Constant Sub-second Cycling between Representations of Possible Futures in the Hippocampus.

Cognitive faculties such as imagination, planning, and decision-making entail the ability to represent hypothetical experience. Crucially, animal behavior in natural settings implies that the brain can represent hypothetical future experience not only quickly but also constantly over time, as external events continually unfold. To determine how this is possible, we recorded neural activity in the hippocampus of rats navigating a maze with multiple spatial paths. We found neural activity encoding two possible future scenarios (two upcoming maze paths) in constant alternation at 8 Hz: one scenario per ∼125-ms cycle. Further, we found that the underlying dynamics of cycling (both inter- and intra-cycle dynamics) generalized across qualitatively different representational correlates (location and direction). Notably, cycling occurred across moving behaviors, including during running. These findings identify a general dynamic process capable of quickly and continually representing hypothetical experience, including that of multiple possible futures.

The translational inhibitor and amnestic agent emetine also suppresses ongoing hippocampal neural activity similarly to other blockers of protein synthesis.

The consolidation of memory is thought to ultimately depend on the synthesis of new proteins, since translational inhibitors such as anisomycin and cycloheximide adversely affect the permanence of long-term memory. However, when applied directly in brain, these agents also profoundly suppress neural activity to an extent that is directly correlated to the degree of protein synthesis inhibition caused. Given that neural activity itself is likely to help mediate consolidation, this finding is a serious criticism of the strict de novo protein hypothesis of memory. Here, we test the neurophysiological effects of another translational inhibitor, emetine. Unilateral intra-hippocampal infusion of emetine suppressed ongoing local field and multiunit activity at ipsilateral sites as compared to the contralateral hippocampus in a fashion that was positively correlated to the degree of protein synthesis inhibition as confirmed by autoradiography. This suppression of activity was also specific to the circumscribed brain region in which protein synthesis inhibition took place. These experiments provide further evidence that ongoing protein synthesis is necessary and fundamental for neural function and suggest that the disruption of memory observed in behavioral experiments using translational inhibitors may be due, in large part, to neural suppression.

Cortical origin of theta error signals.

A multi-scale approach elucidated the origin of the error-related-negativity (ERN), with its associated theta-rhythm, and the post-error-positivity (Pe) in macaque supplementary eye field (SEF). Using biophysical modeling, synaptic inputs to a subpopulation of layer-3 (L3) and layer-5 (L5) pyramidal cells (PCs) were optimized to reproduce error-related spiking modulation and inter-spike intervals. The intrinsic dynamics of dendrites in L5 but not L3 error PCs generate theta rhythmicity with random phases. Saccades synchronized the phases of the theta-rhythm, which was magnified on errors. Contributions from error PCs to the laminar current source density (CSD) observed in SEF were negligible and could not explain the observed association between error-related spiking modulation in L3 PCs and scalp-EEG. CSD from recorded laminar field potentials in SEF was comprised of multipolar components, with monopoles indicating strong electro-diffusion, dendritic/axonal electrotonic current leakage outside SEF, or violations of the model assumptions. Our results also demonstrate the involvement of secondary cortical regions, in addition to SEF, particularly for the later Pe component. The dipolar component from the observed CSD paralleled the ERN dynamics, while the quadrupolar component paralleled the Pe. These results provide the most advanced explanation to date of the cellular mechanisms generating the ERN.

Directional Tuning of Phase Precession Properties in the Hippocampus.

