Phase precession of grid cells in a network model without external pacemaker

Rodent brains encode space in both the firing rate and the spike timing of neurons in the medial entorhinal cortex. The rate code is realized by grid fields, that is, the neurons fire at multiple places that are arranged on a hexagonal lattice. Such activity is accompanied by theta oscillations of the local field potential. The phase of spikes thereby encodes space as well, since it decreases with the distance traveled in the field—a phenomenon called phase precession. A likely candidate for grid cells are entorhinal cortex stellate cells, which are type II oscillators and have been suggested to act as pacemakers. It is unclear how spiking of such putative pacemaker neurons would be able to precess in phase relative to a self‐generated oscillation. This article presents a computational model of how this paradox can be resolved although the periodicity of the grid fields interferes with the periodic firing of the neurons. Our simulations show that the connections between stellate cells synchronize small cell groups, which allows a population oscillation during grid field activity that is accompanied by theta phase precession. Direct excitatory coupling between the stellate cells, indirect inhibitory coupling via a gamma‐oscillating network of interneurons, or both could mediate this phase coordination. Our model further suggests modulation of h‐currents to be a feasible mechanism to adjust phase precession to running‐speed. The coexistence of rate and timing code for space hence follows as a natural consequence of the self‐organization in a recurrent network. © 2013 Wiley Periodicals, Inc.     

Navigating with grid and place cells in cluttered environments

Hippocampal formation contains several classes of neurons thought to be involved in navigational processes, in particular place cells and grid cells. Place cells have been associated with a topological strategy for navigation, while grid cells have been suggested to support metric vector navigation. Grid cell‐based vector navigation can support novel shortcuts across unexplored territory by providing the direction toward the goal. However, this strategy is insufficient in natural environments cluttered with obstacles. Here, we show how navigation in complex environments can be supported by integrating a grid cell‐based vector navigation mechanism with local obstacle avoidance mediated by border cells and place cells whose interconnections form an experience‐dependent topological graph of the environment. When vector navigation and object avoidance fail (i.e., the agent gets stuck), place cell replay events set closer subgoals for vector navigation. We demonstrate that this combined navigation model can successfully traverse environments cluttered by obstacles and is particularly useful where the environment is underexplored. Finally, we show that the model enables the simulated agent to successfully navigate experimental maze environments from the animal literature on cognitive mapping. The proposed model is sufficiently flexible to support navigation in different environments, and may inform the design of experiments to relate different navigational abilities to place, grid, and border cell firing.     

Lateral entorhinal neurons are not spatially selective in cue‐rich environments

The hippocampus is a brain region that is critical for spatial learning, context‐dependent memory, and episodic memory. It receives major inputs from the medial entorhinal cortex (MEC) and the lateral EC (LEC). MEC neurons show much greater spatial firing than LEC neurons in a recording chamber with a single, salient landmark. The MEC cells are thought to derive their spatial tuning through path integration, which permits spatially selective firing in such a cue‐deprived environment. In accordance with theories that postulate two spatial mapping systems that provide input to the hippocampus—an internal, path‐integration system and an external, landmark‐based system—it was possible that LEC neurons can also convey a spatial signal, but that the signal requires multiple landmarks to define locations, rather than movement integration. To test this hypothesis, neurons from the MEC and LEC were recorded as rats foraged for food in cue‐rich environments. In both environments, LEC neurons showed little spatial specificity, whereas many MEC neurons showed a robust spatial signal. These data strongly support the notion that the MEC and LEC convey fundamentally different types of information to the hippocampus, in terms of their spatial firing characteristics, under various environmental and behavioral conditions. © 2010 Wiley Periodicals, Inc.     

Grid cell spatial tuning reduced following systemic muscarinic receptor blockade

Grid cells of the medial entorhinal cortex exhibit a periodic and stable pattern of spatial tuning that may reflect the output of a path integration system. This grid pattern has been hypothesized to serve as a spatial coordinate system for navigation and memory function. The mechanisms underlying the generation of this characteristic tuning pattern remain poorly understood. Systemic administration of the muscarinic antagonist scopolamine flattens the typically positive correlation between running speed and entorhinal theta frequency in rats. The loss of this neural correlate of velocity, an important signal for the calculation of path integration, raises the question of what influence scopolamine has on the grid cell tuning as a read out of the path integration system. To test this, the spatial tuning properties of grid cells were compared before and after systemic administration of scopolamine as rats completed laps on a circle track for food rewards. The results show that the spatial tuning of the grid cells was reduced following scopolamine administration. The tuning of head direction cells, in contrast, was not reduced by scopolamine. This is the first report to demonstrate a link between cholinergic function and grid cell tuning. This work suggests that the loss of tuning in the grid cell network may underlie the navigational disorientation observed in Alzheimer's patients and elderly individuals with reduced cholinergic tone. © 2014 Wiley Periodicals, Inc.     

