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Miles A Whittington

Publications and source records attributed to Miles A Whittington.

At least 19 recordsLinked to original sources
PubMed2006

A beta2-frequency (20-30 Hz) oscillation in nonsynaptic networks of somatosensory cortex.

Beta2 frequency (20-30 Hz) oscillations appear over somatosensory and motor cortices in vivo during motor preparation and can be coherent with muscle electrical activity. We describe a beta2 frequency oscillation occurring in vitro in networks of layer V pyramidal cells, the cells of origin of the corticospinal tract. This beta2 oscillation depends on gap junctional coupling, but it survives a cut through layer 4 and, hence, does not depend on apical dendritic electrogenesis. It also survives a blockade of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors or a blockade of GABA(A) receptors that is sufficient to suppress gamma (30-70 Hz) oscillations in superficial cortical layers. The oscillation period is determined by the M type of K+ current.

Action Potentials↗
PubMed2006

Region-specific reduction in entorhinal gamma oscillations and parvalbumin-immunoreactive neurons in animal models of psychiatric illness.

Psychiatric illnesses, particularly schizophrenia, are associated with disrupted markers for interneuronal function and interneuron-mediated brain rhythms such as gamma frequency oscillations. Here we investigate a possible link between these two observations in the entorhinal cortex and hippocampus by using a genetic and an acute model of psychiatric illness. Lysophosphatidic acid 1 receptor-deficient (LPA1-deficient) mice show psychomotor-gating deficits and neurochemical changes resembling those seen in postmortem schizophrenia studies. Similar deficits are seen acutely with antagonism of the NMDA subtype of glutamate receptor. Neither model induced any change in power or frequency of gamma rhythms generated by kainate in hippocampal slices. In contrast, a dramatic decrease in the power of gamma oscillations was seen in superficial, but not deep, medial entorhinal cortex layers in both models. Immunolabeling for GABA, parvalbumin, and calretinin in medial entorhinal cortex from LPA1-deficient mice showed an approximately 40% reduction in total GABA- and parvalbumin-containing neurons, but no change in the number of calretinin-positive neurons. This deficit was specific for layer II (LII). No change in the number of neurons positive for these markers was seen in the hippocampus. Acute NMDA receptor blockade, which selectively reduces synaptic drive to LII entorhinal interneurons, also disrupted gamma rhythms in a similar manner in superficial entorhinal cortex, but not in hippocampus. These data demonstrate an area-specific deficit in gamma rhythmogenesis in animal models of psychiatric illness and suggest that loss, or reduction in function, of interneurons having a large NMDA receptor expression may underlie the network dysfunction that is seen.

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PubMed2006

Low-dimensional maps encoding dynamics in entorhinal cortex and hippocampus.

Cells that produce intrinsic theta oscillations often contain the hyperpolarization-activated current I(h). In this article, we use models and dynamic clamp experiments to investigate the synchronization properties of two such cells (stellate cells of the entorhinal cortex and O-LM cells of the hippocampus) in networks with fast-spiking (FS) interneurons. The model we use for stellate cells and O-LM cells is the same, but the stellate cells are excitatory and the O-LM cells are inhibitory, with inhibitory postsynaptic potential considerably longer than those from FS interneurons. We use spike time response curve methods (STRC), expanding that technique to three-cell networks and giving two different ways in which the analysis of the three-cell network reduces to that of a two-cell network. We show that adding FS cells to a network of stellate cells can desynchronize the stellate cells, while adding them to a network of O-LM cells can synchronize the O-LM cells. These synchronization and desynchronization properties critically depend on I(h). The analysis of the deterministic system allows us to understand some effects of noise on the phase relationships in the stellate networks. The dynamic clamp experiments use biophysical stellate cells and in silico FS cells, with connections that mimic excitation or inhibition, the latter with decay times associated with FS cells or O-LM cells. The results obtained in the dynamic clamp experiments are in a good agreement with the analytical framework.

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PubMed2005

Orthogonal arrangement of rhythm-generating microcircuits in the hippocampus.

