Neurons In Medial Entorhinal Cortex Research Articles

Medial entorhinal cortex mediates learning of context-dependent interval timing behavior.

Episodic memory requires encoding the temporal structure of experience and relies on brain circuits in the medial temporal lobe, including the medial entorhinal cortex (MEC). Recent studies have identified MEC 'time cells', which fire at specific moments during interval timing tasks, collectively tiling the entire timing period. It has been hypothesized that MEC time cells could provide temporal information necessary for episodic memories, yet it remains unknown whether they display learning dynamics required for encoding different temporal contexts. To explore this, we developed a new behavioral paradigm requiring mice to distinguish temporal contexts. Combined with methods for cellular resolution calcium imaging, we found that MEC time cells display context-dependent neural activity that emerges with task learning. Through chemogenetic inactivation we found that MEC activity is necessary for learning of context-dependent interval timing behavior. Finally, we found evidence of a common circuit mechanism that could drive sequential activity of both time cells and spatially selective neurons in MEC. Our work suggests that the clock-like firing of MEC time cells can be modulated by learning, allowing the tracking of various temporal structures that emerge through experience.

Treadmill exercise prevents the hyperexcitability of pyramidal neurons in medial entorhinal cortex in the 3xTg-AD mouse model of Alzheimer's disease

Neuronal hyperactivity is a key abnormality in early stage Alzheimer's disease (AD). Medial entorhinal cortex (mEC) plays a vital role in memory function and is affected early in AD. Growing evidence indicates benefits of regular exercise on memory and cognitive function in humans with AD, although, the underlying mechanisms are not clear. Therefore, this study was designed to test the effects of 16 weeks treadmill exercise on spatial learning memory and the underlying cellular mechanisms in 6-month-old 3xTg-AD mice. Whole-cell patch clamp was used to examine neuronal intrinsic excitability, spontaneous excitatory postsynaptic currents (sEPSCs) and spontaneous inhibitory postsynaptic currents (sIPSCs) of mEC layer II/III pyramidal neurons in the following groups: wild type (WT + sham), 3xTg-AD (AD+sham), WT receiving exercise (WT + Ex), and AD receiving exercise (AD+Ex). We found that at a behavioral level, treadmill exercise decreased working memory errors in radial arm maze (RAM) test in 6-month-old AD mice. At a cellular level, we found that treadmill exercise prevented the abnormal increase in mEC pyramidal neuron input resistance and action potential firing in 6-month-old 3xTg-AD mice compared with WT + sham and AD+Ex mice; further, sEPSC amplitude and frequency were normal in AD+Ex but overactive in AD+sham; additionally, GABAergic inhibition was normal in AD+Ex mice but reduced in AD+sham. In conclusion, our results indicate that treadmill exercise improves spatial learning memory and prevents network hyperexcitability in mEC by reducing pyramidal neuronal intrinsic excitability and normalizing excitatory and inhibitory synaptic transmission in 3xTg-AD mice.

Spatial memory deficits in Alzheimer's disease and their connection to cognitive maps' formation by place cells and grid cells.

Whenever we navigate through different contexts, we build a cognitive map: an internal representation of the territory. Spatial navigation is a complex skill that involves multiple types of information processing and integration. Place cells and grid cells, collectively with other hippocampal and medial entorhinal cortex neurons (MEC), form a neural network whose activity is critical for the representation of self-position and orientation along with spatial memory retrieval. Furthermore, this activity generates new representations adapting to changes in the environment. Though there is a normal decline in spatial memory related to aging, this is dramatically increased in pathological conditions such as Alzheimer's disease (AD). AD is a multi-factorial neurodegenerative disorder affecting mainly the hippocampus-entorhinal cortex (HP-EC) circuit. Consequently, the initial stages of the disease have disorientation and wandering behavior as two of its hallmarks. Recent electrophysiological studies have linked spatial memory deficits to difficulties in spatial information encoding. Here we will discuss map impairment and remapping disruption in the HP-EC network, as a possible circuit mechanism involved in the spatial memory and navigation deficits observed in AD, pointing out the benefits of virtual reality as a tool for early diagnosis and rehabilitation.

Impaired Spatial Firing Representations of Neurons in the Medial Entorhinal Cortex of the Epileptic Rat Using Microelectrode Arrays.

