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     

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.     

Unilateral blockade of the dorsal ascending noradrenergic bundle and septal elicitation of hippocampal theta rhythm

Unilateral blockade of the dorsal ascending noradrenergic bundle was produced by injections of procaine or of 6-hydroxydopamine. The threshold current of septal stimulation required to drive the hippocampal theta rhythm was then investigated at frequencies between 5.9 and 10.0 Hz. With both types of blockade the threshold-frequency function showed a normal 7.7 Hz minimum ipsilaterally and an abolition of the minimum contralaterally. Ventral noradrenergic bundle lesions had no effect.Septal elicitation of hippocampal theta rhythm may, therefore, be dependent on a noradrenergic mechanism controlling aspects of the theta rhythm, e.g. interhemispheric balance, which would not be obvious in ordinary spontaneous records.     

A distinctive subpopulation of medial septal slow-firing neurons promote hippocampal activation and theta oscillations

The medial septum-vertical limb of the diagonal band of Broca (MSvDB) is important for normal hippocampal functions and theta oscillations. Although many previous studies have focused on understanding how MSVDB neurons fire rhythmic bursts to pace hippocampal theta oscillations, a significant portion of MSVDB neurons are slow-firing and thus do not pace theta oscillations. The function of these MSVDB neurons, especially their role in modulating hippocampal activity, remains unknown. We recorded MSVDB neuronal ensembles in behaving rats, and identified a distinct physiologically homogeneous subpopulation of slow-firing neurons (overall firing <4 Hz) that shared three features: 1) much higher firing rate during rapid eye movement sleep than during slow-wave (SW) sleep; 2) temporary activation associated with transient arousals during SW sleep; 3) brief responses (latency 15～30 ms) to auditory stimuli. Analysis of the fine temporal relationship of their spiking and theta oscillations showed that unlike the theta-pacing neurons, the firing of these "pro-arousal" neurons follows theta oscillations. However, their activity precedes short-term increases in hippocampal oscillation power in the theta and gamma range lasting for a few seconds. Together, these results suggest that these pro-arousal slow-firing MSvDB neurons may function collectively to promote hippocampal activation.     

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.     

Frontal-midline theta from the perspective of hippocampal "theta"

Electrical recordings from the surface of the skull have a wide range of rhythmic components. A major task of analysis of this EEG is to determine their source and functional significance. The hippocampal "theta rhythm" has been extensively studied in rats and its rhythmicity has recently been shown to be functionally significant, per se. Here, we use relevant aspects of the hippocampal literature to provide perspective on one of the most studied human EEG rhythms: frontal-midline theta. We review its electrographic features, localization, prevalence, age distribution, behavioural modulation (particularly in relation to working memory, spatial navigation, episodic memory, internalised attention and meditation), relationship to personality, drug interactions, neurochemical relationships, and coherence with rhythmic activity at other sites. We conclude that FM-theta, like hippocampal theta, appears to play a role in (or at least occur during) processing of memory and emotion. It is correlated with working memory and/or sustained attention; but this does not entail a role in function since clear behavioural correlates of hippocampal theta have been demonstrated that are not sensitive to hippocampal damage. FM-theta is increased by anxiolytic drug action and personality-related reductions in anxiety, whereas hippocampal theta is decreased by anxiolytic drugs. In animals, frontal theta and hippocampal theta can be phase-locked or independent, depending on behavioural state. So, the cognitive functions of FM-theta, and their relationship to hippocampal theta, are unclear and definitive evidence for functional involvement in cognitive or emotional processing is lacking. One possible solution to this problem is analysis of FM-theta in animals-provided homology can be determined. The issues of sporadicity and low incidence of FM-theta also need to be addressed in the future. Changes in functional connectivity, indicated by changes in coherence, are also a largely untapped resource. We suggest that the most hopeful path to assessing the functions of FM-theta will be through the use of drugs, and the variation of their effects depending on baseline levels of FM-theta. Finally, we review some theories of theta function. Despite the apparent richness of the current data, we conclude that it is difficult (and may ultimately be impossible) to formulate a theory that attributes a specific cognitive function to FM-theta. However, the theories share some general computational assumptions and these should be a useful guide to future work and, ultimately, a definite theory of the function or functions of FM-theta.     

