A low noise multichannel integrated circuit for recording neuronal signals using microelectrode arrays

This paper reports on the development of a fully integrated 32-channel integrated circuit (IC) for recording neuronal signals in neurophysiological experiments using microelectrode arrays. The IC consists of 32 channels of low-noise preamplifiers and bandpass filters, and an output analog multiplexer. The continuous-time RC active filters have a typical passband of 20-2000 Hz; the low and the high cut-off frequencies can be separately controlled by external reference currents. This chip provides a satisfactory signal-to-noise ratio for neuronal signals with amplitudes greater than 50 microV. For the nominal passband setting, an equivalent input noise of 3 microV rms has been achieved. A single channel occupies 0.35 mm(2) of silicon area and dissipates 1.7 mW of power. The chip was fabricated in a 0.7 microm CMOS process.     

Ligand-gated ion channels: mechanisms underlying ion selectivity

Anion/cation selectivity is a critical property of ion channels and underpins their physiological function. Recently, there have been numerous mutagenesis studies, which have mapped sites within the ion channel-forming segments of ligand-gated ion channels that are determinants of the ion selectivity. Site-directed mutations to specific amino acids within or flanking the M2 transmembrane segments of the anion-selective glycine, GABA(A) and GABA(C) receptors and the cation-selective nicotinic acetylcholine and serotonin (type 3) receptors have revealed discrete, equivalent regions within the ion channel that form the principal selectivity filter, leading to plausible molecular mechanisms and mathematical models to describe how ions preferentially permeate these channels. In particular, the dominant factor determining anion/cation selectivity seems to be the sign and exposure of charged amino acids lining the selectivity filter region of the open channel. In addition, the minimum pore diameter, which can be influenced by the presence of a local proline residue, also makes a contribution to such ion selectivity in LGICs with smaller diameters increasing anion/cation selectivity and larger ones decreasing it.     

IgCAMs: bidirectional signals underlying neurite growth

Understanding how immunoglobulin superfamily cell adhesion molecules (IgCAMs) regulate nervous system development has lagged behind studies on integrins and cadherins. The recent characterization of IgCAM structures combined with cell biological studies on protein-protein interactions and membrane targeting/trafficking demonstrate that IgCAMs interact in exceedingly complex ways to regulate axonal growth and pathfinding.     

Computational principles underlying the recognition of acoustic signals in insects

Many animals produce pulse-like signals during acoustic communication. These signals exhibit structure on two time scales: they consist of trains of pulses that are often broadcast in packets—so called chirps. Temporal parameters of the pulse and of the chirp are decisive for female preference. Despite these signals being produced by animals from many different taxa (e.g. frogs, grasshoppers, crickets, bushcrickets, flies), a general framework for their evaluation is still lacking. We propose such a framework, based on a simple and physiologically plausible model. The model consists of feature detectors, whose time-varying output is averaged over the signal and then linearly combined to yield the behavioral preference. We fitted this model to large data sets collected in two species of crickets and found that Gabor filters—known from visual and auditory physiology—explain the preference functions in these two species very well. We further explored the properties of Gabor filters and found a systematic relationship between parameters of the filters and the shape of preference functions. Although these Gabor filters were relatively short, they were also able to explain aspects of the preference for signal parameters on the longer time scale due to the integration step in our model. Our framework explains a wide range of phenomena associated with female preference for a widespread class of signals in an intuitive and physiologically plausible fashion. This approach thus constitutes a valuable tool to understand the functioning and evolution of communication systems in many species.     

The evolution of neuronal circuits underlying species-specific behavior.

The nervous system is evolutionarily conservative compared to the peripheral appendages that it controls. However, species-specific behaviors may have arisen from very small changes in neuronal circuits. In particular, changes in neuromodulatory systems may allow multifunctional circuits to produce different sets of behaviors in closely related species. Recently, it was demonstrated that even species differences in complex social behavior may be attributed to a change in the promoter region of a single gene regulating a neuromodulatory action.     

