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.     

A theory of hippocampal memory based on theta phase precession

 The neural dynamics of the hippocampal network for memory encoding of novel temporal sequences is proposed based on the theta rhythm modulated firing of place cells called theta phase precession. It is hypothesized that theta phase precession is generated at the entorhinal cortex by phase locking between local field theta oscillation and neural oscillators and that the hippocampal closed network with feedforward and backward projections employ theta phase precession to create selectivity in the associative connections needed for temporal sequence storage. Our analyses and computer experiments reveal that the phase precession generated by phase locking instantaneously endows stable phase relations among neural activities in the successively changing neural population. It is concluded that theta phase precession provides biologically plausible dynamics for the memory encoding of novel temporal sequences as episodic events. Received: 18 December 2002 / Accepted: 18 March 2003 / Published online: 20 May 2003 Correspondence to: Y. Yamaguchi (e-mail: yokoy@brain.riken.go.jp, Fax: +81-48-4676938) Acknowledgements. The author would like to express acknowledgement to Drs. McNaughton and Skaggs for their discussion and comment and to Dr. Amari for his continuous encouragement. Further thanks are given to Mr. Haga and Dr. Wu for their discussion and cooperation.     

Representing episodes in the mammalian brain

Memory lets the past inform the present so that we can attain future goals. In many species, these abilities require the hippocampus. Recent experiments, in which memory demand was varied while overt behavior and the environment were kept constant, have revealed firing patterns of hippocampal neurons that corresponded with memory demands and predicted performance. Although the active population appeared to be 'place cells' that signalled location, it actually included cells the activity patterns of which distinguished the recent or pending history of behavior during identical actions that occurred in the same place. Different populations of hippocampal cells fired as a rat walked along the same spatial path on the way to different goals, and coded past, present and pending events. Other experiments provide converging data that neuronal activity is modulated by goal-directed behavioral episodes. Together, these firing patterns suggest a testable mechanism of episodic memory coding: that hippocampal dynamics encode a temporally extended, hierarchically organized representation of goal-directed behavior.     

Ripple-associated high-firing interneurons in the hippocampal CA1 region

By simultaneously recording the activity of individual neurons and field potentials in freely behaving mice, we found two types of interneurons firing at high frequency in the hippocampal CA1 region, which had high correlations with characteristic sharp wave-associated ripple oscillations (100–250 Hz) during slow-wave sleep. The firing of these two types of interneurons highly synchronized with ripple oscillations during slow-wave sleep, with strongly increased firing rates corresponding to individual ripple episodes. Interneuron type I had at most one spike in each sub-ripple cycle of ripple episodes and the peak firing rate was 310±33.17 Hz. Interneuron type II had one or two spikes in each sub-ripple cycle and the peak firing rate was 410±47.61 Hz. During active exploration, their firing was phase locked to theta oscillations with the highest probability at the trough of theta wave. Both two types of interneurons increased transiently their firing rates responding to the startling shake stimuli. The results showed that these two types of high-frequency interneurons in the hippocampal CA1 region were involved in the modulation of the hippocampal neural network during different states.     

Hippocampal theta-driving cells revealed by Granger causality

The two-dipole model of theta generation in hippocampal CA1 suggests that the inhibitory perisomatic theta dipole is generated by local GABAergic interneurons. Various CA1 interneurons fire preferentially at different theta phases, raising the question of how these theta-locked interneurons contribute to the generation of theta oscillations. We here recorded interneurons in the hippocampal CA1 area of freely behaving mice, and identified a unique subset of theta-locked interneurons by using the Granger causality approach. These cells fired in an extremely reliable theta-burst pattern at high firing rates (～90 Hz) during exploration and always locked to ascending phases of the theta waves. Among theta-locked interneurons we recorded, only these cells generated strong Granger causal influences on local field potential (LFP) signals within the theta band (4-12 Hz), and the influences were persistent across behavioral states. Our results suggest that this unique type of theta-locked interneurons serve as the local inhibitory theta dipole control cells in shaping hippocampal theta oscillations.     

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.     

