A Neanderthal Sodium Channel Increases Pain Sensitivity in Present-Day Humans.

The sodium channel Nav1.7 is crucial for impulse generation and conduction in peripheral pain pathways [1]. In Neanderthals, the Nav1.

Synaptic proximity enables NMDAR signalling to promote brain metastasis.

Metastasis-the disseminated growth of tumours in distant organs-underlies cancer mortality. Breast-to-brain metastasis (B2BM) is a common and disruptive form of cancer and is prevalent in the aggressive basal-like subtype, but is also found at varying frequencies in all cancer subtypes. Previous studies revealed parameters of breast cancer metastasis to the brain, but its preference for this site remains an enigma.

Autocrine, paracrine and necrotic NMDA receptor signalling in mouse pancreatic neuroendocrine tumour cells.

-Methyl-d-aspartate receptor (NMDAR) activation is implicated in the malignant progression of many cancer types, as previously shown by the growth-inhibitory effects of NMDAR antagonists. NMDAR-mediated calcium influx and its downstream signalling depend critically, however, on the dynamics of membrane potential and ambient glutamate concentration, which are poorly characterized in cancer cells. Here, we have used low-noise whole-cell patch-clamp recording to investigate the electrophysiology of glutamate signalling in pancreatic neuroendocrine tumour (PanNET) cells derived from a genetically-engineered mouse model (GEMM) of PanNET, in which NMDAR signalling is known to promote cancer progression.

Kv4.2 channel activity controls intrinsic firing dynamics of arcuate kisspeptin neurons.

Key Points: Neurons in the hypothalamus of the brain which secrete the peptide kisspeptin are important regulators of reproduction, and normal reproductive development. Electrical activity, in the form of action potentials, or spikes, leads to secretion of peptides and neurotransmitters, influencing the activity of downstream neurons; in kisspeptin neurons, this activity is highly irregular, but the mechanism of this is not known. In this study, we show that irregularity depends on the presence of a particular type of potassium ion channel in the membrane, which opens transiently in response to electrical excitation.

Fluctuation Analysis in Nonstationary Conditions: Single Ca Channel Current in Pyramidal Neurons.

Fluctuation analysis is a method that allows measurement of the single-channel current of ion channels even when it is too small to be resolved directly with the patch-clamp technique. This is the case for voltage-gated calcium channels. They are present in all mammalian central neurons, controlling presynaptic release of transmitter, postsynaptic signaling, and synaptic integration.

Intrinsic Cornu Ammonis Area 1 Theta-Nested Gamma Oscillations Induced by Optogenetic Theta Frequency Stimulation.

Unlabelled: Gamma oscillations (30-120 Hz) are thought to be important for various cognitive functions, including perception and working memory, and disruption of these oscillations has been implicated in brain disorders, such as schizophrenia and Alzheimer's disease. The cornu ammonis area 1 (CA1) of the hippocampus receives gamma frequency inputs from upstream regions (cornu ammonis area 3 and medial entorhinal cortex) and generates itself a faster gamma oscillation. The exact nature and origin of the intrinsic CA1 gamma oscillation is still under debate.

Development and function of human cerebral cortex neural networks from pluripotent stem cells in vitro.

A key aspect of nervous system development, including that of the cerebral cortex, is the formation of higher-order neural networks. Developing neural networks undergo several phases with distinct activity patterns in vivo, which are thought to prune and fine-tune network connectivity. We report here that human pluripotent stem cell (hPSC)-derived cerebral cortex neurons form large-scale networks that reflect those found in the developing cerebral cortex in vivo.

Density of voltage-gated potassium channels is a bifurcation parameter in pyramidal neurons.

Several types of intrinsic dynamics have been identified in brain neurons. Type 1 excitability is characterized by a continuous frequency-stimulus relationship and, thus, an arbitrarily low frequency at threshold current. Conversely, Type 2 excitability is characterized by a discontinuous frequency-stimulus relationship and a nonzero threshold frequency.

libNeuroML and PyLEMS: using Python to combine procedural and declarative modeling approaches in computational neuroscience.

