Publications by authors named "Roger D Traub"

67 Publications

Processing of cell assemblies in the lateral entorhinal cortex.

Rev Neurosci 2022 Apr 22. Epub 2022 Apr 22.

Hull York Medical School, Heslington, York, YO10 5DD, UK.

There is evidence that olfactory cortex responds to its afferent input with the generation of cell assemblies: collections of principal neurons that fire together over a time scale of tens of ms. If such assemblies form an odor representation, then a fundamental question is how each assembly then induces neuronal activity in downstream structures. We have addressed this question in a detailed model of superficial layers of lateral entorhinal cortex, a recipient of input from olfactory cortex and olfactory bulb. Our results predict that the response of the fan cell subpopulation can be approximated by a relatively simple Boolean process, somewhat along the lines of the McCulloch/Pitts scheme; this is the case because of the sparsity of recurrent excitation amongst fan cells. However, because of recurrent excitatory connections between layer 2 and layer 3 pyramidal cells, synaptic and probably also gap junctional, the response of pyramidal cell subnetworks cannot be so approximated. Because of the highly structured anatomy of entorhinal output projections, our model suggests that downstream targets of entorhinal cortex (dentate gyrus, hippocampal CA3, CA1, piriform cortex, olfactory bulb) receive differentially processed information.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/revneuro-2022-0011DOI Listing
April 2022

A hypothesis concerning distinct schemes of olfactory activation evoked by perceived versus nonperceived input.

Proc Natl Acad Sci U S A 2022 03 1;119(10):e2120093119. Epub 2022 Mar 1.

Department of Biology, Hull York Medical School, York YO10 5DD, United Kingdom.

SignificanceThe authors propose that odors are consciously perceived or not, depending on whether the olfactory cortex succeeds in activating the endopiriform nucleus-a structure that, in turn, is capable of activating multiple downstream brain areas. The authors further propose that the cellular mechanisms of endopiriform nucleus activation are an attenuated form of cellular events that occur during epileptic seizure initiation. If correct, the authors' hypothesis could help explain the mechanisms of action of certain general anesthetics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2120093119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8915958PMC
March 2022

Cell assembly formation and structure in a piriform cortex model.

Rev Neurosci 2022 02 15;33(2):111-132. Epub 2021 Jul 15.

Hull York Medical School, Heslington, York YO10 5DD, UK.

The piriform cortex is rich in recurrent excitatory synaptic connections between pyramidal neurons. We asked how such connections could shape cortical responses to olfactory lateral olfactory tract (LOT) inputs. For this, we constructed a computational network model of anterior piriform cortex with 2000 multicompartment, multiconductance neurons (500 semilunar, 1000 layer 2 and 500 layer 3 pyramids; 200 superficial interneurons of two types; 500 deep interneurons of three types; 500 LOT afferents), incorporating published and unpublished data. With a given distribution of LOT firing patterns, and increasing the strength of recurrent excitation, a small number of firing patterns were observed in pyramidal cell networks: first, sparse firings; then temporally and spatially concentrated epochs of action potentials, wherein each neuron fires one or two spikes; then more synchronized events, associated with bursts of action potentials in some pyramidal neurons. We suggest that one function of anterior piriform cortex is to transform ongoing streams of input spikes into temporally focused spike patterns, called here "cell assemblies", that are salient for downstream projection areas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/revneuro-2021-0056DOI Listing
February 2022

Alkaline brain pH shift in rodent lithium-pilocarpine model of epilepsy with chronic seizures.

Brain Res 2021 05 5;1758:147345. Epub 2021 Feb 5.

Harvard Medical School, Boston, MA, 02115, USA; Division of Newborn Medicine, Dept. Pediatrics, Boston Children's Hospital, Boston, MA, 02115, USA. Electronic address:

Brain pH is thought to be important in epilepsy. The regulation of brain pH is, however, still poorly understood in animal models of chronic seizures (SZ) as well as in patients with intractable epilepsy. We used chemical exchange saturation transfer (CEST) MRI to noninvasively determine if the pH is alkaline shifted in a rodent model of the mesial temporal lobe (MTL) epilepsy with chronic SZ. Taking advantage of its high spatial resolution, we determined the pH values in specific brain regions believed to be important in this model produced by lithium-pilocarpine injection. All animals developed status epilepticus within 90 min after the lithium-pilocarpine administration, but one animal died within 24 hrs. All the surviving animals developed chronic SZ during the first 2 months. After SZ developed, brain pH was determined in the pilocarpine and control groups (n = 8 each). Epileptiform activity was documented in six pilocarpine rats with scalp EEG. The brain pH was estimated using two methods based on magnetization transfer asymmetry and amide proton transfer ratio. The pH was alkaline shifted in the pilocarpine rats (one outlier excluded) compared to the controls in the hippocampus (7.29 vs 7.17, t-test, p < 0.03) and the piriform cortex (7.34 vs. 7.06, p < 0.005), marginally more alkaline in the thalamus (7.13 vs. 7.01, p < 0.05), but not in the cerebral cortex (7.18 vs. 7.08, p > 0.05). Normalizing the brain pH may lead to an effective non-surgical method for treating intractable epilepsy as it is known that SZ can be eliminated by lowering the pH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brainres.2021.147345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987840PMC
May 2021

Connexin36 localization along axon initial segments in the mammalian CNS.