Running direction in the hippocampus is encoded by rate modulations of place field activity but also by spike timing correlations known as theta sequences. Whether directional rate codes and the directionality of place field correlations are related, however, has so far not been explored, and therefore the nature of how directional information is encoded in the cornu ammonis remains unresolved. Here, using a previously published dataset that contains the spike activity of rat hippocampal place cells in the CA1, CA2, and CA3 subregions during free foraging of male Long-Evans rats in a 2D environment, we found that rate and spike timing codes are related. Opposite to a preferred firing rate direction of a place field, spikes are more likely to undergo theta phase precession and, hence, more strongly affect paired correlations. Furthermore, we identified a subset of field pairs whose theta correlations are intrinsic in that they maintain the same firing order when the running direction is reversed. Both effects are associated with differences in theta phase distributions and are more prominent in CA3 than in CA1. We thus hypothesize that intrinsic spiking is most prominent when the directionally modulated sensory-motor drive of hippocampal firing rates is minimal, suggesting that extrinsic and intrinsic sequences contribute to phase precession as two distinct mechanisms.SIGNIFICANCE STATEMENT Hippocampal theta sequences, on the one hand, are thought to reflect the running trajectory of an animal, connecting past and future locations. On the other hand, sequences have been proposed to reflect the rich, recursive hippocampal connectivity, related to memories of previous trajectories or even to experience-independent prestructure. Such intrinsic sequences are inherently one dimensional and cannot be easily reconciled with running trajectories in two dimensions as place fields can be approached on multiple one-dimensional paths. In this article, we dissect phase precession along different directions in all hippocampal subareas and find that CA3 in particular shows a high level of direction-independent correlations that are inconsistent with the notion of representing running trajectories. These intrinsic correlations are associated with later spike phases.

Hyper-Rigid Phasic Organization of Hippocampal Activity But Normal Spatial Properties of CA1 Place Cells in the Ts65Dn Mouse Model of Down Syndrome.

Down syndrome (DS) in humans is caused by trisomy of chromosome 21 and is marked by prominent difficulties in learning and memory. Decades of research have demonstrated that the hippocampus is a key structure in learning and memory, and recent work with mouse models of DS has suggested differences in hippocampal activity that may be the substrate of these differences. One of the primary functional differences in DS is thought to be an excess of GABAergic innervation from medial septum to the hippocampus. In these experiments, we probe in detail the activity of region CA1 of the hippocampus using in vivo electrophysiology in male Ts65Dn mice compared with their male nontrisomic 2N littermates. We find the spatial properties of place cells in CA1 are normal in Ts65Dn animals. However, we find that the phasic relationship of both CA1 place cells and gamma rhythms to theta rhythm in the hippocampus is profoundly altered in these mice. Since the phasic organization of place cell activity and gamma oscillations on the theta wave are thought to play a critical role in hippocampal function, the changes we observe agree with recent findings that organization of the hippocampal network is potentially of more relevance to its function than the spatial properties of place cells.SIGNIFICANCE STATEMENT Recent evidence has disrupted the view that spatial deficits are associated with place cell abnormalities. In these experiments, we record hippocampal place cells and local field potential from the Ts65Dn mouse model of Down syndrome, and find phenomenologically normal place cells, but profound changes in the association of place cells and gamma rhythms with theta rhythm, suggesting that the overall network state is critically important for hippocampal function. These findings also agree with evidence suggesting that excess inhibitory control is the cause of hippocampal dysfunction in Down syndrome. The findings also confirm new avenues for pharmacological treatment of Down syndrome.

Bidirectional Communication between the Pontine Nucleus Incertus and the Medial Septum Is Carried Out by Electrophysiologically-Distinct Neuronal Populations.