Alternating predictive and short‐term memory modes of entorhinal grid cells

Several lines of evidence indicate that the entorhinal cortex has memory functions, but such functions have not been previously found in grid cells, a cell type that provides major input to the hippocampus. We examined the firing of grid cells as rats crossed (runs) through grid cell vertices. We found that on some runs, firing tended to occur mostly inbound as the rat approached a vertex center while on other runs firing occurred mainly outbound. These results suggest that cells have a predictive mode (inbound firing) in which they represent a position ahead of the animal and a short term memory (STM) mode (outbound firing) in which they represent positions just passed through. Analysis of cell pairs showed that when vertex crossings were less than 1 second apart, the two cells tended to have the same mode. This indicates that modes are a network property. The tendency to have the same mode disappeared if crossings were separated by 2‐3 seconds, suggesting that modes alternate on the time scale of seconds. There was a small but statistically significant behavioral correlate of modes: velocity was slightly less in the STM mode. Both modes were organized by theta and gamma oscillations. The results suggest that the dual requirement for hippocampal storage and recall is met by rapidly alternating modes appropriate for predicting the future and storing the recent past. © 2012 Wiley Periodicals, Inc.     

The transformation from grid cells to place cells is robust to noise in the grid pattern

Spatial navigation in rodents has been attributed to place‐selective cells in the hippocampus and entorhinal cortex. However, there is currently no consensus on the neural mechanisms that generate the place‐selective activity in hippocampal place cells or entorhinal grid cells. Given the massive input connections from the superficial layers of the entorhinal cortex to place cells in the hippocampal cornu ammonis (CA) regions, it was initially postulated that grid cells drive the spatial responses of place cells. However, recent experiments have found that place cell responses are stable even when grid cell responses are severely distorted, thus suggesting that place cells cannot receive their spatial information chiefly from grid cells. Here, we offer an alternative explanation. In a model with linear grid‐to‐place‐cell transformation, the transformation can be very robust against noise in the grid patterns depending on the nature of the noise. In the two more realistic noise scenarios, the transformation was very robust, while it was not in the other two scenarios. Although current experimental data suggest that other types of place‐selective cells modulate place cell responses, our results show that the simple grid‐to‐place‐cell transformation alone can account for the origin of place selectivity in the place cells. © 2014 Wiley Periodicals, Inc.     

Voltage dependence of subthreshold resonance frequency in layer ii of medial entorhinal cortex

The resonance properties of individual neurons in entorhinal cortex (EC) may contribute to their functional properties in awake, behaving rats. Models propose that entorhinal grid cells could arise from shifts in the intrinsic frequency of neurons caused by changes in membrane potential owing to depolarizing input from neurons coding velocity. To test for potential changes in intrinsic frequency, we measured the resonance properties of neurons at different membrane potentials in neurons in medial and lateral EC. In medial entorhinal neurons, the resonant frequency of individual neurons decreased in a linear manner as the membrane potential was depolarized between ?70 and ?55 mV. At more hyperpolarized membrane potentials, cells asymptotically approached a maximum resonance frequency. Consistent with the previous studies, near resting potential, the cells of the medial EC possessed a decreasing gradient of resonance frequency along the dorsal to ventral axis, and cells of the lateral EC lacked resonant properties, regardless of membrane potential or position along the medial to lateral axis within lateral EC. Application of 10 μM ZD7288, the H‐channel blocker, abolished all resonant properties in MEC cells, and resulted in physiological properties very similar to lateral EC cells. These results on resonant properties show a clear change in frequency response with depolarization that could contribute to the generation of grid cell firing properties in the medial EC. © 2012 Wiley Periodicals, Inc.     

