Membrane and network theta-rhythm generation in hippocampal slices

The hippocampal rhythms observed in vivo are the result of a complex interplay between cellular and synaptic properties within the hippocampus, and extra-hippocampal tonic as well as periodic inputs. For the stable rhythm to occur, the hippocampal circuitry should have the potential to oscillate at the specific frequencies. The in vitro studies revealed multiple mechanisms supporting the generation of the theta rhythm, which is the main operational mode of the hippocampus. In the hippocampus and related structures cellular membranes can oscillate at theta rhythm when they are depolarized to near-threshold membrane potentials; membranes are also adjusted to resonate with the external signal applied at theta frequency. Synaptically connected hippocampal network alone can generate theta rhythm when a necessary tonic excitation is provided. Finally, rhythmic inputs in theta range from the septum and entorhinal cortex have a propensity to synchronize oscillations in the whole hippocampal formation and associated structures to operate in a unified mode of activity. Based on the results obtained in slices and slice cultures, the present review shows this multilevel hierarchy, which serves to guarantee easy occurrence and reliable maintenance of the theta rhythm in the hippocampus.     

Mechanisms of the regulation and functional significance of the theta rhythm. Roles of serotonergic and noradrenergic systems

The evidence for the role of serotonergic and noradrenergic effects on the septohippocampal theta oscillations obtained by the author and her colleagues are reviewed. Analysis of neuronal activity in the medial septal area or hippocampus and hippocampal EEG simultaneously recorded in awake rabbits exposed to different kinds of brainstem influences led to the following conclusions. 1. Serotonergic median raphe nucleus and noradrenergic locus ceruleus act as functional antagonists in theta regulation: the former structure restricts the theta rhythm generation, whereas the latter enhances this process. 2. Both transmitter systems control sensory reactions of septal and hippocampal neurons through up and down regulation of the theta activity. 3. When continuous theta activity induced by various experimental manipulations is recorded, responsiveness of septohippocampal neurons to sensory stimulation is strongly reduced. These findings provide support for the view that the theta oscillations act as an active filter in the information selection and registration. Interaction of different transmitter systems in the theta rhythm control as well as attention and memory is discussed.     

Theta rhythmicity in the medial septum: entraining by the GABA-ergic neurons

The medial septal/diagonal band complex (MS/DB) is believed to play an important role in the generation and maintenance of the hippocampal theta rhythm, which has been implicated in the mnemonic and information-processing capacity of the brain. Although the physiological and morphological diversity of the septal neurons indicates their different functions, it is not known which cell type within the population contributes most critically to the theta rhythm. Here we review the chemical identity of different cell groups within the MS/DB complex, the anatomical connectivity between them, the electrophysiological properties of immunochemically-defined cell types, and their contribution to theta rhythmicity in the medial septum and the hippocampal theta rhythm. In order to better understand the mechanisms involved in rhythmic burst firing of the MS/DB neurons, a number of relevant theoretical models related to the generation/synchronization in neural networks are discussed.     

Artificial Theta Stimulation Impairs Encoding of Contextual Fear Memory

Several experiments have demonstrated an intimate relationship between hippocampal theta rhythm (4–12 Hz) and memory. Lesioning the medial septum or fimbria-fornix, a fiber track connecting the hippocampus and the medial septum, abolishes the theta rhythm and results in a severe impairment in declarative memory. To assess whether there is a causal relationship between hippocampal theta and memory formation we investigated whether restoration of hippocampal theta by electrical stimulation during the encoding phase also restores fimbria-fornix lesion induced memory deficit in rats in the fear conditioning paradigm. Male Wistar rats underwent sham or fimbria-fornix lesion operation. Stimulation electrodes were implanted in the ventral hippocampal commissure and recording electrodes in the septal hippocampus. Artificial theta stimulation of 8 Hz was delivered during 3-min free exploration of the test cage in half of the rats before aversive conditioning with three foot shocks during 2 min. Memory was assessed by total freezing time in the same environment 24 h and 28 h after fear conditioning, and in an intervening test session in a different context. As expected, fimbria-fornix lesion impaired fear memory and dramatically attenuated hippocampal theta power. Artificial theta stimulation produced continuous theta oscillations that were almost similar to endogenous theta rhythm in amplitude and frequency. However, contrary to our predictions, artificial theta stimulation impaired conditioned fear response in both sham and fimbria-fornix lesioned animals. These data suggest that restoration of theta oscillation per se is not sufficient to support memory encoding after fimbria-fornix lesion and that universal theta oscillation in the hippocampus with a fixed frequency may actually impair memory.     