Antimicrobial selectivity based on zwitterionic lipids and underlying balance of interactions

An important feature of antimicrobial peptides is their ability to distinguish pro- from eukaryotic membranes. In vitro experiments on the antimicrobial peptide NK-2 indicate that the discrimination between zwitterionic phosphatidylethanolamine lipids exposed by prokaryotes and phosphatidylcholine lipids exposed by eukaryotes plays an important role. The underlying mechanism is not understood. Here we present molecular dynamics simulations in conjunction with a coarse grained model and thermodynamic integration showing that NK-2 binds more strongly to palmitoyloleoylphosphatidylethanolamine (POPE) than to palmitoyloleoylphosphatidylcholine (POPC) bilayers. Finite size effects on the relative free energy have been corrected for with a method that may also be useful in future studies of the affinities of macromolecules for lipid membranes. Our results support the previous hypothesis that the stronger binding to PE compared to PC arises from a better accessibility of the phosphates of the lipids to the cationic peptide in a sense that a similar number of peptide-lipid salt bridges requires to break more favorable electrostatic headgroup-headgroup interactions for PC relative to PE. The transfer of NK-2 from POPC to POPE is found to lead to a decrease in electrostatic peptide-lipid but an increase in lipid-lipid and ion-lipid interactions, correlating with a dehydration of the lipids and the ions but an increased hydration of the peptide. The increase in affinity of NK-2 for POPE compared to POPC hence arises from a complex interplay of competing interactions. This work opens the perspective to study how the affinity of antimicrobial peptides changes with amino acid sequence and lipid composition.     

Intracellular mechanisms participating in the formation of neuronal calcium signals

Ion and metabolic processes in the endoplasmic reticulum, mitochondria, plasma membrane, etc. providing calcium signaling in the cells of excitable and nonexcitable tissues are discussed.Neirofiziologiya/Neurophysiology, Vol. 36, Nos. 5/6, pp. 405–417, September–December, 2004.This revised version was published online in April 2005 with a corrected cover date and copyright year.     

Long-range neuronal circuits underlying the interaction between sensory and motor cortex

In the rodent vibrissal system, active sensation and sensorimotor integration are mediated in part by connections between barrel cortex and vibrissal motor cortex. Little is known about how these structures interact at the level of neurons. We used Channelrhodopsin-2 (ChR2) expression, combined with anterograde and retrograde labeling, to map connections between barrel cortex and pyramidal neurons in mouse motor cortex. Barrel cortex axons preferentially targeted upper layer (L2/3, L5A) neurons in motor cortex; input to neurons projecting back to barrel cortex was particularly strong. Barrel cortex input to deeper layers (L5B, L6) of motor cortex, including neurons projecting to the brainstem, was weak, despite pronounced geometric overlap of dendrites with axons from barrel cortex. Neurons in different layers received barrel cortex input within stereotyped dendritic domains. The cortico-cortical neurons in superficial layers of motor cortex thus couple motor and sensory signals and might mediate sensorimotor integration and motor learning.     

The relationship between a neuronal cross-correlogram and the underlying postsynaptic current

Cross-correlations between stimuli and neuronal discharges yield information about synaptic events at the investigated neuron. In this paper it is shown that the time course estimated by a cross-correlogram, the cross-correlation function (ccf), represents the input current that upon injection into the perfect integrator model evokes spike sequences that are (almost) identical to those used for estimation of the ccf. Thus, the shape of a ccf may be regarded as an estimate of the underlying postsynaptic current, if the neuron investigated behaves, at least to a first approximation, like a perfect integrator model.     

