Intracellular recordings from medial septal neurons during hippocampal theta rhythm

 The electrophysiological properties of neurons of the medial septal nucleus and the nucleus of the diagnonal band of Broca (MS/DB) were studied using intracellular methods in urethane-anesthetized rats. Three types of rhythmically bursting neurons were identified in vivo on the basis of their action potential shapes and durations, afterhyperpolarizations (AHPs), membrane characteristics, firing rates and sensitivities to the action of muscarinic antagonist: (1) Cells with short-duration action potentials and no AHPs (2 of 34 rhythmic cells, 6%) had high firing rates and extremely reliable bursts with 6–16 spikes per theta cycle, which were highly resistant to scopolamine action. (2) Cells with short-duration action potentials and short-duration AHPs (8 of 34 rhythmic cells, 24%) also had high firing rates and reliable bursts with 4–13 spikes per theta cycle, phase-locked to the negative peak of the dentate theta wave. Hyperpolarizing current injection revealed a brief membrane time constant, time-dependent membrane rectification and a burst of firing at the break. Depolarizing current steps produced high-frequency repetitive trains of action potentials without spike frequency adaptation. The action potential and membrane and characteristics of this cell type are consistent with those described for GABAergic septal neurons. Many of these neurons retained their theta-bursting pattern in the presence of muscarinic antagonist. (3) Cells with long-duration action potentials and long-duration AHPs (24 of 34 rhythmic cells, 70%) had low firing rates, and usually only 1–3 spikes per theta cycle, locked mainly to the positive peak of the dentate theta rhythm. Hyperpolarizing current injection revealed a long membrane time constant and a break potential; a depolarizing pulse caused a train of action potentials with pronounced spike frequency adaptation. The action potential and membrane properties of this cell type are consistent with those reported for cholinergic septal neurons. The theta-related rhythmicity of this cell type was abolished by muscarinic antagonists. The phasic inhibition of ”cholinergic” MS/DB neurons by ”GABAergic” MS/DB neurons, followed by a rebound of their firing, is proposed as a mechanism contributing to recruitment of the whole MS/DB neuronal population into the synchronized rhythmic bursting pattern of activity that underlies the occurrence of the hippocampal theta rhythm. Received: 5 February 1996 / Accepted: 6 November 1996     

Modulation of septal influences on hippocampal neurons by cholinergic substances

The effects of electrical stimulation of the medial septal area (MS-DB) for the purpose of distinguishing and assessing the cholinergic component of the septohippocampal input were investigated in awake rabbits in chronic experiments. Initial inhibitory effects of a standard duration of 40–140 msec (54%) predominated in the intact rabbits. In animals with chronic basal undercutting of the MS-DB, initial inhibitory reactions predominated absolutely (90%). An increase in the level of endogenous acetylcholine by administration of eserine led to a partial or complete suppression of all effects of stimulation in 78% of the hippocampal neurons of the intact rabbits against the background of intensification of the theta modulation of the activity of hippocampal neurons. Scopolamine removed theta modulation and restored the reactivity of neurons to stimulation of the MS-DB. These influences of cholinergic substances were maintained in the animals with basal undercutting of the MS-DB. It is inferred that the general initial influence of septal input on neurons of the hippocampus is expressed in the suppression of their activity (“reset”), which depends on the noncholinergic (GABAergic) component of the septohippocampal connections. The cholinergic component limits the effectiveness of both extraseptal (brainstem) and primary inhibitory septal influences on hippocampal neurons. This study was supported by the Russian Basic Research Fund (project No. 93-04-21907). Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino. Translated from Zhurnal Vysshei Nervnoi Deyatel'nosti imeni I. P. Pavlova, Vol. 44, No. 4–5, pp. 751–761, July–October, 1994.     