Sensitization and hippocampal type 2 theta in the rat

Previous research has consistently demonstrated that there are two types of theta which can be recorded from the hippocampus of a variety of species. Type 1 theta occurs during voluntary movements such as walking, running and rearing while type 2 theta occurs during alert immobility. Large amplitude irregular activity (LIA) occurs during more automatic behaviors such as grooming and chewing as well as during non-alert immobility. Type 2 theta can be readily elicited in the unrestrained guinea pig and rabbit. While spontaneous type 2 theta rarely occurs in the rat, short trains of type 2 theta have been observed during conditioning. The purpose of the present study was to examine the relationship between type 2 theta and inescapable shock when the temporal characteristics of the conditioning stimulus (CS) were varied. Three conditioning paradigms (delay, trace, random) were utilized. Type 2 theta production increased over time as a function of the number of shocks and was not due to conditioning. There were no differences in the three groups in the occurrence of type 2 theta during CS presentations or during the inter-stimulus intervals. Previously neutral sensory stimulation also produced type 2 theta after conditioning in all groups. The inescapable shocks placed the rat in a high state of arousal which subsequently sensitized the animal to produce type 2 theta. The data was used to support the hypothesis that a state of arousal is a necessary precursor for the production of type 2 theta.     

Eyeblink conditioning contingent on hippocampal theta enhances hippocampal and medial prefrontal responses

Trace eyeblink classical conditioning (tEBCC) can be accelerated by making training trials contingent on the naturally generated hippocampal 3- to 7-Hz theta rhythm. However, it is not well-understood how the presence (or absence) of theta affects stimulus-driven changes within the hippocampus and how it correlates with patterns of neural activity in other essential trace conditioning structures, such as the medial prefrontal cortex (mPFC). In the present study, a brain-computer interface delivered paired or unpaired conditioning trials to rabbits during the explicit presence (T(+)) or absence (T(-)) of theta, yielding significantly faster behavioral learning in the T(+)-paired group. The stimulus-elicited hippocampal unit responses were larger and more rhythmic in the T(+)-paired group. This facilitation of unit responses was complemented by differences in the hippocampal local field potentials (LFP), with the T(+)-paired group demonstrating more coherent stimulus-evoked theta than T(-)-paired animals and both unpaired groups. mPFC unit responses in the rapid learning T(+)-paired group displayed a clear inhibitory/excitatory sequential pattern of response to the tone that was not seen in any other group. Furthermore, sustained mPFC unit excitation continued through the trace interval in T(+) animals but not in T(-) animals. Thus theta-contingent training is accompanied by 1) acceleration in behavioral learning, 2) enhancement of the hippocampal unit and LFP responses, and 3) enhancement of mPFC unit responses. Together, these data provide evidence that pretrial hippocampal state is related to enhanced neural activity in critical structures of the distributed network supporting the acquisition of tEBCC.     

Modulation of theta rhythmicity in the medial septal neurons and the hippocampal electroencephalogram in the awake rabbit via actions at noradrenergic alpha2-receptors

The modulation of the firing discharge of medial septal neurons and of the hippocampal electroencephalogram (EEG) mediated by actions on alpha2-adrenoreceptors (ARs) was investigated in awake rabbits. Bilateral i.c.v. infusion of a relatively low dose (0.5 microg) of the alpha2-AR agonist clonidine produced a reduction in the theta rhythmicity of both medial septal neurons and the hippocampal EEG. In contrast, a high dose of clonidine (5 microg) increased the percentage and degree of rhythmicity of theta bursting medial septal neurons as well as the theta power of the hippocampal EEG. On the other hand, administration of alpha2-AR antagonist idazoxan produced the opposite dose-dependent effect. While a low dose of the antagonist (20 microg) produced an increase in both the theta rhythmicity of medial septal neurons and the theta power of the hippocampal EEG, a high dose (100 microg) caused a reduction of theta rhythmicity in both the medial septum and hippocampus. These results suggest that low doses of alpha2-ARs agents may act at autoreceptors regulating the synaptic release of noradrenaline, while high doses of alpha2-ARs drugs may have a predominant postsynaptic action. Similar results were observed after local injection of the alpha2-AR drugs into the medial septum suggesting that the effects induced by the i.c.v. infusion were primarily mediated at the medial septal level. We suggest that noradrenergic transmission via the postsynaptic alpha2-ARs produces fast and strong activation of the septohippocampal system in situations that require urgent selective attention to functionally significant information (alert, aware), whereas the action via the presynaptic alpha2-ARs allows a quick return of the activity to the initial level.     

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.     

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.     