Theta oscillations are key brain rhythm involved in memory formation, sensorimotor integration, and control of locomotion and behavioral states. Generation and spatiotemporal synchronization of theta oscillations rely on interactions between brain nuclei forming a large neural network, which includes pontine nucleus incertus (NI). Here we identified distinct populations of NI neurons, based on the relationship of their firing to hippocampal waves, with a special focus on theta oscillations, and the direction and type of interaction with the medial septum (MS) in male, urethane-anesthetized rats. By recording NI neuronal firing and hippocampal LFP, we described NI neurons that fire action potentials in a theta phase-independent or theta phase-locked and delta wave-independent or delta wave-locked manner. Among hippocampal activity-independent NI neurons, irregular, slow-firing, and regular, fast-firing cells were observed, while hippocampal oscillation-/wave-locked NI neurons were of a bursting or nonbursting type. By projection-specific optotagging, we revealed that only fast-firing theta phase-independent NI neurons innervate the MS, rarely receiving feedback information. In contrast, the majority of theta-bursting NI neurons were inhibited by MS stimulation, and this effect was mediated by direct GABAergic input. Described NI neuronal populations differ in reciprocal connections with the septohippocampal system, plausibly forming separate neuronal loops. Our results suggest that theta phase-independent NI neurons participate in theta rhythm generation through direct innervation of the MS, while theta-bursting NI neurons further transmit the rhythmic signal received from the MS to stabilize and/or strengthen rhythmic activity in other structures.SIGNIFICANCE STATEMENT The generation and spatiotemporal synchronization of theta oscillations rely on interactions between nuclei forming a large neural network, part of which is the pontine nucleus incertus (NI). Here we describe that within NI there are populations of neurons that can be distinguished based on the relationship of their firing to hippocampal theta oscillations and delta waves. We show that these neuronal populations largely do not have reciprocal connections with the septohippocampal system, but form separate neuronal loops. Our results suggest that medial septum (MS)-projecting, fast-firing, theta phase-independent NI neurons may participate in theta rhythm generation through direct innervation of the MS, while theta-bursting NI neurons may further transmit the rhythmic signal received from the MS to other structures.

Transcranial ultrasound stimulation at the peak-phase of theta-cycles in the hippocampus improve memory performance.

The present study aimed to investigate the effectiveness of closed-loop transcranial ultrasound stimulation (closed-loop TUS) as a non-invasive, high temporal-spatial resolution method for modulating brain function to enhance memory. For this purpose, we applied closed-loop TUS to the CA1 region of the rat hippocampus for 7 consecutive days at different phases of theta cycles. Following the intervention, we evaluated memory performance through behavioral testing and recorded the neural activity. Our results indicated that closed-loop TUS applied at the peak phase of theta cycles significantly improves the memory performance in rats, as evidenced by behavioral testing. Furthermore, we observed that closed-loop TUS modifies the power and cross-frequency coupling strength of local field potentials (LFPs) during memory task, as well as modulates neuronal activity patterns and synaptic transmission, depending on phase of stimulation relative to theta rhythm. We demonstrated that closed-loop TUS can modulate neural activity and memory performance in a phase-dependent manner. Specifically, we observed that effectiveness of closed-loop TUS in regulating neural activity and memory is dependent on the timing of stimulation in relation to different theta phase. The findings implied that closed-loop TUS may have the capability to alter neural activity and memory performance in a phase-sensitive manner, and suggested that the efficacy of closed-loop TUS in modifying neural activity and memory was contingent on timing of stimulation with respect to the theta rhythm. Moreover, the improvement in memory performance after closed-loop TUS was found to be persistent.

Posterior hypothalamic theta rhythm: Electrophysiological basis and involvement of glutamatergic receptors.

The posterior hypothalamic area (PHa), including the supramammillary nucleus (SuM) and posterior hypothalamic nuclei, forms a crucial part of the ascending brainstem hippocampal synchronizing pathway, that is involved in the frequency programming and modulation of rhythmic theta activity generated in limbic structures. Recent investigations show that in addition to being a modulator of limbic theta activity, the PHa is capable of producing well-synchronized local theta field potentials by itself. The purpose of this study was to examine the ability of the PHa to generate theta field potentials and accompanying cell discharges in response to glutamatergic stimulation under both in vitro and in vivo conditions. The second objective was to examine the electrophysiological properties of neurons located in the SuM and posterior hypothalamic nuclei. Extracellular in vivo and in vitro as well as intracellular in vitro experiments revealed that glutamatergic stimulation of PHa with kainic acid induces well-synchronized local theta field oscillations in both the supramammillary and posterior hypothalamic nuclei. Furthermore, the glutamatergic PHa theta rhythm recorded extracellularly was accompanied by the activity of specific subtypes of theta-related neurons. We identify, for the first time, a subpopulation of supramammillary and posterior hypothalamic neurons that express clear subthreshold membrane potential oscillations in the theta frequency range.

