Dopaminergic regulation of theta activity of septohippocampal neuron in the awake rabbit

The effects of dopamine reuptake blocker nomifensine and nonselective antagonist of dopamine receptors haloperidol on the theta rhythmicity of the medial septal neurons and hippocampal EEG were investigated in the rabbit. Bilateral intracerebroventricular infusion of nomifensine (9 micrograms in each ventriculus) produced an increase in both the rate of firing and the theta modulation of medial septal neurons; the theta power of the hippocampal EEG also augmented. The degree of neuronal theta stability (time constant of damping, tao theta) significantly increased. The frequency of rhythmic bursts in the neuronal firing also substantially elevated. The amplitude, regularity and frequency of theta waves in the hippocampal EEG also increased. The antagonist haloperidol (12.5 mg) caused the opposite effect. The theta activity of medial septal neurons and the theta power of the hippocampal EEG decreased after haloperidol injection. Theta rhythmicity of septal neurons significantly diminished, the rate of rhythmic bursts in the neuronal firing also decreased, although not substantially. The theta amplitude and regularity in the hippocampal EEG also decreased. Effects of both drugs built up rapidly and then gradually attenuated. Nomifensine infusion against the background of exposure to haloperidol provoked neither increasing neuronal firing rate, nor elevating theta activity. These finding suggest that dopaminergic system produces activation of the septohippocampal system in situations that require selective attention to functionally important information.     

The EEG activity after lesions of the diencephalic part of the zona incerta in rats

Neocortical and hippocampal EEG activity was recorded in 23 rats subjected to the bilateral electrolytic lesions of the diencephalic zona incerta (ZI). The aim was to find whether damage to ZI can replicate insomnia and disturbances in cortical EEG desynchronization and hippocampal theta rhythm found after lesions of the lateral hypothalamic (LH) area. No effect of the ZI lesions on waking-sleep cycle was found. The amplitude and frequency of cortical waves and hippocampal theta rhythm during waking were changed only in some rats. These changes were small, short-lasting and bidirectional (toward and increase or decrease in different subjects). Both the amplitude and frequency of paradoxical sleep theta were depressed in part of animals. Thus the marked EEG changes after LH lesions can not be attributed to simultaneous damage of the adjacent subthalamic region. However, the ZI seems to constitute a part of a larger system regulating cortical arousal and hippocampal theta rhythm.     

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.     

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.     

Rhythmic modulation of theta oscillations supports encoding of spatial and behavioral information in the rat hippocampus

Oscillatory patterns of activity in various frequency ranges are ubiquitously expressed in cortical circuits. While recent studies in humans emphasized rhythmic modulations of neuronal oscillations ("second-order" rhythms), their potential involvement in information coding remains an open question. Here, we show that a rhythmic (～0.7?Hz) modulation of hippocampal theta power, unraveled by second-order spectral analysis, supports encoding of spatial and behavioral information. The phase preference of neuronal discharge within this slow rhythm significantly increases the amount of information carried by action potentials in various motor/cognitive behaviors by (1) distinguishing between the spikes fired within versus outside the place field of hippocampal place cells, (2) disambiguating place firing of neurons having multiple place fields, and (3) predicting between alternative future spatial trajectories. This finding demonstrates the relevance of second-order spectral components of brain rhythms for decoding neuronal information.     

Effect of transection of afferent pathways on evoked potentials,theta rhythm,and neuronal activity in the hippocampus

The effect of destruction of septo-hippocampal and subiculo-hippocampal connections on the electrical activity in the hippocampus was studied in tubocurarized rabbits. The theta rhythm and the so-called "intracellular theta rhythm" [7] were found to disappear on destruction of the septo-hippocampal connections, other consequences being the loss of neuronal capacity for responding to sciatic nerve stimulation, loss of neuronal inhibitory responses, and total or partial suppression of the negative phase of the evoked potential (EP). Destruction of subiculo-hippocampal connections entails a decrease in amplitude of the theta rhythm recorded from the hippocampal surface, retention of the "intracellular theta rhythm," and a slight decrease in amplitude of both EP phases. The number of neurons failing to respond to sciatic stimulation is increased; the character of cellular response remains unchanged. It is hypothesized that hyperpolarization of hippocampal pyramidal neurons may be responsible for generating the negative phase of the EP, and that this phase and the hippocampal theta rhythm may be of a common origin.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 2, No. 4, pp. 439–444, July–August, 1970.     

