Faculty Bibliography

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

Genetic engineering of the mouse brain allows investigators to address novel hypotheses in vivo. Because of the paucity of information on the network patterns of the mouse hippocampus, we investigated the electrical patterns in the behaving animal using multisite silicon probes and wire tetrodes. Theta (6-9 Hz) and gamma (40-100 Hz) oscillations were present during exploration and rapid eye movement sleep. Gamma power and theta power were comodulated and gamma power varied as a function of the theta cycle. Pyramidal cells and putative interneurons were phase-locked to theta oscillations. During immobility, consummatory behaviors and slow-wave sleep, sharp waves were present in cornu ammonis region CA1 of the hippocampus stratum radiatum associated with 140-200-Hz 'ripples' in the pyramidal cell layer and population burst of CA1 neurons. In the hilus, large-amplitude 'dentate spikes' occurred in association with increased discharge of hilar neurons. The amplitude of field patterns was larger in the mouse than in the rat, likely reflecting the higher neuron density in a smaller brain. We suggest that the main hippocampal network patterns are mediated by similar pathways and mechanisms in mouse and rat

Information in neuronal networks is thought to be represented by the rate of discharge and the temporal relationship between the discharging neurons. The discharge frequency of neurons is affected by their afferents and intrinsic properties, and shows great individual variability. The temporal coordination of neurons is greatly facilitated by network oscillations. In the hippocampus, population synchrony fluctuates during theta and gamma oscillations (10-100 ms scale) and can increase almost 10-fold during sharp wave bursts. Despite these large changes in excitability in the sub-second scale, longer-term (minute-scale) firing rates of individual neurons are relatively constant in an unchanging environment. As a result, mean hippocampal output remains stable over time. To understand the mechanisms responsible for this homeostasis, we address the following issues: (i) Can firing rates of single cells be modified? (ii) Once modified, what mechanism(s) can maintain the changes? We show that firing rates of hippocampal pyramidal cells can be altered in a novel environment and by Hebbian pairing of physiological input patterns with postsynaptic burst discharge. We also illustrate a competition between single spikes and the occurrence of spike bursts. Since spike-inducing (suprathreshold) inputs decrease the ability of strong ('teaching') inputs to induce a burst discharge, we propose that the single spike versus burst competition presents a homeostatic regulatory mechanism to maintain synaptic strength and, consequently, firing rate in pyramidal cells

Processing of neuronal information depends on interactions between the anatomical connectivity and cellular properties of single cells. We examined how these computational building blocks work together in the intact rat hippocampus. Single spikes in dentate granule cells, controlled intracellularly, generally failed to discharge either interneurons or CA3 pyramidal cells. In contrast, trains of spikes effectively discharged both CA3 cell types. Increasing the discharge rate of the granule cell increased the discharge probability of its target neuron and decreased the delay between the onset of a granule cell train and evoked firing in postsynaptic targets. Thus, we conclude that the granule cell to CA3 synapses are 'conditional detonators,' dependent on granule cell firing pattern. In addition, we suggest that information in single granule cells is converted into a temporal delay code in target CA3 pyramidal cells and interneurons. These data demonstrate how a neural circuit of the CNS may process information

The behavior of immature cortical networks in vivo remains largely unknown. Using multisite extracellular and patch-clamp recordings, we observed recurrent bursts of synchronized neuronal activity lasting 0.5 to 3 seconds that occurred spontaneously in the hippocampus of freely moving and anesthetized rat pups. The influence of slow rhythms (0.33 and 0.1 hertz) and the contribution of both gamma-aminobutyric acid A-mediated and glutamate receptor-mediated synaptic signals in the generation of hippocampal bursts was reminiscent of giant depolarizing potentials observed in vitro. This earliest pattern, which diversifies during the second postnatal week, could provide correlated activity for immature neurons and may underlie activity-dependent maturation of the hippocampal network

According to the temporal coding hypothesis, neurons encode information by the exact timing of spikes. An example of temporal coding is the hippocampal phase precession phenomenon, in which the timing of pyramidal cell spikes relative to the theta rhythm shows a unidirectional forward precession during spatial behaviour. Here we show that phase precession occurs in both spatial and non-spatial behaviours. We found that spike phase correlated with instantaneous discharge rate, and processed unidirectionally at high rates, regardless of behaviour. The spatial phase precession phenomenon is therefore a manifestation of a more fundamental principle governing the timing of pyramidal cell discharge. We suggest that intrinsic properties of pyramidal cells have a key role in determining spike times, and that the interplay between the magnitude of dendritic excitation and rhythmic inhibition of the somatic region is responsible for the phase assignment of spikes

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

The interplay between principal cells and interneurons plays an important role in timing the activity of individual cells. We investigated the influence of single hippocampal CA1 pyramidal cells on putative interneurons. The activity of CA1 pyramidal cells was controlled intracellularly by current injection, and the activity of neighboring interneurons was recorded extracellularly in the urethane-anesthetized rat. Spike transmission probability between monosynaptically connected pyramidal cell-interneuron pairs was frequency dependent and highest between 5 and 25 Hz. In the awake animal, interneurons were found that had place-modulated firing rates, with place maps similar to their presynaptic pyramidal neuron. Thus, single pyramidal neurons can effectively determine the firing patterns of their interneuron targets

Cortical pyramidal cells fire single spikes and complex spike bursts. However, neither the conditions necessary for triggering complex spikes, nor their computational function are well understood. CA1 pyramidal cell burst activity was examined in behaving rats. The fraction of bursts was not reliably higher in place field centers, but rather in places where discharge frequency was 6-7 Hz. Burst probability was lower and bursts were shorter after recent spiking activity than after prolonged periods of silence (100 ms-1 s). Burst initiation probability and burst length were correlated with extracellular spike amplitude and with intracellular action potential rising slope. We suggest that bursts may function as 'conditional synchrony detectors,' signaling strong afferent synchrony after neuronal silence, and that single spikes triggered by a weak input may suppress bursts evoked by a subsequent strong input

Oscillations within and across neuronal systems are believed to serve various complex functions, such as perception, cognition, movement initiation, plasticity and memory. GABAergic interneurons and their inhibitory synapses play a major role in these oscillatory patterns. Networks of inhibitory interneurons impose a coordinated oscillatory 'context' for the 'content' carried by networks of principal cells. This hypothesis implies that GABAergic neuronal 'supernetworks' may cooperatively entrain large populations of pyramidal cells throughout the forebrain. Experiments on hippocampal interneurons are reviewed and possible solutions for some of these complex functions are illustrated