may also benefit by removing cellular debris and secreting neurotrophic factors. These paradoxical roles remain controversial because the nature and time-course of the injury that defines their role is unknown. The aim of this study was to determine if pharmacological manipulation of microglia to acquire a pro-inflammatory or pro-survival phenotype will exacerbate or enhance neuronal survival after injury.Material and methods: Treated HAP I (highly aggressively proliferating immortalized) microglia were injected into the vitreous or tail vein (T V) of female Sprague-Dawley rats. Retinas were examined at 4-14 days following optic nerve crush (ONC) and the number of surviving RGCs was determined.Results: Injection of untreated HAP I cells resulted in the greater loss of RGCs early after ONC when injected into the vitreous and later after ONC when injected into the T V. LP S activated HAP I cells injected into the vitreous resulted in greater RGC loss with and without injury. When injected into the T V with ONC there was no loss of RGCs 4 days after ONC but greater loss afterwards. Minocycline treated HAP I cells injected into the vitreous resulted in greater RGC survival than untreated HAP I cells. However, when injected into the T V with ONC there was greater loss of RGCs. These results suggest that optic nerve signals attract extrinsic microglia to the retina, resulting in a proinflammatory response.Conclusion: Neuroprotection or cytotoxicity of microglia depends on the type of activation, time course of the injury, and if they act on the axon or cell body.

The time course of lexical and sublexical phonological activation in Chinese written production

The time course of sublexical processing in written production is scarcely investigated due to transparent sound-to-spelling correspondence in most alphabetical languages. By taking advantage of the opaque orthography of Chinese, we were able to dissociatively manipulate sublexical relatedness and lexical relatedness in a picture-word interference task. The ERP technique was also used to provide a fine-grained time course of sublexical processing. Participants were asked to handwrite picture names while ignoring distractors overlain on the pictures. Distractors were phonologically related to the picture names (lexically related), phonologically related to the phonetic radicals of picture names (sublexically related), or unrelated to picture names. ERP results revealed that sublexical relatedness affected ERPs in the time window of 370–470 ms after picture onset, which was later than the early time window (200–260 ms) of the effect of lexical relatedness. We suggest that the sublexical phonological activation happens in the stages of sublexical POC procedure and/or the graphemic output buffer in written production. The relatively later time window of the sublexical effect is consistent with the later loci of the sublexical processes in the model of written production.

Relating individual cell division events to single-cell ERK and Akt activity time courses

Biochemical correlates of stochastic single-cell fates have been elusive, even for the well-studied mammalian cell cycle. We monitored single-cell dynamics of the ERK and Akt pathways, critical cell cycle progression hubs and anti-cancer drug targets, and paired them to division events in the same single cells using the non-transformed MCF10A epithelial line. Following growth factor treatment, in cells that divide both ERK and Akt activities are significantly higher within the S-G2 time window (~ 8.5–40 h). Such differences were much smaller in the pre-S-phase, restriction point window which is traditionally associated with ERK and Akt activity dependence, suggesting unappreciated roles for ERK and Akt in S through G2. Simple metrics of central tendency in this time window are associated with subsequent cell division fates. ERK activity was more strongly associated with division fates than Akt activity, suggesting Akt activity dynamics may contribute less to the decision driving cell division in this context. We also find that ERK and Akt activities are less correlated with each other in cells that divide. Network reconstruction experiments demonstrated that this correlation behavior was likely not due to crosstalk, as ERK and Akt do not interact in this context, in contrast to other transformed cell types. Overall, our findings support roles for ERK and Akt activity throughout the cell cycle as opposed to just before the restriction point, and suggest ERK activity dynamics may be more important than Akt activity dynamics for driving cell division in this non-transformed context.

