Faster Time Course Research Articles

Functional Dynamics and Selectivity of Two Parallel Corticocortical Pathways from Motor Cortex to Layer 5 Circuits in Somatosensory Cortex.

In the rodent whisker system, active sensing and sensorimotor integration are mediated in part by the dynamic interactions between the motor cortex (M1) and somatosensory cortex (S1). However, understanding these dynamic interactions requires knowledge about the synapses and how specific neurons respond to their input. Here, we combined optogenetics, retrograde labeling, and electrophysiology to characterize the synaptic connections between M1 and layer 5 (L5) intratelencephalic (IT) and pyramidal tract (PT) neurons in S1 of mice (both sexes). We found that M1 synapses onto IT cells displayed modest short-term depression, whereas synapses onto PT neurons showed robust short-term facilitation. Despite M1 inputs to IT cells depressing, their slower kinetics resulted in summation and a response that increased during short trains. In contrast, summation was minimal in PT neurons due to the fast time course of their M1 responses. The functional consequences of this reduced summation, however, were outweighed by the strong facilitation at these M1 synapses, resulting in larger response amplitudes in PT neurons than IT cells during repetitive stimulation. To understand the impact of facilitating M1 inputs on PT output, we paired trains of inputs with single backpropagating action potentials, finding that repetitive M1 activation increased the probability of bursts in PT cells without impacting the time dependence of this coupling. Thus, there are two parallel but dynamically distinct systems of M1 synaptic excitation in L5 of S1, each defined by the short-term dynamics of its synapses, the class of postsynaptic neurons, and how the neurons respond to those inputs.

Expression of hyperpolarization-activated current (Ih) in zonally defined vestibular calyx terminals of the crista.

Calyx terminals make afferent synapses with type I hair cells in vestibular epithelia and express diverse ionic conductances that influence action potential generation and discharge regularity in vestibular afferent neurons. Here we investigated the expression of hyperpolarization-activated current (Ih) in calyx terminals in central and peripheral zones of mature gerbil crista slices, using whole cell patch-clamp recordings. Slowly activating Ih was present in >80% calyces tested in both zones. Peak Ih and half-activation voltages were not significantly different; however, Ih activated with a faster time course in peripheral compared with central zone calyces. Calyx Ih in both zones was blocked by 4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride (ZD7288; 100 µM), and the resting membrane potential became more hyperpolarized. In the presence of dibutyryl-cAMP (dB-cAMP), peak Ih was increased, activation kinetics became faster, and the voltage of half-activation was more depolarized compared with control calyces. In current clamp, calyces from both zones showed three different categories of firing: spontaneous firing, phasic firing where a single action potential was evoked after a hyperpolarizing pulse, or a single evoked action potential followed by membrane potential oscillations. In the absence of Ih, the latency to peak of the action potential increased; Ih produces a small depolarizing current that facilitates firing by driving the membrane potential closer to threshold. Immunostaining showed the expression of HCN2 subunits in calyx terminals. We conclude that Ih is found in calyx terminals across the crista and could influence conventional and novel forms of synaptic transmission at the type I hair cell-calyx synapse.NEW & NOTEWORTHY Calyx afferent terminals make synapses with vestibular hair cells and express diverse conductances that impact action potential firing in vestibular primary afferents. Conventional and nonconventional synaptic transmission modes are influenced by hyperpolarization-activated current (Ih), but regional differences were previously unexplored. We show that Ih is present in both central and peripheral calyces of the mammalian crista. Ih produces a small depolarizing resting current that facilitates firing by driving the membrane potential closer to threshold.