As a structure involved in learning and memory, the hippocampus functions as a network. The functional differentiation along the longitudinal axis of the hippocampus is poorly demarcated in comparison with the transverse axis. Using patch clamp recordings in conjunction with post hoc anatomy, we have examined the pattern of connectivity and the functional differentiation along the long axis of the hippocampus. Here, we provide anatomical and physiological evidence that the prominent rhythmic network activities of the hippocampus, the behavior-specific gamma and theta oscillations, are seen predominantly along the transverse and longitudinal axes respectively. This orthogonal relationship is the result of the axonal field trajectories and the consequential interaction of the principal cells and major interneuron subtypes involved in generating each rhythm. Thus, the axonal arborization patterns of hippocampal inhibitory cells may represent a structural framework for the spatiotemporal distribution of activity observed within the hippocampus.

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PubMed2005

Slow and fast inhibition and an H-current interact to create a theta rhythm in a model of CA1 interneuron network.

The oriens-lacunosum moleculare (O-LM) subtype of interneuron is a key component in the formation of the theta rhythm (8-12 Hz) in the hippocampus. It is known that the CA1 region of the hippocampus can produce theta rhythms in vitro with all ionotropic excitation blocked, but the mechanisms by which this rhythmicity happens were previously unknown. Here we present a model suggesting that individual O-LM cells, by themselves, are capable of producing a single-cell theta-frequency firing, but coupled O-LM cells are not capable of producing a coherent population theta. By including in the model fast-spiking (FS) interneurons, which give rise to IPSPs that decay faster than those of the O-LM cells, coherent theta rhythms are produced. The inhibition to O-LM cells from the FS cells synchronizes the O-LM cells, but only when the FS cells themselves fire at a theta frequency. Reciprocal connections from the O-LM cells to the FS cells serve to parse the FS cell firing into theta bursts, which can then synchronize the O-LM cells. A component of the model O-LM cell critical to the synchronization mechanism is the hyperpolarization-activated h-current. The model can robustly reproduce relative phases of theta frequency activity in O-LM and FS cells.

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PubMed2005

Transient depression of excitatory synapses on interneurons contributes to epileptiform bursts during gamma oscillations in the mouse hippocampal slice.

Persistent gamma frequency (30-70 Hz) network oscillations occur in hippocampal slices under conditions of metabotropic glutamate receptor (mGluR) activation. Excessive mGluR activation generated a bistable pattern of network activity during which epochs of gamma oscillations of increasing amplitude were terminated by synchronized bursts and very fast oscillations (>70 Hz). We provide experimental evidence that, during this behavior, pyramidal cell-to-interneuron synaptic depression takes place, occurring spontaneously during the gamma rhythm and associated with the onset of epileptiform bursts. We further provide evidence that excitatory postsynaptic potentials (EPSPs) in pyramidal cells are potentiated during the interburst gamma oscillation. When these two types of synaptic plasticity are incorporated, phenomenologically, into a network model previously shown to account for many features of persistent gamma oscillations, we find that epochs of gamma do indeed alternate with epochs of very fast oscillations and epileptiform bursts. Thus the same neuronal network can generate either gamma oscillations or epileptiform bursts, in a manner depending on the degree of network drive and network-induced fluctuations in synaptic efficacies.

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PubMed2005

Induction by kainate of theta frequency rhythmic activity in the rat medial septum-diagonal band complex in vitro.

The medial septum-diagonal band (MSDB) complex, via the septohippocampal pathway, is thought to be critical for the generation and/or maintenance of the hippocampal theta rhythm in vivo. The aim was to determine whether the MSDB is capable of generating and maintaining its own rhythmic firing activity, a mechanism by which it could impose a theta frequency oscillatory activity on the hippocampus. Bath application of 50-300 nM kainate to an in vitro preparation of 20- to 25-day-old rat MSDB elicited rhythmic extracellular field activity primarily within the theta frequency band (4-12 Hz). This activity was observed both at 33 degrees C and at 37 degrees C, and was localized to the midline part of the MSDB that is rich in parvalbumin-containing neurones. The application of neurotransmitter receptor antagonists and putative gap junction blockers showed that the oscillatory field activity was dependent upon the activation of GABA(A) receptors and possibly gap junctions, but not on the activation of NMDA, GABA(B), muscarinic or nicotinic receptors. The frequency of the oscillatory activity was reduced by the application of diazepam or low doses of baclofen. Intracellular recording showed that concomitant action potential firing activity in putative GABAergic and cholinergic neurone populations was of a single spiking rather than a bursting firing nature, and was coherent with extracellularly recorded oscillatory field activity. We conclude that kainate activation of neuronal circuitry in the MSDB is capable of synchronization of rhythmic activity in the MSDB, and that this may underlie the mechanism for phase-locking rhythmic burst activity in the MSDB in vivo.