Int J Physiol Pathophysiol Pharmacol 2020 15;12(6):153-165. Epub 2020 Dec 15.

Department of Physiology and Pathophysiology, Max Rady College of Medicine, University of Manitoba Winnipeg, Canada.

Electrical synapses formed by gap junctions occur at a variety of neuronal subcellular sites in the mammalian central nervous system (CNS), including at somatic, dendritic and axon terminal compartments. Numerous electrophysiological studies using mice and rats, as well as computer modelling approaches, have predicted the additional occurrence of electrical synapses between axons near their emergence from neuronal somata. Here, we used immunofluorescence methods to search for localization of the neuronal gap junction-forming protein connexin36 (Cx36) along axon initial segments (AISs) labelled for the AIS marker ankyrinG. Immunofluorescent Cx36-puncta were found to be associated with AISs in several CNS regions of mice, including the spinal cord, inferior olive and cerebral cortex. Localization of Cx36-puncta at AISs was confirmed by confocal single scan and 3D imaging, immunofluorescence intensity profiling and high resolution structured illumination microscopy (SIM). AISs measuring up to 30 µm in length displayed typically a single Cx36-punctum and the incidence of these long AISs displaying Cx36-puncta ranged from 3% to 7% in the inferior olive and in various layers of the cerebral cortex. In the inferior olive, the gap junction associated protein zonula occludens-1 (ZO-1) was found to be co-localized with Cx36-puncta on AISs, indicating that these puncta have some of the molecular constituents of gap junctions. Our results add to the neuronal subcellular locations at which Cx36 is deployed, and raise possibilities for its involvement in novel functions in the AIS compartment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811956PMC
December 2020

Epileptic Activity Intrinsically Generated in the Human Cerebellum.

Ann Neurol 2020 08 5;88(2):418-422. Epub 2020 Jun 5.

Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.

Neoplastic or dysplastic neuronal tissue in the brain stem and cerebellum can become epileptogenic in pediatric patients. However, it is unknown whether such tissue may transform intrinsic properties of the human cerebellum, making it capable of generating epileptic population activity. We noninvasively detected epileptiform signals unaveraged in a pediatric patient with epilepsy due to a tumor in the middle cerebellar peduncle. Analysis of generators of the signals revealed that the cerebellum ipsilateral and contralateral to the tumor was the dominant interictal spike generator and could initiate ictal activity, suggesting that human cerebellum may become capable of intrinsically generating epileptic activity. ANN NEUROL 2020;88:418-422.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25779DOI Listing
August 2020

Layer 4 pyramidal neuron dendritic bursting underlies a post-stimulus visual cortical alpha rhythm.

Commun Biol 2020 05 11;3(1):230. Epub 2020 May 11.

HYMS, University of York, Heslington, YO10 5DD, UK.

Alpha rhythms (9-11 Hz) are a dominant feature of EEG recordings, particularly over occipital cortex on cessation of a visual stimulation. Little is known about underlying neocortical mechanisms so here we constructed alpha rhythm models that follow cessation of cortical stimulation. The rhythm manifests following a period of gamma frequency activity in local V1 networks in layer 4. It associates with network level bias of excitatory synaptic activity in favour of NMDA- rather than AMPA-mediated signalling and reorganisation of synaptic inhibition in favour of fast GABA receptor-mediated events. At the cellular level the alpha rhythm depended upon the generation of layer 4 pyramidal neuron dendritic bursting mediated primarily by PPDA-sensitive NR2C/D-containing NMDA receptors, which lack the magnesium-dependent open channel block. Subthreshold potassium conductances are also critical. The rhythm dynamically filters outputs from sensory relay neurons (stellate neurons in layer 4) such that they become temporally uncoupled from downstream population activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42003-020-0947-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214406PMC
May 2020

A future for neuronal oscillation research.

Brain Neurosci Adv 2018 Jan-Dec;2:2398212818794827. Epub 2019 Mar 1.

Hull York Medical School, University of York, Heslington, UK.

Neuronal oscillations represent the most obvious feature of electrical activity in the brain. They are linked in general with global brain state (awake, asleep, etc.) and specifically with organisation of neuronal outputs during sensory perception and cognitive processing. Oscillations can be generated by individual neurons on the basis of interaction between inputs and intrinsic conductances but are far more commonly seen at the local network level in populations of interconnected neurons with diverse arrays of functional properties. It is at this level that the brain's rich and diverse library of oscillatory time constants serve to temporally organise large-scale neural activity patterns. The discipline is relatively mature at the microscopic (cell, local network) level - although novel discoveries are still commonplace - but requires a far greater understanding of mesoscopic and macroscopic brain dynamics than we currently hold. Without this, extrapolation from the temporal properties of neurons and their communication strategies up to whole brain function will remain largely theoretical. However, recent advances in large-scale neuronal population recordings and more direct, higher fidelity, non-invasive measurement of whole brain function suggest much progress is just around the corner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2398212818794827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058255PMC
March 2019

Could electrical coupling contribute to the formation of cell assemblies?

Rev Neurosci 2020 01;31(2):121-141

Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg R3E OJ9, MB, Canada.