The genesis and functional consequences of cortico-subthalamic beta augmentation and excessive subthalamic burst discharges after dopaminergic deprivation

The cardinal electrophysiological signs in Parkinson's disease (PD) include augmented beta oscillations in the motor cortex-subthalamic nucleus (MC-STN) axis and excessive burst discharges in STN. We have shown that excessive STN burst discharges have a direct causal relation with the locomotor deficits in PD. To investigate the correlation between the two cardinal signs, we characterized the courses of development of the electrophysiological abnormalities in the hemiparkinsonian rat model. The loss of dopaminergic neurons develops fast, and is histologically completed within 4–7 days of the lesion. The increase in STN burst discharges is limited to the lesioned side, and follows a very similar course. In contrast, beta augmentation has a bilateral presentation, and requires 14–21 days for full development. Behaviorally, the gross locomotor deficits in open field test and limb akinesia in stepping test match the foregoing fast and slow time courses, respectively. A further look into the spike entrainment shows that the oscillations in local field potential (LFP) of the MC effectively entrain the multi-unit (MU) spikes of MC, STN and entopeduncular nucleus (EPN), a rat homolog of human globus pallidus interna (GPi), whereas the LFP of STN or EPN (GPi) cannot entrain the spikes in MC. We conclude that excessive STN burst discharges are a direct consequence, whereas beta augmentation is probably a secondary or adaptive changes in the cortico-subcortical re-entrant loops, to dopaminergic deprivation. Beta augmentation is therefore not so consistently present as excessive STN burst discharges, but could signal more delicate derangements at the level of cortical programming in PD.

Abstract P3-02-09: Three timepoint pharmacokinetic modeling to incorporate within standard of care MRI breast exams

Abstract Background: Standard of care (SOC) breast MRI exams typically acquire 4-7 frames of dynamic contrast-enhanced MRI (DCE-MRI) for cancer screening and staging. Post-contrast images depict lesion spiculations and boundaries to identify and characterize tumors. Pharmacokinetic (PK) analysis of DCE-MRI involves modeling blood flow to the lesion and surrounding tissue and has shown promise in diagnosis and prediction of therapeutic response. Currently, SOC DCE-MRI requires ~60-90 seconds per volume for images with sufficient quality and spatial resolution. However, PK analysis of DCE-MRI requires faster time course sampling. For this reason, PK modeling is limited to research scans with lower spatial resolution and higher temporal resolution. PK modeling would improve feedback of treatment response, and implementation in the SOC exam would increase imaging trial participation. In this study, we tested the estimation of Ktrans, a mixed perfusion and permeability PK parameter, from three images at optimal time points after contrast agent (CA) injection, and compared it to the Ktrans estimation from analysis of the full-length time course.. Methods: Women (N=23) with newly diagnosed invasive breast cancers who were eligible for neoadjuvant therapy (NAT) were scanned with a research MRI protocol as part of a treatment-monitoring study. Images acquired prior to the start of NAT were used. MRI was performed on 3.0T Siemens Skyra scanners at two sites with bilateral breast coils. The research protocol included ten sagittal slices centered about the primary tumor. The DCE-MRI images came from a fast sequence with 1.3 × 1.3 × 5.0 mm resolution acquired at 7.3 seconds per frame (66 frames total,) with a gadolinium-based CA injected one minute into the scan. A population arterial input function was used to implement a mathematical graph-based search of possible tissue CA concentration curves from the expected range of PK parameters. The search results gave a set of three optimized sub-sampled timepoints, Topt, from the full set of sample times, Tfull, at which to best sample the CA concentration curves to optimally estimate PK values. The imaging data was analyzed to find one parameter map from image times Tfull, and another from the subset of images at times Topt. The difference in Ktrans was computed at each parameter map voxel, and the concordance correlation coefficient (CCC) was computed per patient to determine agreement. The median Ktrans values were also compared for each patient. Results: The graph-based search of CA concentration curves found optimal times Topt of 37, 66, and 153 seconds after injection. The averaged values over all patients for median and maximum Ktrans from the original Tfull image set were 0.07 and 0.5 (min)-1. The average difference in Ktrans values between the Topt and Tfull sets was 0.02 (min)-1. When the median Ktrans values for each patient were compared, the average difference in median Ktrans values was 15% +/- 9%. The concordance correlation coefficients comparing the Topt and Tfull -sampled parameter maps for each patient were 0.89 +/- 0.12, showing high agreement. Discussion: This retrospective analysis suggests that it is possible to estimate PK parameters from a few properly selected post-contrast images inserted into a SOC DCE-MRI exam. The combination of optimal timing with fast acquisition techniques for high-resolution imaging could be used to provide quantitative data while preserving post-contrast images with the necessary spatial resolution for clinical reading. Importantly, the test images were acquired in the community setting with widely available MRI hardware, further indicating the potential for integration with SOC exams. Funding: NCI U24 CA226110, NCI U01 CA174706, NCI U01 CA142565, CPRIT RR160005 Citation Format: Julie C DiCarlo, Angela M Jarrett, Anum S Kazerouni, John Virostko, Anna G Sorace, Kalina P Slavkova, Debra Patt, Boone W Goodgame, Sarah Avery, Thomas E Yankeelov. Three timepoint pharmacokinetic modeling to incorporate within standard of care MRI breast exams [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-02-09.