Behavioral correlates of hippocampal type 2 theta in the rat

Previous research has indicated that there are two types of theta activity which can be recorded from the hippocampus in most rodents. One type (type 1) of theta is correlated with voluntary movements while the second (type 2) occurs during immobility. A third waveform termed LIA (Large Amplitude Irregular Activity) occurs during more automatic behaviors, e.g., grooming, shivering or immobility. In the rabbit and guinea pig type 2 theta can readily be elicited in unrestrained animals. However, type 2 theta is rarely seen in the unrestrained rat. The purpose of the present study was to determine the stimulus conditions that are necessary for the elicitation of type 2 theta in the rat. In the present study 20 unrestrained rats were observed in the presence of a cat or a ferret. Movements by the cat or ferret produced theta in immobile rats. Sensory stimuli which did not ordinarily produce type 2 theta would reliably do so in the presence of the cat or ferret. It is hypothesized that type 2 theta in the unrestrained immobile rat occurs during sensory processing but only when the animal is in a high state of "arousal."     

Sex and strain differences in septal driving of the hippocampal theta rhythm as a function of frequency: Effects of gonadectomy and gonadal hormones

The function relating septal stimulation frequency to threshold current for driving a hippocampal theta rhythm has a minimum at 7.7 Hz in the unselected free-moving male rat. This minimum is absent in the female. The female function is unaffected by the oestrous cycle or ovariectomy: the male function changes to one characteristic of the female 7–11 weeks after castration. Treatment with testosterone restores the function in the castrated male rat to one typical of the intact male and also produces such a function in the ovariectomised female rat.We also investigated this function in rats selectively bred for high (the Maudsley Reactive or MR strain) and low (the Maudsley Non-reactive or MNR) fearfulness. MR males resembled unselected males in having a minimum threshold at 7.7 Hz. MNR males lack this minimum and thus resemble unselected males after administration of fear-reducing drugs. Neither MR nor MNR females display a minimum threshold at 7.7 Hz; MR females responded to exogenous testosterone by developing a 7.7 Hz minimum threshold, but MNR females were unresponsive to the hormone. These results suggest that selective breeding for low fearfulness in the MNR strain has produced permanent changes in the functioning of the septo-hippocampal system which resemble those produced temporarily in unselected rats by fear-reducing drugs.     

Golgi study on cat hippocampal formation

Summary The Golgi architecture of the Fascia dentata and hippocampus is described in the cat. The main cell types are like those found in other species. The initial collaterals of granule cell axons were demonstrated and are commented on. The interneurons proved to be of several types and subtypes not observed in lower species. The intrinsic fibers and few of the afferents — both in the dentate fascia and in the hippocampus — are discussed.     

Dendritic spikes and their influence on extracellular calcium signaling

Extracellular calcium is critical for many neural functions, including neurotransmission, cell adhesion, and neural plasticity. Experiments have shown that normal neural activity is associated with changes in extracellular calcium, which has motivated recent computational work that employs such fluctuations in an information-bearing role. This possibility suggests that a new style of computing is taking place in the mammalian brain in addition to current 'circuit' models that use only neurons and connections. Previous computational models of rapid external calcium changes used only rough approximations of calcium channel dynamics to compute the expected calcium decrements in the extracellular space. Using realistic calcium channel models, experimentally measured back-propagating action potentials, and a model of the extracellular space, we computed the fluctuations in external calcium that accrue during neural activity. In this realistic setting, we showed that rapid, significant changes in local external calcium can occur when dendrites are invaded by back-propagating spikes, even in the presence of an extracellular calcium buffer. We further showed how different geometric arrangements of calcium channels or dendrites prolong or amplify these fluctuations. Finally, we computed the influence of experimentally measured synaptic input on peridendritic calcium fluctuations. Remarkably, appropriately timed synaptic input can amplify significantly the decrement in external calcium. The model shows that the extracellular space and the calcium channels that access it provide a medium that naturally integrates coincident spike activity from different dendrites that intersect the same tissue volume.     

Differential effects of age on subpopulations of hippocampal theta cells

The possible contribution of age-related changes in the firing properties of hippocampal theta cells to spatial learning deficits was addressed in the present study. The behavioral correlates of theta cells in strata oriens, pyramidale, and granulosum were compared as young and old rats performed a radial maze spatial working memory task. Behaviorally, the old animals made significantly more errors on the maze and required more time to solve the task than did young animals. Firing rates were compared in four different locomotion states: still, running radially inward and radially outward, and forwadd motion. The discharge rates of theta cells in strata pyramidale and granulosum were significantly modulated by these movements in both age groups. Stratum oriens theta cells recorded from young animals, on the other hand, were not movement-sensitive, while similar cells from old animals demonstrated exaggerated responses to movement. In old animals, the mean discharge rates were higher in stratum granulosum and lower in stratum oriens than in the young rats. The discharge rates of cells in stratum pyramidale did not differ between age groups. These region specific changes in the firing characteristics of hippocampal theta cells are likely to have important consequences for information processing in this structure.