Threshold Neurons Research Articles

Novel quantum inspired binary neural network algorithm

In this paper, a quantum based binary neural network algorithm is proposed, named as novel quantum binary neural network algorithm (NQ-BNN). It forms a neural network structure by deciding weights and separability parameter in quantum based manner. Quantum computing concept represents solution probabilistically and gives large search space to find optimal value of required parameters using Gaussian random number generator. The neural network structure forms constructively having three number of layers input layer: hidden layer and output layer. A constructive way of deciding the network eliminates the unnecessary training of neural network. A new parameter that is a quantum separability parameter (QSP) is introduced here, which finds an optimal separability plane to classify input samples. During learning, it searches for an optimal separability plane. This parameter is taken as the threshold of neuron for learning of neural network. This algorithm is tested with three benchmark datasets and produces improved results than existing quantum inspired and other classification approaches.

Single neuron transcriptomics identify SRSF/SR protein B52 as a regulator of axon growth and Choline acetyltransferase splicing

We removed single identified neurons from living Drosophila embryos to gain insight into the transcriptional control of developing neuronal networks. The microarray analysis of the transcriptome of two sibling neurons revealed seven differentially expressed transcripts between both neurons (threshold: log21.4). One transcript encodes the RNA splicing factor B52. Loss of B52 increases growth of axon branches. B52 function is also required for Choline acetyltransferase (ChAT ) splicing. At the end of embryogenesis, loss of B52 function impedes splicing of ChAT, reduces acetylcholine synthesis, and extends the period of uncoordinated muscle twitches during larval hatching. ChAT regulation by SRSF proteins may be a conserved feature since changes in SRSF5 expression and increased acetylcholine levels in brains of bipolar disease patients have been reported recently.

Regulation of Nociceptive Plasticity Threshold and DARPP-32 Phosphorylation in Spinal Dorsal Horn Neurons by Convergent Dopamine and Glutamate Inputs.

Dopamine can influence NMDA receptor function and regulate glutamate-triggered long-term changes in synaptic strength in several regions of the CNS. In spinal cord, regulation of the threshold of synaptic plasticity may determine the proneness to undergo sensitization and hyperresponsiveness to noxious input. In the current study, we increased endogenous dopamine levels in the dorsal horn by using re-uptake inhibitor GBR 12935. During the so-induced hyperdopaminergic transmission, conditioning low-frequency (1 Hz) stimulation (LFS) to the sciatic nerve induced long-term potentiation (LTP) of C-fiber-evoked potentials in dorsal horn neurons. The magnitude of LTP was attenuated by blockade of either dopamine D1-like receptors (D1LRs) by with SCH 23390 or NMDA receptor subunit NR2B with antagonist Ro25-6981. Conditioning LFS during GBR 12935 administration increased phosphorylation of dopamine- and cAMP-regulated phosphoprotein of Mr 32kDa (DARPP-32) at threonine 34 residue in synaptosomal (P3) fraction of dorsal horn homogenates, as assessed by Western blot analysis, which was partially prevented by NR2B blockade prior to conditioning stimulation. Conditioning LFS also was followed by higher co-localization of phosphorylated form of NR2B at tyrosine 1472 and pDARPP-32Thr34- with postsynaptic marker PSD-95 in transverse L5 dorsal horn sections. Such increase could be significantly attenuated by D1LR blockade with SCH 23390. The current results support that coincidental endogenous recruitment of D1LRs and NR2B in dorsal horn synapses plays a role in regulating afferent-induced nociceptive plasticity. Parallel increases in DARPP-32 phosphorylation upon LTP induction suggests a role for this phosphoprotein as intracellular detector of convergent D1L- and NMDA receptor activation.