Multiple traces and altered signal-to-noise in systems consolidation: Evidence from the 7T fMRI Natural Scenes Dataset

The brain mechanisms of memory consolidation remain elusive. Here, we examine blood-oxygen-level-dependent (BOLD) correlates of image recognition through the scope of multiple influential systems consolidation theories. We utilize the longitudinal Natural Scenes Dataset, a 7-Tesla functional magnetic resonance imaging human study in which ∼135,000 trials of image recognition were conducted over the span of a year among eight subjects. We find that early- and late-stage image recognition associates with both medial temporal lobe (MTL) and visual cortex when evaluating regional activations and a multivariate classifier. Supporting multiple-trace theory (MTT), parts of the MTL activation time course show remarkable fit to a 20-y-old MTT time-dynamical model predicting early trace intensity increases and slight subsequent interference (R2 > 0.90). These findings contrast a simplistic, yet common, view that memory traces are transferred from MTL to cortex. Next, we test the hypothesis that the MTL trace signature of memory consolidation should also reflect synaptic "desaturation," as evidenced by an increased signal-to-noise ratio. We find that the magnitude of relative BOLD enhancement among surviving memories is positively linked to the rate of removal (i.e., forgetting) of competing traces. Moreover, an image-feature and time interaction of MTL and visual cortex functional connectivity suggests that consolidation mechanisms improve the specificity of a distributed trace. These neurobiological effects do not replicate on a shorter timescale (within a session), implicating a prolonged, offline process. While recognition can potentially involve cognitive processes outside of memory retrieval (e.g., re-encoding), our work largely favors MTT and desaturation as perhaps complementary consolidative memory mechanisms.

Effective Modulation by Lacosamide on Cumulative Inhibition of INa during High-Frequency Stimulation and Recovery of INa Block during Conditioning Pulse Train.

The effects of lacosamide (LCS, Vimpat®), an anti-convulsant and analgesic, on voltage-gated Na+ current (INa) were investigated. LCS suppressed both the peak (transient, INa(T)) and sustained (late, INa(L)) components of INa with the IC50 values of 78 and 34 μM found in GH3 cells and of 112 and 26 μM in Neuro-2a cells, respectively. In GH3 cells, the voltage-dependent hysteresis of persistent INa (INa(P)) during the triangular ramp pulse was strikingly attenuated, and the decaying time constant (τ) of INa(T) or INa(L) during a train of depolarizing pulses was further shortened by LCS. The recovery time course from the INa block elicited by the preceding conditioning train can be fitted by two exponential processes, while the single exponential increase in current recovery without a conditioning train was adequately fitted. The fast and slow τ’s of recovery from the INa block by the same conditioning protocol arose in the presence of LCS. In Neuro-2a cells, the strength of the instantaneous window INa (INa(W)) during the rapid ramp pulse was reduced by LCS. This reduction could be reversed by tefluthrin. Moreover, LCS accelerated the inactivation time course of INa activated by pulse train stimulation, and veratridine reversed its decrease in the decaying τ value in current inactivation. The docking results predicted the capability of LCS binding to some amino-acid residues in sodium channels owing to the occurrence of hydrophobic contact. Overall, our findings unveiled that LCS can interact with the sodium channels to alter the magnitude, gating, voltage-dependent hysteresis behavior, and use dependence of INa in excitable cells.

Germline de novo variant F747S extends the phenotypic spectrum of CACNA1D Ca2+ channelopathies.

Germline gain-of-function missense variants in the pore-forming Cav1.3 α1-subunit (CACNA1D gene) confer high risk for a severe neurodevelopmental disorder with or without endocrine symptoms. Here, we report a 4-week-old new-born with the novel de novo missense variant F747S with a so far not described prominent jittering phenotype in addition to symptoms previously reported for CACNA1D mutations including developmental delay, elevated aldosterone level and transient hypoglycemia. We confirmed the pathogenicity of this variant in whole-cell patch-clamp experiments with wild-type and F747S mutant channels heterologously expressed together with α2δ1 and cytosolic β3 or membrane-bound β2a subunits. Mutation F747S caused the quantitatively largest shift in the voltage dependence of activation (-28mV) reported so far for CACNA1D germline mutations. It also shifted inactivation to more negative voltages, slowed the time course of current inactivation and slowed current deactivation upon repolarization with both co-expressed β-subunits. In silico modelling and molecular docking, simulations revealed that this gain-of-function phenotype can be explained by formation of a novel inter-domain hydrogen bond between mutant residues S747 (IIS6) with N1145 (IIIS6) stabilizing selectively the activated open channel state. F747S displayed 2-6-fold increased sensitivity for the L-type Ca2+ channel blocker isradipine compared to wild type. Our data confirm the pathogenicity of the F747S variant with very strong gain-of-function gating changes, which may contribute to the novel jittering phenotype. Increased sensitivity for isradipine suggests this drug for potential symptomatic off-label treatment for carriers of this mutation.

