György Buzsáki

Theta Oscillations in the Hippocampus

Theta oscillations represent the on-line state of the hippocampus. The extracellular currents underlying theta waves are generated mainly by the entorhinal input, CA3 (Schaffer) collaterals, and voltage-dependent Ca(2+) currents in pyramidal cell dendrites. The rhythm is believed to be critical for temporal coding/decoding of active neuronal ensembles and the modification of synaptic weights. Nevertheless, numerous critical issues regarding both the generation of theta oscillations and their functional significance remain challenges for future research.

Two-stage model of memory trace formation: A role for “noisy” brain states

Review of the normally occurring neuronal patterns of the hippocampus suggests that the two principal cell types of the hippocampus, the pyramidal neurons and granule cells, are maximally active during different behaviors. Granule cells reach their highest discharge rates during theta-concurrent exploratory activities, while population synchrony of pyramidal cells is maximum during immobility, consummatory behaviors, and slow wave sleep associated with field sharp waves. Sharp waves reflect the summed postsynaptic depolarization of large numbers of pyramidal cells in the CA1 and subiculum as a consequence of synchronous discharge of bursting CA3 pyramidal neurons. The trigger for the population burst in the CA3 region is the temporary release from subcortical tonic inhibition. An overview of the experimentally explored criteria of synaptic enhancement (intensity, frequency, and pattern of postsynaptic depolarization, calcium influx, cooperativity, threshold) suggests that these requirements may be present during sharp wave-concurrent population bursts of pyramidal cells. Experimental evidence is cited showing that (a) population bursts in CA3 may lead to long-term potentiation in their postsynaptic CA1 targets, (b) tetanizing stimuli are capable of increasing the synchrony of the sharp wave-burst, and (c) activity patterns of the neocortical input to the hippocampus determine which subgroup of CA3 neurons will trigger subsequently occurring population bursts (initiator cells). Based on the experimental evidence reviewed a formal model of memory trace formation is outlined. During exploratory (theta) behaviors the neocortical information is transmitted to the hippocampus via the fast-firing granule cells which may induce a weak and transient heterosynaptic potentiation in a subgroup of CA3 pyramidal cells. The weakly potentiated CA3 neurons will then initiate population bursts upon the termination of exploratory activity (sharp wave state). It is assumed that recurrent excitation during the population burst is strongest on those cells which initiated the population event. It is suggested that the strong excitatory drive brought about by the sharp wave-concurrent population bursts during consummatory behaviors, immobility, and slow wave sleep may be sufficient for the induction of long-term synaptic modification in the initiator neurons of the CA3 region and in their targets in CA1. In this two-stage model both exploratory (theta) and sharp wave states of the hippocampus are essential and any interference that might modify the structure of the population bursts (e.g. epileptic spikes) is detrimental to memory trace formation.

Gamma (40-100 Hz) oscillation in the hippocampus of the behaving rat

The cellular generation and spatial distribution of gamma frequency (40– 100 Hz) activity was examined in the hippocampus of the awake rat. Field potentials and unit activity were recorded by multiple site silicon probes (5- and 16-site shanks) and wire electrode arrays. Gamma waves were highly coherent along the long axis of the dentate hilus, but average coherence decreased rapidly in the CA3 and CA1 directions. Analysis of short epochs revealed large fluctuations in coherence values between the dentate and CA1 gamma waves. Current source density analysis revealed large sinks and sources in the dentate gyrus with spatial distribution similar to the dipoles evoked by stimulation of the perforant path. The frequency changes of gamma and theta waves positively correlated (40–100 Hz and 5–10 Hz, respectively). Putative interneurons in the dentate gyrus discharged at gamma frequency and were phase-locked to the ascending part of the gamma waves recorded from the hilus. Following bilateral lesion of the entorhinal cortex the power and frequency of hilar gamma activity significantly decreased or disappeared. Instead, a large amplitude but slower gamma pattern (25–50 Hz) emerged in the CA3-CA1 network. We suggest that gamma oscillation emerges from an interaction between intrinsic oscillatory properties of interneurons and the network properties of the dentate gyrus. We also hypothesize that under physiological conditions the hilar gamma oscillation may be entrained by the entorhinal rhythm and that gamma oscillation in the CA3-CA1 circuitry is suppressed by either the hilar region or the entorhinal cortex.

