Integrating Spatial Working Memory and Remote Memory: Interactions between the Medial Prefrontal Cortex and Hippocampus

In recent years, two separate research streams have focused on information sharing between the medial prefrontal cortex (mPFC) and hippocampus (HC). Research into spatial working memory has shown that successful execution of many types of behaviors requires synchronous activity in the theta range between the mPFC and HC, whereas studies of memory consolidation have shown that shifts in area dependency may be temporally modulated. While the nature of information that is being communicated is still unclear, spatial working memory and remote memory recall is reliant on interactions between these two areas. This review will present recent evidence that shows that these two processes are not as separate as they first appeared. We will also present a novel conceptualization of the nature of the medial prefrontal representation and how this might help explain this area’s role in spatial working memory and remote memory recall

Memory: Theta Rhythm Couples Periodic Reactivation during Memory Retrieval

Memory retrieval involves the reactivation of memory traces distributed throughout the brain. New research suggests that these memory reactivations have an oscillatory nature and that they are coupled to preferential stages of the hippocampal theta cycle

An optimal oscillatory phase for pattern reactivation during memory retrieval

Computational models and in vivo studies in rodents suggest that the hippocampal system oscillates between states that are optimal for encoding and states that are optimal for retrieval. Here, we show that in humans, neural signatures of memory reactivation are modulated by the phase of a theta oscillation. Electroencephalography (EEG) was recorded while participants were cued to recall previously learned word-object associations, and time-resolved pattern classifiers were trained to detect neural reactivation of the target objects. Classifier fidelity rhythmically fluctuated at 7 or 8 Hz and was modulated by theta phase across the entire recall period. The phase of optimal classification was shifted approximately 180° between encoding and retrieval. Inspired by animal work, we then computed “classifier-locked averages” to analyze how ongoing theta oscillations behaved around the time points at which the classifier indicated memory retrieval. We found strong theta (7 or 8 Hz) phase consistency approximately 300 ms before the time points of maximal neural memory reactivation. Our findings provide important evidence that the neural signatures of memory retrieval fluctuate and are time locked to the phase of an ongoing theta oscillation

Human hippocampal theta power indicates movement onset and distance travelled

Theta frequency oscillations in the 6- to 10-Hz range dominate the rodent hippocampal local field potential during translational movement, suggesting that theta encodes self-motion. Increases in theta power have also been identified in the human hippocampus during both real and virtual movement but appear as transient bursts in distinct high- and low-frequency bands, and it is not yet clear how these bursts relate to the sustained oscillation observed in rodents. Here, we examine depth electrode recordings from the temporal lobe of 13 presurgical epilepsy patients performing a selfpaced spatial memory task in a virtual environment. In contrast to previous studies, we focus on movement-onset periods that incorporate both initial acceleration and an immediately preceding stationary interval associated with prominent theta oscillations in the rodent hippocampal formation. We demonstrate that movementonset periods are associated with a significant increase in both low (2–5 Hz)- and high (6–9 Hz)-frequency theta power in the human hippocampus. Similar increases in low- and high-frequency theta power are seen across lateral temporal lobe recording sites and persist throughout the remainder of movement in both regions. In addition, we show that movement-related theta power is greater both before and during longer paths, directly implicating human hippocampal theta in the encoding of translational movement. These findings strengthen the connection between studies of theta-band activity in rodents and humans and offer additional insight into the neural mechanisms of spatial navigation

Medial prefrontal-medial temporal theta phase coupling in dynamic spatial imagery

Hippocampal–medial prefrontal interactions are thought to play a crucial role in mental simulation. Notably, the frontal midline/medial pFC (mPFC) theta rhythm in humans has been linked to introspective thought and working memory. In parallel, theta rhythms have been proposed to coordinate processing in the medial temporal cortex, retrosplenial cortex (RSc), and parietal cortex during the movement of viewpoint in imagery, extending their association with physical movement in rodent models. Here, we used noninvasive whole-head MEG to investigate theta oscillatory power and phase-locking during the 18-sec postencoding delay period of a spatial working memory task, in which participants imagined previously learned object sequences either on a blank background (object maintenance), from a first-person viewpoint in a scene (static imagery), or moving along a path past the objects (dynamic imagery). We found increases in 4- to 7-Hz theta power in mPFC when comparing the delay period with a preencoding baseline. We then examined whether the mPFC theta rhythm was phase-coupled with ongoing theta oscillations elsewhere in the brain. The same mPFC region showed significantly higher theta phase coupling with the posterior medial temporal lobe/RSc for dynamic imagery versus either object maintenance or static imagery. mPFC theta phase coupling was not observed with any other brain region. These results implicate oscillatory coupling between mPFC and medial temporal lobe/RSc theta rhythms in the dynamic mental exploration of imagined scenes

EEG oscillations during sleep and dream recall. State- or trait-like individual differences?

