Faculty Bibliography

The computational model described here is driven by the hypothesis that a major function of the entorhinal cortex (EC)-hippocampal system is to alter synaptic connections in the neocortex. It is based on the following postulates: (1) The EC compares the difference between neocortical representations (primary input) and feedback information conveyed by the hippocampus (the 'reconstructed input'). The difference between the primary input and the reconstructed input (termed 'error') initiates plastic changes in the hippocampal networks (error compensation). (2) Comparison of the primary input and reconstructed input requires that these representations are available simultaneously in the EC network. We suggest that compensation of time delays is achieved by predictive structures, such as the CA3 recurrent network and EC-CA1 connections. (3) Alteration of intrahippocampal connections gives rise to a new hippocampal output. The hippocampus generates separated (independent) outputs, which, in turn, train long-term memory traces in the EC (independent components, IC). The ICs of the long-term memory trace are generated in a two-step manner, the operations of which we attribute to the activities of the CA3 (whitening) and CA1 (separation) fields. (4) The different hippocampal fields can perform both nonlinear and linear operations, albeit at different times (theta and sharp phases). We suggest that long-term memory is represented in a distributed and hierarchical reconstruction network, which is under the supervision of the hippocampal output. Several of these model predictions can be tested experimentally

This paper describes the procedure of assembling a miniature microdrive and silicon probe system for surgical implantation into the adult rat brain. Successful recordings of single and multiunit activity with parallel depth profiles of spontaneous and evoked field potentials are shown. The procedure for histological verification of the position of the silicon probe is described

The anatomical connectivity and intrinsic properties of entorhinal cortical neurons give rise to ordered patterns of ensemble activity. How entorhinal ensembles form, interact, and accomplish emergent processes such as memory formation is not well-understood. We lack sufficient understanding of how neuronal ensembles in general can function transiently and distinctively from other neuronal ensembles. Ensemble interactions are bound, foremost, by anatomical connectivity and temporal constraints on neuronal discharge. We present an overview of the structure of neuronal interactions within the entorhinal cortex and the rest of the hippocampal formation. We wish to highlight two principle features of entorhinal-hippocampal interactions. First, large numbers of entorhinal neurons are organized into at least two distinct high-frequency population patterns: gamma (40-100 Hz) frequency volleys and ripple (140-200 Hz) frequency volleys. These patterns occur coincident with other well-defined electrophysiological patterns. Gamma frequency volleys are modulated by the theta cycle. Ripple frequency volleys occur on each sharp wave event. Second, these patterns occur dominantly in specific layers of the entorhinal cortex. Theta/gamma frequency volleys are the principle pattern observed in layers I-III, in the neurons that receive cortical inputs and project to the hippocampus. Ripple frequency volleys are the principle population pattern observed in layers V-VI, in the neurons that receive hippocampal output and project primarily to the neocortex. Further, we will highlight how these ensemble patterns organize interactions within distributed forebrain structures and support memory formation

In the hippocampus, spatial representation of the environment has been suggested to be coded by either the firing rate of pyramidal cell assemblies or the relative timing of the action potentials during the theta EEG cycle. Here, we used a behavioural 'space clamp' method, which involved the confinement of the actively running animal in a defined position in space (running wheel) to examine how 'spatial' and other inputs affect firing rate and timing of hippocampal CA1 pyramidal cells and interneurons. Nineteen per cent of the recorded CA1 pyramidal cells were selectively active while the rat was running in the wheel in a given direction ('wheel' cells). Spatial rotation of the apparatus showed that selective discharge of pyramidal cells in the wheel was under the combined influence of distal and apparatus cues. During steady running, both discharge rate and theta phase were constant. Rotation of the wheel apparatus resulted in a shift of both firing rate and preferred theta phase. The discharge frequency of 'wheel' cells increased threefold (on average) with increasing running velocity. In contrast, change in running speed had relatively little effect on the theta phase-related discharge of 'wheel' cells. Our findings indicate that mechanisms that regulate rate and phase of spikes are overlapping but not necessarily identical

1. The study of the physiological role of long-term potentiation (LTP) is often hampered by the challenge of finding a physiological event that can be used to assess synaptic strength. We explored the possibility of utilising a naturally occurring event, the hippocampal sharp wave (SPW), for the assessment of synaptic strength and the induction of LTP in vivo. 2. We used two methods in which hippocampal cells were either recorded intracellularly or extracellularly in vivo. In both cases, a linear association between the magnitude of the SPW and cellular responsiveness was observed. 3. LTP was induced by depolarising cells during SPWs by either direct intracellular current injection or extracellular microstimulation adjacent to the cell body. Both of these approaches led to an increase in the slope of the linear association between SPWs and cellular responsiveness. 4. This change was achieved without a rise in overall cell excitability, implying that the synapses providing input to CA1 cells during sharp waves had undergone potentiation. 5. Our findings show that the Hebbian pairing of cellular activation with spontaneous, naturally occurring synaptic events is capable of inducing LTP

Information in neuronal networks may be represented by the spatiotemporal patterns of spikes. Here we examined the temporal coordination of pyramidal cell spikes in the rat hippocampus during slow-wave sleep. In addition, rats were trained to run in a defined position in space (running wheel) to activate a selected group of pyramidal cells. A template-matching method and a joint probability map method were used for sequence search. Repeating spike sequences in excess of chance occurrence were examined by comparing the number of repeating sequences in the original spike trains and in surrogate trains after Monte Carlo shuffling of the spikes. Four different shuffling procedures were used to control for the population dynamics of hippocampal neurons. Repeating spike sequences in the recorded cell assemblies were present in both the awake and sleeping animal in excess of what might be predicted by random variations. Spike sequences observed during wheel running were 'replayed' at a faster timescale during single sharp-wave bursts of slow-wave sleep. We hypothesize that the endogenously expressed spike sequences during sleep reflect reactivation of the circuitry modified by previous experience. Reactivation of acquired sequences may serve to consolidate information