Introducing an Innovative Method to Treat Spastic Cerebral Palsy with Faster Recovery Time: Post-Achilles Tendon Lengthening with Bandaging

Equinus deformity is one of the most common musculoskeletal deformities of Cerebral Palsy (CP) which is defined as an abnormality in ankle dorsiflexion that can cause severe walking disability. The standard surgical intervention for Equinus deformity is Achilles Tendon Lengthening (ATL) with post-operative leg casting, however in some cases, it requires months of recovery post-operation to regain movement. The objective of this study was to find an alternative to leg casting that would provide a safe and faster time course to recovery. Therefore, we conducted a semi-experimental clinical trial study of a population that included 62 CP patients between the ages of 6 - 15 years of age with diplegia, hemiplegia, or quadriplegia that randomly underwent ATL followed by subsequent leg casting (control, 32 patients) or bandage and ankle-foot orthosis (AFO; experimental, 30 patients). Patients were periodically evaluated for mobility and walking ability pre-operation and at 2 weeks post- operation, 6 weeks post-operation, and then every month for 6 months. We found that all 32 patients in the experimental group regained their walking ability within two weeks (100%), while majority of patients in the control group (84%) regained their walking ability after 4 - 6 weeks, regardless of CP type. We also found that on 6-month follow-up, progression of walking abilities was similar in both groups. Rupture of the repaired tendon was not observed in any of the participants in either group. This study suggests applying a bandage with a foot or ankle orthosis as an alternative to long leg cast in children of 15 years of age or younger with CP treated with ATL for Equinus deformity to facilitate faster post-operative recovery. It also recommends follow-up studies on confounding factors, categorization of pre- and post-operative range of movement, and post-op complications with longer follow up while treating CP patient with ATL followed by AFO.

Serotonergic control of GABAergic inhibition in the lateral amygdala.

Much evidence implicates the serotonergic regulation of the amygdala in anxiety. Thus the present study was undertaken to characterize the influence of serotonin (5-HT) on principal neurons (PNs) of the rat lateral amygdala (LA), using whole cell recordings in vitro. Because inhibition is a major determinant of PN activity, we focused on the control of GABAergic transmission by 5-HT. IPSCs were elicited by local electrical stimulation of LA in the presence of glutamate receptor antagonists. We found that 5-HT reduces GABAA inhibitory postsynaptic currents (IPSCs) via presynaptic 5-HT1B receptors. While the presynaptic inhibition of GABA release also attenuated GABAB currents, this effect was less pronounced than for GABAA currents because 5-HT also induced a competing postsynaptic enhancement of GABAB currents. That is, GABAB currents elicited by pressure application of GABA or baclofen were enhanced by 5-HT. In addition, we obtained evidence suggesting that 5-HT differentially regulates distinct subsets of GABAergic synapses. Indeed, GABAA IPSCs were comprised of two components: a relatively 5-HT-insensitive IPSC that had a fast time course and a 5-HT-sensitive component that had a slower time course. Because the relative contribution of these two components varied depending on whether neurons were recorded at proximity versus at a distance from the stimulating electrodes, we speculate that distinct subtypes of local-circuit cells contribute the two contingents of GABAergic synapses. Overall, our results indicate that 5-HT is a potent regulator of synaptic inhibition in LA.NEW & NOTEWORTHY We report that 5-HT, acting via presynaptic 5-HT1B receptors, attenuates GABAA IPSCs by reducing GABA release in the lateral amygdala (LA). In parallel, 5-HT enhances GABAB currents postsynaptically, such that GABAB inhibitory postsynaptic currents (IPSCs) are relatively preserved from the presynaptic inhibition of GABA release. We also found that the time course of 5-HT-sensitive and -insensitive GABAA IPSCs differ. Together, these results indicate that 5-HT is a potent regulator of synaptic inhibition in LA.