A circadian rhythm of hippocampal theta activity in the mouse

Hippocampal theta activity dominates the cortical EEG of the mouse during certain behaviors. We have therefore been able to study the circadian distribution of hippocampal theta activity by means of chronic EEG implantation and computerized EEG state scoring. Observations in six mice indicate consistent and significant circadian patterns of theta-dominated EEG, both during wakefulness (theta-dominated wake, or TDW) and during sleep (REM sleep). The probability of REM rises gradually to a maximum during the sleep period and then falls abruptly at activity onset and then falls gradually. The complementary circadian patterns of REM and TDW suggest that they may be two episodes of each coincide remarkably, as do their circadian distributions. The probability of TDW rises to a very high level at activity onset and then falls gradually. The complementary circadian patterns of REM and TDW suggest that they may be two halves of a single circadian rhythm of theta probability. This concept would be relevant in interpreting the abnormally phase-advanced pattern of REM sleep observed in human depressives.     

Discharge properties of neurons of the median raphe nucleus during hippocampal theta rhythm in the rat

The serotonin (5-HT)-containing median raphe nucleus has been shown to be critically involved in the control of desynchronized (non theta) states of the hippocampal electroencephalogram (EEG). We examined the activity of 181 cells of the median raphe nucleus in the urethane-anesthetized rat and found that approximately 80% (145/181) of them showed changes in activity associated with changes in the hippocampal EEG. These cells were subdivided into theta-on (68%) and theta-off (32%) based on increased or decreased rates of activity with theta, respectively. They were further classified as slow-firing (~1 Hz), moderate-firing (5-11 Hz), or fast-firing (>12 Hz) theta-on or theta-off cells. The slow-firing cells as well as a subset of moderate-firing theta-off cells displayed characteristics of "classic" serotonin-containing raphe neurons. All fast-firing neurons were theta-on cells and showed either tonic or phasic (rhythmical) increases in activity with theta. We propose that: (1) the slow-firing cells (on and off) as well as a subset of moderate-firing theta-off cells are serotonergic neurons; (2) the phasic and tonic fast-firing theta-on cells are GABAergic cells; and (3) these populations of cells mutually interact in the modulation of the hippocampal EEG. An activation of local serotonergic and GABAergic theta-on cells would inhibit 5-HT slow- or moderate-firing theta-off projection cells to release or generate theta, whereas the suppression of serotonergic- or GABAergic theta-on cells would disinhibit 5-HT theta-off cells, resulting in a blockade of theta or a desynchronization of the hippocampal EEG. A role for the median raphe nucleus in memory-associated functions of the hippocampus is discussed.     

Modulation of the influences of cortical input on hippocampal neurons by cholinergic substances

The cholinergic modulation of responses of individual neurons and of the focal potentials of the hippocampus, induced by electrical stimulation of the perforant path or mossy fibers were studied in two groups of unanesthetized rabbits, one with an intact septal region (IS), and one with its basal undercutting (BU). In all of the animals the responses to stimulation were blocked or markedly suppressed in a substantial portion of the neurons (50% in IS, 69% in BU) against the background of the administration of eserine. Facilitation of the responses was observed in 10 and 8% of cases, respectively. Scopolamine restored the initial reactivity of hippocampal neurons and intensified responses to stimulation of the perforant path. The effect of eserine was reproduced by stimulation of the medial septal region (MS-DB). The depressive effect of stimulation of the MS-DB was intensified by the administration of eserine and blocked by scopolamine. Brief conditioning stimulation of the MS-DB which imitates a theta salvo facilitated responses to test stimulation of the MS-DB with delays of 70–150 msec, but suppressed them at smaller and greater intervals. Focal potentials in response to stimulation of the perforant path in CA₁ were suppressed to an equal extent (by 43%) during sensory stimulation inducing natural theta rhythm, during the action of eserine, and with stimulation of the MS-DB. In the BU group, these effects led to the complete suppression of focal potentials; scopolamine restored them. It is hypothesized that the principal function of the septohippocampal cholinergic input resided in the negative filtration of signals arriving against the background of theta rhythm that has been turned on by another, preceding influence, as a result of which their interference with the processing and recording of received information is prevented. Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino. Translated from Zhurnal Vysshei Nervnoi Deyatel'nosti imeni I. P. Pavlova, Vol. 44, No. 6, pp. 1026–1037, November–December, 1994.     