Cell assemblies and central pattern generators (CPGs) are related types of neuronal networks: both consist of interacting groups of neurons whose collective activities lead to defined functional outputs. In the case of a cell assembly, the functional output may be interpreted as a representation of something in the world, external or internal; for a CPG, the output 'drives' an observable (i.e. motor) behavior. Electrical coupling, via gap junctions, is critical for the development of CPGs, as well as for their actual operation in the adult animal. Electrical coupling is also known to be important in the development of hippocampal and neocortical principal cell networks. We here argue that electrical coupling - in addition to chemical synapses - may therefore contribute to the formation of at least some cell assemblies in adult animals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/revneuro-2019-0059DOI Listing
January 2020

Seizure initiation in infantile spasms vs. focal seizures: proposed common cellular mechanisms.

Rev Neurosci 2020 01;31(2):181-200

Hull York Medical School, University of York, Heslington YO10 5DD, UK.

Infantile spasms (IS) and seizures with focal onset have different clinical expressions, even when electroencephalography (EEG) associated with IS has some degree of focality. Oddly, identical pathology (with, however, age-dependent expression) can lead to IS in one patient vs. focal seizures in another or even in the same, albeit older, patient. We therefore investigated whether the cellular mechanisms underlying seizure initiation are similar in the two instances: spasms vs. focal. We noted that in-common EEG features can include (i) a background of waves at alpha to delta frequencies; (ii) a period of flattening, lasting about a second or more - the electrodecrement (ED); and (iii) often an interval of very fast oscillations (VFO; ~70 Hz or faster) preceding, or at the beginning of, the ED. With IS, VFO temporally coincides with the motor spasm. What is different between the two conditions is this: with IS, the ED reverts to recurring slow waves, as occurring before the ED, whereas with focal seizures the ED instead evolves into an electrographic seizure, containing high-amplitude synchronized bursts, having superimposed VFO. We used in vitro data to help understand these patterns, as such data suggest cellular mechanisms for delta waves, for VFO, for seizure-related burst complexes containing VFO, and, more recently, for the ED. We propose a unifying mechanistic hypothesis - emphasizing the importance of brain pH - to explain the commonalities and differences of EEG signals in IS versus focal seizures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/revneuro-2019-0030DOI Listing
January 2020

Theta/delta coupling across cortical laminae contributes to semantic cognition.

J Neurophysiol 2019 04 30;121(4):1150-1161. Epub 2019 Jan 30.

Hull York Medical School, University of York , York , United Kingdom.

Rhythmic activity in populations of neurons is associated with cognitive and motor function. Our understanding of the neuronal mechanisms underlying these core brain functions has benefitted from demonstrations of cellular, synaptic, and network phenomena, leading to the generation of discrete rhythms at the local network level. However, discrete frequencies of rhythmic activity rarely occur alone. Despite this, little is known about why multiple rhythms are generated together or what mechanisms underlie their interaction to promote brain function. One overarching theory is that different temporal scales of rhythmic activity correspond to communication between brain regions separated by different spatial scales. To test this, we quantified the cross-frequency interactions between two dominant rhythms-theta and delta activity-manifested during magnetoencephalography recordings of subjects performing a word-pair semantic decision task. Semantic processing has been suggested to involve the formation of functional links between anatomically disparate neuronal populations over a range of spatial scales, and a distributed network was manifest in the profile of theta-delta coupling seen. Furthermore, differences in the pattern of theta-delta coupling significantly correlated with semantic outcome. Using an established experimental model of concurrent delta and theta rhythms in neocortex, we show that these outcome-dependent dynamics could be reproduced in a manner determined by the strength of cholinergic neuromodulation. Theta-delta coupling correlated with discrete neuronal activity motifs segregated by the cortical layer, neuronal intrinsic properties, and long-range axonal targets. Thus, the model suggested that local, interlaminar neocortical theta-delta coupling may serve to coordinate both cortico-cortical and cortico-subcortical computations during distributed network activity. NEW & NOTEWORTHY Here, we show, for the first time, that a network of spatially distributed brain regions can be revealed by cross-frequency coupling between delta and theta frequencies in subjects using magnetoencephalography recording during a semantic decision task. A biological model of this cross-frequency coupling suggested an interlaminar, cell-specific division of labor within the neocortex may serve to route the flow of cortico-cortical and cortico-subcortical information to promote such spatially distributed, functional networks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/jn.00686.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485732PMC
April 2019

Electrical coupling between hippocampal neurons: contrasting roles of principal cell gap junctions and interneuron gap junctions.

Cell Tissue Res 2018 Sep 15;373(3):671-691. Epub 2018 Aug 15.

Institut für Physiologie und Pathophysiologie, Universität Heidelberg, Im Neuenheimer Feld 326, 69120, Heidelberg, Germany.

There is considerable experimental evidence, anatomical and physiological, that gap junctions exist in the hippocampus. Electrical coupling through these gap junctions may be divided into three types: between principal neurons, between interneurons and at mixed chemical (glutamatergic)/electrical synapses. An approach, combining in vitro experimental with modeling techniques, sheds some light on the functional consequences of electrical coupling, for network oscillations and for seizures. Additionally, in vivo experiments, using mouse connexin knockouts, suggest that the presence of electrical coupling is important for optimal performance on selected behavioral tasks; however, the interpretation of such data, in cellular terms, has so far proven difficult. Given that invertebrate central pattern generators so often depend on both chemical and electrical synapses, our hypothesis is that hippocampus-mediated and -influenced behaviors will act likewise. Experiments, likely hard ones, will be required to test this intuition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00441-018-2881-3DOI Listing
September 2018

Does Epileptiform Activity Represent a Failure of Neuromodulation to Control Central Pattern Generator-Like Neocortical Behavior?

