Comparison of spontaneous and septally driven hippocampal theta field and theta-related cellular activity

Experiments were carried out for the purpose of comparing the electrophysiological properties of spontaneously occurring hippocampal theta field activity with those of theta-like field activity elicited by 5-Hz and 7-Hz electrical stimulation of the medial septum in urethane-anesthetized rats. Experiment 1 compared the amplitude and phase depth profiles for the three conditions of spontaneously occurring theta, theta elicited by 5-Hz medial septal stimulation, and theta elicited by 7-Hz medial septal stimulation. The results supported the conclusion that septally elicited theta field activity exhibited characteristics similar to those of spontaneously occurring theta field activity. Experiment 2 compared the discharge properties of hippocampal theta-related cellular discharges during spontaneous and septally elicited theta field activity. In contrast to the results of Experiment 1, the findings of Experiment 2 supported the conclusion that electrical stimulation of medial septal nuclei did not produce typical responses of hippocampal theta-related cellular activity. During spontaneously occurring field conditions, HPC theta-ON cells increased their discharge rates during spontaneous theta field activity, relative to LIA, and theta-OFF cells decreased (often to zero) their discharge rates during theta field activity relative to LIA. During septally elicited theta-like activity, phasic and tonic theta-ON cells decreased their discharge rates (some were totally inhibited), and most tonic theta-OFF cells increased their discharge rates (although two were totally inhibited). In addition, the discharges (albeit reduced) of the majority of both phasic and tonic theta-ON cells during septal driving became entrained to the stimulation pulses and thus exhibited rhythmicity and strong phase relations with the field activity. Furthermore, both cell types discharged near the positive peak of the septally elicited theta field activity during 5-Hz stimulation and near the negative peak during 7-Hz stimulation. The discharges of most tonic theta-OFF cells also became entrained to the stimulation pulses and exhibited similar phase relations to theta-ON cells during the 5-Hz and 7-Hz driving frequencies. Thus, based on cellular evidence, electrical stimulation of the medial septum activates the hippocampal neural circuitry involved in the generation of theta field activity in a nonphysiological manner. The findings of the present paper provide an explanation for why electrical stimulation of the medial septum in freely moving rats elicits a theta-like field activity that is dissociated from the normal behavioral correlates, in contrast to those elicited by stimulation of the posterior nucleus of the hypothalamus (Bland and Oddie. 2001. Behav Brain Res 127:119-136).     

Effects of atropine on hippocampal theta cells and complex-spike cells

The medial septal nuclei are essential for the naturally occurring hippocampal theta rhythm. Evidence that the rhythmic activity of the septum is carried via cholinergic afferents to the hippocampus has been: (a) the existence of a cholinergic septo-hippocampal projection, and (b) the sensitivity of one type of theta rhythm to antimuscarinic agents or cholinergic depletion. The muscarinic action of acetylcholine on pyramidal cells, however, is too slow to carry even a 4 Hz signal. Recent in vitro studies have confirmed a fast excitatory response by some hippocampal interneurons to muscarinic agonists. In urethane anesthetized rats, iontophoretic application of atropine to 17 hippocampal theta cells (presumed interneurons) during the theta rhythm, reduced their firing rates to an average of 24% of control rates. The effect of iontophoretic atropine application to 4 CA1 complex-spike cells (presumed pyramidal cells) was a selective elimination of their bursting activity with no significant effect on overall firing rate. The data suggest that: (1) interneuronal firing, during the hippocampal theta rhythm, is dominated by an excitatory cholinergic input and not by excitatory collaterals of pyramidal cells; and (2) somatic burst firing by CA1 pyramidal cells requires the presence of acetylcholine.     