Hippocampal rhythm generation: Gamma-related theta-frequency resonance in CA3 interneurons

 During different behavioral states different population activities are present in the hippocampal formation. These activities are not independent: sharp waves often occur together with high-frequency ripples, and gamma-frequency activity is usually superimposed on theta oscillations. There is both experimental and theoretical evidence supporting the notion that gamma oscillation is generated intrahippocampally, but there is no generally accepted view about the origin of theta waves. Precise timing of population bursts of pyramidal cells may be due to a synchronized external drive. Membrane potential oscillations recorded in the septum are unlikely to fulfill this purpose because they are not coherent enough. We investigated the prospects of an intrahippocampal mechanism supplying pyramidal cells with theta frequency periodic inhibition, by studying a model of a network of hippocampal inhibitory interneurons. As shown previously, interneurons are capable of generating synchronized gamma-frequency action potential oscillations. Exciting the neurons by periodic current injection, the system could either be entrained in an oscillation with the frequency of the inducing current or exhibit in-phase periodic changes at the frequency of single cell (and network) activity. Simulations that used spatially inhomogeneous stimulus currents showed anti-phase frequency changes across cells, which resulted in a periodic decrease in the synchrony of the network. As this periodic change in synchrony occurred in the theta frequency range, our network should be able to exhibit the theta-frequency weakening of inhibition of pyramidal cells, thus offering a possible mechanism for intrahippocampal theta generation. Received: 23 February 2000 / Accepted in revised form: 30 June 2000     

Computational experiments support a competitive function in the the CA3 region of the hippocampus

The comprehension of activities and functions of complex brain structures requires, among other things, information on simultaneous activities in several regions. Results reported in the literature using multi(micro/macro)electrode recordings or imaging techniques provide incomplete information due either to the small size and/or small number of investigated regions or to the poor spatiotemporal resolution, respectively. This is particularly true for the hippocampus and its subfields, and mathematical modeling and computer simulation have been used with the aim of obtaining information when this is lacking. Global activities in the CA3 field of the hippocampus, and in particular the genesis of theta rhythm and sharp waves, have been investigated here by a mathematical model formulated within the frame of a kinetic theory of neural systems. The model has taken into account data of experimental results both on different PSPs recorded in hippocampal neurons and on recurrent pyramidal collateral geometries. The computational ‘experiments’ to which the model was subjected suggest that the sharp waves arise through a selective and short block of the fast inhibitory neurons of CA3, produced by a medial septum inhibitory input, whereas the theta activity is produced by a durable, continuous inhibition of the slow inhibitory neurons. Information obtained also suggests that the recurrent pyramidal collaterals subserve a competitive, rather than a cooperative, organization. Based on these results a hypothesis on the possible functional organization of the CA3 field and of the entire hippocampus has been formulated. According to this hypothesis, the CA3 imposes a serial order on the flow of activity arriving at the hippocampus from the entorhinal cortex and from its connected polymodal cortical regions. This ordering permits cortical activities, arriving at CA3 on appropriate time intervals, to produce effects in regions of brain to which the CA3 projects. The competing cortical activities are lost.     