Modulation of the reaction of hippocampal neurons to sensory stimuli by cholinergic substances

The influences of increasing endogenous acetylcholine (eserine) and its blockade (scopolamine) on the effects of sensory stimuli were analyzed through the extracellular recording of the activity of individual hippocampal neurons of awake rabbits. An increase in the level of acetylcholine, accompanied by the appearance of stable theta rhythm, leads to a substantial decrease in the reactivity of neurons, the suppression, attenuation, and inversion of the majority of inhibitory reactions and of a substantial proportion of activational reactions including on-responses of a specific type. At the same time, a limited group of activational reactions is intensified and extended against the background of eserine. Scopolamine, which blocks theta rhythm, does not change or intensifies inhibitory and some activational reactions, including on-responses. Tonic reactions are shortened; however, their gradual extinction disappears. The effects described are preserved in the hippocampus in the presence of basal undercutting of the septum which eliminates ascending brainstem pathways. These data make it possible to draw the conclusion that, under normal conditions, a new (significant) sensory stimulus elicits in the hippocampus an initial stoppage (reset) of activity with the coordinated triggering of theta rhythm and the passage against this background of signals along the cortical input in a specific phase relationship to it. The period of theta modulation switched on by the signal fosters its recording and the limitation of the passage of subsequent, interfering signals. The septohippocampal influences may thus support the mechanism of selective attention, as a necessary precondition for memory. This study carried out with the financial support of the Russian Basic Research Fund (Project No. 93-04-21907). Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino. Translated from Zhurnal Vysshei Nervnoi Deyatel'nosti imeni I. P. Pavlova, Vol. 45, No. 1, pp. 118–131, January–February, 1995.     

Spatio-temporal cholinergic modulation in cultured networks of rat cortical neurons: spontaneous activity

Activation of the cholinergic innervation of the cortex has been implicated in sensory processing, learning, and memory. At the cellular level, acetylcholine both increases excitability and depresses synaptic transmission, and its effects on network firing are hard to predict. We studied the effects of carbachol, a cholinergic agonist, on network firing in cultures of rat cortical neurons, using electrode arrays to monitor the activity of large numbers of neurons simultaneously. These cultures show stable spontaneous synchronized burst firing which propagates through dense synaptic connections. Carbachol (10-50 microM), acting through muscarinic receptors, was found to induce a switch to asynchronous single-spike firing and to result in a loss of regularity and fragmentation of the burst structure. To obtain a quantitative measure of cholinergic actions on cortical networks, we applied a cluster Poisson-process model to sets of paralleled spike-trains in the presence and absence of carbachol. This revealed that the time series can be well-characterized by such a simple model, consistent with the observed 1/f(b)-like spectra (0.04相似文献   

Disinhibition of hippocampal pyramidal cells during the transition into theta rhythm

The activity of hippocampal complex-spike cells (presumed pyramidal cells) and theta cells (presumed interneurons) was examined during transitions from non-theta electroencephalogram (EEG) states to theta EEG states in freely moving and sleeping rats. Theta cell firing rates were significantly depressed in a 1-s period centered on the EEG transition relative to the surrounding 1-s periods (normalized rates±SEM): 1.05±0.02 for the non-theta period, 0.59±0.03 for the transition period, and 1.36±0.04 for the theta period (n = 26 cells). Conversely, complex-spike cell firing was significantly increased during the transition period: 0.51±0.11 for the non-theta period, 2.24±0.19 for the transition period, and 0.24±0.04 for the theta period (n = 27 cells). This diametrically altered activity indicates that theta cells must be actively inhibited during the transition. The increased activity in complex-spike cells during the transition may be simply a release from inhibitory control by interneurons. The pattern of theta cell inhibition together with increased complex-spike cell activity appears to be a general property of transitions into the theta EEG state, irrespective of behavior. It is suggested that increased activity in septal afferents (GABAergic cell activity greater than cholinergic cell activity) initially inhibits hippocampal interneurons. The inhibition is not sustained because of an activity-dependent decrease in the potency of the septointerneuronal inhibition, leaving the rhythmic excitatory (cholinergic) septointerneuronal inputs, together with principal cell inputs, to increase interneuron firing rates.     

