Theta Trough Research Articles

Closed-loop auditory stimulation targeting alpha and theta oscillations during REM sleep induces phase-dependent power and frequency changes.

Alpha and theta oscillations characterize the waking human electroencephalogram (EEG) and can be modulated by closed-loop auditory stimulation (CLAS). These oscillations also occur during rapid eye movement (REM) sleep, but their function here remains elusive. CLAS represents a promising tool to pinpoint how these brain oscillations contribute to brain function in humans. Here we investigate whether CLAS can modulate alpha and theta oscillations during REM sleep in a phase-dependent manner. We recorded high-density EEG during an extended overnight sleep period in 18 healthy young adults. Auditory stimulation was delivered during both phasic and tonic REM sleep in alternating 6s ON and 6s OFF windows. During the ON windows, stimuli were phase-locked to four orthogonal phases of ongoing alpha or theta oscillations detected in a frontal electrode. The phases of ongoing alpha and theta oscillations were targeted with high accuracy during REM sleep. Alpha and theta CLAS induced phase-dependent changes in power and frequency at the target location. Frequency-specific effects were observed for alpha trough (speeding up) and rising (slowing down) and theta trough (speeding up) conditions. CLAS-induced phase-dependent changes were observed during both REM sleep substages, even though auditory evoked potentials were very much reduced in phasic compared to tonic REM sleep. This study provides evidence that faster REM sleep rhythms can be modulated by CLAS in a phase-dependent manner. This offers a new approach to investigate how modulation of REM sleep oscillations affects the contribution of this vigilance state to brain function.

Theta-phase-specific modulation of dentate gyrus memory neurons.

The theta rhythm, a quasi-periodic 4-10 Hz oscillation, is observed during memory processing in the hippocampus, with different phases of theta hypothesized to separate independent streams of information related to the encoding and recall of memories. At the cellular level, the discovery of hippocampal memory cells (engram neurons), as well as the modulation of memory recall through optogenetic activation of these cells, has provided evidence that certain memories are stored, in part, in a sparse ensemble of neurons in the hippocampus. In previous research, however, engram reactivation has been carried out using open-loop stimulation at fixed frequencies; the relationship between engram neuron reactivation and ongoing network oscillations has not been taken into consideration. To address this concern, we implemented a closed-loop reactivation of engram neurons that enabled phase-specific stimulation relative to theta oscillations in the local field potential in CA1. Using this real-time approach, we tested the impact of activating dentate gyrus engram neurons during the peak (encoding phase) and trough (recall phase) of theta oscillations. Consistent with previously hypothesized functions of theta oscillations in memory function, we show that stimulating dentate gyrus engram neurons at the trough of theta is more effective in eliciting behavioral recall than either fixed-frequency stimulation or stimulation at the peak of theta. Moreover, phase-specific trough stimulation is accompanied by an increase in the coupling between gamma and theta oscillations in CA1 hippocampus. Our results provide a causal link between phase-specific activation of engram cells and the behavioral expression of memory.

Hippocampal theta coordinates memory processing during visual exploration.

The hippocampus supports memory encoding and retrieval, which may occur at distinct phases of the theta cycle. These processes dynamically interact over rapid timescales, especially when sensory information conflicts with memory. The ability to link hippocampal dynamics to memory-guided behaviors has been limited by experiments that lack the temporal resolution to segregate encoding and retrieval. Here, we simultaneously tracked eye movements and hippocampal field potentials while neurosurgical patients performed a spatial memory task. Phase-locking at the peak of theta preceded fixations to retrieved locations, indicating that the hippocampus coordinates memory-guided eye movements. In contrast, phase-locking at the trough of theta followed fixations to novel object-locations and predicted intact memory of the original location. Theta-gamma phase amplitude coupling increased during fixations to conflicting visual content, but predicted memory updating. Hippocampal theta thus supports learning through two interleaved processes: strengthening encoding of novel information and guiding exploration based on prior experience.