Ripple-associated high-firing interneurons in the hippocampal CA1 region

By simultaneously recording the activity of individual neurons and field potentials in freely behaving mice, we found two types of interneurons firing at high frequency in the hippocampal CA1 region, which had high correlations with characteristic sharp wave-associated ripple oscillations (100―250 Hz) during slow-wave sleep. The firing of these two types of interneurons highly synchronized with ripple oscillations during slow-wave sleep, with strongly increased firing rates corresponding to individual ripple episodes. Interneuron type I had at most one spike in each sub-ripple cycle of ripple episodes and the peak firing rate was 310±33.17 Hz. Interneuron type II had one or two spikes in each sub-ripple cycle and the peak firing rate was 410±47.61 Hz. During active exploration, their firing was phase locked to theta oscillations with the highest probability at the trough of theta wave. Both two types of interneurons increased transiently their firing rates responding to the startling shake stimuli. The results showed that these two types of high-frequency interneurons in the hippocampal CA1 region were involved in the modulation of the hippocampal neural network during different states.     

Transient Decline in Hippocampal Theta Activity during the Acquisition Process of the Negative Patterning Task

Hippocampal function is important in the acquisition of negative patterning but not of simple discrimination. This study examined rat hippocampal theta activity during the acquisition stages (early, middle, and late) of the negative patterning task (A+, B+, AB-). The results showed that hippocampal theta activity began to decline transiently (for 500 ms after non-reinforced stimulus presentation) during the late stage of learning in the negative patterning task. In addition, this transient decline in hippocampal theta activity in the late stage was lower in the negative patterning task than in the simple discrimination task. This transient decline during the late stage of task acquisition may be related to a learning process distinctive of the negative patterning task but not the simple discrimination task. We propose that the transient decline of hippocampal theta activity reflects inhibitory learning and/or response inhibition after the presentation of a compound stimulus specific to the negative patterning task.     

Selective reduction of AMPA currents onto hippocampal interneurons impairs network oscillatory activity

Reduction of excitatory currents onto GABAergic interneurons in the forebrain results in impaired spatial working memory and altered oscillatory network patterns in the hippocampus. Whether this phenotype is caused by an alteration in hippocampal interneurons is not known because most studies employed genetic manipulations affecting several brain regions. Here we performed viral injections in genetically modified mice to ablate the GluA4 subunit of the AMPA receptor in the hippocampus (GluA4(HC-/-) mice), thereby selectively reducing AMPA receptor-mediated currents onto a subgroup of hippocampal interneurons expressing GluA4. This regionally selective manipulation led to a strong spatial working memory deficit while leaving reference memory unaffected. Ripples (125-250 Hz) in the CA1 region of GluA4(HC-/-) mice had larger amplitude, slower frequency and reduced rate of occurrence. These changes were associated with an increased firing rate of pyramidal cells during ripples. The spatial selectivity of hippocampal pyramidal cells was comparable to that of controls in many respects when assessed during open field exploration and zigzag maze running. However, GluA4 ablation caused altered modulation of firing rate by theta oscillations in both interneurons and pyramidal cells. Moreover, the correlation between the theta firing phase of pyramidal cells and position was weaker in GluA4(HC-/-) mice. These results establish the involvement of AMPA receptor-mediated currents onto hippocampal interneurons for ripples and theta oscillations, and highlight potential cellular and network alterations that could account for the altered working memory performance.     

Are spatial memories strengthened in the human hippocampus during slow wave sleep?

In rats, the firing sequences observed in hippocampal ensembles during spatial learning are replayed during subsequent sleep, suggesting a role for posttraining sleep periods in the offline processing of spatial memories. Here, using regional cerebral blood flow measurements, we show that, in humans, hippocampal areas that are activated during route learning in a virtual town are likewise activated during subsequent slow wave sleep. Most importantly, we found that the amount of hippocampal activity expressed during slow wave sleep positively correlates with the improvement of performance in route retrieval on the next day. These findings suggest that learning-dependent modulation in hippocampal activity during human sleep reflects the offline processing of recent episodic and spatial memory traces, which eventually leads to the plastic changes underlying the subsequent improvement in performance.     

Coherence between Rat Sensorimotor System and Hippocampus Is Enhanced during Tactile Discrimination

Rhythms with time scales of multiple cycles per second permeate the mammalian brain, yet neuroscientists are not certain of their functional roles. One leading idea is that coherent oscillation between two brain regions facilitates the exchange of information between them. In rats, the hippocampus and the vibrissal sensorimotor system both are characterized by rhythmic oscillation in the theta range, 5–12 Hz. Previous work has been divided as to whether the two rhythms are independent or coherent. To resolve this question, we acquired three measures from rats—whisker motion, hippocampal local field potential (LFP), and barrel cortex unit firing—during a whisker-mediated texture discrimination task and during control conditions (not engaged in a whisker-mediated memory task). Compared to control conditions, the theta band of hippocampal LFP showed a marked increase in power as the rats approached and then palpated the texture. Phase synchronization between whisking and hippocampal LFP increased by almost 50% during approach and texture palpation. In addition, a greater proportion of barrel cortex neurons showed firing that was phase-locked to hippocampal theta while rats were engaged in the discrimination task. Consistent with a behavioral consequence of phase synchronization, the rats identified the texture more rapidly and with lower error likelihood on trials in which there was an increase in theta-whisking coherence at the moment of texture palpation. These results suggest that coherence between the whisking rhythm, barrel cortex firing, and hippocampal LFP is augmented selectively during epochs in which the rat collects sensory information and that such coherence enhances the efficiency of integration of stimulus information into memory and decision-making centers.     