Septo-hippocampal relationships during EEG theta rhythm

The firing pattern of 96 neuron in the medial septal nucleus (MSN) and diagonal band of Broca (DBB) and their functional relationships with hippocampal theta generators were investigated in rats during physostigmine-induced hippocampal theta rhythm (theta). Three types of discharge were found. (a) Type 1 (74%), in rhythmic bursts phase-locked with theta. (b) Type 2 (19%), non-rhythmic but phase-related to theta. (c) Type 3 (7%), unrelated to theta and non-rhythmic. Three sub-patterns of type 1 discharges were found. (1) Type 1A (56%), with regular bursts at high intraburst rates. (2) Type 1B (11%), with short bursts, or a single spike per theta cycle, and long interburst silent intervals. (3) Type 1C (6%), without clearly separate bursts, but with a rate modulation related to theta. Electrical stimulation of structures projecting to MSN-DBB or hippocampus tended to determine a constant poststimulus phase of theta and type 1 unit activity (i.e., reset). Our findings are in agreement with the hypothesis that MSN-DBB type 1 cells function as the theta "pacemaker', type 1A probably being the most influential in generating theta. Type 1B may be local interneurons and type 1C may receive rhythmic information from both septal and hippocampal neurons. Type 2 cells, although non-rhythmic, carry information of theta rhythmicity. Stimulus effects suggest that hippocampal theta reset is generated in the MSN-DBB.     

Place cell firing cannot support navigation without intact septal circuits

Though it has been known for over half a century that interference with the normal activity of septohippocampal neurons can abolish hippocampal theta rhythmicity, a definitive answer to the question of its function has remained elusive. To clarify the role of septal circuits and theta in location‐specific activity of place cells and spatial behavior, three drugs were delivered to the medial septum of rats: Tetracaine, a local anesthetic; muscimol, a GABA‐A agonist; and gabazine, a GABA‐A antagonist. All three drugs disrupted normal oscillatory activity in the hippocampus. However, tetracaine and muscimol both reduced spatial firing and interfered with the rat's ability to navigate to a hidden goal. After gabazine, location‐specific firing was preserved in the absence of theta, but rats were unable to accurately locate the hidden goal. These results indicate that theta is unnecessary for location‐specific firing of hippocampal cells, and that place cell activity cannot support accurate navigation when septal circuits are disrupted.     

Preserved spatial coding in hippocampal CA1 pyramidal cells during reversible suppression of CA3c output: evidence for pattern completion in hippocampus

Medial septal modulation of hippocampal single-unit activity was examined by assessing the behavioral and physiological consequences of reversibly inactivating the medial septum via microinjection of a local anesthetic (tetracaine) in freely behaving rats trained to solve a working memory problem on a radial maze. Reversible septal inactivation resulted in a dramatic, but temporary (15-20 min), impairment in choice accuracy. In addition, movement-induced theta (theta) modulation of the hippocampal EEG was eliminated. Septal injection of tetracaine also produced a significant reduction in location-specific firing by hilar/CA3c complex-spike cells (about 50%), with no significant change in the place-specific firing properties of CA1 complex-spike units. The mean spontaneous rates of stratum granulosum and CA1 theta cells were temporarily reduced by about 50% following septal injection of tetracaine. Although there was a significant reduction in the activities of inhibitory interneurons (theta cells) in CA1, there was no loss of spatial selectivity in the CA1 pyramidal cell discharge patterns. We interpret these results as support for the proposal originally put forth by Marr (1969, 1971) that hippocampal circuits perform pattern completion on fragmentary input information as a result of a normalization operation carried out by inhibitory interneurons. A second major finding in this study was that location specific firing of CA1 cells can be maintained in the virtual absence of the hippocampal theta-rhythm.     