Serotonergic modulation of hippocampal theta activity in relation to hippocampal information processing

Hippocampal theta activity is the result of the concerted activity of a group of nuclei located in the brain stem and the caudal diencephalic area, which are together referred to as the synchronizing ascending system. Serotonin is recognized as the only neurotransmitter able to desynchronize the hippocampal electroencephalographic. A theory has been developed in which serotonin, acting on medial septal neurons, modulates cholinergic/GABAergic inputs to the hippocampus and, thus, the cognitive processing mediated by this area. However, few studies have addressed the relationship between serotonin modulation of theta activity and cognition. In this review, we present a summary and analysis of the data relating serotonin and its theta activity modulation with cognition, and we also discuss the few works relating serotonin, theta activity and cognition as well as the theories regarding the serotonin regulation of memory processes organized by the hippocampus. We propose that serotonin depletion induces impairment of the relays coding the frequency of hippocampal theta activity, whereas depletion of the relays in which frequency is not coded induces improvements in spatial learning that are related to increased expression of high-frequency theta activity.     

Background activity of rabbit hippocampal neurons in conditions of functional exclusion of structures which regulate the theta rhythm

The functional importance of theta modulation in the activity of hippocampal neurons was further analyzed using a method consisting of controlled sequential short-term (25–30 min) inclusion or exclusion of the theta rhythm by local administration of lidocaine into the median cervical nucleus and medial septal region respectively. Studies were carried out using conscious rabbits with extracellular recording of hippocampal neuron activity in field CA1. Administration of lidocaine into the medial septal nucleus and diagnoal tract nucleus (MS-DT) led to complete inhibition of theta modulation in neuronal and total hippocampus activity. The mean frequency of background discharges underwent no change in most neurons, but decreased significantly in a limited group of cells with high-frequency activity (presumptive inhibitory neurons). Administration of lidocaine into the median cervical nucleus (MCN), the source of serotoninergic pathways to the MS-DT and hippocampus, was accompanied by increases in the stability and frequency of theta modulation of neuronal activity, induction of theta modulation in an additional group of neurons, and expression of a continuous theta rhythm in the electrical activity (EA) of the hippocampus. The mean frequency and regularity of discharges increased in most cells. These data support the existence of tonic inhibitory effects on the part of the MCN on the septa-hippocampal system generating the theta rhythm; in this regard, the MCN can be regarded as an antagonist of the activating reticular formation. Translated from Zhurnal Vysshei Nervnoi Deyatel'nosti imeni I. P. Pavlova, Vol. 48, No. 3, pp. 505–515, May–June, 1998.     

Septo-hippocampal connections and the hippocampal theta rhythm

Summary Recordings were made of spontaneous hippocampal theta activity in free-moving rats, before and after a variety of lesions. Three recording sites were used to monitor activity in the dorsal hippocampus, the ventral hippocampus, or close to the site of the hippocampal flexure. Electrolytic lesions were made in the medial septal area or the dorso-lateral septal area; surgical transections were made of the fimbria or dorso-medial area of the fornix. Following lesions restricted to the medial septal area, theta was abolished throughout the hippocampus; after lesions restricted to the dorso-lateral septal area theta was retained. Fimbria lesions abolished theta in the ventral, but not the dorsal hippocampus; dorso-medial fornix lesions abolished it in the dorsal, but not the ventral, hippocampus. In some subjects the hippocampal formation was subsequently stained for cholinesterase: cholinesterase staining loss was generally associated with theta loss, but this was not clear at the flexure recording site. It was confirmed that theta is dependent upon the integrity of the medial septal area. It was concluded that damage to hippocampal afferents from the septum does abolish theta, while damaging the feedback efferents does not.     