Neuronal septal activity during hippocampal seizure discharges generation in acute model of epilepsy

The activity of the neurones of the medial septal region (MS) and the hippocampal EEG in control and during the appearance of seizure discharges provoked by electrical stimulation of the perforant path were investigated in the awake rabbit. During afterdischarge generation in the hippocampus the dense neuronal bursts separated by periods of inhibition were recorded in the MS. In one group of neurons the bursts of spikes coincided with the discharges in the hippocampus, in other group-occured during inhibitory periods. When the afterdischarge stopped, in the septal neurons with theta activity the disruption of theta pattern was recorded, which have been correlated with the occurrence of low amplitude high frequency (20-25 Hz) waves in the hippocampal EEG. As a rule, the neuronal activivity of the MS recovered much quickly than EEG of the hippocampus; in some cases the increasing of the theta regularity was observed. The definite accordance of the electrical activity of the hippocampus and MS during seizure discharges suggests that the septohippocampal system operate as integral nervous circuit in these conditions. Diverse in the temporal interrelations between the discharges of MS neurones and ictal discharges in the hippocampus in the different cells possible indicate that various groups of the septal nervous elements have different participation in the seizure development. Appearance of the high frequency bursts in the MS is a possible "precursor" of the seizure onsets.     

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.     

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.     

Computational theories on the function of theta oscillations

Neural rhythms can be studied in terms of conditions for their generation, or in terms of their functional significance. The theta oscillation is a particularly prominent rhythm, reported to be present in many brain areas, and related to many important cognitive processes. The generating mechanisms of theta have extensively been studied and reviewed elsewhere; here we discuss ideas that have accumulated over the past decades on the computational roles it may subserve. Theories propose different aspects of theta oscillations as being relevant for their cognitive functions: limit cycle oscillations in neuronal firing rates, subthreshold membrane potential oscillations, periodic modulation of synaptic transmission and plasticity, and phase precession of hippocampal place cells. The relevant experimental data is briefly summarized in the light of these theories. Specific models proposing a function for theta in pattern recognition, memory, sequence learning and navigation are reviewed critically. Difficulties with testing and comparing alternative models are discussed, along with potentially important future research directions in the field.     

Oscillatory entrainment of striatal neurons in freely moving rats

Oscillations and synchrony in basal ganglia circuits may play a key role in the organization of voluntary actions and habits. We recorded single units and local field potentials from multiple striatal and cortical locations simultaneously, over a range of behavioral states. We observed opposite gradients of oscillatory entrainment, with dorsal/lateral striatal neurons entrained to high-voltage spindle oscillations ("spike wave discharges") and ventral/medial striatal neurons entrained to the hippocampal theta rhythm. While the majority of units were likely medium-spiny projection neurons, a second neuronal population showed characteristic features of fast-spiking GABAergic interneurons, including tonic activity, brief waveforms, and high-frequency bursts. These fired at an earlier spindle phase than the main neuronal population, and their density within striatum corresponded closely to the intensity of spindle oscillations. The orchestration of oscillatory activity by networks of striatal interneurons may be an important mechanism in the pathophysiology of neurological disorders such as Parkinson's disease.     

Endoplasmic reticulum and mitochondria as elements of mechanism of intracellular signaling in neurons

The temporal and spatial characteristics of a transitory increase in free Ca2+ ("calcium signals") concentration were determined in various types of the mice and rat neurones. Intracellular structures: endoplasmatic reticulum and mitochondria, were shown to play a major part in formation of these signals, the structures being able to absorb the Ca2+ ions from cytosol and release them back. The contribution of these processes proves rather varying depending on internal organisation and functional assignment of a neurone.     

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.     

Reciprocal actions between sensory signals and sleep

To the best of our knowledge, there is no simple way to induce neural networks to shift from waking mode into sleeping mode. Our best guess is that a whole group of neurons would be involved and that the process would develop in a period of time and a sequence which are mostly unknown. The quasi-total sensory deprivation elicits a new behavioral state called somnolence. Auditory stimulation as well as total auditory deprivation alter sleep architecture. Auditory units exhibiting firing shifts on passing to sleep (augmenting or diminishing) are postulated to be locked to sleep-related networks. Those ( approximately 50%) that did not change during sleep are postulated to continue informing the brain as in wakefulness. A rhythmic functional plasticity of involved networks is postulated. A number of auditory and visual cells have demonstrated a firing phase locking to the hippocampal theta rhythm. This phase locking occurs both during wakefulness and sleep phases. The theta rhythm may act as an organizer of sensory information in visual and auditory systems, in all behavioral states adding a temporal dimension to the sensory processing. Sensory information from the environment and body continuously modulates the central nervous system activity, over which sleep phenomenology must develop. It also produces a basal tonus during wakefulness and sleep, determining changes in the networks that contribute to sleep development and maintenance and, eventually, it also leads to sleep interruption.     