Dreaming represents a peculiar form of cognitive activity during sleep. On the basis of the well-known relationship between sleep and memory, there has been a growing interest in the predictive role of human brain activity during sleep on dream recall. Neuroimaging studies indicate that rapid eye movement (REM) sleep is characterized by limbic activation and prefrontal cortex deactivation. This pattern could explain the presence of emotional contents in dream reports. Furthermore, the morphoanatomical measures of amygdala and hippocampus predict some features of dream contents (bizarreness, vividness, and emotional load). More relevant for a general view of dreaming mechanisms, empirical data from neuropsychological and electroencephalographic (EEG) studies support the hypothesis that there is a sort of continuity between the neurophysiological mechanisms of encoding and retrieval of episodic memories across sleep and wakefulness. A notable overlap between the electrophysiological mechanisms underlying emotional memory formation and some peculiar EEG features of REM sleep has been suggested. In particular, theta (5–8 Hz) EEG oscillations on frontal regions in the pre-awakening sleep are predictive of dream recall, which parallels the predictive relation during wakefulness between theta activity and successful retrieval of episodic memory. Although some observations support an interpretation more in terms of an intraindividual than interindividual mechanism, the existing empirical evidence still precludes from definitely disentangling if this relation is explained by state- or trait-like differences

Harnessing the power of theta: natural manipulations of cognitive performance during hippocampal theta-contingent eyeblink conditioning

Neurobiological oscillations are regarded as essential to normal information processing, including coordination and timing of cells and assemblies within structures as well as in long feedback loops of distributed neural systems. The hippocampal theta rhythm is a 3-12 Hz oscillatory potential observed during cognitive processes ranging from spatial navigation to associative learning. The lower range, 3-7 Hz, can occur during immobility and depends upon the integrity of cholinergic forebrain systems. Several studies have shown that the amount of pre-training theta in the rabbit strongly predicts the acquisition rate of classical eyeblink conditioning and that impairment of this system substantially slows the rate of learning. Our lab has used a brain-computer interface that delivers eyeblink conditioning trials contingent upon the explicit presence or absence of hippocampal theta. A behavioral benefit of theta-contingent training has been demonstrated in both delay and trace forms of the paradigm with a two- to four-fold increase in learning speed. This behavioral effect is accompanied by enhanced amplitude and synchrony of hippocampal local field potentials, multiple-unit excitation, and single-unit response patterns that depend on theta state. Additionally, training in the presence of hippocampal theta has led to increases in the salience of tone-induced unit firing patterns in the medial prefrontal cortex, followed by persistent multi-unit activity during the trace interval. In cerebellum, rhythmicity and precise synchrony of stimulus time-locked local field potentials with those of hippocampus occur preferentially under the theta condition. Here we review these findings, integrate them into current models of hippocampal-dependent learning and suggest how improvement in our understanding of neurobiological oscillations is critical for theories of medial temporal lobe processes underlying intact and pathological learning

