Stochastic self-tuning hybrid algorithm for reaction-diffusion systems.

Many biochemical phenomena involve reactants with vastly different concentrations, some of which are amenable to continuum-level descriptions, while the others are not. We present a hybrid self-tuning algorithm to model such systems. The method combines microscopic (Brownian) dynamics for diffusion with mesoscopic (Gillespie-type) methods for reactions and remains efficient in a wide range of regimes and scenarios with large variations of concentrations. Its accuracy, robustness, and versatility are balanced by redefining propensities and optimizing the mesh size and time step. We use a bimolecular reaction to demonstrate the potential of our method in a broad spectrum of scenarios: from almost completely reaction-dominated systems to cases where reactions rarely occur or take place very slowly. The simulation results show that the number of particles present in the system does not degrade the performance of our method. This makes it an accurate and computationally efficient tool to model complex multireaction systems.

Disruption of mGluR5 in parvalbumin-positive interneurons induces core features of neurodevelopmental disorders.

Alterations in glutamatergic transmission onto developing GABAergic systems, in particular onto parvalbumin-positive (Pv(+)) fast-spiking interneurons, have been proposed as underlying causes of several neurodevelopmental disorders, including schizophrenia and autism. Excitatory glutamatergic transmission, through ionotropic and metabotropic glutamate receptors, is necessary for the correct postnatal development of the Pv(+) GABAergic network. We generated mutant mice in which the metabotropic glutamate receptor 5 (mGluR5) was specifically ablated from Pv(+) interneurons postnatally, and investigated the consequences of such a manipulation at the cellular, network and systems levels. Deletion of mGluR5 from Pv(+) interneurons resulted in reduced numbers of Pv(+) neurons and decreased inhibitory currents, as well as alterations in event-related potentials and brain oscillatory activity. These cellular and sensory changes translated into domain-specific memory deficits and increased compulsive-like behaviors, abnormal sensorimotor gating and altered responsiveness to stimulant agents. Our findings suggest a fundamental role for mGluR5 in the development of Pv(+) neurons and show that alterations in this system can produce broad-spectrum alterations in brain network activity and behavior that are relevant to neurodevelopmental disorders.

Monitoring Spiking Activity of Many Individual Neurons in Invertebrate Ganglia.

Optical recording with fast voltage sensitive dyes makes it possible, in suitable preparations, to simultaneously monitor the action potentials of large numbers of individual neurons. Here we describe methods for doing this, including considerations of different dyes and imaging systems, methods for correlating the optical signals with their source neurons, procedures for getting good signals, and the use of Independent Component Analysis for spike-sorting raw optical data into single neuron traces. These combined tools represent a powerful approach for large-scale recording of neural networks with high temporal and spatial resolution.

Perspectives on cognitive neuroscience.

How is it that we can perceive, learn and be aware of the world? The development of new techniques for studying large-scale brain activity, together with insights from computational modeling and a better understanding of cognitive processes, have opened the door for collaborative research that could lead to major advances in our understanding of ourselves.

Computational neuroscience.

The ultimate aim of computational neuroscience is to explain how electrical and chemical signals are used in the brain to represent and process information. This goal is not new, but much has changed in the last decade. More is known now about the brain because of advances in neuroscience, more computing power is available for performing realistic simulations of neural systems, and new insights are available from the study of simplifying models of large networks of neurons. Brain models are being used to connect the microscopic level accessible by molecular and cellular techniques with the systems level accessible by the study of behavior.

Reliability of spike timing in neocortical neurons.

It is not known whether the variability of neural activity in the cerebral cortex carries information or reflects noisy underlying mechanisms. In an examination of the reliability of spike generation using recordings from neurons in rat neocortical slices, the precision of spike timing was found to depend on stimulus transients. Constant stimuli led to imprecise spike trains, whereas stimuli with fluctuations resembling synaptic activity produced spike trains with timing reproducible to less than 1 millisecond. These data suggest a low intrinsic noise level in spike generation, which could allow cortical neurons to accurately transform synaptic input into spike sequences, supporting a possible role for spike timing in the processing of cortical information by the neocortex.

Thalamocortical oscillations in the sleeping and aroused brain.

Sleep is characterized by synchronized events in billions of synaptically coupled neurons in thalamocortical systems. The activation of a series of neuromodulatory transmitter systems during awakening blocks low-frequency oscillations, induces fast rhythms, and allows the brain to recover full responsiveness. Analysis of cortical and thalamic networks at many levels, from molecules to single neurons to large neuronal assemblies, with a variety of techniques, ranging from intracellular recordings in vivo and in vitro to computer simulations, is beginning to yield insights into the mechanisms of the generation, modulation, and function of brain oscillations.

Motion integration and postdiction in visual awareness.