Restoring theta-like rhythmicity in rats restores initial learning in the Morris water maze

Neural activity often becomes rhythmic during mental processing. But there has been no direct proof that rhythmicity, per se, is important for mental function. We assessed this issue in relation to the contribution of hippocampal theta-frequency rhythmicity to learning in the Morris water maze by blocking theta (and other septal inputs to the hippocampus) and then using electrical stimulation to restore rhythmicity. We injected tetracaine into the medial septal area, and so blocked septal input to the hippocampus in rats throughout 16 consecutive trials in a Morris water maze. Rats with no hippocampal theta also showed no initial learning in the maze. Theta rhythmicity in the supramammillary area remained after septal blockade, and we used this to trigger electrical stimulation of the fornix superior. This substantially restored hippocampal theta-like rhythmicity throughout training at a normal frequency but with abnormal wave forms. This treatment applied throughout training substantially restored initial learning. Fixed frequency (7.7 Hz) stimulation produced rhythmic activity and a brief improvement in learning. Irregular stimulation with an average frequency of 7.7 Hz produced little rhythmicity and little improvement in learning. These results demonstrate that brain rhythmicity, per se, can be important for mental processing even when the detailed information originally carried by neurons is lost and when the reinstated pattern of population firing is not normal. The results suggest that the precise frequency of rhythmicity may be important for hippocampal function. Functional rhythmicity needs, therefore, to be included in neural models of cognitive processing. The success of our procedure also suggests that simple alterations of rhythmicity could be used to ameliorate deficits in learning and memory. (c) 2006 Wiley-Liss, Inc.     

The pharmacology of hippocampal theta cells: Evidence that the sensory processing correlate is cholinergic

The firing repertoires of theta cells in the CA1 and dentate layers of the hippocampal formation of the freely moving rabbit were analyzed during 3 behavioral conditions: (1) voluntary motor patterns, termed type 1 theta behaviors; (2) automatic motor patterns, termed type 2LIA behaviors; (3) alert immobility with presentation of sensory stimuli, termed type 2 theta behavior. Cholinergic manipulations were shown to effect the firing repertoires of theta cells during the type 2 theta behavior condition (sensory processing) and not the other two behavioral conditions. A hypothesis of a sensorimotor processing function of the hippocampal formation is presented and discussed.     

Respiratory cycle entrainment of septal neurons mediates the fast coupling of sniffing rate and hippocampal theta rhythm

Memory for odour information may result from temporal coupling between the olfactory and hippocampal systems. Respiration defines the frequency of olfactory perception, but how the respiratory rate affects hippocampal oscillations remains poorly understood. The afferent connectivity of the medial septum/diagonal band of Broca complex (MS/DB) proposes this region as a crossroads between respiratory and limbic pathways. Here we investigate if the firing rates of septal neurons integrate respiratory rate signals. We demonstrate that approximately 50% of MS/DB neurons are temporally correlated with sniffing frequency. Moreover, a group of slow‐spiking septal neurons are phase‐locked to the sniffing cycle. We show that inter‐burst intervals of MS/DB theta cells relate to the sniff rate. Intranasal odour infusion evokes sniff phase preference for the activity of fast‐spiking MS/DB neurons. Concurrently, the infusion augments the correlation between sniffing and limbic theta oscillations. During periods of sniffing–theta correlation, CA1 place cells fired preferentially during the inhalation phase, suggesting the theta cycle as a coherent time frame for central olfactory processing. Furthermore, injection of the GABAergic agonist muscimol into medial septum induces a parallel decrease of sniffing and theta frequencies. Our findings provide experimental evidence that MS/DB does not merely generate theta rhythm, but actively integrates sensorimotor stimuli that reflect sniffing rate. Such integration may provide temporal oscillatory synchronisation of MS/DB‐innervated limbic structures with the sniffing cycle.     

Mechanisms of neural synchrony in the septohippocampal pathways underlying hippocampal theta generation.