Periodic behavioral changes during hippocampal theta rhythm elicited by septal stimulation in rats

The influence of an electrical stimulation of the medial septum on the electroencephologram of the dorsal hippocampus and behavior was studied in freely moving rats. A short stimulation at 4–12 Hz frequency always induced orienting behavior (searching, rearing, sniffing, exploration) as soon as hippocampal rhythmic slow activity, or theta rhythm is elicited. An increase in stimulation intensity or in pulse duration led to an increased occurrence of theta rhythm and likewise, to an increase of orienting behavior. Both the theta rhythm and orienting behavior were dependent on the stimulation frequency.During long-lasting septal stimulation at 7 Hz, which elicited a continuous hippocampal theta rhythm, periodic behavioral changes were observed, consisting of orienting behavior alternating with grooming behavior (cleaning, washing, licking, scratching). These rhythmic periods lasted for 3–5 min.The significance of the rhythmic behavioral changes are discussed in relation to the activity of the cholinergic septohippocampal system and to rapid-eye-movement sleep and memory consolidation.     

Firing relations of medial septal neurons to the hippocampal theta rhythm in urethane anesthetized rats

Summary On the basis of spontaneous firing patterns and relations to the hippocampal theta rhythm, three cell types were identified within the medial septal nucleus and vertical limb of the nucleus of the diagonal band of Broca (MSN-NDB). In addition to the well known rhythmically bursting cells that fired in bursts on each cycle of the hippocampal theta rhythm, two other cell types are distinguished. Clock cells fired at high rates with a very regular, periodic firing pattern that was unrelated to the theta rhythm. Irregular cells fired at much lower rates, especially during theta rhythm, and had a pseudo-random firing pattern. The firing of irregular cells was often significantly phase-locked to the hippocampal theta rhythm. Crude estimates of the relative proportions of these cell types suggest that the rhythmically bursting cells comprise about 75% of the cells of the MSN-NDB. These three cell types bear a remarkable resemblance, in firing patterns and relative proportions, to the three principal cell types of the medial septal nuclei described in the freely moving rat (Ranck 1976). Measurements of the preferred phases of firing of 128 rhythmically bursting septal neurons (including 22 atropine-resistant and 11 atropine-sensitive cells) indicate that there is no single preferred phase of firing for the population. Rather the distribution of phases over the theta cycle is statistically flat. Variations in recording locations cannot account for this distribution since large differences in preferred phase were found for pairs of cells at the same location. Similarly, plotting only the group of cells identified as projection cells by antidromic activation from the fimbria/fornix, failed to reveal a peak in the distribution. In contrast to the rhythmically bursting cells, the distribution of preferred firing phases for the irregular cells with a significant phase-locking to the theta rhythm did have a clear peak. The peak occurred near the dentate theta rhythm positivity, consistent with the hypothesis that they are driven by feedback from CA1 complex-spike cells.     

Firing relations of lateral septal neurons to the hippocampal theta rhythm in urethane anesthetized rats

Summary The firing of lateral septal neurons was examined in relation to the hippocampal theta rhythm in urethane anesthetized rats. In general, the firing rates of these cells were low during both theta and non-theta EEG states. There was no significant change in firing rate between the two states (theta: 8.5±9.9 spks/sec; non-theta: 6.0±5.3). Sixty-four of 68 cells fired simple spikes and 4 cells were found to fire bursts of action potentials (complex-spikes). Approximately 30% (21/65) of the cells showed a significant phase relation to the hippocampal theta rhythm. The preferred phases of firing of these 21 cells were broadly distributed. The possibility that the phase-locked firing of LSN cells is due to the phase-locked firing of hippocampal projection cells is discussed.     