In the flash-lag illusion, a flash and a moving object in the same location appear to be offset. A series of psychophysical experiments yields data inconsistent with two previously proposed explanations: motion extrapolation (a predictive model) and latency difference (an online model). We propose an alternative in which visual awareness is neither predictive nor online but is postdictive, so that the percept attributed to the time of the flash is a function of events that happen in the approximately 80 milliseconds after the flash. The results here show how interpolation of the past is the only framework of the three models that provides a unified explanation for the flash-lag phenomenon.

Control of spatiotemporal coherence of a thalamic oscillation by corticothalamic feedback.

The mammalian thalamus is the gateway to the cortex for most sensory modalities. Nearly all thalamic nuclei also receive massive feedback projections from the cortical region to which they project. In this study, the spatiotemporal properties of synchronized thalamic spindle oscillations (7 to 14 hertz) were investigated in barbiturate-anesthetized cats, before and after removal of the cortex. After complete ipsilateral decortication, the long-range synchronization of thalamic spindles in the intact cortex hemisphere changed into disorganized patterns with low spatiotemporal coherence. Local thalamic synchrony was still present, as demonstrated by dual intracellular recordings from nearby neurons. In the cortex, synchrony was insensitive to the disruption of horizontal intracortical connections. These results indicate that the global coherence of thalamic oscillations is determined by corticothalamic projections.

Simulating human sleep spindle MEG and EEG from ion channel and circuit level dynamics.

BACKGROUND: Although they form a unitary phenomenon, the relationship between extracranial M/EEG and transmembrane ion flows is understood only as a general principle rather than as a well-articulated and quantified causal chain. METHOD: We present an integrated multiscale model, consisting of a neural simulation of thalamus and cortex during stage N2 sleep and a biophysical model projecting cortical current densities to M/EEG fields. Sleep spindles were generated through the interactions of local and distant network connections and intrinsic currents within thalamocortical circuits. 32,652 cortical neurons were mapped onto the cortical surface reconstructed from subjects' MRI, interconnected based on geodesic distances, and scaled-up to current dipole densities based on laminar recordings in humans. MRIs were used to generate a quasi-static electromagnetic model enabling simulated cortical activity to be projected to the M/EEG sensors. RESULTS: The simulated M/EEG spindles were similar in amplitude and topography to empirical examples in the same subjects. Simulated spindles with more core-dominant activity were more MEG weighted. COMPARISON WITH EXISTING METHODS: Previous models lacked either spindle-generating thalamic neural dynamics or whole head biophysical modeling; the framework presented here is the first to simultaneously capture these disparate scales. CONCLUSIONS: This multiscale model provides a platform for the principled quantitative integration of existing information relevant to the generation of sleep spindles, and allows the implications of future findings to be explored. It provides a proof of principle for a methodological framework allowing large-scale integrative brain oscillations to be understood in terms of their underlying channels and synapses.

Heterogeneous release properties of visualized individual hippocampal synapses.

We have used endocytotic uptake of the styryl dye FM1-43 at synaptic terminals (Betz and Bewick, 1992) to study properties of individual synapses formed by axons of single hippocampal neurons in tissue culture. The distribution of values for probability of evoked transmitter release p estimated by dye uptake is continuous, with a preponderance of low p synapses and a broad spread of probabilities. We have validated this method by demonstrating that the optically estimated distribution of p at autapses in single-neuron microislands predicts, with no free parameters, the rate of blocking of NMDA responses by the noncompetitive antagonist MK-801 at the same synapses. Different synapses made by a single axon exhibited varying amounts of paired-pulse modulation; synapses with low p tended to be facilitated more than those with high p. The increment in release probability produced by increasing external calcium ion concentration also depended on a synapse's initial p value. The size of the recycling pool of vesicles was strongly correlated with p as well, suggesting that synapses with higher release probabilities had more vesicles. Finally, p values of neighboring synapses were correlated, indicating local interactions in the dendrite or axon, or both.

Calcium-induced release of calcium regulates differentiation of cultured spinal neurons.

Voltage-dependent calcium influx has been shown to regulate the differentiation of cultured amphibian spinal neurons. We have examined the transient elevation of intracellular calcium induced by depolarization, using calcium indicators and confocal microscopy with high temporal and spatial resolution. Rapid calcium elevations in both the nucleus and the cytosol are primarily due to calcium-dependent release of calcium from intracellular stores. Depletion of stores associated with the endoplasmic reticulum reduces all transients. Elevations diminish with neuronal maturation. Depletion of stores of intracellular calcium at early times affects neuronal differentiation in a manner similar to the prevention of influx. The results indicate that both influx and release are necessary to promote neuronal differentiation.

Model of cellular and network mechanisms for odor-evoked temporal patterning in the locust antennal lobe.

Locust antennal lobe (AL) projection neurons (PNs) respond to olfactory stimuli with sequences of depolarizing and hyperpolarizing epochs, each lasting hundreds of milliseconds. A computer simulation of an AL network was used to test the hypothesis that slow inhibitory connections between local neurons (LNs) and PNs are responsible for temporal patterning. Activation of slow inhibitory receptors on PNs by the same GABAergic synapses that underlie fast oscillatory synchronization of PNs was sufficient to shape slow response modulations. This slow stimulus- and neuron-specific patterning of AL activity was resistant to blockade of fast inhibition. Fast and slow inhibitory mechanisms at synapses between LNs and PNs can thus form dynamical PN assemblies whose elements synchronize transiently and oscillate collectively, as observed not only in the locust AL, but also in the vertebrate olfactory bulb.