The single place fields of CA3 cells: a two-stage transformation from grid cells

Granule cells of the dentate gyrus (DG) generally have multiple place fields, whereas CA3 cells, which are second order, have only a single place field. Here, we explore the mechanisms by which the high selectivity of CA3 cells is achieved. Previous work showed that the multiple place fields of DG neurons could be quantitatively accounted for by a model based on the number and strength of grid cell inputs and a competitive network interaction in the DG that is mediated by gamma frequency feedback inhibition. We have now built a model of CA3 based on similar principles. CA3 cells receive input from an average of one active DG cell and from 1,400 cortical grid cells. Based on experimental findings, we have assumed a linear interaction of the two pathways. The results show that simulated CA3 cells generally have a single place field, as observed experimentally. Thus, a two-step process based on simple rules (and that can occur without learning) is able to explain how grid cell inputs to the hippocampus give rise to cells having ultimate spatial selectivity. The CA3 processes that produce a single place depend critically on the competitive network processes and do not require the direct cortical inputs to CA3, which are therefore likely to perform some other unknown function.     

Hyperpolarization‐activated cyclic nucleotide‐gated 1 independent grid cell‐phase precession in mice

Cell assemblies code information in both the temporal and spatial domain. One tractable example of temporal coding is the phenomenon of phase precession. In medial entorhinal cortex, theta‐phase precession is observed in spatially specific grid cells, with grid spike‐times shifting to earlier phases of the extracellular theta rhythm as the animal passes through the grid field. Although the exact mechanisms underlying spatial–temporal coding remain unknown, computational work points to single‐cell oscillatory activity as a biophysical mechanism capable of producing phase precession. Support for this idea comes from observed correlations between single‐cell resonance and entorhinal neurons characterized by phase precession. Here, we take advantage of the absence of single‐cell theta‐frequency resonance in hyperpolarization‐activated cyclic nucleotide‐gated (HCN) 1 knockout (KO) mice to examine the relationship between intrinsic rhythmicity and phase precession. We find phase precession is highly comparable between forebrain‐restricted HCN1 KO and wild‐type mice. Grid fields in HCN1 KO mice display more experience‐dependent asymmetry however, consistent with reports of enhanced long‐term potentiation in the absence of HCN1 and raising the possibility that the loss of HCN1 improves temporal coding via the rate‐phase transformation. Combined, our results clarify the role of HCN1 channels in temporal coding and constrain the number of possible mechanisms generating phase precession. © 2013 Wiley Periodicals, Inc.     

From grid cells to place cells: a mathematical model

Anatomical connectivity and recent neurophysiological results imply that grid cells in the medial entorhinal cortex are the principal cortical inputs to place cells in the hippocampus. The authors propose a model in which place fields of hippocampal pyramidal cells are formed by linear summation of appropriately weighted inputs from entorhinal grid cells. Single confined place fields could be formed by summing input from a modest number (10-50) of grid cells with relatively similar grid phases, diverse grid orientations, and a biologically plausible range of grid spacings. When the spatial phase variation in the grid-cell input was higher, multiple, and irregularly spaced firing fields were formed. These observations point to a number of possible constraints in the organization of functional connections between grid cells and place cells.     

Independent coding of connected environments by place cells

Place cells are hippocampal neurons that have a strong location-specific firing activity in the rat's current environment. Collectively, place cells also provide a signature of the rat's environment as their ensemble activity is markedly different when recorded in distinct apparatuses. This phenomenon, referred to as 'remapping', suggests that each environment activates a different hippocampal map. In this study, we sought to determine the independence of such maps. In Experiment 1, we used a cylinder apparatus that was divided into two equal halves by a central barrier with an aperture allowing the rat to freely commute between the two sides. A local change in one side failed to induce field remapping in the changed side, thus precluding any significant conclusion to be drawn. We therefore designed Experiment 2 in which place cells were first recorded while rats explored three distinct high-walled boxes. Most cells had distinctive firing fields in each box. A runway was then added to connect two initially unrelated boxes. This manipulation altered the firing of some cells but the fields in each box were still clearly distinguishable. The final manipulation consisted of changing one box and allowing the rat to commute freely between the changed and unchanged boxes. While the firing fields remapped in the changed box, they were most usually unaltered in the unchanged box. These results suggest that the hippocampus holds a set of independent maps for each box, and that each specific map is activated mainly according to the rat's current sensory environment.     