Depletion of plasma membrane–associated phosphoinositides mimics inhibition of TRPM7 channels by cytosolic Mg2+, spermine, and pH

Transient receptor potential cation channel subfamily M member 7 (TRPM7) is an ion channel/protein kinase belonging to the TRP melastatin and eEF2 kinase families. Under physiological conditions, most native TRPM7 channels are inhibited by cytoplasmic Mg2+, protons, and polyamines. Currents through these channels (ITRPM7) are robustly potentiated when the cell interior is exchanged with low Mg2+-containing buffers. ITRPM7 is also potentiated by phosphatidyl inositol bisphosphate (PI(4,5)P2) and suppressed by its hydrolysis. Here we characterized internal Mg2+- and pH-mediated inhibition of TRPM7 channels in HEK293 cells overexpressing WT voltage-sensing phospholipid phosphatase (VSP) or its catalytically inactive variant VSP-C363S. VSP-mediated depletion of membrane phosphoinositides significantly increased channel sensitivity to Mg2+ and pH. Proton concentrations that were too low to inhibit ITRPM7 when the VSP-C363S variant was expressed (pH 8.2) became inhibitory in WT VSP–expressing cells. At pH 6.5, protons inhibited ITRPM7 both in WT and VSP C363S–expressing cells but with a faster time course in the WT VSP–expressing cells. Inhibition by 150 μm Mg2+ was also significantly faster in the WT VSP–expressing cells. Cellular PI(4,5)P2 depletion increased the sensitivity of TRPM7 channels to the inhibitor 2-aminoethyl diphenyl borinate, which acidifies the cytosol. Single substitutions at Ser-1107 of TRPM7, reducing its sensitivity to Mg2+, also decreased its inhibition by spermine and acidic pH. Furthermore, these channel variants were markedly less sensitive to VSP-mediated PI(4,5)P2 depletion than the WT. We conclude that the internal Mg2+-, polyamine-, and pH-mediated inhibition of TRPM7 channels is not direct but, rather, reflects electrostatic screening and resultant disruption of PI(4,5)P2–channel interactions.

In vivo observation of transient photoreceptor movement correlated with oblique light stimulation.

Rod-dominated transient retinal phototropism (TRP) has been observed in freshly isolated retinas, promising a noninvasive biomarker for high resolution assessment of retinal physiology. However, in vivo mapping of TRP is challenging due to its fast time course and sub-cellular signal magnitude. By developing a line-scanning and virtually structured detection based super-resolution ophthalmoscope, we report here in vivo observation of TRP in frog retina. In vivo characterization of TRP time course and magnitude were implemented by using variable light stimulus intensities.

A perspective on Na and K channel inactivation.

We are wired with conducting cables called axons that rapidly transmit electrical signals (e.g., "Ouch!") from, for example, the toe to the spinal cord. Because of the high internal resistance of axons (salt water rather than copper), a signal must be reinforced after traveling a short distance. Reinforcement is accomplished by ion channels, Na channels for detecting the signal and reinforcing it by driving it further positive (to near 50 mV) and K channels for then restoring it to the resting level (near -70 mV). The signal is called an action potential and has a duration of roughly a millisecond. The return of membrane voltage (Vm) to the resting level after an action potential is facilitated by "inactivation" of the Na channels: i.e., an internal particle diffuses into the mouth of any open Na channel and temporarily blocks it. Some types of K channels also show inactivation after being open for a time. N-type inactivation of K channels has a relatively fast time course and involves diffusion of the N-terminal of one of the channel's four identical subunits into the channel's inner mouth, if it is open. This mechanism is similar to Na channel inactivation. Both Na and K channels also display slower inactivation processes. C inactivation in K channels involves changes in the channel's outer mouth, the "selectivity filter," whose normal function is to prevent Na+ ions from entering the K channel. C inactivation deforms the filter so that neither K+ nor Na+ can pass.