Medial septal region as a target for modulation of seizure discharges in the hippocampus in a model of acute temporal lobe epilepsy

Investigation of changes in the hippocampal EEG produced by GABAergic and cholinergic substances delivered into the medial septum region was performed in awake rabbits. Changes in the threshold of seizure discharges in the hippocampus evoked by perforant path stimulation (model of acute epilepsy) were also examined. Injections of GABAA receptor antagonist picrotoxin or agonist of cholinergic receptors carbacholine in low doses induced an increase in the power of delta- and theta modulation and appearance of 7-12-Hz oscillations. The threshold of hippocampal seizure afterdischarges decreased. In higher doses, these substances evoked 7-15-Hz oscillations followed by seizures. GABAA receptor agonist muscimol and muscarinic receptor antagonist scopolamine decreased the power of the theta rhythm and increased the seizure threshold. Picrotoxin or carbacholine injected after muscimol or scopolamine, respectively, did not evoke seizures. Thus, we have shown the possibility to control hippocampal activity by local changes in the GABAergic and cholinergic systems of the medial septum region.     

GABAergic contributions to gating, timing, and phase precession of hippocampal neuronal activity during theta oscillations

Successful spatial exploration requires gating, storage, and retrieval of spatial memories in the correct order. The hippocampus is known to play an important role in the temporal organization of spatial information. Temporally ordered spatial memories are encoded and retrieved by the firing rate and phase of hippocampal pyramidal cells and inhibitory interneurons with respect to ongoing network theta oscillations paced by intra- and extrahippocampal areas. Much is known about the anatomical, physiological, and molecular characteristics as well as the connectivity and synaptic properties of various cell types in the hippocampal microcircuits, but how these detailed properties of individual neurons give rise to temporal organization of spatial memories remains unclear. We present a model of the hippocampal CA1 microcircuit based on observed biophysical properties of pyramidal cells and six types of inhibitory interneurons: axo-axonic, basket, bistratistified, neurogliaform, ivy, and oriens lacunosum-moleculare cells. The model simulates a virtual rat running on a linear track. Excitatory transient inputs come from the entorhinal cortex (EC) and the CA3 Schaffer collaterals and impinge on both the pyramidal cells and inhibitory interneurons, whereas inhibitory inputs from the medial septum impinge only on the inhibitory interneurons. Dopamine operates as a gate-keeper modulating the spatial memory flow to the PC distal dendrites in a frequency-dependent manner. A mechanism for spike-timing-dependent plasticity in distal and proximal PC dendrites consisting of three calcium detectors, which responds to the instantaneous calcium level and its time course in the dendrite, is used to model the plasticity effects. The model simulates the timing of firing of different hippocampal cell types relative to theta oscillations, and proposes functional roles for the different classes of the hippocampal and septal inhibitory interneurons in the correct ordering of spatial memories as well as in the generation and maintenance of theta phase precession of pyramidal cells (place cells) in CA1. The model leads to a number of experimentally testable predictions that may lead to a better understanding of the biophysical computations in the hippocampus and medial septum.     

Hippocampal Theta Modulation of Neocortical Spike Times and Gamma Rhythm: A Biophysical Model Study

The hippocampal theta and neocortical gamma rhythms are two prominent examples of oscillatory neuronal activity. The hippocampus has often been hypothesized to influence neocortical networks by its theta rhythm, and, recently, evidence for such a direct influence has been found. We examined a possible mechanism for this influence by means of a biophysical model study using conductance-based model neurons. We found, in agreement with previous studies, that networks of fast-spiking GABA -ergic interneurons, coupled with shunting inhibition, synchronize their spike activity at a gamma frequency and are able to impose this rhythm on a network of pyramidal cells to which they are coupled. When our model was supplied with hippocampal theta-modulated input fibres, the theta rhythm biased the spike timings of both the fast-spiking and pyramidal cells. Furthermore, both the amplitude and frequency of local field potential gamma oscillations were influenced by the phase of the theta rhythm. We show that the fast-spiking cells, not pyramidal cells, are essential for this latter phenomenon, thus highlighting their crucial role in the interplay between hippocampus and neocortex.     