Two different avian cold-sensitive sensory neurons: Transient receptor potential melastatin 8 (TRPM8)-dependent and -independent activation mechanisms

Sensing the ambient temperature is an important function for survival in animals. Some TRP channels play important roles as detectors of temperature and irritating chemicals. There are functional differences of TRP channels among species. TRPM8 in mammals is activated by cooling compounds and cold temperature, but less information is available on the functional role of TRPM8 in avian species. Here we investigated the pharmacological properties and thermal sensitivities of chicken TRPM8 (cTRPM8) and cold-sensitive mechanisms in avian sensory neurons. In heterologously expressed cTRPM8, menthol and its derivative, WS-12 elicited [Ca2+]i increases, but icilin did not. In chicken sensory neurons, icilin increased [Ca2+]i, in a TRPA1-dependent manner. Icilin selectively stimulated heterologously expressed chicken TRPA1 (cTRPA1). Similar to mammalian orthologue, cTRPM8 was activated by cold. Both heterologous and endogenous expressed cTRPM8 were sensitive to mammalian TRPM8 antagonists. There are two types of cold-sensitive cells regarding menthol sensitivity in chicken sensory neurons. The temperature threshold of menthol-insensitive neurons was significantly lower than that of menthol-sensitive ones. The population of menthol-insensitive neurons was large in chicken but almost little in mammals. The cold-induced [Ca2+]i increases were not abolished by the external Ca2+ removal or by blockades of PLC-IP3 pathways and ryanodine channels. The cold stimulation failed to evoke [Ca2+]i increases after intracellular Ca2+ store-depletion. These results indicate that cTRPM8 acts as a cold-sensor similar to mammals. It is noteworthy that TRPM8-independent cold-sensitive neurons are abundant in chicken sensory neurons. Our results suggest that most of the cold-induced [Ca2+]i increases are mediated via Ca2+ release from intracellular stores and that these mechanisms may be specific to avian species.

Regulation of intracellular heme trafficking revealed by subcellular reporters

Heme is an essential prosthetic group in proteins that reside in virtually every subcellular compartment performing diverse biological functions. Irrespective of whether heme is synthesized in the mitochondria or imported from the environment, this hydrophobic and potentially toxic metalloporphyrin has to be trafficked across membrane barriers, a concept heretofore poorly understood. Here we show, using subcellular-targeted, genetically encoded hemoprotein peroxidase reporters, that both extracellular and endogenous heme contribute to cellular labile heme and that extracellular heme can be transported and used in toto by hemoproteins in all six subcellular compartments examined. The reporters are robust, show large signal-to-background ratio, and provide sufficient range to detect changes in intracellular labile heme. Restoration of reporter activity by heme is organelle-specific, with the Golgi and endoplasmic reticulum being important sites for both exogenous and endogenous heme trafficking. Expression of peroxidase reporters in Caenorhabditis elegans shows that environmental heme influences labile heme in a tissue-dependent manner; reporter activity in the intestine shows a linear increase compared with muscle or hypodermis, with the lowest heme threshold in neurons. Our results demonstrate that the trafficking pathways for exogenous and endogenous heme are distinct, with intrinsic preference for specific subcellular compartments. We anticipate our results will serve as a heuristic paradigm for more sophisticated studies on heme trafficking in cellular and whole-animal models.

Serotonin Application Effects on Electrical Characteristics of the Premotor Interneurons in Intact and Trained Snails

Experimentally, it was shown that the action potential threshold in neurons of the trained snails increases in response to serotonin (5-HT) application, in contrast to intact snails. This result demonstrates a decrease of excitability of the premotor interneurons in response to extracellular 5-HT after the training.

Spike-Threshold Variability Originated from Separatrix-Crossing in Neuronal Dynamics.

The threshold voltage for action potential generation is a key regulator of neuronal signal processing, yet the mechanism of its dynamic variation is still not well described. In this paper, we propose that threshold phenomena can be classified as parameter thresholds and state thresholds. Voltage thresholds which belong to the state threshold are determined by the ‘general separatrix’ in state space. We demonstrate that the separatrix generally exists in the state space of neuron models. The general form of separatrix was assumed as the function of both states and stimuli and the previously assumed threshold evolving equation versus time is naturally deduced from the separatrix. In terms of neuronal dynamics, the threshold voltage variation, which is affected by different stimuli, is determined by crossing the separatrix at different points in state space. We suggest that the separatrix-crossing mechanism in state space is the intrinsic dynamic mechanism for threshold voltages and post-stimulus threshold phenomena. These proposals are also systematically verified in example models, three of which have analytic separatrices and one is the classic Hodgkin-Huxley model. The separatrix-crossing framework provides an overview of the neuronal threshold and will facilitate understanding of the nature of threshold variability.