Social Buffering Effects during Craft Activities in Parallel Group Session Revealed by EEG Analysis and Parasympathetic Activity.

INTRODUCTION: The therapeutic structure of occupational therapy (OT) includes groups. Although the presence of others is expected to be relaxing due to the social buffering effect and the tend and befriend theory, it has not been sufficiently validated in accordance with the therapeutic structure of OT. The aim of this study was to investigate the electrophysiological evidence for the effectiveness of parallel groups and states of concentration on craft activities used in OT. METHODS: Thirty healthy young adults were used as controls to measure EEG and autonomic activity during craft activities in three conditions: alone, parallel, and nonparallel. EEG was analyzed using exact low-resolution electromagnetic tomography, and autonomic activity was analyzed using Lorenz plot analysis. RESULTS: Parasympathetic activity was significantly higher in the parallel condition than in the alone condition. A significant negative correlation was found between current source density and parasympathetic activity in the region centered on the right insular cortex in the α1 band, and functional connectivity in regions including the anterior cingulate cortex and insular cortex was associated with autonomic activity. CONCLUSION: Craft activities that occurred during frontal midline theta rhythm also increased parasympathetic activity. The results suggest that the parallel groups used in OT and the intensive state of craft activities induce a social buffering effect that increases parasympathetic activity despite the absence of physical contact or social support. This provides evidence for the effectiveness of the therapeutic structure of occupational activities and groups in OT.

Perceptual Integration Compensates for Attention Deficit in Elderly during Repetitive Auditory-Based Sensorimotor Task.

Sensorimotor integration (SI) brain functions that are vital for everyday life tend to decline in advanced age. At the same time, elderly people preserve a moderate level of neuroplasticity, which allows the brain's functionality to be maintained and slows down the process of neuronal degradation. Hence, it is important to understand which aspects of SI are modifiable in healthy old age. The current study focuses on an auditory-based SI task and explores: (i) if the repetition of such a task can modify neural activity associated with SI, and (ii) if this effect is different in young and healthy old age. A group of healthy older subjects and young controls underwent an assessment of the whole-brain electroencephalography (EEG) while repetitively executing a motor task cued by the auditory signal. Using EEG spectral power and functional connectivity analyses, we observed a differential age-related modulation of theta activity throughout the repetition of the SI task. Growth of the anterior stimulus-related theta oscillations accompanied by enhanced right-lateralized frontotemporal phase-locking was found in elderly adults. Their young counterparts demonstrated a progressive increase in prestimulus occipital theta power. Our results suggest that the short-term repetition of the auditory-based SI task modulates sensory processing in the elderly. Older participants most likely progressively improve perceptual integration rather than attention-driven processing compared to their younger counterparts.

Dopamine D4 Receptor Agonist Drastically Increases Delta Activity in the Thalamic Nucleus Reuniens: Potential Role in Communication between Prefrontal Cortex and Hippocampus.

Network oscillations are essential for all cognitive functions. Oscillatory deficits are well established in psychiatric diseases and are recapitulated in animal models. They are significantly and specifically affected by pharmacological interventions using psychoactive compounds. Dopamine D4 receptor (D4R) activation was shown to enhance gamma rhythm in freely moving rats and to specifically affect slow delta and theta oscillations in the urethane-anesthetized rat model. The goal of this study was to test the effect of D4R activation on slow network oscillations at delta and theta frequencies during wake states, potentially supporting enhanced functional connectivity during dopamine-induced attention and cognitive processing. Network activity was recorded in the prefrontal cortex (PFC), hippocampus (HC) and nucleus reuniens (RE) in control conditions and after injecting the D4R agonist A-412997 (3 and 5 mg/kg; systemic administration). We found that A-412997 elicited a lasting (~40 min) wake state and drastically enhanced narrow-band delta oscillations in the PFC and RE in a dose-dependent manner. It also preferentially enhanced delta synchrony over theta coupling within the PFC-RE-HC circuit, strongly strengthening PFC-RE coupling. Thus, our findings indicate that the D4R may contribute to cognitive processes, at least in part, through acting on wake delta oscillations and that the RE, providing an essential link between the PFC and HC, plays a prominent role in this mechanism.