Behavior-Dependent Activity and Synaptic Organization of Septohippocampal GABAergic Neurons Selectively Targeting the Hippocampal CA3 Area

Rhythmic medial septal (MS) GABAergic input coordinates cortical theta oscillations. However, the rules of innervation of cortical cells and regions by diverse septal neurons are unknown. We report a specialized population of septal GABAergic neurons, the Teevra cells, selectively innervating the hippocampal CA3 area bypassing CA1, CA2 and DG. Teevra cells are parvalbumin-immunopositive, show the highest rhythmicity amongst MS neurons and fire with short burst duration (median, 38ms) preferentially at the trough of both CA1 theta and slow irregular oscillations, coincident with the highest hippocampal excitability. Each Teevra cell synaptically targets GABAergic axo-axonic and CCK basket cells in a restricted septo-temporal CA3 segment. The rhythmicity of their firing decreases from septal to temporal termination of individual axons. Teevra neurons coordinate oscillatory activity across the septotemporal axis and phase the firing of specific CA3 interneurons, thereby contributing to the selection of pyramidal cell assemblies at the theta trough via disinhibition.

Behavior-Dependent Activity and Synaptic Organization of Septo-hippocampal GABAergic Neurons Selectively Targeting the Hippocampal CA3 Area

SummaryRhythmic medial septal (MS) GABAergic input coordinates cortical theta oscillations. However, the rules of innervation of cortical cells and regions by diverse septal neurons are unknown. We report a specialized population of septal GABAergic neurons, the Teevra cells, selectively innervating the hippocampal CA3 area bypassing CA1, CA2, and the dentate gyrus. Parvalbumin-immunopositive Teevra cells show the highest rhythmicity among MS neurons and fire with short burst duration (median, 38 ms) preferentially at the trough of both CA1 theta and slow irregular oscillations, coincident with highest hippocampal excitability. Teevra cells synaptically target GABAergic axo-axonic and some CCK interneurons in restricted septo-temporal CA3 segments. The rhythmicity of their firing decreases from septal to temporal termination of individual axons. We hypothesize that Teevra neurons coordinate oscillatory activity across the septo-temporal axis, phasing the firing of specific CA3 interneurons, thereby contributing to the selection of pyramidal cell assemblies at the theta trough via disinhibition.Video

Hippocampal theta phase–contingent memory retrieval in delay and trace eyeblink conditioning

Hippocampal theta oscillations (3–12Hz) play a prominent role in learning. It has been suggested that encoding and retrieval of memories are supported by different phases of the theta cycle. Our previous study on trace eyeblink conditioning in rabbits suggests that the timing of the conditioned stimulus (CS) in relation to theta phase affects encoding but not retrieval of the memory trace. Here, we directly tested the effects of hippocampal theta phase on memory retrieval in two experiments conducted on adult female New Zealand White rabbits. In Experiment 1, animals were trained in trace eyeblink conditioning followed by extinction, and memory retrieval was tested by presenting the CS at troughs and peaks of the theta cycle during different stages of learning. In Experiment 2, animals were trained in delay conditioning either contingent on a high level of theta or at a random neural state. Conditioning was then followed by extinction conducted either at a random state, contingent on theta trough or contingent on theta peak. Our current results indicate that the phase of theta at CS onset has no effect on the performance of the behavioral learned response at any stage of classical eyeblink conditioning or extinction. In addition, theta-contingent trial presentation does not improve learning during delay eyeblink conditioning. The results are consistent with our earlier findings and suggest that the theta phase alone is not sufficient to affect learning at the behavioral level. It seems that the retrieval of recently acquired memories and consequently performing a learned response is moderated by neural mechanisms other than hippocampal theta.

Theta Phase Segregation of Input-Specific Gamma Patterns in Entorhinal-Hippocampal Networks

Precisely how rhythms support neuronal communication remains obscure. We investigated interregional coordination of gamma oscillations using high-density electrophysiological recordings in the rat hippocampus and entorhinal cortex. We found that 30-80 Hz gamma dominated CA1 local field potentials (LFPs) on the descending phase of CA1 theta waves during navigation, with 60-120 Hz gamma at the theta peak. These signals corresponded to CA3 and entorhinal input, respectively. Above 50 Hz, interregional phase-synchronization of principal cell spikes occurred mostly for LFPs in the axonal target domain. CA1 pyramidal cells were phase-locked mainly to fast gamma (>100 Hz) LFP patterns restricted to CA1, which were strongest at the theta trough. While theta phase coordination of spiking across entorhinal-hippocampal regions depended on memory demands, LFP gamma patterns below 100 Hz in the hippocampus were consistently layer specific and largely reflected afferent activity. Gamma synchronization as a mechanism for interregional communication thus rapidly loses efficacy at higher frequencies.

Enhancement of encoding and retrieval functions through theta phase-specific manipulation of hippocampus.