Epilepsy severely impairs the cognitive behavior of patients. It remains unclear whether epilepsy-induced cognitive impairment is associated with neuronal activities in the medial entorhinal cortex (MEC), a region known for its involvement in spatial cognition. To explore this neural mechanism, we recorded the spikes and local field potentials from MEC neurons in lithium-pilocarpine-induced epileptic rats using self-designed microelectrode arrays. Through the open field test, we identified spatial cells exhibiting spatially selective firing properties and assessed their spatial representations in relation to the progression of epilepsy. Meanwhile, we analyzed theta oscillations and theta modulation in both excitatory and inhibitory neurons. Furthermore, we used a novel object recognition test to evaluate changes in spatial cognitive ability of epileptic rats. After the epilepsy modeling, the spatial tuning of various types of spatial cells had suffered a rapid and pronounced damage during the latent period (1 to 5 d). Subsequently, the firing characteristics and theta oscillations were impaired. In the chronic period (>10 d), the performance in the novel object experiment deteriorated. In conclusion, our study demonstrates the detrimental effect on spatial representations and electrophysiological properties of MEC neurons in the epileptic latency, suggesting the potential use of these changes as a "functional biomarker" for predicting cognitive impairment caused by epilepsy.

Distance-tuned neurons drive specialized path integration calculations in medial entorhinal cortex.

SUMMARYDuring navigation, animals estimate their position using path integration and landmarks, engaging many brain areas. Whether these areas follow specialized or universal cue integration principles remains incompletely understood. We combine electrophysiology with virtual reality to quantify cue integration across thousands of neurons in three navigation-relevant areas: primary visual cortex (V1), retrosplenial cortex (RSC), and medial entorhinal cortex (MEC). Compared with V1 and RSC, path integration influences position estimates more in MEC, and conflicts between path integration and landmarks trigger remapping more readily. Whereas MEC codes position prospectively, V1 codes position retrospectively, and RSC is intermediate between the two. Lowered visual contrast increases the influence of path integration on position estimates only in MEC. These properties are most pronounced in a population of MEC neurons, overlapping with grid cells, tuned to distance run in darkness. These results demonstrate the specialized role that path integration plays in MEC compared with other navigation-relevant cortical areas.

Optogenetic pacing of medial septum parvalbumin-positive cells disrupts temporal but not spatial firing in grid cells.

Grid cells in the medial entorhinal cortex (MEC) exhibit remarkable spatial activity patterns with spikes coordinated by theta oscillations driven by the medial septal area (MSA). Spikes from grid cells progress relative to the theta phase in a phenomenon called phase precession, which is suggested as essential to create the spatial periodicity of grid cells. Here, we show that optogenetic activation of parvalbumin-positive (PV+) cells in the MSA enabled selective pacing of local field potential (LFP) oscillations in MEC. During optogenetic stimulation, the grid cells were locked to the imposed pacing frequency but kept their spatial patterns. Phase precession was abolished, and speed information was no longer reflected in the LFP oscillations but was still carried by rate coding of individual MEC neurons. Together, these results support that theta oscillations are not critical to the spatial pattern of grid cells and do not carry a crucial velocity signal.

Two septal-entorhinal GABAergic projections differentially control coding properties of spatially tuned neurons in the medial entorhinal cortex

Septal parvalbumin-expressing (PV+) and calbindin-expressing (CB+) projections inhibit low-threshold and fast-spiking interneurons, respectively, in the medial entorhinal cortex (MEC). We investigate how the two inputs control neuronal activity in the MEC in freely moving mice. Stimulation of PV+ and CB+ terminals causes disinhibition of spatially tuned MEC neurons, but exerts differential effects on temporal coding and burst firing. Thus, recruitment of PV+ projections disrupts theta-rhythmic firing of MEC neurons, while stimulation of CB+ projections increases burst firing of grid cells and enhances phase precession in a cell-type-specific manner. Inactivation of septal PV+ or CB+ neurons differentially affects context, reference, and working memory. Together, our results reveal how specific connectivity of septal GABAergic projections with MEC interneurons translates into differential modulation of MEC neuronal coding.

Impaired speed encoding and grid cell periodicity in a mouse model of tauopathy.

Dementia is associated with severe spatial memory deficits which arise from dysfunction in hippocampal and parahippocampal circuits. For spatially sensitive neurons, such as grid cells, to faithfully represent the environment these circuits require precise encoding of direction and velocity information. Here, we have probed the firing rate coding properties of neurons in medial entorhinal cortex (MEC) in a mouse model of tauopathy. We find that grid cell firing patterns are largely absent in rTg4510 mice, while head-direction tuning remains largely intact. Conversely, neural representation of running speed information was significantly disturbed, with smaller proportions of MEC cells having firing rates correlated with locomotion in rTg4510 mice. Additionally, the power of local field potential oscillations in the theta and gamma frequency bands, which in wild-type mice are tightly linked to running speed, was invariant in rTg4510 mice during locomotion. These deficits in locomotor speed encoding likely severely impact path integration systems in dementia.

