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Synchronous hippocampal electroencephalographic activity occurring in a frequency range of 3 to12 Hz (i.e., hippocampal theta rhythm) has been associated with mnemonic processes in vivo. However, this link is tenuous and theta rhythm may be secondary to processes that underlie mnemonic function. If theta rhythm is associated with mnemonic or cognitive function, cognition-enhancing drugs should enhance theta rhythm regardless of their primary biological target. In the current study, we evaluated several drugs that were shown to have cognition-enhancing properties in preclinical behavioral models and that vary with respect to their primary biological target: 1) the nootropic piracetam (250 and 500 mg/kg); 2) the small-conductance calcium-activated potassium-channel blocker apamin (0.1 and 0.4 mg/kg); and 3) the acetylcholinesterase inhibitor donepezil (0.1-10.0 mg/kg). All of the cognition-enhancing drugs produced dose-dependent increases in hippocampal theta rhythm amplitude elicited by stimulation of the brainstem reticular formation at doses that did not affect peak theta frequency in the urethane-anesthetized rat. These increases were reversed by the muscarinic receptor antagonist scopolamine, suggesting a common final cholinergic action of these compounds. The use-dependent N-methyl-D-aspartate antagonist dizocilipine maleate and scopolamine reduced theta amplitude (both) and frequency (dizocilipine maleate only). These data demonstrate that hippocampal theta rhythm is sensitive to cognition-modulating compounds, suggesting that theta rhythm may be closely associated with cognitive function.

Previous research has demonstrated that brainstem injections of acetylcholine agonists (e.g., carbachol) produced electrophysiological indicators of rapid-eye-movement (REM) sleep in the cat. Recent reports now indicate that this phenomenon may hold true for rats as well. Relatively few reports, however, have examined the effect of these injections on REM indicators in the anesthetized rat, a preparation useful for elucidating underlying neurobiological mechanisms controlling REM sleep processes. The present study compared the effect of injections of carbachol (5 micrograms in 250 nl) into the pedunculopontine tegmental nucleus (PPTg) or the nucleus pontis oralis (NPO) on two tonic indicators of REM sleep in the urethane-anesthetized rat. Namely, changes in the hippocampal EEG and in the cortical EEG. Carbachol injections into either site produced a change in both the hippocampal EEG and cortical EEG to a REM-like state at short latencies. The length of these changes (duration of effect), however, was site-dependent. Thus, PPTg carbachol injections induced significantly longer lasting effects in both the hippocampal and cortical EEG than did NPO injections. The results that brainstem carbachol injections in rats, as in cats, may provide a useful model for investigating tonic REM sleep processes.

It has previously been shown that serotonergic [5-hydroxytryptamine (5-HT)] neurons of the median raphe nucleus (MR) are critically involved in the control of the hippocampal electroencephalogram (EEG). Activation of MR 5-HT neurons desynchronizes the hippocampal EEG, whereas inhibition of MR 5-HT activity produces hippocampal theta rhythm. The MR contains an intrinsic population of gamma-aminobutyric acid (GABA) containing neurons that synapse on 5-HT cells of the MR. The present study examined the effects on the hippocampal EEG of injections of the GABAA agonist muscimol hydrobromide into the MR. Low doses of muscimol (0.5 microgram) produced hippocampal theta rhythm at a mean latency of 6.81 min and for a mean duration of 23.6 min. Higher doses (1.0 microgram and 3.0 micrograms, respectively) produced theta at mean latencies of 2.24 min and 3.2 min and for mean durations of 31.84 min and 24.88 min. Injections of muscimol into regions adjacent to the MR generated theta at significantly longer latencies or were without effect. The present results indicate that MR injections of muscimol produce theta by inhibiting the activity of MR 5-HT neurons. It is concluded that MR GABAergic systems, via their influence on MR 5-HT cells, serve an important role in the control of the hippocampal EEG.

Recent evidence suggests that the supramammillary nucleus of the posterior hypothalamus serves as an important relay in a brainstem to septum/hippocampus pathway involved in the generation of hippocampal theta rhythm. In order to examine the role of the supramammillary nucleus as a possible relay/mediator of hippocampal theta rhythm, electrolytic lesions and procaine injections were administered to the supramammillary nucleus of freely moving and urethane-anesthetized rats, respectively. In the urethane-anesthetized rat, it was found that procaine injections attenuated both the frequency and amplitude of theta rhythm elicited by stimulation of the pontine reticular formation. These data suggest that the pontine reticular elicitation of hippocampal theta rhythm is mediated through connections with the supramammillary nucleus. However, it was found that lesions of the supramammillary nucleus failed to produce significant changes in the hippocampal electroencephalogram of freely moving animals. Several explanations concerning this apparent discrepancy are discussed. The most compelling is that multiple brainstem to septum/hippocampus pathways may serve to generate or facilitate the generation of theta rhythm in the freely moving animal. The present report demonstrates that the supramammillary nucleus plays a questionable role in the mediation of hippocampal electroencephalogram signals which are thought to be important for mnemonic processes.