How do glutamatergic and GABAergic cells contribute to synchronization in the medial septum?

The medial septum-diagonal band (MSDB) complex is considered as a pacemaker for the hippocampal theta rhythm. Identification of the different cell types, their electro-physiological properties and their possible function in the generation of a synchronized activity in the MSDB is a hot topic. A recent electro-physiological study showed the presence of two antiphasically firing populations of parvalbumin containing GABAergic neurons in the MSDB. Other papers described a network of cluster-firing glutamatergic neurons, which is able to generate synchronized activity in the MSDB. We propose two different computer models for the generation of synchronized population theta oscillation in the MSDB and compare their properties. In the first model GABAergic neurons are intrinsically theta periodic cluster-firing cells; while in the second model GABAergic cells are fast-firing cells and receive periodic input from local glutamatergic neurons simulated as cluster-firing cells. Using computer simulations we show that the GABAergic neurons in both models are capable of generating antiphasic theta periodic population oscillation relying on local, septal mechanisms. In the first model antiphasic theta synchrony could emerge if GABAergic neurons form two populations preferentially innervate each other. In the second model in-phase synchronization of glutamatergic neurons does not require specific network structure, and the network of these cells are able to act as a theta pacemaker for the local fast-firing GABAergic circuit. Our simulations also suggest that neurons being non-cluster-firing in vitro might exhibit clustering properties when connected into a network in vivo. Action Editor: David Golomb     

Network effects of glutamate on neuronal activity in the medial septum/diagonal band complex in vitro

Inter-neuronal interactions within the medial septum/diagonal band complex (MSDB) are of great interest as this region is believed to be the hippocampal theta rhythm pacemaker. However, the role of glutamatergic system in functioning of the septal cells is yet unclear. Here, we demonstrate for the first time the effects of glutamate in physiological concentration (1 microM) on the MSDB neuronal spontaneous and evoked activities in vitro. These effects (activation of 70% and inhibition of 30% of responsive neurons) differed in pacemaker and non-pacemaker cells. Pacemaker cells were always activated under glutamate, whereas non-pacemaker neurons could be either activated or inhibited. Indeed, in the burst pacemakers, glutamate increased the frequency of rhythmic activity. In a total MSDB neuron population, in 30% of neurons glutamate applications modified responses to the electrical stimulation by unifying the temporal parameters of neuron responses. Along with the increase in the theta-burst frequency, this indicates that the glutamatergic system is involved in the process ofintraseptal synchronization. Obtained data shed light on the role ofglutamatergic system in septal neuron interactions and broaden our understanding of theta oscillation mechanisms in the septo-hippocampal system.     

Locomotion-related oscillatory body movements at 6-12 Hz modulate the hippocampal theta rhythm

The hippocampal theta rhythm is required for accurate navigation and spatial memory but its relation to the dynamics of locomotion is poorly understood. We used miniature accelerometers to quantify with high temporal and spatial resolution the oscillatory movements associated with running in rats. Simultaneously, we recorded local field potentials in the CA1 area of the hippocampus. We report that when rats run their heads display prominent vertical oscillations with frequencies in the same range as the hippocampal theta rhythm (i.e., 6-12 Hz). In our behavioral set-up, rats run mainly with speeds between 50 and 100 cm/s. In this range of speeds, both the amplitude and frequency of the "theta" head oscillations were increasing functions of running speed, demonstrating that the head oscillations are part of the locomotion dynamics. We found evidence that these rhythmical locomotor dynamics interact with the neuronal activity in the hippocampus. The amplitude of the hippocampal theta rhythm depended on the relative phase shift with the head oscillations, being maximal when the two signals were in phase. Despite similarity in frequency, the head movements and LFP oscillations only displayed weak phase and frequency locking. Our results are consistent with that neurons in the CA1 region receive inputs that are phase locked to the head acceleration signal and that these inputs are integrated with the ongoing theta rhythm.     