Cellular bases of hippocampal EEG in the behaving rat

Rats implanted with recording and stimulating electrodes were trained to run in an activity wheel for a water reward. Unitary discharges and slow activity were recorded by a movable tungsten microelectrode and by fixed electrodes. Single cells were classified according to their spontaneous and evoked response properties as pyramidal cells, granule cells and interneurons. Unit activity, EEG and their interrelations were studied by spectral and spike-triggered averaging methods. Gradual phase-shifts of RSA were observed both in CA1 and the dentate gyrus. Movement-related RSA was correlated with a decrease in firing rate of pyramidal cells and an increase in the firing of both interneurons and granule cells. In the CA1 region pyramidal cells and interneurons fired preferentially on the negative and positive phases of the locally derived RSA, respectively. In the dentate gyrus both granule cells and interneurons discharged mainly on the positive portion of the local RSA waves, about 90 degrees before the CA1 pyramidal cells. Fourier analysis of the spike trains of interneurons and granule cells showed high power at RSA frequency, coherent with the concurrent EEG. Phase relations between discharges of interneurons and RSA remained unchanged following urethane anesthesia. In waking rats, atropine administration resulted in a decreased discharge of interneurons at RSA frequency, and reduced coherence with RSA. Lesions of the septum or the fimbria-fornix abolished RSA and the rhythmic discharges of the interneurons. Isolation of the entorhinal cortex (EC) from its cortical inputs did not change either EEG or neuronal firing. However, in such a preparation atropine completely abolished RSA and related rhythmicity of interneurons. During drinking and immobility but not during walking, sharp waves (SPW) of about 40-100 ms duration appeared in the EEG. SPWs were invariably accompanied by synchronous discharges of several pyramidal cells and interneurons. CA3 pyramidal cells also discharged in synchronous bursts but without local SPWs. Laminar profiles of SPWs and the field potentials evoked by stimulation of Schaffer collaterals were essentially identical. The behavior-dependent occurrence of SPWs was retained following atropine administration, septal lesion or EC isolation but was lost after fimbria-fornix-neocortex lesion or following atropine administration in EC isolated rats. In addition to relations to RSA and SPWs, interneurons were phase-locked to the fast EEG pattern (25-70 Hz). This relationship was preserved following lesions of the septum or the fimbria-fornix complex.(ABSTRACT TRUNCATED AT 400 WORDS)

Large-scale recording of neuronal ensembles

How does the brain orchestrate perceptions, thoughts and actions from the spiking activity of its neurons? Early single-neuron recording research treated spike pattern variability as noise that needed to be averaged out to reveal the brains representation of invariant input. Another view is that variability of spikes is centrally coordinated and that this brain-generated ensemble pattern in cortical structures is itself a potential source of cognition. Large-scale recordings from neuronal ensembles now offer the opportunity to test these competing theoretical frameworks. Currently, wire and micro-machined silicon electrode arrays can record from large numbers of neurons and monitor local neural circuits at work. Achieving the full potential of massively parallel neuronal recordings, however, will require further development of the neuron–electrode interface, automated and efficient spike-sorting algorithms for effective isolation and identification of single neurons, and new mathematical insights for the analysis of network properties.

Brain-state- and cell-type-specific firing of hippocampal interneurons in vivo

Neural-network oscillations at distinct frequencies have been implicated in the encoding, consolidation and retrieval of information in the hippocampus. Some GABA (γ-aminobutyric acid)-containing interneurons fire phase-locked to theta oscillations (4–8u2009Hz) or to sharp-wave-associated ripple oscillations (120–200u2009Hz), which represent different behavioural states. Interneurons also entrain pyramidal cells in vitro. The large diversity of interneurons poses the question of whether they have specific roles in shaping distinct network activities in vivo. Here we report that three distinct interneuron types—basket, axo-axonic and oriens–lacunosum-moleculare cells—visualized and defined by synaptic connectivity as well as by neurochemical markers, contribute differentially to theta and ripple oscillations in anaesthetized rats. The firing patterns of individual cells of the same class are remarkably stereotyped and provide unique signatures for each class. We conclude that the diversity of interneurons, innervating distinct domains of pyramidal cells, emerged to coordinate the activity of pyramidal cells in a temporally distinct and brain-state-dependent manner.