A model of spike initiation in neocortical pyramidal neurons.

Neocortical pyramidal cells possess voltage-dependent dendritic sodium channels that promote propagation of action potentials into the dendritic tree but paradoxically may fail to originate dendritic spikes. A biophysical model was constructed to reconcile these observations with known anatomical and physiological properties. When dendritic and somatic sodium channel densities compatible with electrophysiological measurements were combined with much higher densities in the axon initial segment then, regardless of the site of stimulation, spikes initiated at the initial segment and subsequently invaded the dendrites. The lower initial segment threshold arose from high current density and electrical isolation from the soma. Failure of dendritic channels to initiate spikes was due to inactivation and source-load considerations, which were more favorable for conduction of back-propagated spikes.

Model of transient oscillatory synchronization in the locust antennal lobe.

Transient pairwise synchronization of locust antennal lobe (AL) projection neurons (PNs) occurs during odor responses. In a Hodgkin-Huxley-type model of the AL, interactions between excitatory PNs and inhibitory local neurons (LNs) created coherent network oscillations during odor stimulation. GABAergic interconnections between LNs led to competition among them such that different groups of LNs oscillated with periodic Ca(2+) spikes during different 50-250 ms temporal epochs, similar to those recorded in vivo. During these epochs, LN-evoked IPSPs caused phase-locked, population oscillations in sets of postsynaptic PNs. The model shows how alternations of the inhibitory drive can temporally encode sensory information in networks of neurons without precisely tuned intrinsic oscillatory properties.

The role of RNA editing of kainate receptors in synaptic plasticity and seizures.

The ionotropic glutamate receptor subunit GluR6 undergoes developmentally and regionally regulated Q/R site RNA editing that reduces the calcium permeability of GluR6-containing kainate receptors. To investigate the functional significance of this editing in vivo, we engineered mice deficient in GluR6 Q/R site editing. In these mutant mice but not in wild types, NMDA receptor-independent long-term potentiation (LTP) could be induced at the medial perforant path-dentate gyrus synapse. This indicates that kainate receptors with unedited GluR6 subunits can mediate LTP. Behavioral analyses revealed no differences from wild types, but mutant mice were more vulnerable to kainate-induced seizures. Together, these results suggest that GluR6 Q/R site RNA editing may modulate synaptic plasticity and seizure vulnerability.

Self-sustained rhythmic activity in the thalamic reticular nucleus mediated by depolarizing GABAA receptor potentials.

Intracellular recordings from reticular thalamic (RE) neurons in vivo revealed inhibitory postsynaptic potentials (IPSPs) between RE cells that reversed and became depolarizing at the hyperpolarized membrane potentials that occur during sleep. These excitatory IPSPs can directly trigger low-threshold spikes (LTSs). The oscillatory mechanisms underlying IPSP-triggered LTSs crowned by spike bursts were investigated in models of isolated RE networks. In a one-dimensional network model, external stimulation evoked waves of excitation propagating at a constant velocity of 25-150 cells per second. In a large-scale, two-dimensional model of the reticular nucleus, the network showed transient or self-sustained oscillations controlled by the maximum conductance of the low-threshold calcium current and the membrane potential. This model predicts that the isolated reticular nucleus could initiate sequences of spindle oscillations in thalamocortical networks in vivo.

Neurocomputational models of working memory.

During working memory tasks, the firing rates of single neurons recorded in behaving monkeys remain elevated without external cues. Modeling studies have explored different mechanisms that could underlie this selective persistent activity, including recurrent excitation within cell assemblies, synfire chains and single-cell bistability. The models show how sustained activity can be stable in the presence of noise and distractors, how different synaptic and voltage-gated conductances contribute to persistent activity, how neuromodulation could influence its robustness, how completely novel items could be maintained, and how continuous attractor states might be achieved. More work is needed to address the full repertoire of neural dynamics observed during working memory tasks.

Neural networks. Sleep and memory.

Recent experimental and theoretical advances suggest that memories may be reorganized in the cortex during sleep.

Time series prediction of plasma hormone concentration. Evidence for differences in predictability of parathyroid hormone secretion between osteoporotic patients and normal controls.

Recent evidence links osteoporosis, a disease of bone remodeling, to changes in the dynamics of parathyroid hormone secretion. We use nonlinear and linear time series prediction to characterize the secretory dynamics of parathyroid hormone in both healthy human subjects and patients with osteoporosis. Osteoporotic patients appear to lack the periods of high predictability found in normal humans. Our results may provide an explanation for why an intermittent administration of parathyroid hormone is effective in restoring bone mass in osteoporotic patients.