Using urethane-anesthetized rats, 18 simultaneously recorded septohippocampal cell pairs (36 individual cells), each classified as theta-related according to the criteria of, were studied during four spontaneously occurring hippocampal field conditions: (1) large amplitude irregular activity (LIA) only; (2) the transition from LIA to theta; (3) theta only; and (4) the transition from theta to LIA. The main objective was to study the temporal relationships and degree of neural synchrony between the discharges of the cell pairs, using both time-averaged and time-dependent joint peristimulus time histogram correlation techniques, during the four conditions, to determine their contribution to the control of oscillation and synchrony (theta) in the hippocampus. The study demonstrated that the transition from the LIA state to the theta field state in the hippocampus required a temporal sequence of changes in theta-related cellular activity occurring on average 500 msec preceding the transition: (1) the medial septum inhibits hippocampal theta-OFF cells; (2) medial septal tonic theta-ON cells provide tonic depolarizing inputs to initiate membrane potential oscillations (MPOs) in hippocampal phasic theta-ON cells, whereas medial septal phasic theta-ON cells synchronize the MPOs of hippocampal phasic theta-ON cells and the discharges of hippocampal tonic theta-ON cells. Much of the time preceding the LIA to theta transition is accounted for by recruitment of these theta-related cell populations. Conversely, "turning off" the theta state occurs abruptly and involves the medial septal disinhibition of hippocampal theta-OFF cells.     

Ventral tegmental nucleus of Gudden: A pontine hippocampal theta generator?

It is well-established that rhythmically bursting (RB) activity in the medial septum is crucial for the generation of the hippocampal theta rhythm, but the contribution of other diencephalic-pontine structures is less documented. The ventral tegmental nucleus (VTn) of Gudden is related to the Papez's circuit via its interconnections with the medial mammillary nucleus, and therefore it may play a role in the generation of hippocampal theta. In the present study, extracellular activity from VTn neurons were recorded in unanesthetized restrained rats (n = 9). Hippocampal activity (EEG) and electromyograms were recorded simultaneously to identify sleep-waking states. RB activity was observed in VTn during wakefulness, with periods of hippocampal theta and during rapid eye movement (REM) sleep. Rhythmicity in VTn preceded theta activity in hippocampus. The frequency of RB neurons in VTn was 5.6 Hz during wakefulness and 6.8 Hz during REM sleep. It was similar to that of hippocampal theta. The rhythmicity was particularly stable and the firing rates were strikingly high during REM sleep. RB activity in VTn was also recorded from urethane-anesthetized rates (n = 3). Rhythmic firing (4.0 Hz) was slower than in unanesthetized rats and matched the urethane-related theta frequency. Our results show that neurons in VTn exhibit a marked RB activity during states of vigilance accompanied by hippocampal theta rhythm. They suggest that VTn may be a pontine hippocampal theta generator.     

The effect of descending theta rhythmic input from the septohippocampal system on firing in the supramammillary nucleus

The supramammillary nucleus (SUM) is part of an ascending pathway conveying behavior-dependent drive to the septal generator of limbic theta rhythm. The SUM is, however, reciprocally connected to the septohippocampal system and there is strong evidence that both septum and SUM are capable of generating theta rhythmic activity. The present study examined the possible role of a descending rhythmic input to the SUM using simultaneously recorded hippocampal EEG and SUM neuronal activity in anesthetized rats. Fourier based phase analysis was performed on recordings in which fast theta rhythmic activity was elicited by tail pinch and in which a slower theta rhythm persisted after cessation of the sensory stimulus. It was found that the firing of a subpopulation of SUM neurons followed the hippocampal theta waves with a constant time delay, rather than a constant phase, suggesting that during deceleration associated with a shift from sensory-elicited theta to spontaneous theta rhythm they followed a descending rhythmic input, most likely from the medial septum. Neurons of a second group, which fired at the hippocampal theta peaks, did not show such relationship demonstrating heterogeneity in the population of rhythmic SUM neurons and their possible roles in theta generation. Combined with previous studies focusing on the role of the ascending theta drive from the SUM, these results demonstrate dynamic bidirectional coupling between subcortical theta generators. Thus, during certain states, rhythmically firing SUM neurons lead the septal theta oscillator, in others the direction may reverse and SUM follows a theta drive of septal origin.     