The theta modulation of rabbit hippocampal neurons and its correlation with other indices of spontaneous and evoked activity]

Reliability of the existing functional criteria for differentiation of pyramidal ("complex spike neurones") and inhibitory ("theta neurones") cells in the hippocampus of waking rabbit is evaluated on the basis of statistical analysis of neuronal spontaneous and evoked activity. The analysis shows, that the criteria of mean frequency, presence of theta modulation, neuronal behaviour in situations provoking EEG theta rhythm (e.g., excitation or inhibition during presentation of sensory stimuli), effects of medial septum and intrahippocampal stimulation do not permit reliable identification of the hippocampal neuronal types in the waking rabbit. The data on functional classification of the hippocampal neurones are discussed in connection with existing suggestions about their state in situations inducing theta rhythm generation.     

Global rhythmic activities in hippocampal neural fields and neural coding

Global oscillations of the neural field represent some of the most interesting expressions of the hippocampal activity, being related also to learning and memory. To study oscillatory activities of the CA3 field in theta range, a model of this sub-field of Hippocampus has been formulated. The model describes the firing activity of CA3 neuronal populations within the frame of a kinetic theory of neural systems and it has been used for computer simulations. The results show that the propagation of activities induced in the neural field by hippocampal afferents occurs only in narrow time windows confined by inhibitory barrages, whose time-course follows the theta rhythm. Moreover, during each period of a theta wave, the entire CA3 field bears a firing activity with peculiar space-time patterns, a sort of specific imprint, which can induce effects with similar patterns on brain regions driven by the hippocampal formation. The simulation has also demonstrated the ability of medial septum to influence the global activity of the CA3 pyramidal population through the control of the population of inhibitory interneurons. At last, the possible involvement of global population oscillations in neural coding has been discussed.     

Neuronal rebound spiking,resonance frequency and theta cycle skipping may contribute to grid cell firing in medial entorhinal cortex

Data show a relationship of cellular resonance and network oscillations in the entorhinal cortex to the spatial periodicity of grid cells. This paper presents a model that simulates the resonance and rebound spiking properties of entorhinal neurons to generate spatial periodicity dependent upon phasic input from medial septum. The model shows that a difference in spatial periodicity can result from a difference in neuronal resonance frequency that replicates data from several experiments. The model also demonstrates a functional role for the phenomenon of theta cycle skipping in the medial entorhinal cortex.     

Computational study of hippocampal-septal theta rhythm changes due to β-amyloid-altered ionic channels

Electroencephagraphy (EEG) of many dementia patients has been characterized by an increase in low frequency field potential oscillations. One of the characteristics of early stage Alzheimer's disease (AD) is an increase in theta band power (4-7 Hz). However, the mechanism(s) underlying the changes in theta oscillations are still unclear. To address this issue, we investigate the theta band power changes associated with β-Amyloid (Aβ) peptide (one of the main markers of AD) using a computational model, and by mediating the toxicity of hippocampal pyramidal neurons. We use an established biophysical hippocampal CA1-medial septum network model to evaluate four ionic channels in pyramidal neurons, which were demonstrated to be affected by Aβ. They are the L-type Ca2? channel, delayed rectifying K? channel, A-type fast-inactivating K? channel and large-conductance Ca2?-activated K? channel. Our simulation results demonstrate that only the Aβ inhibited A-type fast-inactivating K? channel can induce an increase in hippocampo-septal theta band power, while the other channels do not affect theta rhythm. We further deduce that this increased theta band power is due to enhanced synchrony of the pyramidal neurons. Our research may elucidate potential biomarkers and therapeutics for AD. Further investigation will be helpful for better understanding of AD-induced theta rhythm abnormalities and associated cognitive deficits.     