A Multi-Hop Clustering Fusion Routing on Water Environment Wireless Sensor Network

Sensor technology has been used in water environment, which comes into being a water environment wireless sensor monitoring network. Monitoring data in the network slowly change, so we propose a geographical energy-efficient multi-hop clustering fusion routing algorithm based on multilayer perceptron (MLP-GEEMHCFR) in this paper to reduce transmittingdata and save the network energy.The algorithm is implemented by initialization phase, stabilization phase and data fusion phase. A multilayer perceptron (MLP) neuronal function model is designed in the data fusion stage using the MLP, and effect of neuron thresholds on the algorithm fusion efficiency is analyzed in detail. The simulation results show that the performance of the MLP-GEEMHCFR is better than a geographical energy-efficient multi-hop clustering routing (GEEMHCR) algorithm without fusion. The data fusion efficiency increases with the neuron threshold.But when the neuron threshold is up to 1 or more, the increasing trend becomesslowly.

Roles for Coincidence Detection in Coding Amplitude-Modulated Sounds.

Many sensory neurons encode temporal information by detecting coincident arrivals of synaptic inputs. In the mammalian auditory brainstem, binaural neurons of the medial superior olive (MSO) are known to act as coincidence detectors, whereas in the lateral superior olive (LSO) roles of coincidence detection have remained unclear. LSO neurons receive excitatory and inhibitory inputs driven by ipsilateral and contralateral acoustic stimuli, respectively, and vary their output spike rates according to interaural level differences. In addition, LSO neurons are also sensitive to binaural phase differences of low-frequency tones and envelopes of amplitude-modulated (AM) sounds. Previous physiological recordings in vivo found considerable variations in monaural AM-tuning across neurons. To investigate the underlying mechanisms of the observed temporal tuning properties of LSO and their sources of variability, we used a simple coincidence counting model and examined how specific parameters of coincidence detection affect monaural and binaural AM coding. Spike rates and phase-locking of evoked excitatory and spontaneous inhibitory inputs had only minor effects on LSO output to monaural AM inputs. In contrast, the coincidence threshold of the model neuron affected both the overall spike rates and the half-peak positions of the AM-tuning curve, whereas the width of the coincidence window merely influenced the output spike rates. The duration of the refractory period affected only the low-frequency portion of the monaural AM-tuning curve. Unlike monaural AM coding, temporal factors, such as the coincidence window and the effective duration of inhibition, played a major role in determining the trough positions of simulated binaural phase-response curves. In addition, empirically-observed level-dependence of binaural phase-coding was reproduced in the framework of our minimalistic coincidence counting model. These modeling results suggest that coincidence detection of excitatory and inhibitory synaptic inputs is essential for LSO neurons to encode both monaural and binaural AM sounds.

Adaptive Spike Threshold Enables Robust and Temporally Precise Neuronal Encoding.

Neural processing rests on the intracellular transformation of information as synaptic inputs are translated into action potentials. This transformation is governed by the spike threshold, which depends on the history of the membrane potential on many temporal scales. While the adaptation of the threshold after spiking activity has been addressed before both theoretically and experimentally, it has only recently been demonstrated that the subthreshold membrane state also influences the effective spike threshold. The consequences for neural computation are not well understood yet. We address this question here using neural simulations and whole cell intracellular recordings in combination with information theoretic analysis. We show that an adaptive spike threshold leads to better stimulus discrimination for tight input correlations than would be achieved otherwise, independent from whether the stimulus is encoded in the rate or pattern of action potentials. The time scales of input selectivity are jointly governed by membrane and threshold dynamics. Encoding information using adaptive thresholds further ensures robust information transmission across cortical states i.e. decoding from different states is less state dependent in the adaptive threshold case, if the decoding is performed in reference to the timing of the population response. Results from in vitro neural recordings were consistent with simulations from adaptive threshold neurons. In summary, the adaptive spike threshold reduces information loss during intracellular information transfer, improves stimulus discriminability and ensures robust decoding across membrane states in a regime of highly correlated inputs, similar to those seen in sensory nuclei during the encoding of sensory information.