Empagliflozin and dapagliflozin increase Na current in human cardiomyocytes

Abstract Background Empagliflozin (EMPA) and dapagliflozin (DAPA) are sodium-glucose cotransporter 2 inhibitors (SGLT2i) used for the treatment of type 2 Diabetes Mellitus (T2DM). Both drugs reduce morbidity and mortality in heart failure (HF) patients with reduced or preserved ejection fraction, even in the absence of T2DM. Moreover, these drugs decrease ventricular arrhythmias and sudden cardiac death in HF patients. The sodium current (INa), carried by Nav1.5 channels, is responsible for cardiac action potential (AP) depolarization and determines excitability and conduction velocity. In HF patients, the expression of Nav1.5 channels is reduced, leading to a decrease of ventricular excitability that enhances the arrhythmic risk. Purpose We aimed to determine the effects of EMPA and DAPA on human cardiac INa and AP characteristics. Methods Peak INa and ventricular-like APs were recorded in cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CM) using patch-clamp techniques. INa was also recorded in CHO cells transiently transfected with human Nav1.5+Navβ1 channels. In all cases, EMPA or DAPA (1 μM) were added to culture media and incubated for 24-h. Results APs recorded in hiPSC-CMs exhibited automatic activity and incubation with EMPA or DAPA did not modify spontaneous beating frequency (0.39±0.04 Hz; P>0.05, n≥16). In cells driven at 1 Hz, none of the drugs modified resting membrane potential (−76.7±1.4 mV; P>0.05, n≥11), but significantly increased AP amplitude from 98.6±3.6 to 105±2.2 (DAPA) and 107±2.3 mV (EMPA) (P<0.05). Interestingly, only EMPA lengthened AP duration measured at 20%, 50%, and 90% (from 605.6±31.3 to 760.5±59.0 ms, P<0.05) of repolarization. In hiPSC-CMs EMPA increased maximum INa density by 64% (from −156.0±28.0 to −256.4±28.1 pA/pF, P<0.05, n≥7) and shifted the midpoint (Vh) of the inactivation curve to more hyperpolarized potentials (from −97.3±4.5 to −108.6±4.4 mV, P<0.05, n≥7). In turn, DAPA increased maximum INa density by 24% (to −193.8±26.6 pA/pF) and shifted the Vh of the activation curve to more negative potentials (from −47.2±1.6 mV to −55.5±2.8 mV, P<0.05), an effect that would increase the INa at negative potentials coinciding with channel opening. None of the drugs modified the time course of current activation or inactivation. In CHO cells, EMPA and DAPA effects on INa were identical to those observed on hiPSC-CM. These results suggest that both SGLT2i increase INa by enhancing Nav1.5 expression into the cell membrane, by a direct gating effect on the channel, or by a combination of both. Conclusions In human cardiomyocytes, EMPA and DAPA increase INa and the AP amplitude. Moreover, EMPA, but not DAPA, prolonged AP duration. We propose that EMPA and DAPA exhibit a unique mechanism that increases cardiac excitability and conduction velocity and could contribute to the prevention of arrhythmic events in HF patients. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministerio de Ciencia e innovaciόnInstituto de de Salud Carlos III

Task cue influences on lexical decision performance and masked semantic priming effects: The role of cue-task compatibility

Recent research demonstrated that mere presentation of a task cue influences subsequent unconscious semantic priming by attentional sensitization of related processing pathways. The direction of this influence depended on task-set dominance. Dominant task sets with a compatible cue-task mapping were supposed to be rapidly suppressed, while weak task sets showed more sustainable activation. Building on this research, we manipulated cue-task compatibility as instance of task-set dominance in two experiments and tested how masked semantic priming was influenced by actually performing the cued task (induction-task trials) or by mere cue presentation (task cue-only trials). In induction-task trials, the results of earlier research were replicated; semantic priming was larger following a semantic induction task compared to a perceptual induction task. In task cue-only trials, priming effects were reversed compared to induction-task trials in both experiments. Priming was larger for a perceptual compared to a semantic task set in task cue-only trials, indicating suppression of task sets following mere cue presentation in preparation for the upcoming lexical decision task. This notion of an inhibition of task sets after mere cue presentation was further supported by switching-related costs and changes of task-set implementation throughout the experiment. The absence of a moderator role of cue-task compatibility for task cue effects on priming in the present study suggests that the precise time course of task-set activation and inhibition in response to task cues as a function of cue-task compatibility might depend on specific experimental settings.