Mechanisms of gamma oscillations.

Gamma rhythms are commonly observed in many brain regions during both waking and sleep states, yet their functions and mechanisms remain a matter of debate. Here we review the cellular and synaptic mechanisms underlying gamma oscillations and outline empirical questions and controversial conceptual issues. Our main points are as follows: First, gamma-band rhythmogenesis is inextricably tied to perisomatic inhibition. Second, gamma oscillations are short-lived and typically emerge from the coordinated interaction of excitation and inhibition, which can be detected as local field potentials. Third, gamma rhythm typically concurs with irregular firing of single neurons, and the network frequency of gamma oscillations varies extensively depending on the underlying mechanism. To document gamma oscillations, efforts should be made to distinguish them from mere increases of gamma-band power and/or increased spiking activity. Fourth, the magnitude of gamma oscillation is modulated by slower rhythms. Such cross-frequency coupling may serve to couple active patches of cortical circuits. Because of their ubiquitous nature and strong correlation with the operational modes of local circuits, gamma oscillations continue to provide important clues about neuronal population dynamics in health and disease.

Mechanisms of Gamma Oscillations in the Hippocampus of the Behaving Rat

Gamma frequency oscillations (30-100 Hz) have been suggested to underlie various cognitive and motor functions. Here, we examine the generation of gamma oscillation currents in the hippocampus, using two-dimensional, 96-site silicon probes. Two gamma generators were identified, one in the dentate gyrus and another in the CA3-CA1 regions. The coupling strength between the two oscillators varied during both theta and nontheta states. Both pyramidal cells and interneurons were phase-locked to gamma waves. Anatomical connectivity, rather than physical distance, determined the coupling strength of the oscillating neurons. CA3 pyramidal neurons discharged CA3 and CA1 interneurons at latencies indicative of monosynaptic connections. Intrahippocampal gamma oscillation emerges in the CA3 recurrent system, which entrains the CA1 region via its interneurons.

Hippocampal sharp waves: their origin and significance.

This study investigated the spatial distribution and cellular-synaptic generation of hippocampal sharp waves (SPW) in the dorsal hippocampus of the awake rat. Depth analyses of SPWs were performed by stepping the recording electrode in 82.5 microns increments. SPWs were present during slow wave sleep, awake immobility, drinking, grooming and eating (0.01-2/s). The largest negative SPWs were recorded from the middle part of the stratum radiatum of CA1, the stratum lucidum of CA3, the inner molecular layer of the dentate gyrus and from layer I of the subiculum, in that order. The polarity of the SPWs was positive in layers II-IV of the subiculum, in stratum oriens and stratum pyramidale of CA1 and CA3, and in the hilus of the dentate gyrus. The electrical gradients across the null zones of the field SPWs were as large as 8-14 mV/mm. SPWs were associated with population bursts of pyramidal cells and increased discharges of interneurons and granule cells. During the SPW the excitability of granule cells and pyramidal cells to afferent volleys increased considerably. Picrotoxin and atropine and aspiration lesion of the fimbria-fornix increased either the amplitude or the frequency of SPWs. Diazepam and Nembutal could completely abolish SPWs. It is suggested that: hippocampal SPWs are triggered by a population burst of CA3 pyramidal cells as a result of temporary disinhibition from afferent control; and field SPWs represent summed extracellular PSPs of CA1 and subicular pyramidal cells, and dentate granular cells induced by the Schaffer collaterals and the associational fibers of hilar cells, respectively. The relevance of the physiological SPWs to epileptic interictal spikes and long-term potentiation is discussed.

Selective suppression of hippocampal ripples impairs spatial memory

Sharp wave–ripple (SPW-R) complexes in the hippocampus-entorhinal cortex are believed to be important for transferring labile memories from the hippocampus to the neocortex for long-term storage. We found that selective elimination of SPW-Rs during post-training consolidation periods resulted in performance impairment in rats trained on a hippocampus-dependent spatial memory task. Our results provide evidence for a prominent role of hippocampal SPW-Rs in memory consolidation.