Role of colonic mast cell infiltration and nerve growth factor in visceral hypersensitivity of irritable bowel syndrome

Objective To investigate the role of mucosal mast cells infiltration and degranulation with nerve growth factor (NGF) in development of visceral hypersensitivity in Sprague-Dawley (SD) rats. Methods The model of visceral hypersensitivity of irritable bowel syndrome (IBS) was established in 19 neonate SD rats with intestinal stimulation (rectalballon distention) on 8th, 10th and 12th postnatal days. The other 19 neonate SD rats without colonic distention were assigned to the control group. After rats grew up (six to eight weeks old), the visceral sensitivity was tested by abdominal withdrawal reflex (AWR) in 10 rats of each group. Mast cell infiltration and degranulation were observed with toluidine blue staining in colon tissue slides. The NGF level of intestinal tissues was detected by enzyme-linked immunosorbent assay (ELISA) methods in the left nine rats of each group. The culture system of dorsal root ganglias (DRG) from the neonatal rats was set up. The changes of electrophysilogical characters of DRG stimulated with NGF (100 ng/mL) for four days were recorded with patch-clamp.Paired t test was performed for comparison between groups. Results The results of AWR indicated that neonatal colonic stimulation could significantly increase visceral sensitivity after growing up. Under 20, 40 and 60 mmHg (1 mmHg=0.133 kPa) distention pressure, visceral sensitivity scores of visceral hypersensitivity rats and rats of control group were 1.00±0.50 vs 1.67±0.50, 1.89±0.31 vs 2.89±0.34 and 2.89±0.33 vs 3.89±0.33, the differences were statistically significant (t=-2.83, -6.00 and -6.00, all P<0.05). The results of master cells staining in tissue slides showed colonic master cells infiltration was obvious in rats with visceral hypersensitivity, and part of mast cells were degranulation. The result of ELISA demonstrated that NGF level of visceral hypersensitivity rats was significantly higher than that of control group ((11.07±3.06) pg/mg vs (2.38±1.88) pg/mg, t=-6.93, P<0.05). The results of electrophysilogical tests of primary cultured DRG indicated that compared with blank control growp, the action potential threshold of neuron in NGF 100 ng/mL group significantly decreased ((-18.0±2.1) mV vs (-29.0±2.5) mV, t=12.26, P<0.05) and discharge frequency increased ((5.0±1.4)/800 ms vs (12.0±3.2)/800 ms, t=-8.40, P<0.05). Meanwhile, neuron voltage-gated K+ current density remarkably decreased, most were sustained delayed rectifier K+ current (IK) decreasing ((279.0±48.0) pA/pF vs (203.0±39.0) pA/pF, t=6.18, P<0.05). Conclusion Colonic stimulation in neonatal rats could cause intestinal master cells infiltration and degranulation, which induced changes of neuron electrophysilogical characters and resulted in visceral hypersensitivity after growing up. Key words: Irritable bowel syndrome; Hyperesthesia; Ganglion, spinal; Mast cells; Nerve growth factor

COSNet: An R package for label prediction in unbalanced biological networks

Several problems in computational biology and medicine are modeled as learning problems in graphs, where nodes represent the biological entities to be studied, e.g. proteins, and connections different kinds of relationships among them, e.g. protein–protein interactions. In this context, classes are usually characterized by a high imbalance, i.e. positive examples for a class are much less than those negative. Although several works studied this problem, no graph-based software designed to explicitly take into account the label imbalance in biological networks is available. We propose COSNet, an R package to serve this purpose. COSNet deals with the label imbalance problem by implementing a novel parametric model of Hopfield Network (HN), whose output levels and activation thresholds of neurons are parameters to be automatically learnt. Due to the quasi-linear time complexity, COSNet nicely scales when the number of instances is large, and application examples to challenging problems in biomedicine show the efficiency and the accuracy of the proposed library.

Prostaglandin D2 Modulates Neuronal Excitation of the Trigeminal Ganglion to Augment Allergic Rhinitis in Guinea Pigs.

