Significance: When we are awake, purposeful thinking and behavior require the synchronization of brain cells involved in different aspects of the same task. Cerebral cortex electrical oscillations in the gamma (30–80 Hz) range are particularly important in such synchronization. In this report we identify a particular subcortical cell type which has increased activity during waking and is involved in activating the cerebral cortex and generating gamma oscillations, enabling active cortical processing. Abnormalities of the brain mechanisms controlling gamma oscillations are involved in the disordered thinking typical of neuropsychiatric disorders such as schizophrenia. Thus, these findings may pave the way for targeted therapies to treat schizophrenia and other disorders involving abnormal cortical gamma oscillations.

Hippocampal θ waves recorded during rapid eye movement (REM) sleep are thought to play a critical role in memory consolidation in lower mammals, but previous attempts to detect similar θ oscillations in the human hippocampus have been unsuccessful. Using subdural and depth recordings from epileptic patients, we now report the first evidence of state-dependent hippocampal θ waves (4-7 Hz) in humans. Unlike the continuous θ in rodents, however, these oscillations were consistently observed during REM sleep in short (∼1 sec) bursts and during transitions to wake in longer epochs. θ waves were also observed in the basal temporal lobe and frontal cortex during transitions from sleep to wake and in quiet wakefulness but not in REM, and they were not coherent with hippocampal θ oscillations. The absence of functional coupling between neocortex and hippocampus during θ periods indicates that multiple θ generators exist in the human brain, and that they are dynamically regulated by brain state. γ oscillations were also present during REM θ bursts, but the fluctuations in γ power were not associated with θ phase, pointing out another significant difference between rodent and human θ properties. Together, these findings suggest that the generation mechanisms of θ oscillations in humans might have evolved from tonic to phasic in hippocampus during REM sleep and extended from hippocampus to cortex, where they appear in certain wakefulness-related states.

We examined the activity of single cells of the supramammillary nucleus (SUM), the mammillary body (MB), and adjacent regions of the diencephalon with respect to the hippocampal electroencephalogram (EEG) in urethane-anesthetized rats. Twenty-nine of 170 cells were found to discharge synchronously with the theta rhythm of the hippocampus (theta- related neurons). All of the 29 theta-related cells were localized to the SUM or MB. A subset of theta-related cells of SUM and MB discharged in short-duration bursts comparable to the pyramidal complex spike cells of the hippocampus. In contrast to hippocampal complex spikes, however, which predominantly exhibit this mode of firing during non- theta states, the burst firing of SUM/MB cells was strongly correlated with the theta rhythm. The proportion of bursting neurons was higher in MB than in SUM. Using partial coherence analysis, we examined the relationship between SUM/MB theta-related cells and the two generators of theta of the dorsal hippocampus. The theta-related cells of MB showed a stronger correlation with “CA1” than with “dentate” theta, whereas no such asymmetry was found in the relationship between neuronal firing of SUM cells and the two generators of theta in the hippocampus. The foregoing suggests that the theta-related cells of MB are driven by descending projections from the hippocampal formation (CA1), whereas those of the SUM are not. The SUM and MB are intimately connected with the hippocampal formation--the SUM mainly via ascending projections to the dentate gyrus, and the MB via direct descending projections from the subiculum. Theta-related SUM/MB cells may be directly involved in the generation of theta and/or the transfer of theta rhythmicity to various parts of the limbic system and forebrain.

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.