Front Neural Circuits 2017 18;11:78. Epub 2017 Oct 18.

Department of Biology, Hull York Medical School, University of York, York, United Kingdom.

Rhythmic motor patterns in invertebrates are often driven by specialized "central pattern generators" (CPGs), containing small numbers of neurons, which are likely to be "identifiable" in one individual compared with another. The dynamics of any particular CPG lies under the control of modulatory substances, amines, or peptides, entering the CPG from outside it, or released by internal constituent neurons; consequently, a particular CPG can generate a given rhythm at different frequencies and amplitudes, and perhaps even generate a repertoire of distinctive patterns. The mechanisms exploited by neuromodulators in this respect are manifold: Intrinsic conductances (e.g., calcium, potassium channels), conductance state of postsynaptic receptors, degree of plasticity, and magnitude and kinetics of transmitter release can all be affected. The CPG concept has been generalized to vertebrate motor pattern generating circuits (e.g., for locomotion), which may contain large numbers of neurons - a construct that is sensible, if there is enough redundancy: that is, the number of neurons consists of only a number of classes, and the cells within any one class act stereotypically. Here we suggest that CPG and modulator ideas may also help to understand cortical oscillations, normal ones, and particularly transition to epileptiform pathology. Furthermore, in the case illustrated, the mechanism of the transition appears to be an exaggerated form of a normal modulatory action used to influence sensory processing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fncir.2017.00078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651241PMC
July 2018

Enhanced interlaminar excitation or reduced superficial layer inhibition in neocortex generates different spike-and-wave-like electrographic events in vitro.

J Neurophysiol 2018 01 27;119(1):49-61. Epub 2017 Sep 27.

Hull York Medical School, University of York , Heslington , United Kingdom.

Acute in vitro models have revealed a great deal of information about mechanisms underlying many types of epileptiform activity. However, few examples exist that shed light on spike-and-wave (SpW) patterns of pathological activity. SpW are seen in many epilepsy syndromes, both generalized and focal, and manifest across the entire age spectrum. They are heterogeneous in terms of their severity, symptom burden, and apparent anatomical origin (thalamic, neocortical, or both), but any relationship between this heterogeneity and underlying pathology remains elusive. In this study we demonstrate that physiological delta-frequency rhythms act as an effective substrate to permit modeling of SpW of cortical origin and may help to address this issue. For a starting point of delta activity, multiple subtypes of SpW could be modeled computationally and experimentally by either enhancing the magnitude of excitatory synaptic events ascending from neocortical layer 5 to layers 2/3 or selectively modifying superficial layer GABAergic inhibition. The former generated SpW containing multiple field spikes with long interspike intervals, whereas the latter generated SpW with short-interval multiple field spikes. Both types had different laminar origins and each disrupted interlaminar cortical dynamics in a different manner. A small number of examples of human recordings from patients with different diagnoses revealed SpW subtypes with the same temporal signatures, suggesting that detailed quantification of the pattern of spikes in SpW discharges may be a useful indicator of disparate underlying epileptogenic pathologies. NEW & NOTEWORTHY Spike-and-wave-type discharges (SpW) are a common feature in many epilepsies. Their electrographic manifestation is highly varied, as are available genetic clues to associated underlying pathology. Using computational and in vitro models, we demonstrate that distinct subtypes of SpW are generated by lamina-selective disinhibition or enhanced interlaminar excitation. These subtypes could be detected in at least some noninvasive patient recordings, suggesting more detailed analysis of SpW may be useful in determining clinical pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/jn.00516.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866469PMC
January 2018

Aberrant Network Activity in Schizophrenia.

Trends Neurosci 2017 06 14;40(6):371-382. Epub 2017 May 14.

Hull York Medical School, University of York, Heslington, YO10 5DD, UK. Electronic address:

Brain dynamic changes associated with schizophrenia are largely equivocal, with interpretation complicated by many factors, such as the presence of therapeutic agents and the complex nature of the syndrome itself. Evidence for a brain-wide change in individual network oscillations, shared by all patients, is largely equivocal, but stronger for lower (delta) than for higher (gamma) bands. However, region-specific changes in rhythms across multiple, interdependent, nested frequencies may correlate better with pathology. Changes in synaptic excitation and inhibition in schizophrenia disrupt delta rhythm-mediated cortico-cortical communication, while enhancing thalamocortical communication in this frequency band. The contrasting relationships between delta and higher frequencies in thalamus and cortex generate frequency mismatches in inter-regional connectivity, leading to a disruption in temporal communication between higher-order brain regions associated with mental time travel.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tins.2017.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5523137PMC
June 2017

Electrographic waveform structure predicts laminar focus location in a model of temporal lobe seizures in vitro.

PLoS One 2015 23;10(3):e0121676. Epub 2015 Mar 23.

Hull York Medical School, The University of York, York, United Kingdom.