Spatial and stimulus‐type tuning in the LEC,MEC, POR,PrC, CA1, and CA3 during spontaneous item recognition memory

According to the “two streams” hypothesis, the lateral entorhinal (LEC) and the perirhinal (PrC) cortices process information related to items (a “what” stream), the postrhinal (POR) and the medial entorhinal cortices (MEC) process spatial information (a “where” stream), and both types of information are integrated in the hippocampus (HIP). However, within the framework of memory function, only the HIP is reliably shown to preferentially process spatial information, and the PrC items' features. In contrast, the role of the LEC and MEC in memory is virtually unexplored, and conflicting results emerge for the POR. Moreover, the specific contribution of the hippocampal subfields CA1 and CA3 to spatial and non‐spatial memory is not thoroughly understood. To investigate which of these areas is specifically tuned to spatial demands or stimulus identity (odor or object), we assessed the pattern of activation of these areas during recognition memory by detecting the immediate‐early gene Arc, commonly used as a marker of neuronal activation. We report that all MTL areas were recruited during the spatial and the non‐spatial tasks. However, the LEC, MEC, POR, and CA1 were activated to a comparable level in spatial and non‐spatial tasks, while the PrC was tuned to stimulus‐type, not spatial demands, and CA3 to spatial demands but not stimulus‐type. Results are discussed within the frame of a recent model suggesting that the MTL could be segregated in terms of memory processes, such as recollection and familiarity, rather than information content. © 2013 Wiley Periodicals, Inc.     

Membrane potential‐dependent integration of synaptic inputs in entorhinal stellate neurons

Stellate cells (SCs) of the medial entorhinal cortex exhibit robust spontaneous membrane‐potential oscillations (MPOs) in the theta (4–12 Hz) frequency band as well as theta‐frequency resonance in their membrane impedance spectra. Past experimental and modeling work suggests that these features may contribute to the phase‐locking of SCs to the entorhinal theta rhythm and may be important for forming the hexagonally tiled grid cell place fields exhibited by these neurons in vivo. Among the major biophysical mechanisms contributing to MPOs is a population of persistent (non‐inactivating or slowly inactivating) sodium channels. The resulting persistent sodium conductance (G_NaP) gives rise to an apparent increase in input resistance as the cell approaches threshold. In this study, we used dynamic clamp to test the hypothesis that this increased input resistance gives rise to voltage‐dependent, and thus MPO phase‐dependent, changes in the amplitude of excitatory and inhibitory post‐synaptic potential (PSP) amplitudes. We find that PSP amplitude depends on membrane potential, exhibiting a 5–10% increase in amplitude per mV depolarization. The effect is larger than—and sums quasi‐linearly with—the effect of the synaptic driving force, V ‐ E_syn. Given that input‐driven MPOs 10 mV in amplitude are commonly observed in MEC stellate cells in vivo, this voltage‐ and phase‐dependent synaptic gain is large enough to modulate PSP amplitude by over 50% during theta‐frequency MPOs. Phase‐dependent synaptic gain may therefore impact the phase locking and phase precession of grid cells in vivo to ongoing network oscillations. © 2014 Wiley Periodicals, Inc.     

Overview of computational models of hippocampus and related structures: Introduction to the special issue

Extensive computational modeling has focused on the hippocampal formation and associated cortical structures. This overview describes some of the factors that have motivated the strong focus on these structures, including major experimental findings and their impact on computational models. This overview provides a framework for describing the topics addressed by individual articles in this special issue of the journal Hippocampus.     

Phase precession and variable spatial scaling in a periodic attractor map model of medial entorhinal grid cells with realistic after-spike dynamics

We present a model that describes the generation of the spatial (grid fields) and temporal (phase precession) properties of medial entorhinal cortical (MEC) neurons by combining network and intrinsic cellular properties. The model incorporates network architecture derived from earlier attractor map models, and is implemented in 1D for simplicity. Periodic driving of conjunctive (position × head-direction) layer-III MEC cells at theta frequency with intensity proportional to the rat's speed, moves an 'activity bump' forward in network space at a corresponding speed. The addition of prolonged excitatory currents and simple after-spike dynamics resembling those observed in MEC stellate cells (for which new data are presented) accounts for both phase precession and the change in scale of grid fields along the dorso-ventral axis of MEC. Phase precession in the model depends on both synaptic connectivity and intrinsic currents, each of which drive neural spiking either during entry into, or during exit out of a grid field. Thus, the model predicts that the slope of phase precession changes between entry into and exit out of the field. The model also exhibits independent variation in grid spatial period and grid field size, which suggests possible experimental tests of the model.     