This study examined intermittent, high-frequency (100-200 Hz) oscillatory patterns in the CA1 region of the hippocampus in the absence of theta activity, i.e., during and in between sharp wave (SPW) bursts. Pyramidal and interneuronal activity was phase-locked not only to large amplitude (>7 SD from baseline) oscillatory events, which are present mainly during SPWs, but to smaller amplitude (<4 SD) patterns, as well. Large-amplitude events were in the 140-200 Hz, 'ripple' frequency range. Lower-amplitude events, however, contained slower, 100-130 Hz ('slow') oscillatory patterns. Fast ripple waves reversed just below the CA1 pyramidal layer, whereas slow oscillatory potentials reversed in the stratum radiatum and/or in the stratum oriens. Parallel CA1-CA3 recordings revealed correlated CA3 field and unit activity to the slow CA1 waves but not to fast ripple waves. These findings suggest that fast ripples emerge in the CA1 region, whereas slow (100-130 Hz) oscillatory patterns are generated in the CA3 region and transferred to the CA1 field

The extracellularly recorded theta oscillation reflects a dynamic interaction of various synaptic and cellular mechanisms. Because the spatially overlapping dipoles responsible for the generation of theta field oscillation may represent different mechanisms, their separation might provide clues with regard to their origin and significance. We used a novel approach, partial coherence analysis, to reveal the various components of the theta rhythm and the relationship among its generators. Hippocampal field activity was recorded by a 16-site silicon probe in the CA1-dentate gyrus axis of the awake rat. Field patterns, recorded from various intrahippocampal or entorhinal cortex sites, were used to remove activity caused by a common source by the partialization procedure. The findings revealed highly coherent coupling between theta signals recorded (1) from the hippocampal fissure and stratum (str.) oriens of the CA1 region and (2) between CA1 stratum radiatum and the dentate molecular layer. The results of partial coherence analysis indicated that rhythmic input from the entorhinal cortex explained theta coherence between signals recorded from the hippocampal fissure and str. oriens but not the coherence between signals derived from str. radiatum and the dentate molecular layer. After bilateral lesions of the entorhinal cortex, all signals recorded from both below and above the CA1 hippocampal pyramidal cell layer became highly coherent. These observations indicate the presence of two, relatively independent, theta generators in the hippocampus, which are mediated by the entorhinal cortex and the CA3-mossy cell recurrent circuitry, respectively. The CA3-mossy cell theta generator is partially suppressed by the dentate gyrus interneuronal output in the intact brain. We suggest that timing of the action potentials of pyramidal cells during the theta cycle is determined by the cooperation between the active CA3 neurons and the entorhinal input

The medial septal region and the hippocampus are connected reciprocally via GABAergic neurons, but the physiological role of this loop is still not well understood. In an attempt to reveal the physiological effects of the hippocamposeptal GABAergic projection, we cross-correlated hippocampal sharp wave (SPW) ripples or theta activity and extracellular units recorded in the medial septum and diagonal band of Broca (MSDB) in freely moving rats. The majority of single MSDB cells (60%) were significantly suppressed during SPWs. Most cells inhibited during SPW (80%) fired rhythmically and phase-locked to the negative peak of the CA1 pyramidal layer theta waves. Because both SPW and the negative peak of local theta waves correspond to the maximum discharge probability of CA1 pyramidal cells and interneuron classes, the findings indicate that the activity of medial septal neurons can be negatively (during SPW) or positively (during theta waves) correlated with the activity of hippocampal interneurons. We hypothesize that the functional coupling between medial septal neurons and hippocampal interneurons varies in a state-dependent manner

We examined whether excitation and inhibition are balanced in hippocampal cortical networks. Extracellular field and single-unit activity were recorded by multiple tetrodes and multisite silicon probes to reveal the timing of the activity of hippocampal CA1 pyramidal cells and classes of interneurons during theta waves and sharp wave burst (SPW)-associated field ripples. The somatic and dendritic inhibition of pyramidal cells was deduced from the activity of interneurons in the pyramidal layer [int(p)] and in the alveus and st. oriens [int(a/o)], respectively. Int(p) and int(a/o) discharged an average of 60 and 20 degrees before the population discharge of pyramidal cells during the theta cycle, respectively. SPW ripples were associated with a 2.5-fold net increase of excitation. The discharge frequency of int(a/o) increased, decreased ('anti-SPW' cells), or did not change ('SPW-independent' cells) during SPW, suggesting that not all interneurons are innervated by pyramidal cells. Int(p) either fired together with (unimodal cells) or both before and after (bimodal cells) the pyramidal cell burst. During fast-ripple oscillation, the activity of interneurons in both the int(p) and int(a/o) groups lagged the maximum discharge probability of pyramidal neurons by 1-2 msec. Network state changes, as reflected by field activity, covaried with changes in the spike train dynamics of single cells and their interactions. Summed activity of parallel-recorded interneurons, but not of pyramidal cells, reliably predicted theta cycles, whereas the reverse was true for the ripple cycles of SPWs. We suggest that network-driven excitability changes provide temporal windows of opportunity for single pyramidal cells to suppress, enable, or facilitate selective synaptic inputs