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PubMed2005

Combined experimental/simulation studies of cellular and network mechanisms of epileptogenesis in vitro and in vivo.

The electrical correlates of clinical seizures, and of experimental models of seizures, are recognized because neurons behave differently than normal. Individual neurons do unusual things, and neuronal activities become correlated with each other in ways that are not observed under physiologic conditions. Single neurons may fire bursts of action potentials superimposed on large depolarizations, and the bursts may recur rhythmically over a wide range of frequencies (<1 Hz to 25 Hz); periods of noisy subthreshold activity can occur; and firing can even be suppressed in some neurons. At the population level, nearby neurons tend to fire action potentials, or generate bursts, that are temporally locked together on a few-milliseconds time scale, so that large voltage transients are generated in extracellular fields. Very fast oscillations (>80 Hz) in neuronal aggregates may occur before, during, or after such large field potentials. Finally, cellular activities may even be correlated across large brain regions. The authors review some of the means by which cellular intrinsic properties, synaptic interactions, and electrical coupling via gap junctions, all contribute to the anomalous population activities characteristic of seizures. Also reviewed are some of the data suggesting that the requisite gap junctions are located on the axons of glutamatergic neurons.

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PubMed2004

Oscillatory activity within rat substantia gelatinosa in vitro: a role for chemical and electrical neurotransmission.

Although rhythmic behaviour of mammalian spinal ventral horn networks has been extensively studied little is known about oscillogenesis in the spinal dorsal horn. The aims of this in vitro study were to record and determine the underlying mechanisms of potassium-evoked network field oscillations in the substantia gelatinosa of the neonatal rat dorsal horn, a lamina involved in nociceptive processing. Transient pressure ejection of a potassium solution evoked reproducible rhythmic activity in discrete areas of the substantia gelatinosa which lasted for 5-15 s with a single prominent peak in the 4-12 Hz frequency band (7.7 +/- 0.1 Hz, n = 60). Oscillations of similar frequency and amplitude were also observed in isolated dorsal horn quadrants. Application of CNQX (10 microm) reduced peak power amplitude and integrated power area (from 4 to 12 Hz) of the power spectrum, whereas D-AP5 (50 microm) had no effect on the potassium-evoked rhythm. Bicuculline (30 microm) or strychnine (10 microm) reduced the power amplitude and area. On combination of bicuculline (30 microm) and strychnine (10 microm) the reductions in power amplitude and area were not significantly different (P > 0.05) when compared with application of either drug alone. The gap junction blockers carbenoxolone (100 microm) or octanol (1 mM) significantly reduced power amplitude and area. Although TTX (1 microm) or a calcium-free perfusate both caused reductions in the power amplitude and area, potassium-evoked rhythmic activity persisted. However, this persistent rhythm was further reduced on combination of calcium-free perfusate with octanol (1 mM) and was abolished using a cocktail of drugs. Blockade of the potassium delayed rectifier current by tetraethylammonium (5 mM) or the hyperpolarization-activated current (I(h)) by ZD7288 (10 microm) disrupted the synchronization of the potassium-induced oscillation. The frequency of potassium-induced rhythms was unaffected by any of the drugs tested. These novel findings demonstrate that transient pressure ejection of potassium evokes oscillatory activity in the substantia gelatinosa in vitro. This rhythm is partly dependent upon various receptors (AMPA/kainate, GABA(A) and glycine), ion channels (potassium delayed rectifier and I(h)) and gap junctions. Oscillatory behaviour in the substantia gelatinosa could potentially play a role in the processing of nociceptive signals.

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PubMed2004

Single-column thalamocortical network model exhibiting gamma oscillations, sleep spindles, and epileptogenic bursts.