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.     

Temporal encoding of place sequences by hippocampal cell assemblies

Both episodic memory and spatial navigation require temporal encoding of the relationships between events or locations. In a linear maze, ordered spatial distances between sequential locations were represented by the temporal relations of hippocampal place cell pairs within cycles of theta oscillation in a compressed manner. Such correlations could arise due to spike "phase precession" of independent neurons driven by common theta pacemaker or as a result of temporal coordination among specific hippocampal cell assemblies. We found that temporal correlation between place cell pairs was stronger than predicted by a pacemaker drive of independent neurons, indicating a critical role for synaptic interactions and precise timing within and across cell assemblies in place sequence representation. CA1 and CA3 ensembles, identifying spatial locations, were active preferentially on opposite phases of theta cycles. These observations suggest that interleaving CA3 neuronal sequences bind CA1 assemblies representing overlapping past, present, and future locations into single episodes.     

Differences in activity of hippocampal and neocortical neurons in active and passive rabbits in negative emotional situations

Activities of individual hippocampal (CA1 area) and neocortical parietal-temporal neurons were compared in active and passive rabbits in negative emotional situations during emotionally significant stimuli by plotting histograms of autocorrelations. As compared to passive animals, in active rabbits, the mean firing rate of hippocampal neurons was higher, bursting and periodic oscillations of discharges occurred more frequently. Oscillation periods in the theta 1 band (6.0-9.0 Hz) appeared more frequently (in the baseline state and active exploratory or defensive reactions), whereas those in the theta 2 band (4.0-5.9 Nz), on the contrary, were infrequently observed (during freezing). The greatest changes in activity ofhippocampal neurons were observed during active locomotor responses of active rabbits. Intergroup differences in neocortical neuronal activities were less pronounced than in hippocampus. The results indicate that individual typological features in behaviour of animals appear in negative emotional situations and are reflected in activity of activity ofhippocampal (area CA1) and to lesser extent parietal-temporal neocortical neurons. The results suggest different activation levels of the septohippocampal system of active and passive rabbits and possible differences in the afferent input to the CA1 field.     

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.     

Hippocampal State-Dependent Behavioral Reflex to an Identical Sensory Input in Rats

We examined the local field potential of the hippocampus to monitor brain states during a conditional discrimination task, in order to elucidate the relationship between ongoing brain states and a conditioned motor reflex. Five 10-week-old Wistar/ST male rats underwent a serial feature positive conditional discrimination task in eyeblink conditioning using a preceding light stimulus as a conditional cue for reinforced trials. In this task, a 2-s light stimulus signaled that the following 350-ms tone (conditioned stimulus) was reinforced with a co-terminating 100-ms periorbital electrical shock. The interval between the end of conditional cue and the onset of the conditioned stimulus was 4±1 s. The conditioned stimulus was not reinforced when the light was not presented. Animals successfully utilized the light stimulus as a conditional cue to drive differential responses to the identical conditioned stimulus. We found that presentation of the conditional cue elicited hippocampal theta oscillations, which persisted during the interval of conditional cue and the conditioned stimulus. Moreover, expression of the conditioned response to the tone (conditioned stimulus) was correlated with the appearance of theta oscillations immediately before the conditioned stimulus. These data support hippocampal involvement in the network underlying a conditional discrimination task in eyeblink conditioning. They also suggest that the preceding hippocampal activity can determine information processing of the tone stimulus in the cerebellum and its associated circuits.     