Temporal lobe epilepsy is the most common form of partial-onset epilepsy and accounts for the majority of adult epilepsy cases in most countries. A critical role for the hippocampus (and to some extent amygdala) in the pathology of these epilepsies is clear, with selective removal of these regions almost as effective as temporal lobectomy in reducing subsequent seizure risk. However, there is debate about whether hippocampus is 'victim' or 'perpetrator': The structure is ideally placed to 'broadcast' epileptiform activity to a great many other brain regions, but removal often leaves epileptiform events still occurring in cortex, particularly in adjacent areas, and recruitment of the hippocampus into seizure-like activity has been shown to be difficult in clinically-relevant models. Using a very simple model of acute epileptiform activity with known, single primary pathology (GABAA Receptor partial blockade), we track the onset and propagation of epileptiform events in hippocampus, parahippocampal areas and neocortex. In this model the hippocampus acts as a potential seizure focus for the majority of observed events. Events with hippocampal focus were far more readily propagated throughout parahippocampal areas and into neocortex than vice versa. The electrographic signature of events of hippocampal origin was significantly different to those of primary neocortical origin - a consequence of differential laminar activation. These data confirm the critical role of the hippocampus in epileptiform activity generation in the temporal lobe and suggest the morphology of non-invasive electrical recording of neocortical interictal events may be useful in confirming this role.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121676PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370580PMC
March 2016

What is a seizure network? Very fast oscillations at the interface between normal and epileptic brain.

Adv Exp Med Biol 2014 ;813:71-80

IBM T.J. Watson Research Center, Yorktown Heights, NY, 10598, USA,

Although there is a great multiplicity of normal brain electrical activities, one can observe defined, relatively abrupt, transitions between apparently normal rhythms and clearly abnormal, higher amplitude, "epileptic" signals; transitions occur over tens of ms to many seconds. Transitional activity typically consists of low-amplitude very fast oscillations (VFO). Examination of this VFO provides insight into system parameters that differentiate the "normal" from the "epileptic." Remarkably, VFO in vitro is generated by principal neuron gap junctions, and occurs readily when chemical synapses are suppressed, tissue pH is elevated, and [Ca(2+)]o is low. Because VFO originates in principal cell axons that fire at high frequencies, excitatory synapses may experience short-term plasticity. If the latter takes the form of potentiation of recurrent synapses on principal cells, and depression of these on inhibitory interneurons, then the stage is set for synchronized bursting - if [Ca(2+)]o recovers sufficiently. Our hypothesis can be tested (in part) in patients, once it is possible to measure brain tissue parameters (pH, [Ca(2+)]o) simultaneously with ECoG.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-94-017-8914-1_6DOI Listing
November 2014

Gap junction networks can generate both ripple-like and fast ripple-like oscillations.

Eur J Neurosci 2014 Jan 14;39(1):46-60. Epub 2013 Oct 14.

Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, UK.

Fast ripples (FRs) are network oscillations, defined variously as having frequencies of > 150 to > 250 Hz, with a controversial mechanism. FRs appear to indicate a propensity of cortical tissue to originate seizures. Here, we demonstrate field oscillations, at up to 400 Hz, in spontaneously epileptic human cortical tissue in vitro, and present a network model that could explain FRs themselves, and their relation to 'ordinary' (slower) ripples. We performed network simulations with model pyramidal neurons, having axons electrically coupled. Ripples (< 250 Hz) were favored when conduction of action potentials, axon to axon, was reliable. Whereas ripple population activity was periodic, firing of individual axons varied in relative phase. A switch from ripples to FRs took place when an ectopic spike occurred in a cell coupled to another cell, itself multiply coupled to others. Propagation could then start in one direction only, a condition suitable for re-entry. The resulting oscillations were > 250 Hz, were sustained or interrupted, and had little jitter in the firing of individual axons. The form of model FR was similar to spontaneously occurring FRs in excised human epileptic tissue. In vitro, FRs were suppressed by a gap junction blocker. Our data suggest that a given network can produce ripples, FRs, or both, via gap junctions, and that FRs are favored by clusters of axonal gap junctions. If axonal gap junctions indeed occur in epileptic tissue, and are mediated by connexin 26 (recently shown to mediate coupling between immature neocortical pyramidal cells), then this prediction is testable.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejn.12386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026274PMC
January 2014

Synaptic gating at axonal branches, and sharp-wave ripples with replay: a simulation study.

Eur J Neurosci 2013 Nov 1;38(10):3435-47. Epub 2013 Sep 1.

IBM T. J. Watson Research Center, Yorktown Heights, NY, USA.

Mechanisms of place cell replay occurring during sharp-wave ripples (SPW-Rs) remain obscure due to the fact that ripples in vitro depend on non-synaptic mechanisms, presumably via axo-axonal gap junctions between pyramidal cells. We suggest a model of in vivo SPW-Rs in which synaptic excitatory post-synaptic potentials (EPSPs) control the axonal spiking of cells in SPW-Rs: ripple activity remains hidden in the network of axonal collaterals (connected by gap junctions) due to conduction failures, unless there is a sufficient dendritic EPSP. The EPSP brings the axonal branching point to threshold, and action potentials from the collateral start to propagate to the soma and to the distal axon. The model coherently explains multiple experimental data on SPW-Rs, both in vitro and in vivo. The mechanism of synaptic gating leads to the following implication: a sequence of pyramidal cells can be replayed at ripple frequency by the superposition of subthreshold dendritic EPSPs and ripple activity in the axonal plexus. Replay is demonstrated in both forward and reverse directions. We discuss several testable predictions. In general, the mechanism of synaptic gating suggests that pyramidal cells under certain conditions can act like a transistor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejn.12342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860898PMC
November 2013

A neocortical delta rhythm facilitates reciprocal interlaminar interactions via nested theta rhythms.