To better understand population phenomena in thalamocortical neuronal ensembles, we have constructed a preliminary network model with 3,560 multicompartment neurons (containing soma, branching dendrites, and a portion of axon). Types of neurons included superficial pyramids (with regular spiking [RS] and fast rhythmic bursting [FRB] firing behaviors); RS spiny stellates; fast spiking (FS) interneurons, with basket-type and axoaxonic types of connectivity, and located in superficial and deep cortical layers; low threshold spiking (LTS) interneurons, which contacted principal cell dendrites; deep pyramids, which could have RS or intrinsic bursting (IB) firing behaviors, and endowed either with nontufted apical dendrites or with long tufted apical dendrites; thalamocortical relay (TCR) cells; and nucleus reticularis (nRT) cells. To the extent possible, both electrophysiology and synaptic connectivity were based on published data, although many arbitrary choices were necessary. In addition to synaptic connectivity (by AMPA/kainate, NMDA, and GABA(A) receptors), we also included electrical coupling between dendrites of interneurons, nRT cells, and TCR cells, and--in various combinations--electrical coupling between the proximal axons of certain cortical principal neurons. Our network model replicates several observed population phenomena, including 1) persistent gamma oscillations; 2) thalamocortical sleep spindles; 3) series of synchronized population bursts, resembling electrographic seizures; 4) isolated double population bursts with superimposed very fast oscillations (>100 Hz, "VFO"); 5) spike-wave, polyspike-wave, and fast runs (about 10 Hz). We show that epileptiform bursts, including double and multiple bursts, containing VFO occur in rat auditory cortex in vitro, in the presence of kainate, when both GABA(A) and GABA(B) receptors are blocked. Electrical coupling between axons appears necessary (as reported previously) for persistent gamma and additionally plays a role in the detailed shaping of epileptogenic events. The degree of recurrent synaptic excitation between spiny stellate cells, and their tendency to fire throughout multiple bursts, also appears critical in shaping epileptogenic events.

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PubMed2004

Persistent gamma oscillations in superficial layers of rat auditory neocortex: experiment and model.

Persistent in vitro gamma oscillations, induced by bath application of carbachol and kainate (amongst other drugs), were discovered by Eberhard Buhl and collaborators in 1998. The oscillations are robust, in that they can continue for hours; but the oscillations are also intricate in their mechanisms: they depend upon phasic synaptic excitation and inhibition, upon electrical coupling between interneurones and between pyramidal neurones, and--at least in neocortex--they depend upon complex intrinsic properties of some of the neurones.

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PubMed2004

Differential involvement of oriens/pyramidale interneurones in hippocampal network oscillations in vitro.

Using whole-cell patch-clamp recordings in conjunction with post hoc anatomy we investigated the physiological properties of hippocampal stratum oriens and stratum pyramidale inhibitory interneurones, before and following the induction of pharmacologically evoked gamma frequency network oscillations. Prior to kainate-induced transient epochs of gamma activity, two distinct classes of oriens interneurones, oriens lacunosum-moleculare (O-LM) and trilaminar cells, showed prominent differences in their membrane and firing properties, as well as in the amplitude and kinetics of their excitatory postsynaptic events. In the active network both types of neurone received a phasic barrage of gamma frequency excitatory inputs but, due to their differential functional integration, showed clear differences in their output patterns. While O-LM cells fired intermittently at theta frequency, trilaminar interneurones discharged on every gamma cycle and showed a propensity to fire spike doublets. Two other classes of fast spiking interneurones, perisomatic targeting basket and bistratified cells, in the active network discharged predominantly single action potentials on every gamma cycle. Thus, within a locally excited network, O-LM cells are likely to provide a theta-frequency patterned output to distal dendritic segments, whereas basket and bistratified cells are involved in the generation of locally synchronous gamma band oscillations. The anatomy and output profile of trilaminar cells suggest they are involved in the projection of locally generated gamma rhythms to distal sites. Therefore a division of labour appears to exist whereby different frequencies and spatiotemporal properties of hippocampal rhythms are mediated by different interneurone subtypes.

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PubMed2004

Coexistence of gamma and high-frequency oscillations in rat medial entorhinal cortex in vitro.