Prostaglandin D2(PGD2) is involved in the pathogenesis of allergic rhinitis. However, the sensory nervous system-mediated contributions of PGD2to the symptoms of allergic rhinitis remain unclear. We investigated the involvement of PGD2in these symptoms and in neuronal excitation by in vivo and ex vivo experiments. In an ovalbumin-induced model of allergic rhinitis in guinea pigs, the number of sneezing, nasal rubbing, and nasal secretion events were assessed after the nasal cavity instillation of PGD2, histamine, or a combination of PGD2and histamine. In situ hybridization for PGD2receptor 1 (DP1) mRNA transcripts and immunohistochemical analysis of histamine H1receptor protein expression in guinea pig trigeminal ganglion (TRG) were performed. The effects of DP1receptor activation on the excitability of TRG neurons to electrical and histamine stimuli were assessed using whole-cell patch-clamp recordings. Histamine induced more sneezing, nasal rubbing, and nasal secretion events than PGD2 PGD2augmented histamine-induced responses, whereas pretreatment with a DP1receptor-selective antagonist completely suppressed PGD2-induced augmentation. DP1receptor mRNA transcripts and H1receptor protein expression could be detected in TRG neurons. Moreover, a DP1receptor agonist caused significant increases in the number of histamine-induced action potentials and depolarization, and reduced the current threshold in small-diameter neurons. Our findings show that PGD2-DP1receptor signaling augments the symptoms of allergic rhinitis via the sensory nervous system by modulating nasal neuronal activation to various stimuli, such as histamine. These findings suggest that DP1receptor antagonist has therapeutic potential for the treatment of allergic rhinitis.

Modulation of hippocampal synaptic transmission in a mouse model of chronic intermittent hypoxia: implications for neurocognitive impairments

To investigate the effects of chronic intermittent hypoxia (CIH) on neuronal excitatory synaptic transmission in mice and explore their role in CIH-induced neurocognitive impairments. Three-week old ICR male mice were randomly divided into three experimental groups, the unhandled control + vehicle group (UC+ VEH group), CIH exposure + vehicle group (CIH+ VEH group) and CIH exposure + memantine pretreatment group (CIH+ MEM group) (n=10 each), wherein 5 for electrophysiological recordings, 5 for Western blot. The CIH+ VEH and CIH+ MEM groups were exposed to intermittent hypoxia while UC+ VEH mice to room air for 8 hours per day for 2 weeks. Mice in the CIH+ MEM group were pretreated with intraperitoneal injection of memantine solution 5 ml/kg (concentration of 1 mg/ml) approximately 15 minutes prior to starting daily CIH exposure, and the other two groups were treated with equal saline as vehicle. Using the whole cell patch clamp technique to evaluate the amplitude and frequency of hippocampal neuronal spontaneous excitatory postsynaptic currents (sEPSC) and the electrophysiological characteristics, the western blotting method to measure the expression of N-methyl-D-aspartic acid receptor (NMDAR) subunit 2B (NR2B) and brain derived neurotrophic factor (BDNF) in hippocampus. The neuronal spike threshold in CIH+ VEH group was depolarized compared to the UC+ VEH and CIH+ MEM groups ((-40.4±3.5) vs (-43.3±3.7), (-44.7±5.4) mV, both P<0.05). Furthermore, the frequency and amplitude of sEPSC in hippocampal CA1 neurons in CIH+ VEH group were significantly greater than the UC+ VEH and CIH+ MEM groups ((6.7±4.6) vs (3.6±1.7), (3.2±1.4) Hz, and (18.4±11.6) vs (13.0±2.5), (12.4±2.7) pA, both P<0.05). The expressions of NR2B increased significantly in CIH+ VEH group compared to UC+ VEH and CIH+ MEM groups (1.46±0.14 vs 0.93±0.07, 0.95±0.10, both P<0.01), whereas the expressions of BDNF decreased significantly in CIH+ VEH group versus UC+ VEH and CIH+ MEM groups (0.44±0.16 vs 0.86±0.08, 0.73±0.06, both P<0.05). There was no statistical difference between UC+ VEH group and CIH+ MEM group for these electrophysiological and biochemical assessments. Chronic intermittent hypoxia induces excitatory synaptic transmission abnormal, decreases neuronal excitability, and dysregulates NMDAR mediated signaling pathway, these changes may play an important role in CIH-induced neurocognitive impairments.