J Neurosci 2013 Jun;33(26):10750-61

Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom.

Delta oscillations (1-4 Hz) associate with deep sleep and are implicated in memory consolidation and replay of cortical responses elicited during wake states. A potent local generator has been characterized in thalamus, and local generators in neocortex have been suggested. Here we demonstrate that isolated rat neocortex generates delta rhythms in conditions mimicking the neuromodulatory state during deep sleep (low cholinergic and dopaminergic tone). The rhythm originated in an NMDA receptor-driven network of intrinsic bursting (IB) neurons in layer 5, activating a source of GABAB receptor-mediated inhibition. In contrast, regular spiking (RS) neurons in layer 5 generated theta-frequency outputs. In layer 2/3 principal cells, outputs from IB cells associated with IPSPs, whereas those from layer 5 RS neurons related to nested bursts of theta-frequency EPSPs. Both interlaminar spike and field correlations revealed a sequence of events whereby sparse spiking in layer 2/3 was partially reflected back from layer 5 on each delta period. We suggest that these reciprocal, interlaminar interactions may represent a "Helmholtz machine"-like process to control synaptic rescaling during deep sleep.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.0735-13.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693056PMC
June 2013

Rates and rhythms: a synergistic view of frequency and temporal coding in neuronal networks.

Neuron 2012 Aug;75(4):572-83

Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

In the CNS, activity of individual neurons has a small but quantifiable relationship to sensory representations and motor outputs. Coactivation of a few 10s to 100s of neurons can code sensory inputs and behavioral task performance within psychophysical limits. However, in a sea of sensory inputs and demand for complex motor outputs how is the activity of such small subpopulations of neurons organized? Two theories dominate in this respect: increases in spike rate (rate coding) and sharpening of the coincidence of spiking in active neurons (temporal coding). Both have computational advantages and are far from mutually exclusive. Here, we review evidence for a bias in neuronal circuits toward temporal coding and the coexistence of rate and temporal coding during population rhythm generation. The coincident expression of multiple types of gamma rhythm in sensory cortex suggests a mechanistic substrate for combining rate and temporal codes on the basis of stimulus strength.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuron.2012.08.004DOI Listing
August 2012

Axonal properties determine somatic firing in a model of in vitro CA1 hippocampal sharp wave/ripples and persistent gamma oscillations.

Eur J Neurosci 2012 Sep 15;36(5):2650-60. Epub 2012 Jun 15.

Department of Physical Sciences, IBM T.J. Watson Research Center, Yorktown Heights, NY, USA.

Evidence has been presented that CA1 pyramidal cells, during spontaneous in vitro sharp wave/ripple (SPW-R) complexes, generate somatic action potentials that originate in axons. 'Participating' (somatically firing) pyramidal cells fire (almost always) at most once during a particular SPW-R whereas non-participating cells virtually never fire during an SPW-R. Somatic spikelets were small or absent, while ripple-frequency EPSCs and IPSCs occurred during the SPW-R in pyramidal neurons. These experimental findings could be replicated with a network model in which electrical coupling was present between small pyramidal cell axonal branches. Here, we explore this model in more depth. Factors that influence somatic participation include: (i) the diameter of axonal branches that contain coupling sites to other axons, because firing in larger branches injects more current into the main axon, increasing antidromic firing probability; (ii) axonal K(+) currents and (iii) somatic hyperpolarization and shunting. We predict that portions of axons fire at high frequency during SPW-R, while somata fire much less. In the model, somatic firing can occur by occasional generation of full action potentials in proximal axonal branches, which are excited by high-frequency spikelets. When the network contains phasic synaptic inhibition, at the axonal gap junction site, gamma oscillations result, again with more frequent axonal firing than somatic firing. Combining the models, so as to generate gamma followed by sharp waves, leads to strong overlap between the population of cells firing during gamma and the population of cells firing during a subsequent sharp wave, as observed in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1460-9568.2012.08184.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433594PMC
September 2012

Glissandi: transient fast electrocorticographic oscillations of steadily increasing frequency, explained by temporally increasing gap junction conductance.

Epilepsia 2012 Jul 12;53(7):1205-14. Epub 2012 Jun 12.

Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.

Purpose: We describe a form of very fast oscillation (VFO) in patient electrocorticography (ECoG) recordings, that can occur prior to ictal events, in which the frequency increases steadily from ≈ 30-40 to >120 Hz, over a period of seconds. We dub these events "glissandi" and describe a possible model for them.

Methods: Four patients with epilepsy had presurgical evaluations (with ECoG obtained in two of them), and excised tissue was studied in vitro, from three of the patients. Glissandi were seen spontaneously in vitro, associated with ictal events-using acute slices of rat neocortex-and they were simulated using a network model of 15,000 detailed layer V pyramidal neurons, coupled by gap junctions.

Key Findings: Glissandi were observed to arise from human temporal neocortex. In vitro, they lasted 0.2-4.1 s, prior to ictal onset. Similar events were observed in the rat in vitro in layer V of frontal neocortex when alkaline solution was pressure-ejected; glissandi persisted when γ-aminobutyric acid A (GABA(A)), GABA(B), and N-methyl-d-aspartate (NMDA), and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors were blocked. Nonalkaline conditions prevented glissando generation. In network simulations it was found that steadily increasing gap junction conductance would lead to the observed steady increase in VFO field frequency. This occurred because increasing gap junction conductance shortened the time required for an action potential to cross from cell to cell.