Involvement of the lateral entorhinal cortex for the formation of cross‐modal olfactory‐tactile associations in the rat

While the olfactory and tactile vibrissal systems have been extensively studied in the rat, the neural basis of these cross‐modal associations is still elusive. Here we tested the hypothesis that the lateral entorhinal cortex (LEC) could be particularly involved. In order to tackle this question, we have developed a new behavioral paradigm which consists in finding one baited cup (+) among three, each of the cups presenting a different and specific odor/texture (OT) combination. During the acquisition of a first task (Task OT1), the three cups were associated with the following OT combination: O1T1 for the baited cup; O2T1 and O1T2 for non‐baited ones. Most rats learn this task within three training sessions (20 trials/session). In a second task (Task OT2) animals had to pair another OT combination with the reward using a new set of stimuli (O3T3+, O4T3, and O3T4). Results showed that rats manage to learn Task OT2 within one session only. In a third task (Task OT3) animals had to learn another OT combination based on previously learned items (e.g. O4T4+, O1T4 and O4T1). This task is called the “recombination task.” Results showed that control rats solve the recombination task within one session. Animals bilaterally implanted with cannulae in the LEC were microinfused with d‐APV (3 µg/0.6 µL) just before the acquisition or the test session of each task. The results showed that NMDA receptor blockade in LEC did not affect recall of Task OT1 but strongly impaired acquisition of both Task OT2 and OT3. Moreover, two control groups of animals infused with d‐APV showed no deficit in the acquisition of unimodal olfactory and tactile tasks. Taken together, these data show that the NMDA system in the LEC is involved in the acquisition of association between an olfactory and a tactile stimulus during cross‐modal learning task. © 2014 Wiley Periodicals, Inc.     

On the (a)symmetry between the perception of time and space in large‐scale environments

Cross‐dimensional interference between spatial and temporal processing is well documented in humans, but the direction of these interactions remains unclear. The theory of metaphoric structuring states that space is the dominant concept influencing time perception, whereas time has little effect upon the perception of space. In contrast, theories proposing a common neuronal mechanism representing magnitudes argue for a symmetric interaction between space and time perception. Here, we investigated space‐time interactions in realistic, large‐scale virtual environments. Our results demonstrate a symmetric relationship between the perception of temporal intervals in the supra‐second range and room size (experiment 1), but an asymmetric relationship between the perception of travel time and traveled distance (experiment 2). While the perception of time was influenced by the size of virtual rooms and by the distance traveled within these rooms, time itself affected only the perception of room size, but had no influence on the perception of traveled distance. These results are discussed in the context of recent evidence from rodent studies suggesting that subsets of hippocampal place and entorhinal grid cells can simultaneously code for space and time, providing a potential neuronal basis for the interactions between these domains.     

The role of sleep in forming a memory representation of a two‐dimensional space

There is ample evidence from human and animal models that sleep contributes to the consolidation of newly learned information. The precise role of sleep for integrating information into interconnected memory representations is less well understood. Building on prior findings that following sleep (as compared to wakefulness) people are better able to draw inferences across learned associations in a simple hierarchy, we ask how sleep helps consolidate relationships in a more complex representational space. We taught 60 subjects spatial relationships between pairs of buildings, which (unknown to participants) formed a two‐dimensional grid. Critically, participants were only taught a subset of the many possible spatial relations, which allowed them to potentially infer the remainder. After a 12 h period that either did or did not include a normal period of sleep, participants returned to the lab. We examined the quality of each participant's map of the two‐dimensional space, and their knowledge of relative distances between buildings. After 12 h with sleep, subjects could more accurately map the full space than subjects who experienced only wakefulness. The incorporation of untaught, but inferable, associations was particularly improved. We further found that participants' distance judgment performance related to self‐reported navigational style, but only after sleep. These findings demonstrate that consolidation over a night of sleep begins to integrate relations into an interconnected complex representation, in a way that supports spatial relational inference. © 2013 Wiley Periodicals, Inc.     