Plastic Change in the Auditory Minimum Threshold Induced by Intercollicular Effects in Mice.

In the auditory pathway, the commissure of the inferior colliculus (IC) interconnects the two ICs on both sides of the dorsal midbrain. This interconnection could mediate an interaction between the two ICs during sound signal processing. The intercollicular effects evoked by focal electric stimulation for 30 min could inhibit or facilitate auditory responses and induce plastic changes in the response minimum threshold (MT) of IC neurons. Changes in MT are dependent on the best frequency (BF) and MT difference. The MT shift is larger in IC neurons with BF differences ≤2 kHz than in those with BF differences >2 kHz. Moreover, MTs that shift toward electrically stimulated IC neurons increase with the increasing MT difference between the two ICs. The shift in MT lasts for a certain period of time and then returns to previous levels within ~150 min. The collicular interactions are either reciprocal or unilateral under alternate stimulating and recording conditions in both ICs. Our results suggest that intercollicular effects may be involved in the acoustic experience-dependent plasticity of the MT of IC neurons.

Sound quality prediction of vehicle interior noise and mathematical modeling using a back propagation neural network (BPNN) based on particle swarm optimization (PSO)

To better solve the complex non-linear problem between the subjective sound quality evaluation results and objective psychoacoustics parameters, a method for the prediction of the sound quality is put forward by using a back propagation neural network (BPNN) based on particle swarm optimization (PSO), which is optimizing the initial weights and thresholds of BP network neurons through the PSO. In order to verify the effectiveness and accuracy of this approach, the noise signals of the B-Class vehicles from the idle speed to 120 km h−1 measured by the artificial head, are taken as a target. In addition, this paper describes a subjective evaluation experiment on the sound quality annoyance inside the vehicles through a grade evaluation method, by which the annoyance of each sample is obtained. With the use of Artemis software, the main objective psychoacoustic parameters of each noise sample are calculated. These parameters include loudness, sharpness, roughness, fluctuation, tonality, articulation index (AI) and A-weighted sound pressure level. Furthermore, three evaluation models with the same artificial neural network (ANN) structure are built: the standard BPNN model, the genetic algorithm-back-propagation neural network (GA-BPNN) model and the PSO-back-propagation neural network (PSO-BPNN) model. After the network training and the evaluation prediction on the three models’ network based on experimental data, it proves that the PSO-BPNN method can achieve convergence more quickly and improve the prediction accuracy of sound quality, which can further lay a foundation for the control of the sound quality inside vehicles.

Preclinical Assessment of Inflammatory Pain.

While acute inflammation is a natural physiological response to tissue injury or infection, chronic inflammation is maladaptive and engenders a considerable amount of adverse pain. The chemical mediators responsible for tissue inflammation act on nociceptive nerve endings to lower neuronal excitation threshold and sensitize afferent firing rate leading to the development of allodynia and hyperalgesia, respectively. Animal models have aided in our understanding of the pathophysiological mechanisms responsible for the generation of chronic inflammatory pain and allowed us to identify and validate numerous analgesic drug candidates. Here we review some of the commonly used models of skin, joint, and gut inflammatory pain along with their relative benefits and limitations. In addition, we describe and discuss several behavioral and electrophysiological approaches used to assess the inflammatory pain in these preclinical models. Despite significant advances having been made in this area, a gap still exists between fundamental research and the implementation of these findings into a clinical setting. As such we need to characterize inherent pathophysiological pathways and develop new endpoints in these animal models to improve their predictive value of human inflammatory diseases in order to design safer and more effective analgesics.

A Lognormal Recurrent Network Model for Burst Generation during Hippocampal Sharp Waves.