Significance: The in vitro and modeling data are consistent with the hypothesis that glissandi arise when pyramidal cell gap junction conductances rise over time, possibly as a result of an alkaline fluctuation in brain pH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1528-1167.2012.03530.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389590PMC
July 2012

Mixed Electrical-Chemical Synapses in Adult Rat Hippocampus are Primarily Glutamatergic and Coupled by Connexin-36.

Front Neuroanat 2012 15;6:13. Epub 2012 May 15.

Department of Neurosurgery, Mount Sinai School of Medicine New York, NY, USA.

Dendrodendritic electrical signaling via gap junctions is now an accepted feature of neuronal communication in mammalian brain, whereas axodendritic and axosomatic gap junctions have rarely been described. We present ultrastructural, immunocytochemical, and dye-coupling evidence for "mixed" (electrical/chemical) synapses on both principal cells and interneurons in adult rat hippocampus. Thin-section electron microscopic images of small gap junction-like appositions were found at mossy fiber (MF) terminals on thorny excrescences of CA3 pyramidal neurons (CA3pyr), apparently forming glutamatergic mixed synapses. Lucifer Yellow injected into weakly fixed CA3pyr was detected in MF axons that contacted four injected CA3pyr, supporting gap junction-mediated coupling between those two types of principal cells. Freeze-fracture replica immunogold labeling revealed diverse sizes and morphologies of connexin-36-containing gap junctions throughout hippocampus. Of 20 immunogold-labeled gap junctions, seven were large (328-1140 connexons), three of which were consistent with electrical synapses between interneurons; but nine were at axon terminal synapses, three of which were immediately adjacent to distinctive glutamate receptor-containing postsynaptic densities, forming mixed glutamatergic synapses. Four others were adjacent to small clusters of immunogold-labeled 10-nm E-face intramembrane particles, apparently representing extrasynaptic glutamate receptor particles. Gap junctions also were on spines in stratum lucidum, stratum oriens, dentate gyrus, and hilus, on both interneurons and unidentified neurons. In addition, one putative GABAergic mixed synapse was found in thin-section images of a CA3pyr, but none were found by immunogold labeling, suggesting the rarity of GABAergic mixed synapses. Cx36-containing gap junctions throughout hippocampus suggest the possibility of reciprocal modulation of electrical and chemical signals in diverse hippocampal neurons.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnana.2012.00013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3351785PMC
October 2012

Shortest Loops are Pacemakers in Random Networks of Electrically Coupled Axons.

Front Comput Neurosci 2012 3;6:17. Epub 2012 Apr 3.

IBM T. J. Watson Research Center Yorktown Heights, NY, USA.

High-frequency oscillations (HFOs) are an important part of brain activity in health and disease. However, their origins remain obscure and controversial. One possible mechanism depends on the presence of sparsely distributed gap junctions that electrically couple the axons of principal cells. A plexus of electrically coupled axons is modeled as a random network with bi-directional connections between its nodes. Under certain conditions the network can demonstrate one of two types of oscillatory activity. Type I oscillations (100-200 Hz) are predicted to be caused by spontaneously spiking axons in a network with strong (high conductance) gap junctions. Type II oscillations (200-300 Hz) require no spontaneous spiking and relatively weak (low-conductance) gap junctions, across which spike propagation failures occur. The type II oscillations are reentrant and self-sustained. Here we examine what determines the frequency of type II oscillations. Using simulations we show that the distribution of loop lengths is the key factor for determining frequency in type II network oscillations. We first analyze spike failure between two electrically coupled cells using a model of anatomically reconstructed CA1 pyramidal neuron. Then network oscillations are studied by a cellular automaton model with random network connectivity, in which we control loop statistics. We show that oscillation periods can be predicted from the network's loop statistics. The shortest loop, around which a spike can travel, is the most likely pacemaker candidate. The principle of one loop as a pacemaker is remarkable, because random networks contain a large number of loops juxtaposed and superimposed, and their number rapidly grows with network size. This principle allows us to predict the frequency of oscillations from network connectivity and visa versa. We finally propose that type I oscillations may correspond to ripples, while type II oscillations correspond to so-called fast ripples.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fncom.2012.00017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324298PMC
August 2012

Mixed electrical-chemical transmission between hippocampal mossy fibers and pyramidal cells.

Eur J Neurosci 2012 Jan 13;35(1):76-82. Epub 2011 Dec 13.

Department of Physiology, Biophysics and Neurosciences, Centro de Investigación y Estudios Avanzados del Instituto Politécnico Nacional, México, D.F., México.