High frequency oscillations (> 80-90 Hz) occur in neocortex and hippocampus in vivo where they are associated with specific behavioural states and more classical EEG frequency bands. In the hippocampus in vitro these oscillations can occur in the absence of pyramidal neuronal somatodendritic compartments and are temporally correlated with on-going, persistent gamma frequency oscillations. Their occurrence in the hippocampus is dependent on gap-junctional communication and it has been suggested that these high frequency oscillations originate as collective behaviour in populations of electrically coupled principal cell axonal compartments. Here we demonstrate that the superficial layers of medial entorhinal cortex can also generate high frequency oscillations associated with gamma rhythms. During persistent gamma frequency oscillations high frequency oscillations occur with a high bispectral coherence with the field gamma activity. Bursts of high frequency oscillations are temporally correlated with both the onset of compound excitatory postsynaptic potentials in fast-spiking interneurones and spikelet potentials in both pyramidal and stellate principal neurones. Both the gamma frequency and high frequency oscillations were attenuated by the gap junction blocker carbenoxolone. These data suggest that high frequency oscillations may represent the substrate for phasic drive to interneurones during persistent gamma oscillations in the medial entorhinal cortex.

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PubMed2004

A role for fast rhythmic bursting neurons in cortical gamma oscillations in vitro.

Basic cellular and network mechanisms underlying gamma frequency oscillations (30-80 Hz) have been well characterized in the hippocampus and associated structures. In these regions, gamma rhythms are seen as an emergent property of networks of principal cells and fast-spiking interneurons. In contrast, in the neocortex a number of elegant studies have shown that specific types of principal neuron exist that are capable of generating powerful gamma frequency outputs on the basis of their intrinsic conductances alone. These fast rhythmic bursting (FRB) neurons (sometimes referred to as "chattering" cells) are activated by sensory stimuli and generate multiple action potentials per gamma period. Here, we demonstrate that FRB neurons may function by providing a large-scale input to an axon plexus consisting of gap-junctionally connected axons from both FRB neurons and their anatomically similar counterparts regular spiking neurons. The resulting network gamma oscillation shares all of the properties of gamma oscillations generated in the hippocampus but with the additional critical dependence on multiple spiking in FRB cells.

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PubMed2004

Cellular mechanisms of neuronal population oscillations in the hippocampus in vitro.

A variety of population oscillations, at frequencies approximately 5 Hz up to 200 Hz and above, can be induced in hippocampal slices either by (a) manipulation of the ionic environment, or (b) by stimulation of metabotropic receptors; brief oscillations can even occur spontaneously. In this review, we consider in vitro theta (4-12 Hz), gamma/beta (15-70 Hz), and very fast oscillations (VFO) (>70 Hz). Many in vitro oscillations are gated by synaptic inhibition but are influenced by electrical coupling as well; one type depends solely on electrical coupling. For some oscillations dependent upon inhibition, the detailed firing patterns of interneurons can influence long-range synchronization. Two sorts of electrical coupling are important in modulating or generating various in vitro oscillations: (a) between interneurons, primarily between dendrites; and (b) between axons of pyramidal neurons. VFO can exist in isolation or can act as generators of gamma frequency oscillations. Oscillations at gamma frequencies and below probably create conditions under which synaptic plasticity can occur, between selected neurons-even those separated by significant axonal conduction delays.

Action Potentials↗
PubMed2003

The role of electrical signaling via gap junctions in the generation of fast network oscillations.

In recent years, several key studies have shed new light on the roles of electrical signaling via gap junctions between neurons in the adult brain. In particular, it is now clear that electrical signaling is important, if not essential, for the generation of a wide variety of different network interactions which may underlie rhythmic activity, of cognitive relevance, seen in EEG recordings. Two types of such rhythmic activity observed in the hippocampus both in vivo and in vitro are gamma frequency (30-80Hz) oscillations and ultrafast (>80Hz) "ripple" oscillations. Several lines of work, discussed here, show that gap junction-mediated signaling plays a central role in the generation of both these types of network activity. Recent work also now suggests that a number of different, anatomically discrete, gap junction-mediated networks may exist which could both function and be modulated independently.

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