Molecular Mechanisms for Changing Brain Connectivity in Mice and Humans.

The goal of this study was to examine commonalities in the molecular basis of learning in mice and humans. In previous work we have demonstrated that the anterior cingulate cortex (ACC) and hippocampus (HC) are involved in learning a two-choice visuospatial discrimination task. Here, we began by looking for candidate genes upregulated in mouse ACC and HC with learning. We then determined which of these were also upregulated in mouse blood. Finally, we used RT-PCR to compare candidate gene expression in mouse blood with that from humans following one of two forms of learning: a working memory task (network training) or meditation (a generalized training shown to change many networks). Two genes were upregulated in mice following learning: caspase recruitment domain-containing protein 6 (Card6) and inosine monophosphate dehydrogenase 2 (Impdh2). The Impdh2 gene product catalyzes the first committed step of guanine nucleotide synthesis and is tightly linked to cell proliferation. The Card6 gene product positively modulates signal transduction. In humans, Card6 was significantly upregulated, and Impdh2 trended toward upregulation with training. These genes have been shown to regulate pathways that influence nuclear factor kappa B (NF-κB), a factor previously found to be related to enhanced synaptic function and learning.

Long-Range Respiratory and Theta Oscillation Networks Depend on Spatial Sensory Context.

Neural oscillations can couple networks of brain regions, especially at lower frequencies. The nasal respiratory rhythm, which elicits robust olfactory bulb oscillations, has been linked to episodic memory, locomotion, and exploration, along with widespread oscillatory coherence. The piriform cortex is implicated in propagating the olfactory-bulb-driven respiratory rhythm, but this has not been tested explicitly in the context of both hippocampal theta and nasal respiratory rhythm during exploratory behaviors. We investigated systemwide interactions during foraging behavior, which engages respiratory and theta rhythms. Local field potentials from the olfactory bulb, piriform cortex, dentate gyrus, and CA1 of hippocampus, primary visual cortex, and nasal respiration were recorded simultaneously from male rats. We compared interactions among these areas while rats foraged using either visual or olfactory spatial cues. We found high coherence during foraging compared with home cage activity in two frequency bands that matched slow and fast respiratory rates. Piriform cortex and hippocampus maintained strong coupling at theta frequency during periods of slow respiration, whereas other pairs showed coupling only at the fast respiratory frequency. Directional analysis shows that the modality of spatial cues was matched to larger influences in the network by the respective primary sensory area. Respiratory and theta rhythms also coupled to faster oscillations in primary sensory and hippocampal areas. These data provide the first evidence of widespread interactions among nasal respiration, olfactory bulb, piriform cortex, and hippocampus in awake freely moving rats, and support the piriform cortex as an integrator of respiratory and theta activity.SIGNIFICANCE STATEMENT Recent studies have shown widespread interactions between the nasally driven respiratory rhythm and neural oscillations in hippocampus and neocortex. With this study, we address how the respiratory rhythm interacts with ongoing slow brain rhythms across olfactory, hippocampal, and visual systems in freely moving rats. Patterns of network connectivity change with behavioral state, with stronger interactions at fast and slow respiratory frequencies during foraging as compared with home cage activity. Routing of interactions between sensory cortices depends on the modality of spatial cues present during foraging. Functional connectivity and cross-frequency coupling analyses suggest strong bidirectional interactions between olfactory and hippocampal systems related to respiration and point to the piriform cortex as a key area for mediating respiratory and theta rhythms.