Oscillatory architecture of memory circuits

The coordinated activity between remote brain regions underlies cognition and memory function. Although neuronal oscillations have been proposed as a mechanistic substrate for the coordination of information transfer and memory consolidation during sleep, little is known about the mechanisms that support the widespread synchronization of brain regions and the relationship of neuronal dynamics with other bodily rhythms, such as breathing. During exploratory behavior, the hippocampus and the prefrontal cortex are organized by theta oscillations, known to support memory encoding and retrieval, while during sleep the same structures are dominated by slow oscillations that are believed to underlie the consolidation of recent experiences. The expression of conditioned fear and extinction memories relies on the coordinated activity between the mPFC and the basolateral amygdala (BLA), a neuronal structure encoding associative fear memories. However, to date, the mechanisms allowing this long-range network synchronization of neuronal activity between the mPFC and BLA during fear behavior remain virtually unknown. Using a combination of extracellular recordings and open- and closed-loop optogenetic manipulations, we investigated the oscillatory and coding mechanisms mediating the organization and coupling of the limbic circuit in the awake and asleep brain, as well as during memory encoding and retrieval. We found that freezing, a behavioral expression of fear, is tightly associated with an internally generated brain state that manifests in sustained 4Hz oscillatory dynamics in prefrontal-amygdala circuits. 4Hz oscillations accurately predict the onset and termination of the freezing state. These oscillations synchronize prefrontal-amygdala circuits and entrain neuronal activity to dynamically regulate the development of neuronal ensembles. This enables the precise timing of information transfer between the two structures and the expression of fear responses. Optogenetic induction of prefrontal 4Hz oscillations promotes freezing behavior and the formation of long-lasting fear memory, while closed-loop phase specific manipulations bidirectionally modulate fear expression. Our results unravel a physiological signature of fear memory and identify a novel internally generated brain state, characterized by 4Hz oscillations. This oscillation enables the temporal coordination and information transfer in the prefrontal-amygdala circuit via a phase-specific coding mechanism, facilitating the encoding and expression of fear memory. In the search for the origin of this oscillation, we focused our attention on breathing, the most fundamental and ubiquitous rhythmic activity in life. Using large-scale extracellular recordings from a number of structures, including the medial prefrontal cortex, hippocampus, thalamus, amygdala and nucleus accumbens in mice we identified and characterized the entrainment by breathing of a host of network dynamics across the limbic circuit. We established that fear-related 4Hz oscillations are a state-specific manifestation of this cortical entrainment by the respiratory rhythm. We characterized the translaminar and transregional profile of this entrainment and demonstrated a causal role of breathing in synchronizing neuronal activity and network dynamics between these structures in a variety of behavioral scenarios in the awake and sleep state. We further revealed a dual mechanism of respiratory entrainment, in the form of an intracerebral corollary discharge that acts jointly with an olfactory reafference to coordinate limbic network dynamics, such as hippocampal ripples and cortical UP and DOWN states, involved in memory consolidation. Respiration provides a perennial stream of rhythmic input to the brain. In addition to its role as the condicio sine qua non for life, here we provide evidence that breathing rhythm acts as a global pacemaker for the brain, providing a reference signal that enables the integration of exteroceptive and interoceptive inputs with the internally generated dynamics of the hippocampus and the neocortex. Our results highlight breathing, a perennial rhythmic input to the brain, as an oscillatory scaffold for the functional coordination of the limbic circuit, enabling the segregation and integration of information flow across neuronal networks

Possible role of acetylcholine in regulating spatial novelty effects on theta rhythm and grid cells

Existing pharmacological and lesion data indicate that acetylcholine plays an important role in memory formation. For example, increased levels of acetylcholine in the hippocampal formation are known to be associated with successful encoding while disruption of the cholinergic system leads to impairments on a range of mnemonic tasks. However, cholinergic signaling from the medial septum also plays a central role in generating and pacing theta-band oscillations throughout the hippocampal formation. Recent experimental results suggest a potential link between these distinct phenomena. Environmental novelty, a condition associated with strong cholinergic drive, has been shown to induce an expansion in the firing pattern of entorhinal grid cells and a reduction in the frequency of theta measured from the LFP. Computational modeling suggests the spatial activity of grid cells is produced by interference between neuronal oscillators; scale being determined by theta-band oscillations impinging on entorhinal stellate cells, the frequency of which is modulated by acetylcholine. Here we propose that increased cholinergic signaling in response to environmental novelty triggers grid expansion by reducing the frequency of the oscillations. Furthermore, we argue that cholinergic induced grid expansion may enhance, or even induce, encoding by producing a mismatch between expanded grid cells and other spatial inputs to the hippocampus, such as boundary vector cells. Indeed, a further source of mismatch is likely to occur between grid cells of different native scales which may expand by different relative amounts

Changes in Hippocampal-Anterior Cingulate Cortex Interactions During Remote Memory Recall

Spatial memory is an important cognitive process that relies on extensive neural networks throughout the brain. The hippocampus (HC) is important for the formation of these memories but over time, in a process referred to as consolidation, recall becomes increasingly reliant on other brain areas. The anterior cingulate cortex (ACC), a region within the medial prefrontal cortex, is important for spatial learning, spatial working memory, and remote memory recall, but the mechanisms underlying recall processes are still unknown. To better understand the role of the ACC and HC during memory recall, we introduced rodents into a series of spatially and texturally unique environments at differing delay periods (day 1 (learning), day 11 (recent), and day 18 (remote)) while simultaneously recording local field potentials (LFPs) from both areas. We found significant increases in theta band coherence between ipsilateral ACC and HC LFPs during remote memory recall but not recent memory recall. In addition to these changes, directional analysis revealed a reversal in signal initiation, such that during the learning and recent recall condition, hippocampal theta oscillations led ACC theta oscillations. However, during the remote recall condition, the direction changed, and ACC theta led hippocampal theta activity. This experiment provides evidence of time-dependent changes in ACC – hippocampal network interactions, and illustrates a possible mechanism that describes how the ACC mediates recall of remote spatial memories