Morphological and electrophysiological studies have shown that granule cell axons, the mossy fibers (MFs), establish gap junctions and therefore electrical communication among them. That granule cells express gap junctional proteins in their axons suggests the possibility that their terminals also express them. If this were to be the case, mixed electrical-chemical communication could be supported, as MF terminals normally use glutamate for fast communication with their target cells. Here we present electrophysiological studies in the rat and modeling studies consistent with this hypothesis. We show that MF activation produced fast spikelets followed by excitatory postsynaptic potentials in pyramidal cells (PCs), which, unlike the spikelets, underwent frequency potentiation and were strongly depressed by activation of metabotropic glutamate receptors, as expected from transmission of MF origin. The spikelets, which persisted during blockade of chemical transmission, were potentiated by dopamine and suppressed by the gap junction blocker carbenoxolone. The various waveforms evoked by MF stimulation were replicated in a multi-compartment model of a PC by brief current-pulse injections into the proximal apical dendritic compartment, where MFs are known to contact PCs. Mixed electrical and glutamatergic communication between granule cells and some PCs in CA3 may ensure the activation of sets of PCs, bypassing the strong action of concurrent feed-forward inhibition that granule cells activate. Importantly, MF-to-PC electrical coupling may allow bidirectional, possibly graded, communication that can be faster than chemical synapses and subject to different forms of modulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1460-9568.2011.07930.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3251635PMC
January 2012

Dual γ rhythm generators control interlaminar synchrony in auditory cortex.

J Neurosci 2011 Nov;31(47):17040-51

Institute of Neuroscience, Newcastle University, Newcastle, NE2 4HH, United Kingdom.

Rhythmic activity in populations of cortical neurons accompanies, and may underlie, many aspects of primary sensory processing and short-term memory. Activity in the gamma band (30 Hz up to >100 Hz) is associated with such cognitive tasks and is thought to provide a substrate for temporal coupling of spatially separate regions of the brain. However, such coupling requires close matching of frequencies in co-active areas, and because the nominal gamma band is so spectrally broad, it may not constitute a single underlying process. Here we show that, for inhibition-based gamma rhythms in vitro in rat neocortical slices, mechanistically distinct local circuit generators exist in different laminae of rat primary auditory cortex. A persistent, 30-45 Hz, gap-junction-dependent gamma rhythm dominates rhythmic activity in supragranular layers 2/3, whereas a tonic depolarization-dependent, 50-80 Hz, pyramidal/interneuron gamma rhythm is expressed in granular layer 4 with strong glutamatergic excitation. As a consequence, altering the degree of excitation of the auditory cortex causes bifurcation in the gamma frequency spectrum and can effectively switch temporal control of layer 5 from supragranular to granular layers. Computational modeling predicts the pattern of interlaminar connections may help to stabilize this bifurcation. The data suggest that different strategies are used by primary auditory cortex to represent weak and strong inputs, with principal cell firing rate becoming increasingly important as excitation strength increases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.2209-11.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654396PMC
November 2011

Cellular correlate of assembly formation in oscillating hippocampal networks in vitro.

Proc Natl Acad Sci U S A 2011 Aug 18;108(35):E607-16. Epub 2011 Jul 18.

Institute of Physiology and Pathophysiology, Medical Faculty, University of Heidelberg, D-69120 Heidelberg, Germany.

Neurons form transiently stable assemblies that may underlie cognitive functions, including memory formation. In most brain regions, coherent activity is organized by network oscillations that involve sparse firing within a well-defined minority of cells. Despite extensive work on the underlying cellular mechanisms, a fundamental question remains unsolved: how are participating neurons distinguished from the majority of nonparticipators? We used physiological and modeling techniques to analyze neuronal activity in mouse hippocampal slices during spontaneously occurring high-frequency network oscillations. Network-entrained action potentials were exclusively observed in a defined subset of pyramidal cells, yielding a strict distinction between participating and nonparticipating neurons. These spikes had unique properties, because they were generated in the axon without prior depolarization of the soma. GABA(A) receptors had a dual role in pyramidal cell recruitment. First, the sparse occurrence of entrained spikes was accomplished by intense perisomatic inhibition. Second, antidromic spike generation was facilitated by tonic effects of GABA in remote axonal compartments. Ectopic spike generation together with strong somatodendritic inhibition may provide a cellular mechanism for the definition of oscillating assemblies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1103546108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3167520PMC
August 2011

Wave speed in excitable random networks with spatially constrained connections.

PLoS One 2011 3;6(6):e20536. Epub 2011 Jun 3.

IBM T. J. Watson Research Center, Yorktown Heights, New York, United States of America.

Very fast oscillations (VFO) in neocortex are widely observed before epileptic seizures, and there is growing evidence that they are caused by networks of pyramidal neurons connected by gap junctions between their axons. We are motivated by the spatio-temporal waves of activity recorded using electrocorticography (ECoG), and study the speed of activity propagation through a network of neurons axonally coupled by gap junctions. We simulate wave propagation by excitable cellular automata (CA) on random (Erdös-Rényi) networks of special type, with spatially constrained connections. From the cellular automaton model, we derive a mean field theory to predict wave propagation. The governing equation resolved by the Fisher-Kolmogorov PDE fails to describe wave speed. A new (hyperbolic) PDE is suggested, which provides adequate wave speed v() that saturates with network degree , in agreement with intuitive expectations and CA simulations. We further show that the maximum length of connection is a much better predictor of the wave speed than the mean length. When tested in networks with various degree distributions, wave speeds are found to strongly depend on the ratio of network moments / rather than on mean degree , which is explained by general network theory. The wave speeds are strikingly similar in a diverse set of networks, including regular, Poisson, exponential and power law distributions, supporting our theory for various network topologies. Our results suggest practical predictions for networks of electrically coupled neurons, and our mean field method can be readily applied for a wide class of similar problems, such as spread of epidemics through spatial networks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0020536PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108581PMC
September 2011
-->