Septohippocampal properties of N-methyl-D-aspartate-induced theta-band oscillation and synchrony

Microinfusion of N-methyl-D-aspartate (NMDA) into apical dendrites of hippocampal CA1 pyramidal cells of urethane-anesthetized rats resulted in long lasting (20-30 min) induction of hippocampal synchrony at the field and cellular level. Power but not frequency of NMDA-induced theta was significantly greater than tail pinch-induced theta activity. This effect was antagonized by intrahippocampal infusion of AP5, but unaffected by i.v. atropine sulfate. During AP5 blockade tail pinch theta frequency and power were significantly reduced. Microinfusion of NMDA into the medial septum also resulted in long lasting induction of hippocampal theta field activity. Contrary to the results of hippocampal NMDA microinfusions, frequency but not power of NMDA-induced theta was significantly greater than tail pinch- induced theta activity. Microinfusion of AP5 into the medial septum significantly lowered power of tail pinch-induced theta but did not affect frequency. Wheel running behavior of rats induced by low levels of electrical stimulation of the posterior hypothalamic nucleus (PH) was completely abolished by microinfusion of AP5 into the medial septum, accompanied by a significant reduction in theta power and frequency. Wheel running and theta were maintained at control levels with high intensity PH stimulation. We propose that: (1) the glutamatergic septohippocampal projection represents a third pathway capable of generating hippocampal field and cellular synchrony, independent of that generated by the septohippocampal cholinergic and GABAergic projections, and (2) the septohippocampal glutamatergic projection serves to function as an interface between cholinergic and GABAergic modulated sensory processing Type 2 theta and movement related Type 1 theta.     

The effect of intraseptal procaine injection of hippocampal theta in freely moving cat

Numerous studies have demonstrated that in the rodent, the septum is a critical site for the generation of hippocampla rhythmical field activity (theta, RSA). The aim of the present study was to clarify the role of the medial septal area in theta generation in the cat. Results indicate that (1) the microinfusion of the local anesthetic procaine into the medial septal region temporarily suppressed spontaneous as well as sensory and electrically induced hippocampal theta; (2) the suppression lasted 15 min and then amplitude and power of the hippocampal theta showed a progressive increase reaching preprocaine levels 60 min from the infusion onset. Theta frequency, in contrast, did not differ from control levels. The results provide evidence for the medial septal mediation of the hippocampal theta in the cat. This region is responsible for controlling theta amplitude but not its frequency. The present data supported the earlier results obtained in the rat and determined that the medial septal region plays a critical role in the generation of the hippocampal theta activity in cat.     

Medial septal modulation of entorhinal single unit activity in anesthetized and freely moving rats

Reversible inactivation of the medial septal area results in a spatial memory impairment and selective disruption of hilar/CA3, but not CA1, location-specific discharge. The present study examined the possibility that such septal deafferentation produces effects on hippocampal function by altering physiological properties of the primary input and output structures for hippocampus, the entorhinal cortex and the subiculum, respectively. Single unit activity of hippocampal, entorhinal, and subicular cells was recorded before, during, and after septal injection of lidocaine in anesthetized rats. When compared to hippocampal cells, relatively few subicular and entorhinal cells showed a change in mean firing rate following septal inactivation. Entorhinal unit responses to septal inactivation (via tetracaine injection) were also examined in freely moving rats performing a spatial maze task. About one-third of entorhinal cells showed enhanced or reduced firing rates of 40% or more. Also, the spatial distribution of cells found in the superficial, but not deep, entorhinal layers became less clear following septal inactivation. Together, these data are consistent with the hypothesis that manipulation of the medial septum affects hippocampal function via its septosubicular and septoentorhinal projections in addition to the more direct septohippocampal pathway. Since entorhinal cortical function was affected by tetracaine injection into the septum, it does not appear that direct entorhinal-CA1 afferents were primarily responsible for the maintenance of CA1 location-specific neural activity in previous septal inactivation experiments. Rather, these data are consistent with the hypothesis that the persistence of CA1 place fields was accomplished by intrahippocampal neural network operations.     