Frequency modulation of theta volleys of septal neurons during rhythmic oligosynaptic stimulation in the rabbit

Activity of the neurones with stable theta-bursts was recorded extracellularly in intact and hippocampectomized septum of unanaesthetized chronic rabbits during low-frequency (3-17 Hz) stimulation of horizontal limb of the diagonal band or the lateral septal nucleus. Gradual entrainment and phase-locking of the spontaneous theta-cycles occurred. Two types of entrainment were observed: "entrainment by pause", where interburst interval was reset by the stimuli; and "entrainment by burst", where bursts were time-locked to the stimuli. Such reorganization of the spontaneous bursts occurred in a narrow frequency range of stimulation (from 4 Hz up to 9-12 Hz), with the best resonance following in the range of "basic" theta frequencies of the awake rabbit (5-6 Hz). With stimulation beyond the theta-range three phenomena occurred: shift of the burst frequencies to higher or lower harmonics of stimulation frequencies; complex interactions of basic background frequency with the rhythm of stimulation ("beating"); escape from the influence of the stimuli with return to background theta-burst frequency.     

NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory

Activity of parvalbumin-positive hippocampal interneurons is critical for network synchronization but the receptors involved therein have remained largely unknown. Here we report network and behavioral deficits in mice with selective ablation of NMDA receptors in parvalbumin-positive interneurons (NR1(PVCre-/-)). Recordings of local field potentials and unitary neuronal activity in the hippocampal CA1 area revealed altered theta oscillations (5-10 Hz) in freely behaving NR1(PVCre-/-) mice. Moreover, in contrast to controls, in NR1(PVCre-/-) mice the remaining theta rhythm was abolished by the administration of atropine. Gamma oscillations (35-85 Hz) were increased and less modulated by the concurrent theta rhythm in the mutant. Positional firing of pyramidal cells in NR1(PVCre-/-) mice was less spatially and temporally precise. Finally, NR1(PVCre-/-) mice exhibited impaired spatial working as well as spatial short- and long-term recognition memory but showed no deficits in open field exploratory activity and spatial reference learning.     

Effect of ethanol on the interaction of hippocampal neurons in tissue culture

Background unit activity and that evoked by ethanol of neighbouring neurones in hippocampal tissue culture of 9-19 div was studied by means of cross-correlational analysis. The results obtained point to a possibility of existence of complex neuronal networks consolidated by functional synaptic connections, even in such a simple model system as neuronal tissue culture. Excitatory interactions of neighbouring neurones were more sensitive to ethanol than the inhibitory ones. The effect of ethanol administration consisted mainly in a weakening of correlational connections. Such changes are supposed to be the basis for different coordination disorders in the work of brain structures observed during chronic alcoholic intoxication.     

Comparison of the effects of TRH and D-Ala2-metenkephalinamide on hippocampal electrical activity and behavior in the unanesthetized rat

Administration of TRH into the lateral ventricle of unanesthetized rats produced increases in the incidence of hippocampal theta (5.9–9.1 Hz) rhythm, locomotor activity and shaking behavior. The increase in theta rhythm produced by TRH was brief (<5 min) and was coincident with a brief, large increase in locomotor activity. Intracerebroventricular injection of either TRH or D-Ala²-metenkephalinamide (D-Ala²-ME) also induced episodes of shaking behavior. Shakes induced by D-Ala²-ME were associated with the occurrence of hippocampal epileptiform activity whereas those caused by TRH occurred in the absence of any recorded abnormalities in hippocampal activity. These results suggest that the increase in hippocampal theta rhythm after TRH is secondary to the increase in locomotor activity and, that in contrast to enkephalins, shaking behavior caused by TRH may not be related to an action on the electrographic activity of the hippocampus.     

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.     

Movement-related theta rhythm in humans: coordinating self-directed hippocampal learning

The hippocampus is crucial for episodic or declarative memory and the theta rhythm has been implicated in mnemonic processing, but the functional contribution of theta to memory remains the subject of intense speculation. Recent evidence suggests that the hippocampus might function as a network hub for volitional learning. In contrast to human experiments, electrophysiological recordings in the hippocampus of behaving rodents are dominated by theta oscillations reflecting volitional movement, which has been linked to spatial exploration and encoding. This literature makes the surprising cross-species prediction that the human hippocampal theta rhythm supports memory by coordinating exploratory movements in the service of self-directed learning. We examined the links between theta, spatial exploration, and memory encoding by designing an interactive human spatial navigation paradigm combined with multimodal neuroimaging. We used both non-invasive whole-head Magnetoencephalography (MEG) to look at theta oscillations and Functional Magnetic Resonance Imaging (fMRI) to look at brain regions associated with volitional movement and learning. We found that theta power increases during the self-initiation of virtual movement, additionally correlating with subsequent memory performance and environmental familiarity. Performance-related hippocampal theta increases were observed during a static pre-navigation retrieval phase, where planning for subsequent navigation occurred. Furthermore, periods of the task showing movement-related theta increases showed decreased fMRI activity in the parahippocampus and increased activity in the hippocampus and other brain regions that strikingly overlap with the previously observed volitional learning network (the reverse pattern was seen for stationary periods). These fMRI changes also correlated with participant's performance. Our findings suggest that the human hippocampal theta rhythm supports memory by coordinating exploratory movements in the service of self-directed learning. These findings directly extend the role of the hippocampus in spatial exploration in rodents to human memory and self-directed learning.