Time Course of Motor Activity Wake Inertia Dissipation According to Age.

The time course of motor activity sleep inertia (maSI) dissipation was recently investigated through actigraphy in an everyday life condition from middle childhood to late adulthood. Motor activity sleep inertia was dissipated in 70 min, and the sleep inertia phenomenon was more evident in younger participants than in older participants. The aim of the current secondary analysis of previously published data was to examine, within the same sample, the time course of motor activity wake inertia (maWI) dissipation, i.e., the motor pattern in the transition phase from wakefulness to sleep, according to age. To this end, an overall sample of 374 participants (215 females), ranging in age between 9 and 70 years old, was examined. Each participant was asked to wear an actigraph around their non-dominant wrist for one week. The variation in the motor activity pattern of the wake–sleep transition according to age was examined through functional linear modeling (FLM). FLM showed that motor activity wake inertia dissipated around 20 min after bedtime. Moreover, a lower age was significantly associated with greater motor activity within the last two hours of wakefulness and the first twenty minutes after bedtime. Overall, this pattern of results seems to suggest that maWI dissipation is comparable to that of maSI.

Neural circuits underpinning face tuning in male depression.

Reading bodies and faces is essential for efficient social interactions, though it may be thought-provoking for individuals with depression. Yet aberrations in the face sensitivity and underwriting neural circuits are not well understood, in particular, in male depression. Here, we use cutting-edge analyses of time course and dynamic topography of gamma oscillatory neuromagnetic cortical activity during administration of a task with Arcimboldo-like images. No difference in face tuning was found between individuals with depression and their neurotypical peers. Furthermore, this behavioral outcome nicely dovetails with magnetoencephalographic data: at early processing stages, the gamma oscillatory response to images resembling a face was rather similar in patients and controls. These bursts originated primarily from the right medioventral occipital cortex and lateral occipital cortex. At later processing stages, however, its topography altered remarkably in depression with profound engagement of the frontal circuits. Yet the primary difference in depressive individuals as compared with their neurotypical peers occurred over the left middle temporal cortices, a part of the social brain, engaged in feature integration and meaning retrieval. The outcome suggests compensatory recruitment of neural resources in male depression.

Modulation of KV4.3-KChIP2 Channels by IQM-266: Role of DPP6 and KCNE2.

The transient outward potassium current (Itof) is generated by the activation of KV4 channels assembled with KChIP2 and other accessory subunits (DPP6 and KCNE2). To test the hypothesis that these subunits modify the channel pharmacology, we analyzed the electrophysiological effects of (3-(2-(3-phenoxyphenyl)acetamido)-2-naphthoic acid) (IQM-266), a new KChIP2 ligand, on the currents generated by KV4.3/KChIP2, KV4.3/KChIP2/DPP6 and KV4.3/KChIP2/KCNE2 channels. CHO cells were transiently transfected with cDNAs codifying for different proteins (KV4.3/KChIP2, KV4.3/KChIP2/DPP6 or KV4.3/KChIP2/KCNE2), and the potassium currents were recorded using the whole-cell patch-clamp technique. IQM-266 decreased the maximum peak of KV4.3/KChIP2, KV4.3/KChIP2/DPP6 and KV4.3/KChIP2/KCNE2 currents, slowing their time course of inactivation in a concentration-, voltage-, time- and use-dependent manner. IQM-266 produced an increase in the charge in KV4.3/KChIP2 channels that was intensified when DPP6 was present and abolished in the presence of KCNE2. IQM-266 induced an activation unblocking effect during the application of trains of pulses to cells expressing KV4.3/KChIP2 and KV4.3/KChIP2/KCNE2, but not in KV4.3/KChIP2/DPP6 channels. Overall, all these results are consistent with a preferential IQM-266 binding to an active closed state of Kv4.3/KChIP2 and Kv4.3/KChIP2/KCNE2 channels, whereas in the presence of DPP6, IQM-266 binds preferentially to an inactivated state. In conclusion, DPP6 and KCNE2 modify the pharmacological response of KV4.3/KChIP2 channels to IQM-266.