Dissociable pathways facilitate theta and non-theta states in the median raphe--septohippocampal circuit

Hippocampal theta rhythms in vivo are modulated by a synchronizing projection from the medial septum (MS) and a desynchronizing input from the median raphe nucleus (MRn) of the brainstem. Inactivation of the MS suppresses theta rhythms while inactivation of the median raphe produces persistent theta. However, different pathways arise from within the MS and the median raphe and therefore different brain states could be facilitated by different forms of median raphe or septohippocampal inputs. Here, we found in urethane anesthetized rats that suppression of outputs from the MRn with procaine leads to persistent hippocampal theta as previously reported. The discharge properties of hippocampal theta-related cells recorded during both spontaneously occurring theta and MRn 8-OH-DPAT-induced theta did not differ significantly. This persistent theta was abolished by inactivation of the MS with either procaine or atropine sulfate. Selective inactivation of serotonergic median raphe outputs with the 5-HT-1A agonist (8-OH-DPAT) induced theta that was also abolished by medial septal inactivation using procaine. Thus, persistent theta following complete median raphe inactivation or selective serotonergic inactivation arises from a median raphe to MS pathway. However, 8-OH-DPAT infusions into the median raphe together with atropine infusions in the MS did not abolish theta activity. These data suggest that the non-serotonergic (possibly glutamatergic) median raphe projections to the MS can facilitate the generation of hippocampal theta in the absence of medial septal cholinergic tone. These results demonstrate that dissociable neuronal pathways in the median raphe-MS-hippocampal circuit promote different brain states (theta or non-theta) and a median raphe non-serotonergic (likely glutamatergic) system may serve a separate function from the ascending serotonergic raphe projection in the regulation of hippocampal network activity.     

Dynamic changes in the direction of the theta rhythmic drive between supramammillary nucleus and the septohippocampal system

Neurons in the supramammillary nucleus (SUM) of urethane-anesthetized rats fire rhythmically in synchrony with hippocampal theta rhythm. As these neurons project to the septum and hippocampus, it is generally assumed that their role is to mediate ascending activation, leading to the hippocampal theta rhythm. However, the connections between SUM and the septohippocampal system are reciprocal; there is strong evidence that theta remains in the hippocampus after SUM lesions and in the SUM after lesioning the medial septum. The present study examines the dynamics of coupling between rhythmic discharge in the SUM and hippocampal field potential oscillations, using the directionality information carried by the two signals. Using directed transfer function analysis, we demonstrate that during sensory-elicited theta rhythm and also during short episodes of theta acceleration of spontaneous oscillations, the spike train of a subpopulation of SUM neurons contains information predicting future variations in rhythmic field potentials in the hippocampus. In contrast, during slow spontaneous theta rhythm, it is the SUM spike signal that can be predicted from the preceding segment of the electrical signal recorded in the hippocampus. These findings indicate that, in the anesthetized rat, SUM neurons effectively drive theta oscillations in the hippocampus during epochs of sensory-elicited theta rhythm and short episodes of theta acceleration, whereas spontaneous slow theta in the SUM is controlled by descending input from the septohippocampal system. Thus, in certain states, rhythmically firing SUM neurons function to accelerate the septal theta oscillator, and in others, they are entrained by a superordinate oscillatory network.     

The classification of medial septum-diagonal band cells as theta-on or theta-off in relation to hippocampal EEG states

The discharge patterns of cells located in the medial septum (MS)/vertical limb of the Diagonal Band of Broca (vDBB) were recorded simultaneously with hippocampal formation large amplitude irregular activity (LIA), or theta, in urethane-anesthetized rats. The main conclusion was that the majority of cells in the MS/vDBB were theta-related and could be classified according to the same scheme developed for theta-related cells in the hippocampal formation. That is, cells were classified as theta-on or theta-off, with subtypes defined as tonic or phasic, linear or non-linear. The discharge properties of hippocampal and MS/vDBB cell populations were compared. It was argued that this classification scheme encompassed all the crucial properties of theta-related cells in the hippocampal formation and the MS/vDBB. An alternative model to the septal pacemaker hypothesis, concerning the role of the medial septum in the generation of hippocampal formation theta activity, was presented and discussed.     

Excitotoxic septal lesions result in spatial memory deficits and altered flexibility of hippocampal single-unit representations.