Classification of theta-related cells in the entorhinal cortex: Cell discharges are controlled by the ascending brainstem synchronizing pathway in parallel with hippocampal theta-related cells

Single-unit discharge patterns of entorhinal cortex (EC) cells were characterized in relation to simultaneously recorded hippocampal (HPC) field activity according to criteria used previously to classify cells in the hippocampal formation, medial septum, cingulate cortex, and caudal diencephalon. EC cells related to HPC theta field activity were classified as (1) phasic theta-on, if they discharged rhythmically, and in phase, with ongoing HPC theta, but nonrhythmically during large, irregular hippocampal field activity (LIA); (2) tonic theta-on, if they discharged nonrhythmically and increased their discharge rates during HPC theta relative to LIA; (3) phasic theta-off, if they discharged rhythmically, and in phase, with ongoing HPC theta, but increased their discharge rates during LIA; and (4) tonic theta-off, if they discharged nonrhythmically and decreased their discharge rates during HPC theta relative to LIA. Cells not meeting any of these criteria were classified as nonrelated. A total of 168 EC cells were recorded, and of these 56 (33%) were classified as theta related, with the remaining 112 (67%) classified as nonrelated. Of the 56 theta-related cells, 41 (73%) had significantly higher discharge rates during HPC theta than during LIA and were classified as theta-on cells (15 phasic theta-on cells and 26 tonic theta-on cells). Nine of the 26 tonic theta-on cells showed a phase relation of their arrhythmic discharges to simultaneously recorded HPC theta field activity. EC phasic theta-on cells did not discharge preferentially on any portion of the HPC theta field recorded from the region of the stratum moleculare of the dentate gyrus. In general, cells classified as phasic revealed a wide distribution of phase preferences. The remaining 15 (26.7%) cells were classified as theta-off cells and discharged at higher rates during HPC LIA than during HPC theta field activity (3 phasic theta-off cells and 12 tonic theta-off cells). Systemic administration of physostigmine significantly increased the discharge rate of tonic and phasic theta-on cells relative to LIA. Electrical stimulation in the posterior hypothalamic region (PH) significantly increased the discharge rate of EC theta-on cells and significantly decreased the discharge rate of EC theta-off cells relative to HPC LIA. The discharge rates of nonrelated EC cells were not influenced by electrical stimulation of the PH. Procaine microinfusion into the medial septum (MS) abolished spontaneously occurring HPC theta and theta induced with PH stimulation. In addition, 5 min after MS procaine, the ability of PH stimulation to modulate EC theta-on cell discharge was abolished. The modulation of cellular discharges produced by PH stimulation recovered by 60 min post-procaine infusion into the MS. The findings support two main conclusions: (1) theta-related cells in the EC are comprised of two main populations of cells, theta-on and theta-off, similar to other regions of limbic cortex and nuclei of the ascending brainstem synchronizing pathway; (2) the ascending brainstem synchronizing pathway exerts both similar and parallel effects on theta-related cells in entorhinal cortex and hippocampus. © 1995 Wiley-Liss, Inc.     

Hippocampal‐prefrontal theta phase synchrony in planning of multi‐step actions based on memory retrieval

Planning of multi‐step actions based on the retrieval of acquired information is essential for efficient foraging. The hippocampus (HPC) and prefrontal cortex (PFC) may play critical roles in this process. However, in rodents, many studies investigating such roles utilized T‐maze tasks that only require one‐step actions (i.e., selection of one of two alternatives), in which memory retrieval and selection of an action based on the retrieval cannot be clearly differentiated. In monkeys, PFC has been suggested to be involved in planning of multi‐step actions; however, the synchrony between HPC and PFC has not been evaluated. To address the combined role of the regions in planning of multi‐step actions, we introduced a task in rats that required three successive nose‐poke responses to three sequentially illuminated nose‐poke holes. During the task, local field potentials (LFP) and spikes from hippocampal CA1 and medial PFC (mPFC) were simultaneously recorded. The position of the first hole indicated whether the following two holes would be presented in a predictable sequence or not. During the first nose‐poke period, phase synchrony of LFPs in the theta range (4–10 Hz) between the regions was not different between predictable and unpredictable trials. However, only in trials of predictable sequences, the magnitude of theta phase synchrony during the first nose‐poke period was negatively correlated with latency of the two‐step ahead nose‐poke response. Our findings point to the HPC‐mPFC theta phase synchrony as a key mechanism underlying planning of multi‐step actions based on memory retrieval rather than the retrieval itself.