A Generalized Linear Model of a Navigation Network.

Navigation by mammals is believed to rely on a network of neurons in the hippocampal formation, which includes the hippocampus, the medial entorhinal cortex (MEC), and additional nearby regions. Neurons in these regions represent spatial information by tuning to the position, orientation, and speed of the animal in the form of head direction cells, speed cells, grid cells, border cells, and unclassified spatially modulated cells. While the properties of single cells are well studied, little is known about the functional structure of the network in the MEC. Here, we use a generalized linear model to study the network of spatially modulated cells in the MEC. We found connectivity patterns between all spatially encoding cells and not only grid cells. In addition, the neurons’ past activity contributed to the overall activity patterns. Finally, position-modulated cells and head direction cells differed in the dependence of the activity on the history. Our results indicate that MEC neurons form a local interacting network to support spatial information representations and suggest an explanation for their complex temporal properties.

A Brainstem Locomotor Circuit Drives the Activity of Speed Cells in the Medial Entorhinal Cortex

SummaryLocomotion activates an array of sensory inputs that may help build the self-position map of the medial entorhinal cortex (MEC). In this map, speed-coding neurons are thought to dynamically update representations of the animal’s position. A possible origin for the entorhinal speed signal is the mesencephalic locomotor region (MLR), which is critically involved in the activation of locomotor programs. Here, we describe, in rats, a circuit connecting the pedunculopontine tegmental nucleus (PPN) of the MLR to the MEC via the horizontal limb of the diagonal band of Broca (HDB). At each level of this pathway, locomotion speed is linearly encoded in neuronal firing rates. Optogenetic activation of PPN cells drives locomotion and modulates activity of speed-modulated neurons in HDB and MEC. Our results provide evidence for a pathway by which brainstem speed signals can reach cortical structures implicated in navigation and higher-order dynamic representations of space.

Spike Afterpotentials Shape the In Vivo Burst Activity of Principal Cells in Medial Entorhinal Cortex.

Principal neurons in rodent medial entorhinal cortex (MEC) generate high-frequency bursts during natural behavior. While in vitro studies point to potential mechanisms that could support such burst sequences, it remains unclear whether these mechanisms are effective under in vivo conditions. In this study, we focused on the membrane-potential dynamics immediately following action potentials (APs), as measured in whole-cell recordings from male mice running in virtual corridors (Domnisoru et al., 2013). These afterpotentials consisted either of a hyperpolarization, an extended ramp-like shoulder, or a depolarization reminiscent of depolarizing afterpotentials (DAPs) recorded in vitro in MEC principal neurons. Next, we correlated the afterpotentials with the cells' propensity to fire bursts. All DAP cells with known location resided in Layer II, generated bursts, and their interspike intervals (ISIs) were typically between 5 and 15 ms. The ISI distributions of Layer-II cells without DAPs peaked sharply at around 4 ms and varied only minimally across that group. This dichotomy in burst behavior is explained by cell-group-specific DAP dynamics. The same two groups of bursting neurons also emerged when we clustered extracellular spike-train autocorrelations measured in real 2D arenas (Latuske et al., 2015). Apart from slight variations in grid spacing, no difference in the spatial coding properties of the grid cells across all three groups was discernible. Layer III neurons were only sparsely bursting (SB) and had no DAPs. As various mechanisms for modulating ion-channels underlying DAPs exist, our results suggest that temporal features of MEC activity can be altered while maintaining the cells' overall spatial tuning characteristics.SIGNIFICANCE STATEMENT Depolarizing afterpotentials (DAPs) are frequently observed in principal neurons from slice preparations of rodent medial entorhinal cortex (MEC), but their functional role in vivo is unknown. Analyzing whole-cell data from mice running on virtual tracks, we show that DAPs do occur during behavior. Cells with prominent DAPs are found in Layer II; their interspike intervals (ISIs) reflect DAP time-scales. In contrast, neither the rarely bursting cells in Layer III, nor the high-frequency bursters in Layer II, have a DAP. Extracellular recordings from mice exploring real 2D arenas demonstrate that grid cells within these three groups have similar spatial coding properties. We conclude that DAPs shape the temporal response characteristics of principal neurons in MEC with little effect on spatial properties.

Postnatal Development of Functional Projections from Parasubiculum and Presubiculum to Medial Entorhinal Cortex in the Rat.