Membrane potential and impedance changes in hippocampal pyramidal cells during theta rhythm

Summary Intracellular recordings were made from hippocampal pyramidal cells identified by their depths and their responses to commissural stimulation. Recordings were made during spontaneous bouts of hippocampal theta rhythm in urethane anesthetized rats. Membrane potentials (V _m) of pyramidal cells varied with the phase of the theta rhythm, that is, there was an intracellular theta rhythm. The changes in V _m averaged about 2 mV peak to peak. Averaged intracellular theta waves showed that CA1 pyramids were most depolarized at the time of the positive peak of the extracellular theta rhythm recorded in (and superficial to) the CA1 pyramidal cell layer (CA1 theta). Peak depolarizations for CA3/4 pyramids were more broadly distributed, but occurred mainly in the interval just before the positive peak to just before the negative peak of the CA1 theta. Input impedance minima that were measurable at frequencies as high as 100 Hz occurred at about the same phases of the extracellular theta rhythm as the peak depolarizations (positive-going zero crossing to negative-going zero crossing of the CA1 theta). Such impedance changes imply conductance changes on the soma. The magnitude and localization of the conductance changes suggests that somatic IPSPs make major contributions to the intracellular theta rhythm. The phase relation between the intracellular and extracellular theta rhythms could be reversed by long duration current pulses that depolarized the cells slightly. This implies that either the intracellular theta-related IPSPs are depolarizing potential changes, or that they occur simultaneously with EPSPs. The phase of the intracellular theta rhythm was generally unaffected by long duration hyperpolarizing current pulses. Chloride leakage that reversed the evoked IPSPs usually had no effect on the phase of the intracellular theta rhythm, although in one case it appeared to cause its amplitude to increase.     

Rewarding intracranial stimulation,movement and the hippocampal theta rhythm

Some workers have suggested that hippocampal theta rhythm reflects activity of the neural reward system, while others have thought it to be primarily a correlate of voluntary movement. In order to examine these views, rats were trained to remain immobile while receiving rewarding intracranial stimulation; in this way the effects of the rewarding stimulation on hippocampal electrical activity were separated from the effects of movement (exploratory locomotion) that usually accompanies such stimulation. Rewarding intracranial stimulation was found to be neither necessary nor sufficient for the appearance of theta rhythm. Theta rhythm was present when rats performed large continous movements and absent when they remained immobile or performed small interrupted movements. Thus, theta rhythm is not an intrinsic correlate of rewarding stimulation but is closely associated with mechanisms that produce movement.     

Modulation of hippocampal theta rhythm by the opioid system of the pedunculopontine tegmental nucleus

The pedunculopontine tegmental nucleus (PPN) belongs to the brainstem system which synchronizes hippocampal activity. Theta relevant intra-PPN circuitry involves its cholinergic, GABA-ergic and glutamatergic neurons and Substance P as neuromodulator. Evidence that PPN opioid elements also modulate the hippocampal theta is provided here. In urethane-anesthetized rats a unilateral microinjection of morphine (MF) (1.5 and 5 microg) increased the maximal peak power of tail pinch-induced theta. The higher dose also increased the corresponding frequency. When the theta was evoked by intra-PPN injection of carbachol (10 microg), the addition of MF (5 microg) prolonged theta latency and shortened the duration of the theta. These effects of MF were blocked by naloxone (5 microg). The results obtained suggest that the PPN opioid system can enhance or suppress the hippocampal theta depending on the actual level of PPN activation.     

Characteristics and classification of hippocampal theta rhythm induced by passive translational displacement

Theta rhythms in the hippocampus are believed to be the “metric” relating to various behavior patterns for free roaming rats. In this study, the theta rhythms were studied while rats either walked or were passively translated by a toy car on a linear track (referred to as WALK and TRANS respectively). For the similar running speeds in WALK and TRANS conditions, theta frequency and amplitude were both reduced during TRANS. Theta modulation of pyramidal cells during TRANS was reduced compared to that during WALK. Theta frequency was positively correlated with translation speed during TRANS. Theta rhythm remained apparent during TRANS and WALK after large dose of atropine sulfate (blocking the cholinergic pathway) was injected compared to still states. The present study demonstrated the patterns of theta rhythm induced by passive translation in rats and suggested that the Type I theta rhythm could occur during non-voluntary locomotion. We further argued that the perception of actual self-motion may be the underlying mechanism that initiates and modulates type I theta.