Muscarinic and N-methyl-D-aspartate receptor blockade reveal differences in hippocampal local field potentials in mice with low cholinergic tone.

We hypothesize that hippocampal local field potentials in acetylcholine (ACh)-deficient mutant mice, compared to wild-type (WT) mice, will show lower sensitivity to muscarinic cholinergic antagonist scopolamine (5 mg/kg i.p.) but higher sensitivity to NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP, 10 mg/kg i.p.). Recordings were made during walk and awake-immobility (IMM) in WT mice, and in mice with forebrain knockout (KO) of the vesicular acetylcholine transporter (VAChT) gene, or heterozygous knockdown of VAChT gene (KD). Scopolamine or CPP did not significantly alter walk theta frequency, which was higher in KD than WT/KO mice. Scopolamine decreased theta power peak rise during walk in WT/KD mice but not in KO mice, while CPP suppressed theta peak rise more in WT/KO mice than KD mice. During IMM, scopolamine decreased gamma1 (γ1, 30-58 Hz) power more in KD/WT mice than KO mice, while delta (1-4 Hz) power and delta-gamma cross-frequency coherence (CFC) were increased in all mouse groups during IMM or walk. During walk, scopolamine increased delta and beta (13-30 Hz) power and decreased gamma2 (γ2, 62-100 Hz) power and theta-γ2 CFC more in WT/KD than KO mice. Theta-γ2, but not theta-γ1, CFC increased with theta-peak-frequency in WT/KD mice, and was suppressed by scopolamine at high theta (8-10 Hz) frequency; theta-γ2 CFC in KO mice was not significantly altered by scopolamine. CPP decreased beta and gamma power more in KD/KO mice compared to WT mice, while delta power and delta-gamma CFC were increased in all mouse groups. ACh deficiency exacerbates the attenuation of beta and gamma power by CPP. We conclude that both muscarinic and NMDA transmission contribute toward hippocampal theta, beta, and gamma power, and a decrease in gamma power or theta-gamma CFC may be associated with loss of arousal and cognitive functions.

Homogeneous inhibition is optimal for the phase precession of place cells in the CA1 field.

Place cells are hippocampal neurons encoding the position of an animal in space. Studies of place cells are essential to understanding the processing of information by neural networks of the brain. An important characteristic of place cell spike trains is phase precession. When an animal is running through the place field, the discharges of the place cells shift from the ascending phase of the theta rhythm through the minimum to the descending phase. The role of excitatory inputs to pyramidal neurons along the Schaffer collaterals and the perforant pathway in phase precession is described, but the role of local interneurons is poorly understood. Our goal is estimating of the contribution of field CA1 interneurons to the phase precession of place cells using mathematical methods. The CA1 field is chosen because it provides the largest set of experimental data required to build and verify the model. Our simulations discover optimal parameters of the excitatory and inhibitory inputs to the pyramidal neuron so that it generates a spike train with the effect of phase precession. The uniform inhibition of pyramidal neurons best explains the effect of phase precession. Among interneurons, axo-axonal neurons make the greatest contribution to the inhibition of pyramidal cells.

Evidence supporting deep brain stimulation of the medial septum in the treatment of temporal lobe epilepsy.