Beauty in the blink of an eye: The time course of aesthetic experiences.

Under normal circumstances, perception runs very fast and seemingly automatic. In just a few ms, we go from sensory features to perceiving objects. This fast time course does not only apply to general perceptual aspects but also to what we call higher-level judgements. Inspired by the study on 'very first impressions' by Bar, Neta, and Linz (2006, Emotion, 6, 269) the current research examined the speed and time course of three aspects of the aesthetic experience, namely beauty, specialness, and impressiveness. Participants were presented with 54 reproductions of paintings that covered a wide variety of artistic styles and contents. Presentation times were 10, 50, 100 and 500ms in Experiment 1 and 20, 30 and 40ms in Experiment 2. Our results not only show that consistent aesthetic judgements can be formed based on very brief glances of information, but that this speed of aesthetic impression formation also differs between different aesthetic judgements. Apparently, impressiveness judgements require longer exposure times than impressions of beauty or specialness. The results provide important evidence for our understanding of the time course of aesthetic experiences.

Compliance Accelerates Relaxation in Muscle by Allowing Myosin Heads to Move Relative to Actin

The mechanisms that limit the speed at which striated muscles relax are poorly understood. This work presents, to our knowledge, novel simulations that show that the time course of relaxation is accelerated by interfilamentary movement resulting from series compliance; force drops faster when myosin heads move relative to actin during relaxation. This insight was obtained by using cross-bridge distribution techniques to simulate the mechanical behavior of half-sarcomeres that were connected in series with springs of varying stiffness. (The springs mimic the combined effects of half-sarcomere heterogeneity and muscle’s series elastic component.) Half-sarcomeres that shortened by >∼10 nm when they were activated subsequently relaxed with a biphasic profile; force initially declined slowly and approximately linearly before collapsing with a fast exponential time course. Stretches imposed during the linear phase quickened relaxation, while shortening movements prolonged the time course. These predictions are consistent with data from experiments performed by many other groups using single muscle fibers and isolated myofibrils. When half-sarcomeres were linked to stiff springs (so that they did not shorten appreciably during the simulations), force relaxed with a slow exponential time course and did not show biphasic behavior. Together, these results suggest that fast relaxation of striated muscle is an emergent property that reflects multiscale interactions within the muscle architecture. The nonlinear behavior during relaxation reflects perturbations to the dynamic coupling of regulated binding sites and cycling myosin heads that are induced by interfilamentary movement.

Chronic and progressive Parkinson's disease MPTP model in adult and aged mice.

Despite the different animal models of Parkinson's disease developed during the last years, they still present limitations modelling the slow and progressive process of neurodegeneration. Here, we undertook a histological, neurochemical and behavioural analysis of a new chronic parkinsonian mouse model generated by the subcutaneous administration of low doses of MPTP (20mg/kg, 3 times per week) for 3months, using both young adult and aged mice. The MPTP-induced nigrostriatal neurodegeneration was progressive and was accompanied by a decrease in striatal dopamine levels and motor impairment. We also demonstrated the characteristic neuroinflammatory changes (microglial activation and astrogliosis) associated with the neurodegenerative process. Aged animals showed both a faster time course of neurodegeneration and an altered neuroinflammatory response. The long-term systemic application of low MPTP doses did not induce any increase in mortality in either young adult or aged mice and better resembles the slow evolution of the neurodegenerative process. This treatment could be useful to model different stages of Parkinson's disease, providing a better understanding of the pathophysiology of the disease and facilitating the testing of both protective and restorative treatments. Here, we show a new chronic and progressive parkinsonian mouse model, in young and aged mice. This model produces a stable degeneration of the dopaminergic nigrostriatal pathway, continuous neuroinflammatory reaction and motor deficits. Aged animals showed a faster neurodegeneration and an altered neuroinflammatory response. This treatment could be useful to model different stages of PD and to test both protective and restorative therapeutic approaches.

Electrocardiographic Pad for Efficient Cardiac MR Gating.