Neurons in parasubiculum (PaS), presubiculum (PrS), and medial entorhinal cortex (MEC) code for place (grid cells) and head direction. Directional input has been shown to be important for stable grid cell properties in MEC, and PaS and PrS have been postulated to provide this information to MEC. In line with this, head direction cells in those brain areas are present at postnatal day 11 (P11), having directional tuning that stabilizes shortly after eye opening, which is before premature grid cells emerge in MEC at P16. Whether functional connectivity between these structures exists at those early postnatal stages is unclear. Using anatomical tracing, voltage-sensitive dye imaging and single-cell patch recordings in female and male rat brain slices between P2 and P61, we determined when the pathways from PaS and PrS to MEC emerge, become functional, and how they develop. Anatomical connections from PaS and PrS to superficial MEC emerge between P4 and P6. Monosynaptic connectivity from PaS and PrS to superficial MEC was measurable from P9 to P10 onward, whereas connectivity with deep MEC was measurable from P11 to P12. From P14/P15 on, reactivity of MEC neurons to parasubicular and presubicular inputs becomes adult-like and continues to develop until P28-P30. The maturation of the efficacy of both inputs between P9 and P21 is paralleled by maturation of morphological properties, changes in intrinsic properties of MEC principal neurons, and changes in the GABAergic network of MEC. In conclusion, synaptic projections from PaS and PrS to MEC become functional and adult-like before the emergence of grid cells in MEC.SIGNIFICANCE STATEMENT Head direction information, crucial for grid cells in medial entorhinal cortex (MEC), is thought to enter MEC via parasubiculum (PaS) and presubiculum (PrS). Unraveling the development of functional connections between PaS, PrS, and MEC is key to understanding how spatial navigation, an important cognitive function, may evolve. To gain insight into the development, we used anatomical tracing techniques, voltage-sensitive dye imaging, and single-cell recordings. The combined data led us to conclude that synaptic projections from PaS and PrS to MEC become functional and adult-like before eye opening, allowing crucial head direction information to influence place encoding before the emergence of grid cells in rat MEC.

Episodic memory: Neuronal codes for what, where, and when.

Episodic memory is defined as the ability to recall events in a spatiotemporal context. Formation of such memories is critically dependent on the hippocampal formation and its inputs from the entorhinal cortex. To be able to support the formation of episodic memories, entorhinal cortex and hippocampal formation should contain a neuronal code that follows several requirements. First, the code should include information about position of the agent ("where"), sequence of events ("when"), and the content of the experience itself ("what"). Second, the code should arise instantly thereby being able to support memory formation of one-shot experiences. For successful encoding and to avoid interference between memories during recall, variations in location, time, or in content of experience should result in unique ensemble activity. Finally, the code should capture several different resolutions of experience so that the necessary details relevant for future memory-based predictions will be stored. We review how neuronal codes in entorhinal cortex and hippocampus follow these requirements and argue that during formation of episodic memories entorhinal cortex provides hippocampus with instant information about ongoing experience. Such information originates from (a) spatially modulated neurons in medial entorhinal cortex, including grid cells, which provide a stable and universal positional metric of the environment; (b) a continuously varying signal in lateral entorhinal cortex providing a code for the temporal progression of events; and (c) entorhinal neurons coding the content of experiences exemplified by object-coding and odor-selective neurons. During formation of episodic memories, information from these systems are thought to be encoded as unique sequential ensemble activity in hippocampus, thereby encoding associations between the content of an event and its spatial and temporal contexts. Upon exposure to parts of the encoded stimuli, activity in these ensembles can be reinstated, leading to reactivation of the encoded activity pattern and memory recollection.

Object-vector coding in the medial entorhinal cortex.

The hippocampus and the medial entorhinal cortex are part of a brain system that maps self-location during navigation in the proximal environment1,2. In this system, correlationsbetween neural firing and an animal's position or orientationare so evident that cell types have been given simple descriptive names, such as place cells3, grid cells4, border cells5,6 and head-direction cells7. While the number of identified functionalcell typesis growing at a steady rate, insights remain limited by an almost-exclusive reliance on recordings from rodents foraging in empty enclosures that are different from the richly populated, geometrically irregular environments of the natural world. In environments that contain discrete objects, animals are known to store information about distance and direction to those objects and to use this vector information to guide navigation8-10. Theoretical studies have proposed that such vector operations are supported by neurons that use distance and direction from discrete objects11,12 or boundaries13,14 to determine the animal's location, but-although some cells with vector-coding properties may be present in the hippocampus15 and subiculum16,17-it remains to be determined whether and how vectorial operations are implemented in the wider neural representation of space. Here we show that a large fraction of medial entorhinal cortex neurons fire specifically when mice are at given distances and directions from spatially confined objects. These 'object-vector cells' are tuned equally to a spectrum of discrete objects, irrespective of their location in the test arena, as well as to a broad range of dimensions and shapes, from point-like objects to extended surfaces. Our findings point to vector coding as a predominant form of position coding in the medial entorhinal cortex.