Electrical brain stimulation has become an essential treatment option for more than one third of epilepsy patients who are resistant to pharmacological therapy and are not candidates for surgical resection. However, currently approved stimulation paradigms achieve only moderate success, on average providing approximately 75% reduction in seizure frequency and extended periods of seizure freedom in nearly 20% of patients. Outcomes from electrical stimulation may be improved through the identification of novel anatomical targets, particularly those with significant anatomical and functional connectivity to the epileptogenic zone. Multiple studies have investigated the medial septal nucleus (i.e., medial septum) as such a target for the treatment of mesial temporal lobe epilepsy. The medial septum is a small midline nucleus that provides a critical functional role in modulating the hippocampal theta rhythm, a 4-7-Hz electrophysiological oscillation mechanistically associated with memory and higher order cognition in both rodents and humans. Elevated theta oscillations are thought to represent a seizure-resistant network activity state, suggesting that electrical neuromodulation of the medial septum and restoration of theta-rhythmic physiology may not only reduce seizure frequency, but also restore cognitive comorbidities associated with mesial temporal lobe epilepsy. Here, we review the anatomical and physiological function of the septohippocampal network, evidence for seizure-resistant effects of the theta rhythm, and the results of stimulation experiments across both rodent and human studies, to argue that deep brain stimulation of the medial septum holds potential to provide an effective neuromodulation treatment for mesial temporal lobe epilepsy. We conclude by discussing the considerations necessary for further evaluating this treatment paradigm with a clinical trial.

Interictal Spike and Loss of Hippocampal Theta Rhythm Recorded by Deep Brain Electrodes during Epileptogenesis.

Epileptogenesis is the gradual dynamic process that progressively led to epilepsy, going through the latent stage to the chronic stage. During epileptogenesis, how the abnormal discharges make theta rhythm loss in the deep brain remains not clear. In this paper, a loss of theta rhythm was estimated based on time-frequency power using the longitudinal electroencephalography (EEG), recorded by deep brain electrodes (e.g., the intracortical microelectrodes such as stereo-EEG electrodes) with monitored epileptic spikes in a rat from the first region in the hippocampal circuit. Deep-brain EEG was collected from the period between adjacent sporadic interictal spikes (lasting 3.56 s-35.38 s) to the recovery period without spikes by videos while the rats were performing exploration. We found that loss of theta rhythm became more serious during the period between adjacent interictal spikes than during the recovery period without spike, and during epileptogenesis, more loss was observed at the acute stage than the chronic stage. We concluded that the emergence of the interictal spike was the direct cause of loss of theta rhythm, and the inhibitory effect of the interictal spike on ongoing theta rhythm was persistent as well as time dependent during epileptogenesis. With the help of the intracortical microelectrodes, this study provides a temporary proof of interictal spikes to produce ongoing theta rhythm loss, suggesting that the interictal spikes could correlate with the epileptogenesis process, display a time-dependent feature, and might be a potential biomarker to evaluate the deficits in theta-related memory in the brain.

Differential Effect of Dopamine D4 Receptor Activation on Low-Frequency Oscillations in the Prefrontal Cortex and Hippocampus May Bias the Bidirectional Prefrontal-Hippocampal Coupling.

Dopamine D4 receptor (D4R) mechanisms are implicated in psychiatric diseases characterized by cognitive deficits, including schizophrenia, ADHD, and autism. The cellular mechanisms are poorly understood, but impaired neuronal synchronization in cortical networks was proposed to contribute to these deficits. In animal experiments, D4R activation was shown to generate aberrant increased gamma oscillations and to reduce performance on cognitive tasks requiring functional prefrontal cortex (PFC) and hippocampus (HPC) networks. While fast oscillations in the gamma range are important for local synchronization within neuronal ensembles, long-range synchronization between distant structures is achieved by slow rhythms in the delta, theta, alpha ranges. The characteristics of slow oscillations vary between structures during cognitive tasks. HPC activity is dominated by theta rhythm, whereas PFC generates unique oscillations in the 2-4 Hz range. In order to investigate the role of D4R on slow rhythms, cortical activity was recorded in rats under urethane anesthesia in which slow oscillations can be elicited in a controlled manner without behavioral confounds, by electrical stimulation of the brainstem reticular formation. The local field potential segments during stimulations were extracted and subjected to fast Fourier transform to obtain power density spectra. The selective D4R agonist A-412997 (5 and 10 mg/kg) and antagonists L-745870 (5 and 10 mg/kg) were injected systemically and the peak power in the two frequency ranges were compared before and after the injection. We found that D4R compounds significantly changed the activity of both HPC and PFC, but the direction of the effect was opposite in the two structures. D4R agonist enhanced PFC slow rhythm (delta, 2-4 Hz) and suppressed HPC theta, whereas the antagonist had an opposite effect. Analogous changes of the two slow rhythms were also found in the thalamic nucleus reuniens, which has connections to both forebrain structures. Slow oscillations play a key role in interregional cortical coupling; delta and theta oscillations were shown in particular, to entrain neuronal firing and to modulate gamma activity in interconnected forebrain structures with a relative HPC theta dominance over PFC. Thus, the results of this study indicate that D4R activation may introduce an abnormal bias in the bidirectional PFC-HPC coupling which can be reversed by D4R antagonists.