Assessing the behavioral relevance of the hippocampal theta rhythm has proven difficult, due to a shortage of experiments that selectively manipulate phase-specific information processing. Using closed-loop stimulation, we triggered inhibition of dorsal CA1 at specific phases of the endogenous theta rhythm in freely behaving mice. This intervention enhanced performance on a spatial navigation task that requires the encoding and retrieval of information related to reward location on every trial. In agreement with prior models of hippocampal function, the behavioral effects depended on both the phase of theta and the task segment at which we stimulated. Stimulation in the encoding segment enhanced performance when inhibition was triggered by the peak of theta. Conversely, stimulation in the retrieval segment enhanced performance when inhibition was triggered by the trough of theta. These results suggest that processes related to the encoding and retrieval of task-relevant information are preferentially active at distinct phases of theta.DOI: http://dx.doi.org/10.7554/eLife.03061.001.

Theta phase shift in spike timing and modulation of gamma oscillation: a dynamic code for spatial alternation during fixation in rat hippocampal area CA1

Although hippocampus is thought to perform various memory-related functions, little is known about the underlying dynamics of neural activity during a preparatory stage before a spatial choice. Here we focus on neural activity that reflects a memory-based code for spatial alternation, independent of current sensory and motor parameters. We recorded multiple single units and local field potentials in the stratum pyramidale of dorsal hippocampal area CA1 while rats performed a delayed spatial-alternation task. This task includes a 1-s fixation in a nose-poke port between selecting alternating reward sites and so provides time-locked enter-and-leave events. At the single-unit level, we concentrated on neurons that were specifically active during the 1-s fixation period, when the rat was ready and waiting for a cue to pursue the task. These neurons showed selective activity as a function of the alternation sequence. We observed a marked shift in the phase timing of the neuronal spikes relative to the theta oscillation, from the theta peak at the beginning of fixation to the theta trough at the end of fixation. The gamma-band local field potential also changed during the fixation period: the high-gamma power (60-90 Hz) decreased and the low-gamma power (30-45 Hz) increased toward the end. These two gamma components were observed at different phases of the ongoing theta oscillation. Taken together, our data suggest a switch in the type of information processing through the fixation period, from externally cued to internally generated.

Cholinergic Blockade Reduces Theta-Gamma Phase Amplitude Coupling and Speed Modulation of Theta Frequency Consistent with Behavioral Effects on Encoding

Large-scale neural activation dynamics in the hippocampal-entorhinal circuit local field potential, observable as theta and gamma rhythms and coupling between these rhythms, is predictive of encoding success. Behavioral studies show that systemic administration of muscarinic acetylcholine receptor antagonists selectively impairs encoding, suggesting that they may also disrupt the coupling between the theta and gamma bands. Here, we tested the hypothesis that muscarinic antagonists selectively disrupt coupling between theta and gamma. Specifically, we characterized the effects of systemically administered scopolamine on movement-induced theta and gamma rhythms recorded in the superficial layers of the medial entorhinal cortex (MEC) of freely moving rats. We report the novel result that gamma power at the peak of theta was most reduced following muscarinic blockade, significantly shifting the phase of maximal gamma power to occur at later phases of theta. We also characterize the existence of multiple distinct gamma bands in the superficial layers of the MEC. Further, we observed that theta frequency was significantly less modulated by movement speed following muscarinic blockade. Finally, the slope relating speed to theta frequency, a correlate of familiarity with a testing enclosure, increased significantly less between the preinjection and recovery trials when scopolamine was administered during the intervening injection session than when saline was administered, suggesting that scopolamine reduced encoding of the testing enclosure. These data are consistent with computational models suggesting that encoding and retrieval occur during the peak and trough of theta, respectively, and support the theory that acetylcholine regulates the balance between encoding versus retrieval.