Egocentric coding of external items in the lateral entorhinal cortex.

Episodic memory, the conscious recollection of past events, is typically experienced from a first-person (egocentric) perspective. The hippocampus plays an essential role in episodic memory and spatial cognition. Although the allocentric nature of hippocampal spatial coding is well understood, little is known about whether the hippocampus receives egocentric information about external items. We recorded in rats the activity of single neurons from the lateral entorhinal cortex (LEC) and medial entorhinal cortex (MEC), the two major inputs to the hippocampus. Many LEC neurons showed tuning for egocentric bearing of external items, whereas MEC cells tended to represent allocentric bearing. These results demonstrate a fundamental dissociation between the reference frames of LEC and MEC neural representations.

Egocentric representation of objects

Neuroscience The lateral entorhinal cortex (LEC) and medial entorhinal cortex (MEC) are the two major cortical projections to the hippocampus. The discovery of a variety of functional cell types in MEC has greatly advanced our understanding of the functional anatomy of entorhinal-hippocampal circuits. However, the function of LEC and the behavioral correlates of LEC cells are still not fully understood. Wang et al. analyzed the firing properties of LEC and MEC neurons. They found that LEC and MEC used different reference frames, with LEC encoding objects egocentrically. Science , this issue p. [945][1] [1]: /lookup/doi/10.1126/science.aau4940

Entorhinal fast-spiking speed cells project to the hippocampus

The mammalian positioning system contains a variety of functionally specialized cells in the medial entorhinal cortex (MEC) and the hippocampus. In order for cells in these systems to dynamically update representations in a way that reflects ongoing movement in the environment, they must be able to read out the current speed of the animal. Speed is encoded by speed-responsive cells in both MEC and hippocampus, but the relationship between the two populations has not been determined. We show here that many entorhinal speed cells are fast-spiking putative GABAergic neurons. Using retrograde viral labeling from the hippocampus, we find that a subset of these fast-spiking MEC speed cells project directly to hippocampal areas. This projection contains parvalbumin (PV) but not somatostatin (SOM)-immunopositive cells. The data point to PV-expressing GABAergic projection neurons in MEC as a source for widespread speed modulation and temporal synchronization in entorhinal-hippocampal circuits for place representation.

Stellate Cells in the Medial Entorhinal Cortex Are Required for Spatial Learning

SummarySpatial learning requires estimates of location that may be obtained by path integration or from positional cues. Grid and other spatial firing patterns of neurons in the superficial medial entorhinal cortex (MEC) suggest roles in behavioral estimation of location. However, distinguishing the contributions of path integration and cue-based signals to spatial behaviors is challenging, and the roles of identified MEC neurons are unclear. We use virtual reality to dissociate linear path integration from other strategies for behavioral estimation of location. We find that mice learn to path integrate using motor-related self-motion signals, with accuracy that decreases steeply as a function of distance. We show that inactivation of stellate cells in superficial MEC impairs spatial learning in virtual reality and in a real world object location recognition task. Our results quantify contributions of path integration to behavior and corroborate key predictions of models in which stellate cells contribute to location estimation.

Active dendritic integration as a mechanism for robust and precise grid cell firing.

Understanding how active dendrites are exploited for behaviorally relevant computations is a fundamental challenge in neuroscience. Grid cells in medial entorhinal cortex are an attractive model system for addressing this question, as the computation they perform is clear: they convert synaptic inputs into spatially modulated, periodic firing. Whether active dendrites contribute to the generation of the dual temporal and rate codes characteristic of grid cell output is unknown. We show that dendrites of medial entorhinal cortex neurons are highly excitable and exhibit a supralinear input-output function in vitro, while in vivo recordings reveal membrane potential signatures consistent with recruitment of active dendritic conductances. By incorporating these nonlinear dynamics into grid cell models, we show that they can sharpen the precision of the temporal code and enhance the robustness of the rate code, thereby supporting a stable, accurate representation of space under varying environmental conditions. Our results suggest that active dendrites may therefore constitute a key cellular mechanism for ensuring reliable spatial navigation.

Glutamatergic synaptic integration of locomotion speed via septoentorhinal projections.

The medial septum and diagonal band of Broca (MSDB) send glutamatergic axons to medial entorhinal cortex (MEC). We found that this pathway provides speed-correlated input to several MEC cell-types in layer 2/3. The speed signal is integrated most effectively by pyramidal cells but also excites stellate cells and interneurons. Thus, the MSDB conveys speed information that can be used by MEC neurons for spatial representation of self-location.