Hippocampal and Prefrontal Theta-Band Mechanisms Underpin Implicit Spatial Context Learning.

Humans can rapidly and seemingly implicitly learn to predict typical locations of relevant items when those items are encountered in familiar spatial contexts. Two important questions remain, however, concerning this type of learning: (1) which neural structures and mechanisms are involved in acquiring and exploiting such contextual knowledge? (2) Is this type of learning truly implicit and unconscious? We now answer both these questions after closely examining behavior and recording neural activity using MEG while observers (male and female) were acquiring and exploiting statistical regularities. Computational modeling of behavioral data suggested that, after repeated exposures to a spatial context, participants' behavior was marked by an abrupt switch to an exploitation strategy of the learnt regularities. MEG recordings showed that hippocampus and prefrontal cortex (PFC) were involved in the task and furthermore revealed a striking dissociation: only the initial learning phase was associated with hippocampal theta band activity, while the subsequent exploitation phase showed a shift in theta band activity to the PFC. Intriguingly, the behavioral benefit of repeated exposures to certain scenes was inversely related to explicit awareness of such repeats, demonstrating the implicit nature of the expectations acquired. Together, these findings demonstrate that (1a) hippocampus and PFC play complementary roles in the implicit, unconscious learning and exploitation of spatial statistical regularities; (1b) these mechanisms are implemented in the theta frequency band; and (2) contextual knowledge can indeed be acquired unconsciously, and awareness of such knowledge can even interfere with the exploitation thereof.SIGNIFICANCE STATEMENT Human visual perception is determined not just by the light that strikes our eyes, but also strongly by our prior knowledge and expectations. Such expectations, particularly about where to expect certain objects given scene context, might be learned implicitly and unconsciously, although this is hotly debated. Furthermore, it is unknown which brain mechanisms underpin this type of learning. We now show that, indeed, spatial prior expectations can be learned without awareness; in fact, strikingly, awareness seems to hinder the exploitation of the relevant knowledge. Furthermore, we demonstrate that one brain mechanism (hippocampal theta-band activity) is responsible for learning in these settings, whereas another mechanism (prefrontal theta-band activity) is involved in exploiting the learned associations.

Young infants process prediction errors at the theta rhythm.

Examining how young infants respond to unexpected events is key to our understanding of their emerging concepts about the world around them. From a predictive processing perspective, it is intriguing to investigate how the infant brain responds to unexpected events (i.e., prediction errors), because they require infants to refine their predictions about the environment. Here, to better understand prediction error processes in the infant brain, we presented 9-month-olds (N = 36) a variety of physical and social events with unexpected versus expected outcomes, while recording their electroencephalogram (EEG). We found a pronounced response in the ongoing 4-5 Hz theta rhythm for the processing of unexpected (in contrast to expected) events, for a prolonged time window (2 s) and across all scalp-recorded electrodes. The condition difference in the theta rhythm was not related to the condition difference in infants' event-related activity to unexpected (versus expected) events in the negative central (Nc) component (0.4-0.6 s), a component, which is commonly analyzed in infant violation of expectation studies using EEG. These findings constitute critical evidence that the theta rhythm is involved in the processing of prediction errors from very early in human brain development. We discuss how the theta rhythm may support infants' refinement of basic concepts about the physical and social environment.