Investigation of the functional role of the septum

A spectral-correlation analysis was made of the EEG recorded from the motor and visual cortex, hippocampus, and septum (in some series of experiments, the lateral geniculate body and mesencephalic reticular formation also) of rabbits in the presence or absence (background) of sensory stimulation. To investigate the functional role of the septum as a pacemaker the method of "rhythm binding" by electrical stimulation of the septum (lateral and medial nuclei) was used. By electrical stimulation of the medial nucleus of the septum at a frequency of 4–30 Hz rhythm binding was successfully obtained in all regions studied. Maximal rhythm binding was observed in cortical potentials. It is postulated that cortical rhythmic activity is generated as a result of physiological interaction between cortex and septum.Institute of Higher Nervous Activity and Neurophysiology, Academy of Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 8, No. 3, pp. 267–275, May–June, 1976.     

Hippocampal theta oscillations are slower in humans than in rodents: implications for models of spatial navigation and memory

The theta oscillation is a neuroscience enigma. When a rat runs through an environment, large-amplitude theta oscillations (4–10 Hz) reliably appear in the hippocampus''s electrical activity. The consistency of this pattern led to theta playing a central role in theories on the neural basis of mammalian spatial navigation and memory. However, in fact, hippocampal oscillations at 4–10 Hz are rare in humans and in some other species. This presents a challenge for theories proposing theta as an essential component of the mammalian brain, including models of place and grid cells. Here, I examine this issue by reviewing recent research on human hippocampal oscillations using direct brain recordings from neurosurgical patients. This work indicates that the human hippocampus does indeed exhibit rhythms that are functionally similar to theta oscillations found in rodents, but that these signals have a slower frequency of approximately 1–4 Hz. I argue that oscillatory models of navigation and memory derived from rodent data are relevant for humans, but that they should be modified to account for the slower frequency of the human theta rhythm.     

Role of septal and entorhinal inputs in the generation of hippocampal electrical activity in the cat sleep-wake cycle

The effects of septal lesion and entorhinal cortex section on hippocampal electrical activity during the cat sleep-wake cycle were investigated in chronic experiments. The medial portion of the septum only was found to participate in generation of this activity. Complete suppression of hippocampal theta rhythm during active wakefulness and paradoxical sleep were the main effects of septal lesion. In slow-wave sleep, the effects of septal lesion manifested in a slight attenuation of the intensity of the dominant frequency (of 1 Hz). Widespread septal lesion does not add to the changes occurring when the medial portion of the septum is so isolated. Section of the entorhinal cortex produces a sharp increase in hippocampal theta rhythm during waking and paradoxical sleep. Clearcut attenuation of delta and subdelta rhythm intensities were observed in slowwave sleep. It is postulated that under normal conditions hippocampal entorhinal input exerts a modulating effect on the genesis of hippocampal theta rhythm.I. S. Beritashvili Institute of Physiology, Academy of Sciences of the Georgian SSR, Tbilisi. Translated from Neirofiziologiya, Vol. 19, No. 5, pp. 622–630, September–October, 1987.     

Differential contribution of pacemaker properties to the generation of respiratory rhythms during normoxia and hypoxia

Pacemaker neurons have been described in most neural networks. However, whether such neurons are essential for generating an activity pattern in a given preparation remains mostly unknown. Here, we show that in the mammalian respiratory network two types of pacemaker neurons exist. Differential blockade of these neurons indicates that their relative contribution to respiratory rhythm generation changes during the transition from normoxia to hypoxia. During hypoxia, blockade of neurons with sodium-dependent bursting properties abolishes respiratory rhythm generation, while in normoxia respiratory rhythm generation only ceases upon pharmacological blockade of neurons with heterogeneous bursting properties. We propose that respiratory rhythm generation in normoxia depends on a heterogeneous population of pacemaker neurons, while during hypoxia the respiratory rhythm is driven by only one type of pacemaker.