Mechanisms underlying neuronal death induced by chromogranin A-activated microglia

The neurotoxic effects of activated microglia in neurodegenerative diseases are well established. We recently provided evidence that chromogranin A (CGA), a multifunctional protein localized in dystrophic neurites and in senile plaques, induces an activated phenotype and secretion of neurotoxins by rat microglia in culture. In the present study, we focused on the mechanisms underlying neuronal degeneration triggered by CGA-activated microglia. We found that neuronal death exhibits apoptotic features, characterized by the externalization of phosphatidylserine and the fragmentation of DNA. Microglial neurotoxins markedly stimulate the phosphorylation and activity of neuronal p38 mitogen-activated protein kinase and provoke the release of mitochondrial cytochrome c, which precedes apoptosis. Inhibition of p38 kinase with SB 203580 partially protects neurons from death induced by CGA-activated microglia. Furthermore, neurons are also protected by Fas-Fc, which antagonizes the interactions between the death receptor Fas and its ligand FasL and by cell-permeable peptides that inhibit caspases 8 and 3. Thus, CGA triggers the release of microglial neurotoxins that mobilize several death-signaling pathways in neurons. Our results further support the idea that CGA, which is up-regulated in many neuropathologies, represents a potent endogeneous inflammatory factor possibly responsible for neuronal degeneration.     

Genetic mechanisms underlying abnormal neuronal migration in classical lissencephaly

Classical lissencephaly is a human developmental brain disorder characterized by a paucity of cortical gyration and thickening of the cortical gray matter, leading to severe epilepsy and mental retardation. Loss-of-function mutations in the microtubule-associated protein encoding genes, PAFAH1B1 (encoding the protein LIS1), DCX and TUBA1A have been implicated in the pathogenesis of the condition. Animal models are required to understand the basis of this disease, which is a challenge, given that mice normally have a smooth cortex. Recent advances toward this goal have come from stepwise reduction in gene function, deletion of redundant genes and acute gene inactivation using short hairpin RNA (shRNA). These approaches have implicated genes that regulate the microtubule cytoskeleton during neuronal division, migration and maturation.     

Convergent evolution of sodium ion selectivity in metazoan neuronal signaling

Ion selectivity of metazoan voltage-gated Na(+) channels is critical for neuronal signaling and has long been attributed to a ring of four conserved amino acids that constitute the ion selectivity filter (SF) at the channel pore. Yet, in addition to channels with a preference for Ca(2+) ions, the expression and characterization of Na(+) channel homologs from the sea anemone Nematostella vectensis, a member of the early-branching metazoan phylum Cnidaria, revealed a sodium-selective channel bearing a noncanonical SF. Mutagenesis and physiological assays suggest that pore elements additional to the SF determine the preference for Na(+) in this channel. Phylogenetic analysis assigns the Nematostella Na(+)-selective channel to a channel group unique to Cnidaria, which diverged >540 million years ago from Ca(2+)-conducting Na(+) channel homologs. The identification of Cnidarian Na(+)-selective ion channels distinct from the channels of bilaterian animals indicates that selectivity for Na(+) in neuronal signaling emerged independently in these two animal lineages.     

Neural circuits underlying imitation learning of hand actions: an event-related fMRI study

The neural bases of imitation learning are virtually unknown. In the present study, we addressed this issue using an event-related fMRI paradigm. Musically naive participants were scanned during four events: (1) observation of guitar chords played by a guitarist, (2) a pause following model observation, (3) execution of the observed chords, and (4) rest. The results showed that the basic circuit underlying imitation learning consists of the inferior parietal lobule and the posterior part of the inferior frontal gyrus plus the adjacent premotor cortex (mirror neuron circuit). This circuit, known to be involved in action understanding, starts to be active during the observation of the guitar chords. During pause, the middle frontal gyrus (area 46) plus structures involved in motor preparation (dorsal premotor cortex, superior parietal lobule, rostral mesial areas) also become active. Given the functional properties of area 46, a model of imitation learning is proposed based on interactions between this area and the mirror neuron system.     