Evidence for Encoding versus Retrieval Scheduling in the Hippocampus by Theta Phase and Acetylcholine

The formation of new memories requires new information to be encoded in the face of proactive interference from the past. Two solutions have been proposed for hippocampal region CA1: (1) acetylcholine, released in novelty, selectively suppresses excitatory projections to CA1 from CA3 (mediating the products of retrieval), while sparing entorhinal inputs (mediating novel sensory information) and (2) encoding preferentially occurs at the pyramidal-layer theta peak, coincident with input from entorhinal cortex, and retrieval occurs at the trough, coincident with input from CA3, consistent with theta phase-dependent synaptic plasticity. We examined three predictions of these models: (1) in novel environments, the preferred theta phase of CA1 place cell firing should shift closer to the CA1 pyramidal-layer theta peak, shifting the encoding-retrieval balance toward encoding; (2) the encoding-related shift in novel environments should be disrupted by cholinergic antagonism; and (3) in familiar environments, cholinergic antagonism should shift the preferred theta firing phase closer to the theta trough, shifting the encoding-retrieval balance even further toward retrieval. We tested these predictions by recording from CA1 pyramidal cells in freely moving rats as they foraged in open field environments under the influence of scopolamine (an amnestic cholinergic antagonist) or vehicle (saline). Results confirmed all three predictions, supporting both the theta phase and cholinergic models of encoding versus retrieval dynamics. Also consistent with cholinergic enhancement of encoding, scopolamine attenuated the formation of distinct spatial representations in a new environment, reducing the extent of place cell "remapping."

Control of timing, rate and bursts of hippocampal place cells by dendritic and somatic inhibition

A consortium of inhibitory neurons control the firing patterns of pyramidal cells, but their specific roles in the behaving animal are largely unknown. We performed simultaneous physiological recordings and optogenetic silencing of either perisomatic (parvalbumin (PV) expressing) or dendrite-targeting (somatostatin (SOM) expressing) interneurons in hippocampal area CA1 of head-fixed mice actively moving a treadmill belt rich with visual-tactile stimuli. Silencing of either PV or SOM interneurons increased the firing rates of pyramidal cells selectively in their place fields, with PV and SOM interneurons having their largest effect during the rising and decaying parts of the place field, respectively. SOM interneuron silencing powerfully increased burst firing without altering the theta phase of spikes. In contrast, PV interneuron silencing had no effect on burst firing, but instead shifted the spikes' theta phase toward the trough of theta. These findings indicate that perisomatic and dendritic inhibition have distinct roles in controlling the rate, burst and timing of hippocampal pyramidal cells.

Coherent Theta Oscillations and Reorganization of Spike Timing in the Hippocampal- Prefrontal Network upon Learning

To study the interplay between hippocampus and medial prefrontal cortex (Pfc) and its importance for learning and memory consolidation, we measured the coherence in theta oscillations between these two structures in rats learning new rules on a Y maze. Coherence peaked at the choice point, most strongly after task rule acquisition. Simultaneously, Pfc pyramidal neurons reorganized their phase, concentrating at hippocampal theta trough, and synchronous cell assemblies emerged. This synchronous state may result from increased inhibition exerted by interneurons on pyramidal cells, as measured by cross-correlation, and could be modulated by dopamine: we found similar hippocampal-Pfc theta coherence increases and neuronal phase shifts following local administration of dopamine in Pfc of anesthetized rats. Pfc cell assemblies emerging during high coherence were preferentially replayed during subsequent sleep, concurrent with hippocampal sharp waves. Thus, hippocampal/prefrontal coherence could lead to synchronization of reward predicting activity in prefrontal networks, tagging it for subsequent memory consolidation.

Amplitude, frequency, and phase analysis of hippocampal theta during sensorimotor processing in a jump avoidance task

In the current study, rats implanted with hippocampal recording electrodes were trained to avoid shock in a jump avoidance task, using three separate heights, 28, 33, and 38 cm. The objectives were to measure the progression of Type 2 (immobility-related) hippocampal theta amplitude and frequency recorded during jump avoidances at each of the levels, and determine if there was a consistent relationship between the phase of the Type 1 (movement related) theta jump wave and the moment of movement initiation at each of the jump heights. The results demonstrated that the immobility period prior to the execution of the jump could be divided into two components: a sensory processing period and a movement preparation period. Comparing these two periods, average amplitudes were higher while frequency remained relatively constant during the sensory processing period. During the movement preparation period there was a negative correlation between amplitude and frequency: amplitude declined rapidly and frequency increased rapidly. During the execution of the jump, theta amplitude (Type 1) and frequency were positively correlated, both reaching peak values. The separate analyses of the individual jump heights provided further support for the precise relationships between theta parameters and the magnitude of the required movements. A significant phase preference was demonstrated for the highest jump height, with movement initiation occurring around the trough of theta recorded from the stratum moleculare of the dentate region. The findings supported the conclusion that the generation of hippocampal theta band oscillation and synchrony was related to sensorimotor processing and integration.