NeuroML is an XML-based model description language, which provides a powerful common data format for defining and exchanging models of neurons and neuronal networks. In the latest version of NeuroML, the structure and behavior of ion channel, synapse, cell, and network model descriptions are based on underlying definitions provided in LEMS, a domain-independent language for expressing hierarchical mathematical models of physical entities. While declarative approaches for describing models have led to greater exchange of model elements among software tools in computational neuroscience, a frequent criticism of XML-based languages is that they are difficult to work with directly.

Quantifying network properties in multi-electrode recordings: spatiotemporal characterization and inter-trial variation of evoked gamma oscillations in mouse somatosensory cortex in vitro.

Linking the structural connectivity of brain circuits to their cooperative dynamics and emergent functions is a central aim of neuroscience research. Graph theory has recently been applied to study the structure-function relationship of networks, where dynamical similarity of different nodes has been turned into a "static" functional connection. However, the capability of the brain to adapt, learn and process external stimuli requires a constant dynamical functional rewiring between circuitries and cell assemblies.

Control of layer 5 pyramidal cell spiking by oscillatory inhibition in the distal apical dendrites: a computational modeling study.

The distal apical dendrites of layer 5 pyramidal neurons receive cortico-cortical and thalamocortical top-down and feedback inputs, as well as local recurrent inputs. A prominent source of recurrent inhibition in the neocortical circuit is somatostatin-positive Martinotti cells, which preferentially target distal apical dendrites of pyramidal cells. These electrically coupled cells can fire synchronously at various frequencies, including over a relatively slow range (5∼30 Hz), thereby imposing oscillatory inhibition on the pyramidal apical tuft dendrites.

The Hodgkin-Huxley heritage: from channels to circuits.

The Hodgkin-Huxley studies of the action potential, published 60 years ago, are a central pillar of modern neuroscience research, ranging from molecular investigations of the structural basis of ion channel function to the computational implications at circuit level. In this Symposium Review, we aim to demonstrate the ongoing impact of Hodgkin's and Huxley's ideas. The Hodgkin-Huxley model established a framework in which to describe the structural and functional properties of ion channels, including the mechanisms of ion permeation, selectivity, and gating.

Impact of gamma-oscillatory inhibition on the signal transmission of a cortical pyramidal neuron.

Networks of synchronized fast-spiking interneurons are thought to be key elements in the generation of gamma (γ) oscillations (30-80 Hz) in the brain. We examined how such γ-oscillatory inhibition regulates the output of a cortical pyramidal cell. Specifically, we modeled a situation where a pyramidal cell receives inputs from γ-synchronized fast-spiking inhibitory interneurons.

Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses.

Efforts to study the development and function of the human cerebral cortex in health and disease have been limited by the availability of model systems. Extrapolating from our understanding of rodent cortical development, we have developed a robust, multistep process for human cortical development from pluripotent stem cells: directed differentiation of human embryonic stem (ES) and induced pluripotent stem (iPS) cells to cortical stem and progenitor cells, followed by an extended period of cortical neurogenesis, neuronal terminal differentiation to acquire mature electrophysiological properties, and functional excitatory synaptic network formation. We found that induction of cortical neuroepithelial stem cells from human ES cells and human iPS cells was dependent on retinoid signaling.

Effects of divalent cations on slow unblock of native NMDA receptors in mouse neocortical pyramidal neurons.

The N-methyl-D-aspartate receptor (NMDAR) exhibits strong voltage-dependent block by extracellular Mg(2+) , which is relieved by sustained depolarization and glutamate binding, and which is central to the function of the NMDAR in synaptic plasticity. Rapid membrane depolarization during agonist application reveals a slow unblock of NMDARs, which has important functional implications, for example in the generation of NMDAR spikes, and in determining the narrow time window for spike-timing-dependent plasticity. However, its mechanism is still unclear.

The mechanism of ethanol action on midbrain dopaminergic neuron firing: a dynamic-clamp study of the role of I(h) and GABAergic synaptic integration.

Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels are expressed in dopaminergic (DA) neurons of the ventral tegmental area (VTA) as well as in DA and GABAergic neurons of the substantia nigra (SN). The excitation of DA neurons induced by ethanol has been proposed to result from its enhancing HCN channel current, I(h). Using perforated patch-clamp recordings in rat midbrain slices, we isolated I(h) in these neurons by voltage clamp.