To assess feasibility and reliability of electrocardiographic (ECG)-gated cardiac magnetic resonance (MR) imaging with a simplified reusable electrode design that does not touch the skin. In this institutional review board-approved, HIPAA-compliant study, a silicon positioner held four ECG leads and detected ECG signals without requiring shaving, adhesive, or removal of the gown. The patient lies down on the device and the patient's weight ensures good lead contact against patient's gown; electrode gel that soaks through the gown provides electrical contact with the skin. It was tested at 1.5 T on 12 volunteers and 52 patients by using double inversion recovery, steady-state, fast gradient-echo time course perfusion, and delayed inversion recovery sequences. Paired Student t test was used to assess the significance of differences in durations to apply and remove ECG pad and standard leads. Image quality was assessed and rated on a four-point scale by two readers. The ECG signal quality obtained from pad and leads was rated on a five-point scale. Ventricular septal sharpness and signal-to-noise ratio were measured on images generated by ECG gating from pads and standard leads. Application and removal duration was 444 seconds with standard leads compared with 296 seconds with the ECG pad, and mean difference in setup time was 148 seconds (P = .005). Ventricular septal sharpness (1/slope) was 165 for ECG pad and 152 for standard leads (P = .3). Septal signal-to-noise ratio on images generated by cardiac gating with ECG pad was 38 ± 12 (standard deviation) compared with 39 ± 14 for standard leads (P = .7). The qualitative image quality score for ECG pad (3.9 ± 0.19) was comparable to ECG leads (3.8 ± 0.45; P = .47). The mean ECG signal qualitative scores were also comparable (pad vs leads, 4.9 ± 0.43 vs 4.9 ± 0.14, respectively; P = .9). Volunteers preferred the ECG pad and reported that it was comfortable and convenient. ECG pad was successful in 50 of 52 (96%) patients. Two patients, including one with large pleural effusions and another with ventricular tachycardia, were not successfully gated. This simplified approach to ECG gating is faster to set up and more convenient and comfortable for patients.

Adaptation in the visual cortex: influence of membrane trajectory and neuronal firing pattern on slow afterpotentials.

The input/output relationship in primary visual cortex neurons is influenced by the history of the preceding activity. To understand the impact that membrane potential trajectory and firing pattern has on the activation of slow conductances in cortical neurons we compared the afterpotentials that followed responses to different stimuli evoking similar numbers of action potentials. In particular, we compared afterpotentials following the intracellular injection of either square or sinusoidal currents lasting 20 seconds. Both stimuli were intracellular surrogates of different neuronal responses to prolonged visual stimulation. Recordings from 99 neurons in slices of visual cortex revealed that for stimuli evoking an equivalent number of spikes, sinusoidal current injection activated a slow afterhyperpolarization of significantly larger amplitude (8.5±3.3 mV) and duration (33±17 s) than that evoked by a square pulse (6.4±3.7 mV, 28±17 s; p<0.05). Spike frequency adaptation had a faster time course and was larger during plateau (square pulse) than during intermittent (sinusoidal) depolarizations. Similar results were obtained in 17 neurons intracellularly recorded from the visual cortex in vivo. The differences in the afterpotentials evoked with both protocols were abolished by removing calcium from the extracellular medium or by application of the L-type calcium channel blocker nifedipine, suggesting that the activation of a calcium-dependent current is at the base of this afterpotential difference. These findings suggest that not only the spikes, but the membrane potential values and firing patterns evoked by a particular stimulation protocol determine the responses to any subsequent incoming input in a time window that spans for tens of seconds to even minutes.

Local and long-range phase-amplitude coupling in a cortical spiking network model