Axon pruning: an essential step underlying the developmental plasticity of neuronal connections

Regressive events play a key role in modifying neural connectivity in early development. An important regressive event is the pruning of neuronal processes. Pruning is a strategy often used to selectively remove exuberant neuronal branches and connections in the immature nervous system to ensure the proper formation of functional circuitry. In the following review, we discuss our present understanding of the cellular and molecular mechanisms that regulate the pruning of axons during neuronal development as well as in neurological diseases. The evidence suggests that there are several similarities between the mechanisms that are involved in developmental axon pruning and axon elimination in disease. In summary, these findings provide researchers with a unique perspective on how developmental plasticity is achieved and how to develop strategies to treat complex neurological diseases.     

Calcium and synaptic dynamics underlying reverberatory activity in neuronal networks

Persistent activity is postulated to drive neural network plasticity and learning. To investigate its underlying cellular mechanisms, we developed a biophysically tractable model that explains the emergence, sustenance and eventual termination of short-term persistent activity. Using the model, we reproduced the features of reverberating activity that were observed in small (50-100 cells) networks of cultured hippocampal neurons, such as the appearance of polysynaptic current clusters, the typical inter-cluster intervals, the typical duration of reverberation, and the response to changes in extra-cellular ionic composition. The model relies on action potential-triggered residual pre-synaptic calcium, which we suggest plays an important role in sustaining reverberations. We show that reverberatory activity is maintained by enhanced asynchronous transmitter release from pre-synaptic terminals, which in itself depends on the dynamics of residual pre-synaptic calcium. Hence, asynchronous release, rather than being a 'synaptic noise', can play an important role in network dynamics. Additionally, we found that a fast timescale synaptic depression is responsible for oscillatory network activation during reverberations, whereas the onset of a slow timescale depression leads to the termination of reverberation. The simplicity of our model enabled a number of predictions that were confirmed by additional analyses of experimental manipulations.     

The neuronal dynamics underlying cognitive flexibility in set shifting tasks

The ability to switch attention from one aspect of an object to another or in other words to switch the “attentional set” as investigated in tasks like the “Wisconsin Card Sorting Test” is commonly referred to as cognitive flexibility. In this work we present a biophysically detailed neurodynamical model which illustrates the neuronal base of the processes related to this cognitive flexibility. For this purpose we conducted behavioral experiments which allow the combined evaluation of different aspects of set shifting tasks: uninstructed set shifts as investigated in Wisconsin-like tasks, effects of stimulus congruency as investigated in Stroop-like tasks and the contribution of working memory as investigated in “Delayed-Match-to-Sample” tasks. The work describes how general experimental findings are usable to design the architecture of a biophysical detailed though minimalistic model with a high orientation on neurobiological findings and how, in turn, the simulations support experimental investigations. The resulting model is able to account for experimental and individual response times and error rates and enables the switch of attention as a system inherent model feature: The switching process suggested by the model is based on the memorization of the visual stimuli and does not require any synaptic learning. The operation of the model thus demonstrates with at least a high probability the neuronal dynamics underlying a key component of human behavior: the ability to adapt behavior according to context requirements—cognitive flexibility. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Action Editor: Peter Dayan     

Conjunctive processing of locomotor signals by the ventral tegmental area neuronal population

The ventral tegmental area (VTA) plays an essential role in reward and motivation. How the dopamine (DA) and non-DA neurons in the VTA engage in motivation-based locomotor behaviors is not well understood. We recorded activity of putative DA and non-DA neurons simultaneously in the VTA of awake mice engaged in motivated voluntary movements such as wheel running. Our results revealed that VTA non-DA neurons exhibited significant rhythmic activity that was correlated with the animal's running rhythms. Activity of putative DA neurons also correlated with the movement behavior, but to a lesser degree. More importantly, putative DA neurons exhibited significant burst activation at both onset and offset of voluntary movements. These findings suggest that VTA DA and non-DA neurons conjunctively process locomotor-related motivational signals that are associated with movement initiation, maintenance and termination.