The BDNF Val66Met Polymorphism Has Opposite Effects on Memory Circuits of Multiple Sclerosis Patients and Controls

Episodic memory deficits are frequent symptoms in Multiple Sclerosis and have been associated with dysfunctions of the hippocampus, a key region for learning. However, it is unclear whether genetic factors that influence neural plasticity modulate episodic memory in MS. We thus studied how the Brain Derived Neurotrophic Factor Val⁶⁶Met genotype, a common polymorphism influencing the hippocampal function in healthy controls, impacted on brain networks underlying episodic memory in patients with Multiple Sclerosis. Functional magnetic resonance imaging was used to assess how the Brain Derived Neurotrophic Factor Val⁶⁶Met polymorphism modulated brain regional activity and functional connectivity in 26 cognitively unimpaired Multiple Sclerosis patients and 25 age- and education-matched healthy controls while performing an episodic memory task that included encoding and retrieving visual scenes. We found a highly significant group by genotype interaction in the left posterior hippocampus, bilateral parahippocampus, and left posterior cingulate cortex. In particular, Multiple Sclerosis patients homozygous for the Val⁶⁶ allele, relative to Met⁶⁶ carriers, showed greater brain responses during both encoding and retrieval while the opposite was true for healthy controls. Furthermore, a robust group by genotype by task interaction was detected for the functional connectivity between the left posterior hippocampus and the ipsilateral posterior cingulate cortex. Here, greater hippocampus-posterior cingulate cortex connectivity was observed in Multiple Sclerosis Met⁶⁶ carriers relative to Val⁶⁶ homozygous during retrieval (but not encoding) while, again, the reverse was true for healthy controls. The Val⁶⁶Met polymorphism has opposite effects on hippocampal circuitry underlying episodic memory in Multiple Sclerosis patients and healthy controls. Enhancing the knowledge of how genetic factors influence cognitive functions may improve the clinical management of memory deficits in patients with Multiple Sclerosis.     

Beta-amyloid induced changes in A-type K<Superscript>+</Superscript> current can alter hippocampo-septal network dynamics

Alzheimer’s disease (AD) progression is usually associated with memory deficits and cognitive decline. A hallmark of AD is the accumulation of beta-amyloid (Aβ) peptide, which is known to affect the hippocampal pyramidal neurons in the early stage of AD. Previous studies have shown that Aβ can block A-type K⁺ currents in the hippocampal pyramidal neurons and enhance the neuronal excitability. However, the mechanisms underlying such changes and the effects of the hyper-excited pyramidal neurons on the hippocampo-septal network dynamics are still to be investigated. In this paper, Aβ-blocked A-type current is simulated, and the resulting neuronal and network dynamical changes are evaluated in terms of the theta band power. The simulation results demonstrate an initial slight but significant theta band power increase as the A-type current starts to decrease. However, the theta band power eventually decreases as the A-type current is further decreased. Our analysis demonstrates that Aβ blocked A-type currents can increase the pyramidal neuronal excitability by preventing the emergence of a steady state. The increased theta band power is due to more pyramidal neurons recruited into spiking mode during the peak of pyramidal theta oscillations. However, the decreased theta band power is caused by the spiking phase relationship between different neuronal populations, which is critical for theta oscillation, is violated by the hyper-excited pyramidal neurons. Our findings could provide potential implications on some AD symptoms, such as memory deficits and AD caused epilepsy.     

Relations between hippocampal network free oscillations and the theta activity

The relations between the component of the hippocampal network free oscillations, i.e., sharp potential waves (SPW) and the theta component of the hippocampal EEG are considered. It is commonly accepted that, in the course of changes from the state corresponding to a weak activation of the hippocampal network in the theta rhythm by the septum through the state corresponding to a medium activation to the state of a high activation, the inverse dependence between the magnitudes of these components in the EEG spectra takes place. However, our work shows that this dependence can be deranged in the rat EEG during quiet wakefulness that corresponds to the medium activation of the hippocampal network in theta rhythm. It was also shown that the RF stimulation can evoke abnormal signals with well-pronounced theta activity against the background of a considerable SPW component. This phenomenon demonstrates a possibility of a strong derangement of the dependence, which is, as a rule, observed under the natural conditions. The hypothesis concerning the organization and regulation of the investigated components of the hippocampal EEG is proposed.     

Hippocampal neurons encode information about different types of memory episodes occurring in the same location

Firing patterns of hippocampal complex-spike neurons were examined for the capacity to encode information important to the memory demands of a task even when the overt behavior and location of the animal are held constant. Neuronal activity was recorded as rats continuously alternated left and right turns from the central stem of a modified T maze. Two-thirds of the cells fired differentially as the rat traversed the common stem on left-turn and right-turn trials, even when potentially confounding variations in running speed, heading, and position on the stem were taken into account. Other cells fired differentially on the two trial types in combination with behavioral and spatial factors or appeared to fire similarly on both trial types. This pattern of results suggests that hippocampal representations encode some of the information necessary for representing specific memory episodes.