In order to separate the effect of different theta generators in the hippocampus and to characterize the pattern of relationships between them, in this study, we calculated the coherence that remains between EEG signals, recorded (1) in the stratum oriens of the CA1 region and (2) close to the hippocampal fissure in the dentate gyrus of the right or left hippocampus, after the variations, common also for a third recording site is eliminated (partialization). We found that in both anesthetized and freely moving rats, there is a selective high correlation (coherence) between theta rhythmic activities of contralateral homonymous sites of the hippocampus. The coherence between field potentials recorded in ipsilateral superficial and deep layers was eliminated when allowance was made for any of the contralateral hippocampal recordings. On the other hand, coherence between contralateral homonymous theta dipoles did not decrease when partialized by a heteronymous hippocampal EEG signal. The present results support earlier findings on multiple hippocampal theta dipoles and indicate that they can be separated using partial coherence analysis. The left and right superficial and deep dipoles oscillate as if they formed two separate systems one extending over the superficial CA1 layers on both sides and the other consisting of the left and right deep hippocampal theta dipoles. The results also suggest an important role of the commissural projections in interhemispheric theta synchronization.

The median raphe nucleus (MR) exerts a pronounced desynchronizing influence on the hippocampal EEG. MR stimulation disrupts theta, while MR lesions produce constant uninterrupted theta. The MR receives pronounced excitatory amino acid (EAA)-containing afferents that have been implicated in several MR-mediated behaviors. The present study examined the effects on the hippocampal EEG of MR injections of the following EAA antagonists in the urethane-anesthetized rat: 2-amino-7-phosphonoheptanoate (AP-7), dizocilpine maleate (MK-801), and gamma-glutamyl-aminomethylsulfonic acid (GAMS). MR injections of the competitive (AP-7) and non-competitive (MK-801) N-methyl-D-aspartic acid (NMDA) receptor antagonists produced theta at short latencies (2.86 min; 4.02 min, respectively) and for long durations (116.1 min; 66.8 min, respectively). It was further shown that the theta-eliciting effects of AP-7 injections could be reliably and temporarily reversed with MR injections of NMDA. MR injections of the kainate/quisqualate receptor antagonist (GAMS) also produced theta at relatively short latencies (6.5 min) and for long durations (60.5 min) indicating that EAA effects on the MR are not NMDA receptor specific. Injections of each of the foregoing EAA antagonists into regions of the brainstem adjacent to the MR including the dorsal raphe nucleus and the medullary or pontine reticular formation generated theta at very long latencies or were without effect. The present findings indicate EAA afferents to the MR normally exert an excitatory influence on the MR in its desynchronization of the hippocampal EEG, whereas the removal of EAA inputs to MR produces the opposite: a reduction of MR activity and hence the elicitation of theta.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects on the hippocampal electroencephalogram of microinjections of procaine hydrochloride and the serotonin1A agonists, 8-OH-DPAT and buspirone, into the median raphe nucleus were examined in the urethane anesthetized rat. Injections of procaine, 8-OH-DPAT or buspirone into the median raphe nucleus produced a change in the hippocampal electroencephalogram from a spontaneous desynchronized pattern to a synchronized pattern (theta rhythm) within short latencies and for long durations post-injection. Procaine was shown to elicit theta at a mean latency of 52 s and for a mean duration of 21.75 min; buspirone at a mean latency of 2 min and for a mean duration of 34.5 min. A dose dependent relationship was observed between 8-OH-DPAT injections and latencies but not durations. Small doses (0.5 micrograms) of 8-OH-DPAT produced theta at a mean latency of 1.33 min and large doses (3.0 micrograms) at a mean latency of 1.17 min. 8-OH-DPAT injections generated theta for a mean duration of 62 min. Injections of each of these substances into structures dorsal, lateral or rostrocaudal to the median raphe (dorsal raphe nucleus, pontine reticular formation, caudal linear nucleus or raphe pontis, respectively) failed to generate theta or in a few cases produced theta at very long latencies (> 24 min). Saline injections in the median raphe nucleus or control structures were without effect. The demonstration that agents injected into the median raphe nucleus that inhibit its activity (procaine and serotonin1A agonists) produce theta indicate that serotonin-containing median raphe neurons normally suppress theta or are involved in the control of hippocampal desynchronization. The present findings are consistent with previous work showing that median raphe nucleus stimulation desynchronizes the hippocampal electroencephalogram and that median raphe nucleus lesions produce constant theta, but are at odds with the proposal that serotonergic mechanisms may play a role in the generation of the theta rhythm.