Phase-amplitude coupling (PAC) between neural oscillations in different frequency bands has been observed in population recordings of the hippocampus and neocortex [1,2]. Specifically, bursts of gamma (>30 Hz) oscillations are often found to be phase-locked to a slower oscillation in the theta range (4-8 Hz), raising questions about the mechanisms and computational consequences of this pattern. Recently, inter-areal gamma synchronization was also found to be systematically modulated by theta rhythms [3]. We study mechanisms for these experimental findings and their potential role in long-range inter-areal coupling using spiking neuron network models. Using dynamical systems theory, bursting has previously been analyzed in detail for single neuron dynamics [4], requiring interaction of fast and slow adapting variables, driving the neuron through alternations of active (limit cycle) and resting (stable equilibrium) periods. On the population level, bursting can be studied within the same framework, treating average synaptic activity and time courses as slow/fast variables. Our model (Panel A) is based on observations of dynamically distinct interneuron populations in the cortex, namely fast-spiking, non-adapting (FS) and adapting interneurons (low-threshold spiking, LTS) exhibiting fast and slow synaptic time courses [5]. Coupled with a population of principal cells (regular spiking, RS), this network displays spontaneous phase-amplitude coupling as sparsely synchronized population bursts. Feed-forward connections between populations of this type lead to theta modulated gamma synchronization (Panel B and C). We study in detail the parameter range/bifurcations of this model. Considering that in-vivo neural circuits are generally only sparsely synchronized, we contrast oscillatory patterns on the population level with stochastic firing of single neurons. Figure 1 Local and long-range phase-amplitude coupling in a cortical spiking network model A) Schematic showing two populations of 1,000 spiking neurons and connections on the population level. Intra-/inter-areal connections are shown in black/blue respectively. ...

Kv4 channels underlie A-currents with highly variable inactivation time courses but homogeneous other gating properties in the nucleus tractus solitarii.

In the nucleus of the tractus solitarii (NTS), a large proportion of neurones express transient A-type potassium currents (I KA) having deep influence on the fidelity of the synaptic transmission of the visceral primary afferent inputs to second-order neurones. Up to now, the strong impact of I KA within the NTS was considered to result exclusively from its variation in amplitude, and its molecular correlate(s) remained unknown. In order to identify which Kv channels underlie I KA in NTS neurones, the gating properties and the pharmacology of this current were determined using whole cell patch clamp recordings in slices. Complementary information was brought by immunohistochemistry. Strikingly, two neurone subpopulations characterized by fast or slow inactivation time courses (respectively about 50 and 200 ms) were discriminated. Both characteristics matched those of the Kv4 channel subfamily. The other gating properties, also matching the Kv4 channel ones, were homogeneous through the NTS. The activation and inactivation occurred at membrane potentials around the threshold for generating action potentials, and the time course of recovery from inactivation was rapid. Pharmacologically, I KA in NTS neurones was found to be resistant to tetraethylammonium (TEA), sea anemone toxin blood-depressing substance (BDS) and dendrotoxin (DTX), whereas Androctonus mauretanicus mauretanicus toxin 3 (AmmTX3), a scorpion toxin of the α-KTX 15 family that has been shown to block all the members of the Kv4 family, inhibited 80 % of I KA irrespectively of its inactivation time course. Finally, immunohistochemistry data suggested that, among the Kv4 channel subfamily, Kv4.3 is the prevalent subunit expressed in the NTS.

Time courses of central hemodynamics during rapid changes in posture

Changes in posture cause blood volume redistribution, affecting cardiac filling and stroke volume (SV). We hypothesized that the time courses of ventricular filling would differ between the right and left ventricle during a rapid (2 s) tilt and that changes in right ventricular filling pressure would be more swift because of the direct coupling to the systemic circulation. We further hypothesized that the transient imbalance between right and left ventricular filling pressure would influence left ventricular SV changes. Right atrial pressure (RAP), pulmonary capillary wedge pressure (PCWP), left ventricular stroke volume, heart rate, and arterial pressure were recorded beat-by-beat during rapid tilts from supine to upright positions and back again, during rest and dynamic 100-W leg exercise. RAP changes had a faster time course than PCWP during down-tilts, both during rest and exercise (1 ± 1 vs. 6 ± 2 s and 2 ± 2 vs. 6 ± 2 s, respectively; P < 0.05). This discrepancy caused a transient decrease in the end-diastolic pressure difference between the right and left ventricle. The decreased pressure difference in diastole impeded left ventricular filling because of ventricular interdependence, causing SV to fall transiently. The mechanisms of ventricular interdependence were also involved in reverse during up-tilt, where SV was maintained for 2-3 s despite falling PCWP. Furthermore, the decrease in RAP during up-tilt in the resting condition was biphasic with an initial fast and a second slower component, which might suggest the effect of venous valves. This was not seen during dynamic leg exercise where blood pooling is prevented by the venous muscle pump.