The strength of cortical synapses distributes lognormally, with a long tail of strong synapses. Various properties of neuronal activity, such as the average firing rates of neurons, the rate and magnitude of spike bursts, the magnitude of population synchrony, and the correlations between presynaptic and postsynaptic spikes, also obey lognormal-like distributions reported in the rodent hippocampal CA1 and CA3 areas. Theoretical models have demonstrated how such a firing rate distribution emerges from neural network dynamics. However, how the other properties also display lognormal patterns remain unknown. Because these features are likely to originate from neural dynamics in CA3, we model a recurrent neural network with the weights of recurrent excitatory connections distributed lognormally to explore the underlying mechanisms and their functional implications. Using multi-timescale adaptive threshold neurons, we construct a low-frequency spontaneous firing state of bursty neurons. This state well replicates the observed statistical properties of population synchrony in hippocampal pyramidal cells. Our results show that the lognormal distribution of synaptic weights consistently accounts for the observed long-tailed features of hippocampal activity. Furthermore, our model demonstrates that bursts spread over the lognormal network much more effectively than single spikes, implying an advantage of spike bursts in information transfer. This efficiency in burst propagation is not found in neural network models with Gaussian-weighted recurrent excitatory synapses. Our model proposes a potential network mechanism to generate sharp waves in CA3 and associated ripples in CA1 because bursts occur in CA3 pyramidal neurons most frequently during sharp waves.

Bimodal regulation of an Elk subfamily K+ channel by phosphatidylinositol 4,5-bisphosphate.

Phosphatidylinositol 4,5-bisphosphate (PIP2) regulates Shaker K+ channels and voltage-gated Ca2+ channels in a bimodal fashion by inhibiting voltage activation while stabilizing open channels. Bimodal regulation is conserved in hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, but voltage activation is enhanced while the open channel state is destabilized. The proposed sites of PIP2 regulation in these channels include the voltage-sensor domain (VSD) and conserved regions of the proximal cytoplasmic C terminus. Relatively little is known about PIP2 regulation of Ether-á-go-go (EAG) channels, a metazoan-specific family of K+ channels that includes three gene subfamilies, Eag (Kv10), Erg (Kv11), and Elk (Kv12). We examined PIP2 regulation of the Elk subfamily potassium channel human Elk1 to determine whether bimodal regulation is conserved within the EAG K+ channel family. Open-state stabilization by PIP2 has been observed in human Erg1, but the proposed site of regulation in the distal C terminus is not conserved among EAG family channels. We show that PIP2 strongly inhibits voltage activation of Elk1 but also stabilizes the open state. This stabilization produces slow deactivation and a mode shift in voltage gating after activation. However, removal of PIP2 has the net effect of enhancing Elk1 activation. R347 in the linker between the VSD and pore (S4-S5 linker) and R479 near the S6 activation gate are required for PIP2 to inhibit voltage activation. The ability of PIP2 to stabilize the open state also requires these residues, suggesting an overlap in sites central to the opposing effects of PIP2 on channel gating. Open-state stabilization in Elk1 requires the N-terminal eag domain (PAS domain + Cap), and PIP2-dependent stabilization is enhanced by a conserved basic residue (K5) in the Cap. Our data shows that PIP2 can bimodally regulate voltage gating in EAG family channels, as has been proposed for Shaker and HCN channels. PIP2 regulation appears fundamentally different for Elk and KCNQ channels, suggesting that, although both channel types can regulate action potential threshold in neurons, they are not functionally redundant.

Neuronal thresholds and choice-related activity of otolith afferent fibers during heading perception

How activity of sensory neurons leads to perceptual decisions remains a challenge to understand. Correlations between choices and single neuron firing rates have been found early in vestibular processing, in the brainstem and cerebellum. To investigate the origins of choice-related activity, we have recorded from otolith afferent fibers while animals performed a fine heading discrimination task. We find that afferent fibers have similar discrimination thresholds as central cells, and the most sensitive fibers have thresholds that are only twofold or threefold greater than perceptual thresholds. Unlike brainstem and cerebellar nuclei neurons, spike counts from afferent fibers do not exhibit trial-by-trial correlations with perceptual decisions. This finding may reflect the fact that otolith afferent responses are poorly suited for driving heading perception because they fail to discriminate self-motion from changes in orientation relative to gravity. Alternatively, if choice probabilities reflect top-down inference signals, they are not relayed to the vestibular periphery.