Grouping and classifying electrophysiologically-defined classes of neocortical neurons by single cell, whole-genome expression profiling.

The diversity of neuronal cell types and how to classify them are perennial questions in neuroscience. The advent of global gene expression analysis raised the possibility that comprehensive transcription profiling will resolve neuronal cell types into groups that reflect some or all aspects of their phenotype. This approach has been successfully used to compare gene expression between groups of neurons defined by a common property.

Diversity of intrinsic frequency encoding patterns in rat cortical neurons--mechanisms and possible functions.

Extracellular recordings of single neurons in primary and secondary somatosensory cortices of monkeys in vivo have shown that their firing rate can increase, decrease, or remain constant in different cells, as the external stimulus frequency increases. We observed similar intrinsic firing patterns (increasing, decreasing or constant) in rat somatosensory cortex in vitro, when stimulated with oscillatory input using conductance injection (dynamic clamp). The underlying mechanism of this observation is not obvious, and presents a challenge for mathematical modelling.

Uncovering bifurcation patterns in cortical synapses.

Individual cortical synapses are known to exhibit a very complex short-time dynamic behaviour in response to simple "naturalistic" stimulation. We describe a computational study of the experimentally obtained excitatory post-synaptic potential trains of individual cortical synapses. By adopting a new nonlinear modelling scheme we construct robust and repeatable models of the underlying dynamics.

Recurrent synaptic input and the timing of gamma-frequency-modulated firing of pyramidal cells during neocortical "UP" states.

Gamma (gamma) oscillation, a hallmark of cortical activity during sensory processing and cognition, occurs during persistent, self-sustained activity or "UP" states, which are thought to be maintained by recurrent synaptic inputs to pyramidal cells. During neocortical "UP" states, excitatory regular spiking (RS) (pyramidal) cells and inhibitory fast spiking (FS) (basket) cells fire with distinct phase distributions relative to the gamma oscillation in the local field potential. Evidence suggests that gamma-modulated RS --> FS input serves to synchronize the interneurons and hence to generate gamma-modulated FS --> RS drive.

A scriptable DSP-based system for dynamic conductance injection.

A variety of software and hardware systems have been developed to inject controlled electrical conductances into excitable cells, to investigate the physiological mechanisms of action potential generation. These systems face several challenges: the need to model complex conductances, including voltage-gated ion channels, synaptic conductances controlled by electrical models of entire cells or even networks of cells, to do so rapidly and stably, with precisely controlled update intervals of 20micros or less, and to present an easy and flexible interface to the user, allowing new experiments to be designed and executed easily. In this paper I describe a new software system (SM-2) which is designed to meet these requirements, and which runs on the current generation of digital-signal-processing (DSP) analog input-output I/O boards, hosted in Windows PCs.

Coding with spike shapes and graded potentials in cortical networks.

In cortical neurones, analogue dendritic potentials are thought to be encoded into patterns of digital spikes. According to this view, neuronal codes and computations are based on the temporal patterns of spikes: spike times, bursts or spike rates. Recently, we proposed an 'action potential waveform code' for cortical pyramidal neurones in which the spike shape carries information.

Correlation entropy of synaptic input-output dynamics.

The responses of synapses in the neocortex show highly stochastic and nonlinear behavior. The microscopic dynamics underlying this behavior, and its computational consequences during natural patterns of synaptic input, are not explained by conventional macroscopic models of deterministic ensemble mean dynamics. Here, we introduce the correlation entropy of the synaptic input-output map as a measure of synaptic reliability which explicitly includes the microscopic dynamics.

Electrophysiological and gene expression profiling of neuronal cell types in mammalian neocortex.

It is a challenging question to understand how different neuronal types are organized into a complex architecture in the cortex, an architecture which is also adapted in different regions to subserve very different functions. Recent developments in genetic and molecular techniques have opened up the possibility of using gene expression profiling for neuronal cell typing, with the aim of uncovering novel cell types and the underlying mechanisms which generate and maintain neuronal heterogeneity in the cortex. This review introduces some current ideas about neuronal cell types in the cortex and describes recent approaches to expression profiling for defining cortical neuronal cell types.