The septal nuclei are reciprocally connected with the hippocampal formation and contribute importantly to spatial and memory processing. Using excitotoxic lesions of the septal area, we investigated whether neurodegeneration in subcortical projections to hippocampus can compromise flexible information processing by hippocampal single units. In agreement with the mild effects of excitotoxic septal lesions on hippocampal physiology compared with fimbria-fornix lesions and septal inactivation, we observed limited lesion effects on single-unit activity. The location specificity of hippocampal complex spike cells remained unchanged, but a less reliable location-dependent discharge was observed in experimental animals with a pronounced postoperative working memory deficit. Testing in the absence of ambient illumination and in a new environment revealed that the spatial correlates of complex spike cells in lesioned animals may rely on a more limited set of sensory cues. Altered sensory cues resulted in a significantly different response pattern between the control and lesion group in the new environment, a situation that normally results in place field reorganization. Such a group difference was not observed during dark testing, a condition in which place field reorganization is less prominent. A contribution of hippocampal interneurons to the observed alterations in the spatial properties of the principal cells was suggested by decreased theta modulation in the lesioned group. Because excitotoxic lesions result in memory deficits that resemble age-related memory problems in the absence of age-related degenerative processes, we suggest that septal neurodegeneration could directly contribute to those behavioral changes with advanced age that correlate with functional alterations in the hippocampal formation.     

The septal EEG suggests a distributed organization of the pacemaker of hippocampal theta in the rat

Individual neurons in the medial septum and diagonal band fire in phase with, and appear to act as a 'pacemaker' of, the hippocampal theta rhythm. We investigated the relationships of periodic EEG both among various parts of the septum and with dorsal hippocampal theta recorded concurrently in freely moving rats. Most septal sites showed theta rhythm concurrent with hippocampal theta during locomotion. However, periods with theta at hippocampal but not septal sites were more frequent than the reverse. Theta waves in different parts of the septum were synchronized with each other but medial septal sites showed less frequent theta than other sites. The phase delays between medial and lateral septal sites were < 10 ms, suggesting that the hippocampus does not act as a simple relay between the two. Spectral analysis revealed periods (> 5 s) of theta at hippocampal sites co-occurring with rhythms at multiple septal sites that were slower than theta. Even slower were the 'slow septal waves' (mean 2.7 Hz), which were present in the absence of locomotion and did not 'drive' the hippocampus. Our data suggest that the pacemaker of hippocampal theta may best be thought of as a set of functionally differentiated components rather than as a single homogenous unit.     

Septo-hippocampal networks in chronic epilepsy

The medial septum inhibits the appearance of interictal spikes and seizures through theta rhythm generation. We have determined that medial septal neurons increase their firing rates during chronic epilepsy and that the GABAergic neurons from both medial and lateral septal regions are highly and selectively vulnerable to the epilepsy process. Since the lateral septal region receives a strong projection from the hippocampus and its neurons are vulnerable to epilepsy, their functional properties are probably altered by this disorder. Using the pilocarpine model of temporal lobe epilepsy we examined the pilocarpine-induced functional alterations of lateral septal neurons and provided additional observations on the pilocarpine-induced functional alterations of medial septal neurons. Simultaneous extracellular recordings of septal neurons and hippocampal field potentials were obtained from chronic epileptic rats under urethane anesthesia. Our results show that: (1) the firing rates of lateral septal neurons were chronically decreased by epilepsy, (2) a subset of lateral septal neurons increased their firing rates before and during hippocampal interictal spikes, (3) the discharges of those lateral septal neurons were well correlated to the hippocampal interictal spikes, (4) in contrast, the discharges of medial septal neurons were not correlated with the hippocampal interictal spikes. We conclude that epilepsy creates dysfunctional and uncoupled septo-hippocampal networks. The elucidation of the roles of altered septo-hippocampal neuronal populations and networks during temporal lobe epilepsy will help design new and effective interventions dedicated to reduce or suppress epileptic activity.