Richard Miles's research while affiliated with Institut Pasteur and other places

In the guinea-pig hippocampal CA3 region, the synaptic connection from pyramidal neurons tostratum pyramidale inhibitory neurons is remarkable. Anatomically, the connection usually consists of a single release site on an interneuronal dendrite, sometimes 200 m or more from the soma. Nevertheless, the connection is physiologically powerful, in that a single presynaptic action potential can evoke, with probability 0.1 to 0.6, a postsynaptic action potential with latency 2 to 6 ms. We construct a model interneuron and show that the anatomical and physiological observations can be reconciled if the interneuron dendrites are electrically excitable. Excitable dendrites could also account for depolarization-induced amplification of the pyramidal cell-interneuron EPSP in the voltage range subthreshold for spike generation.

This chapter discusses the neuronal population oscillations. These observations are observed in the hippocampus that depend on particular neuronal biophysical long-duration synaptic interactions (specifically, the NMDA type of glutamate-mediated excitation), as well as on some rather intricate intrinsic membrane properties. These oscillations may be pathological and relevant to seizure-related mnemonic phenomena such as déjà vu. Alternatively, the oscillations may be an exaggeration of a normal population activity. Based on experimental manipulations of synchronized multiple bursts in disinhibited hippocampal slice preparations, particular synaptic currents and membrane properties were added to realistic network simulations. Based on this combined experimental and simulation approach, population oscillation depends on the long duration synaptic interaction of NMDA-activated calcium currents and calcium intracellular kinetics in the dendrites of pyramidal neurons.

In vitro hippocampal slice preparations generate a variety of neuronal behaviors involving populations of 1000 neurons or more. Understanding population behavior requires information on single neuron electrophysiology, synoptic connectivity and the properties of different kinds of individual synapses. We describe a model that incorporates these diverse types of data. The model can account for several epileptic behaviors and EEG-like waves.

From the Publisher: The questions of how a large population of neurons in the brain functions, how synchronized firing of neurons is achieved, and what factors regulate how many and which neurons fire under different conditions form the central theme of this book. Using a combined experimental-theoretical approach unique in neuroscience, the authors present important new techniques for the physiological reconstruction of a large biological neuronal network. They begin by discussing experimental studies of the CA3 hippocampal region in vitro, focusing on single-cell and synaptic electrophysiology, particularly the effects a single neuron exerts on its neighbors. This is followed by a description of a computer model of the system, first for individual cells then for the entire detailed network, and the model is compared with experiments under a variety of conditions. The results shed significant light into the mechanisms of epilepsy, electroencephalograms, and biological oscillations and provide an excellent test case for theories of neural networks.

In this chapter, we shall discuss the structure of one part of the guinea-pig hippocampus, the anatomically simplest type of cortex. We shall describe how the structure of this part (the CA3 region) leads to the existence of a repertoire of different modes of population activity. Selection of a particular mode of population behavior depends on the settings of various functional parameters such as the conductances of the inhibitory synapses. Some of the population activities observed in vitro and in models of the slice appear to have in vivo analogs. We shall tabulate some of the mechanisms which may be available to the brain for setting functional parameters in the hippocampus. Finally, we shall speculate briefly on the behavioral significance of certain population modes.

Field potentials and unitary activity were investigated in the grafted and the host hippocampi in freely moving rats and in vitro. The subcortical afferents and efferents of the hippocampus (fimbria-fornix, FF) were removed by aspiration. Solid pieces of hippocampal grafts derived from 15- to 16-day-old fetuses were placed in the lesion cavity in rats with unilateral FF lesions, and cell suspensions prepared from fetal hippocampi were grafted directly into the host hippocampi in animals with bilateral FF lesions. Reciprocal communication between the grafted and the host hippocampi was monitored with a 16-microelectrode probe from 7 to 10 months after grafting. The fluorescent retrograde tracer, Fluorogold, was used to examine graft-host projections and acetylcholinesterase staining to reveal host-derived fibers in the graft. The most typical neuronal pattern of the hippocampal graft was a highly synchronous population burst with concurrent EEG spike. The speed of propagation of the EEG spike within the graft and across the graft-host interface was either fast (greater than 3 m/s) or slow (less than 0.5 m/s). Large amplitude, short duration EEG spikes usually propagated with a high speed, while smaller amplitude, wider spikes with broad population bursts spread at a lower velocity. The direction of propagation was usually uniform indicating that the population burst was triggered by a localized subgroup of highly excitable neurons ("focus"). Spontaneous seizures were also present in the solid graft which frequently invaded the host hippocampus. The incidence of EEG spikes was three times higher in rats with bilateral suspension grafts than in animals with FF lesion only. In about half of the grafted rats spontaneous behavioral seizures were also observed. Intracellular recordings from putative pyramidal cells in the graft and in the host revealed large amplitude (10-12 mV), spontaneously occurring EPSPs. IPSPs were difficult to detect even during depolarizations of up to 20 mV from rest. We suggest that the increased excitability of the hippocampal graft is due to the high incidence of recurrent excitatory collaterals terminating on or close to the somata of pyramidal neurons. Population bursts may spread fast via extensively arborizing axon collaterals or slowly by successively activating new sets of neighboring neurons. Spontaneous behavioral convulsions are explained by assuming that the grafted hippocampus serves as an epileptic focus which is capable of kindling the host brain by repeated seizure induction.(ABSTRACT TRUNCATED AT 400 WORDS)

One goal of mammalian neurobiology is to understand the generation of neuronal activity in large networks. Conceptual schemes have been based on either the properties of single cells or of individual synapses. For instance, the intrinsic oscillatory properties of individual thalamic neurons are thought to underlie thalamic spindle rhythms. This issue has been pursued with a computer model of the CA3 region of the hippocampus that is based on known cellular and synaptic properties. Over a wide range of parameters, this model generates a rhythmic activity at a frequency faster than the firing of individual cells. During each rhythmic event, a few cells fire while most other cells receive synchronous synaptic inputs. This activity resembles the hippocampal theta rhythm as well as synchronized synaptic events observed in vitro. The amplitude and frequency of this emergent rhythmic activity depend on intrinsic cellular properties and the connectivity and strength of both excitatory and inhibitory synapses.