Anti-allodynic effect of 2-(aminomethyl)adamantane-1-carboxylic acid in a rat model of neuropathic pain: A mechanism dependent on CaV2.2 channel inhibition

Neuropathic pain is a serious physical disabling condition resulting from lesion or dysfunction of the peripheral sensory nervous system. Despite the fact that the mechanisms underlying neuropathic pain are poorly understood, the involvement of voltage-gated calcium (CaV) channels in its pathophysiology has justified the use of drugs that bind the CaV channel α2δ auxiliary subunit, such as gabapentin (GBP), to attain analgesic and anti-allodynic effects in models involving neuronal sensitization and nerve injury. GBP binding to α2δ inhibits nerve injury-induced trafficking of the α1 pore forming subunits of CaV channels, particularly of the N-type, from the cytoplasm to the plasma membrane of pre-synaptic terminals in dorsal root ganglion neurons and dorsal horn spinal neurons. In the search for alternative forms of treatment, in this study we describe the synthesis and pharmacological profile of a GABA derivative, 2-aminoadamantane-1-carboxylic acid (GZ4), which displays a close structure–activity relationship with GBP. Behavioral assessment using von Frey filament stimuli showed that GZ4 treatment reverted mechanical allodynia/hyperalgesia in an animal model of spinal nerve ligation-induced neuropathic pain. In addition, using the patch clamp technique we show that GZ4 treatment significantly decreased whole-cell currents through N-type CaV channels heterologously expressed in HEK-293 cells. Interestingly, the behavioral and electrophysiological time course of GZ4 actions reflects that its mechanism of action is similar but not identical to that of GBP. While GBP actions require at least 24h and imply uptake of the drug, which suggests that the drug acts mainly intracellularly affecting channels trafficking to the plasma membrane, the faster time course (1–3h) of GZ4 effects suggests also a direct inhibition of Ca2+ currents acting on cell surface channels.

β-adrenergic stimulation activates early afterdepolarizations transiently via kinetic mismatch of PKA targets

Sympathetic stimulation regulates cardiac excitation–contraction coupling in hearts but can also trigger ventricular arrhythmias caused by early afterdepolarizations (EADs) in pathological conditions. Isoproterenol (ISO) stimulation can transiently cause EADs which could result from differential kinetics of L-type Ca current (ICaL) vs. delayed rectifier potassium current (IKs) effects, but multiple PKA targets complicate mechanistic analysis. Utilizing a biophysically detailed model integrating Ca and β-adrenergic signaling, we investigate how different phosphorylation kinetics and targets influence β-adrenergic-induced transient EADs. We found that: 1) The faster time course of ICaL vs. IKs increases recapitulates experimentally observed ISO-induced transient EADs (which are due to ICaL reactivation). These EADs disappear at steady state ISO and do not occur during more gradual ISO application. 2) This ICaL vs. IKs kinetic mismatch with ISO can also induce transient EADs due to spontaneous sarcoplasmic reticulum (SR) Ca release and Na/Ca exchange current. The increased ICaL, SR Ca uptake and action potential duration (APD) raise SR Ca to cause spontaneous SR Ca release, but eventual IKs activation and APD shortening abolish these EADs. 3) Phospholemman (PLM) phosphorylation decreases both types of EADs by increasing outward Na/K-ATPase current (INaK) for ICaL-mediated EADs, and reducing intracellular Na and Ca loading for SR Ca-release-mediated EADs. Slowing PLM phosphorylation kinetics abolishes this protective effect. 4) Blocking phospholamban (PLB) phosphorylation has little effect on ICaL-mediated transient EADs, but abolishes SR Ca-release-mediated transient EADs by limiting SR Ca loading. 5) RyR phosphorylation has little effect on either transient EAD type. Our study emphasizes the importance of understanding non-steady state kinetics of several systems in mediating β-adrenergic-induced EADs and arrhythmias. This article is part of a Special Issue entitled "Calcium Signaling in Heart".

What Determines the Kinetics of the Slow Afterhyperpolarization (sAHP) in Neurons?

What Determines the Kinetics of the Slow Afterhyperpolarization (sAHP) in Neurons?