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Entorhinal cortex

The entorhinal cortex (EC) is a pivotal region of the medial temporal lobe in primates, functioning as the primary interface between the neocortex and the hippocampus by relaying multimodal sensory inputs essential for memory formation and spatial navigation.^[1] Located ventrally to the amygdala and anteriorly to the hippocampus, it extends caudally for approximately 45–50 mm in humans^[2] and features a six-layered cortical architecture reminiscent of neocortex, including a distinctive acellular layer IV known as the lamina dissecans.^[1] The EC is subdivided into medial (MEC) and lateral (LEC) portions by the angular bundle, with further anterior-posterior gradients that support specialized processing: the anterior-lateral EC (alEC) emphasizes object and item-based representations, while the posterior-medial EC (pmEC) focuses on spatial and contextual information.^[3] In terms of connectivity, the EC receives major afferents from perirhinal cortex (for object processing) and parahippocampal cortex (for scene and spatial processing), as well as subcortical inputs from structures like the amygdala and frontal lobe regions; its principal outputs to the hippocampus occur via the perforant path, originating primarily from layers II and III to innervate the dentate gyrus and cornu ammonis fields, while layer V projections target subcortical areas for broader integration.^[1] This bidirectional circuit positions the EC as the nodal point in cortico-hippocampal loops, facilitating the consolidation of episodic memories and relational associations.^[4] Functionally, the EC plays a central role in episodic memory, with lesions impairing object recognition and flexible memory retrieval while sparing basic familiarity-based tasks.^[1] In spatial cognition, the MEC harbors grid cells that fire in periodic, hexagonal patterns to form a metric representation of space, scaling with distance from the anterior pole, alongside head-direction and border cells that contribute to path integration and environmental mapping.^[1] These cellular mechanisms, conserved across rodents and primates, underscore the EC's involvement in navigation, time perception, and predictive coding, with early degenerative changes in the EC observed in conditions like Alzheimer's disease.^[3]

Anatomy

Location and Gross Structure

The entorhinal cortex is the medialmost portion of the temporal lobe's neocortex, located within the medial temporal lobe and positioned immediately adjacent to the hippocampus. It serves as a key interface between neocortical regions and the hippocampal formation, bordering the parahippocampal gyrus posteriorly and the olfactory areas, including the uncus and ambient gyrus, anteriorly.^[5]^[6]^[7] The entorhinal cortex is subdivided into the medial entorhinal cortex (MEC), situated closer to the midline, and the lateral entorhinal cortex (LEC), positioned laterally. In humans, it exhibits an approximate bilateral volume of 3–4 cm³ based on MRI measurements in healthy adults, with surface areas estimated at 10–15 cm² across both hemispheres. Gross anatomical features include its embedding within the uncus on the medial aspect and demarcation by the rhinal sulcus laterally, which separates it from adjacent perirhinal structures.^[8]^[9]^[10]^[7]^[11] Individual variations in the size and shape of the entorhinal cortex are common, influenced by factors such as age and genetics, with neuroimaging studies consistently documenting right-left asymmetries, including greater surface area in the left hemisphere and greater thickness in the right hemisphere in many populations. These asymmetries are evident in structural MRI data from large cohorts. It corresponds briefly to Brodmann areas 28 (primarily lateral) and 34 (dorsal/medial portions) in classical cytoarchitectonic mapping.^[12]^[13]^[14]

Cytoarchitecture and Layers

The entorhinal cortex (EC) displays a distinctive six-layered neocortical architecture, blending allocortical and neocortical characteristics, with layers I through VI organized in a relatively regular manner, particularly evident in Nissl-stained sections. Layer I is a molecular layer with few neurons but dense tangential fibers, while layer VI contains fusiform and pyramidal neurons that provide feedback projections. The superficial layers II and III are particularly prominent, housing the principal output neurons of the EC, whereas deep layers V and VI integrate inputs from other cortical regions. This laminar organization is conserved across rodents and primates, though with species-specific variations in cell density and marker expression.^[4] Layer II is dominated by stellate cells in the medial entorhinal cortex (MEC), which are large, multipolar, reelin-positive, and calbindin-negative neurons featuring radiating dendritic arborizations from a round soma, alongside medium-sized pyramidal cells that are predominantly calbindin-positive. In layer III, pyramidal cells predominate, characterized by spiny excitatory morphology with apical dendrites extending toward layer I and basal dendrites arborizing locally, forming a homogeneous population that projects to hippocampal targets. A notable feature is the lamina dissecans, a cell-sparse zone in layer IV that separates the superficial input layers from the deep output layers, visible as an acellular band in histological preparations adjacent to layer Va. Immunohistochemical staining with markers like reelin (for stellate cells) and calbindin (for pyramidal clusters) highlights these laminar distinctions, revealing clustered distributions in MEC layer II.^[4]^[15] The medial entorhinal cortex (MEC) and lateral entorhinal cortex (LEC) exhibit cytoarchitectural differences, particularly in layer II: the MEC appears more granular due to dense clustering of calbindin-positive pyramidal cells superficial to reelin-positive stellate cells, whereas the LEC shows less granularity with a columnar organization, including fan-shaped reelin-positive cells lacking a basal dendritic tree and forming sublayers IIa (reelin-dominant) and IIb (calbindin-dominant). These regional variations are underscored by Brodmann's areas, where the EC corresponds to area 28, subdivided into 28a (lateral EC) and 28b (medial EC), with area 35 representing the adjacent perirhinal transition zone sharing features with area 28 medially. In primates, the EC aligns with von Economo cytoarchitectonic areas TG and TF, characterized by similar laminar patterns but with greater emphasis on agranular features in the deeper layers compared to rodents. Dendritic arborization in principal neurons of layers II and III is extensive, with stellate cells showing radial, fan-like patterns spanning multiple layers and pyramidal cells displaying oriented apical-basal trees that facilitate laminar-specific integration.^[4]^[16]^[17]

Connectivity

The entorhinal cortex (EC) receives major afferent inputs from several cortical and subcortical regions, forming the primary gateway for multimodal sensory information to the hippocampal formation. The olfactory bulb provides direct projections primarily to layer I of the lateral entorhinal cortex (LEC) and, to a lesser extent, the medial entorhinal cortex (MEC), conveying olfactory signals while sparing the caudodorsal MEC. The perirhinal cortex sends inputs predominantly to the dorsolateral LEC, terminating in superficial layers I-III and relaying object-related information.^[18] Similarly, the parahippocampal cortex projects to the MEC, targeting superficial layers I-III with visual and spatial cues.^[19] Subcortical afferents include projections from the basal forebrain, thalamus, and midline nuclei, which distribute across layers but often emphasize superficial and deep laminae to modulate incoming signals.^[20] Efferent projections from the EC primarily target the hippocampus via the perforant path, a major output pathway originating from layer II neurons that innervate the dentate gyrus and CA fields.^[21] Reciprocal connections exist with the subiculum, where EC layer V neurons receive feedback from CA1 and subicular regions, closing the entorhinal-hippocampal loop.^[22] This bidirectional circuitry ensures integrated flow between neocortical inputs and hippocampal processing. Connectivity in the EC exhibits pronounced layer-specific organization, with superficial layers II-III primarily serving as output stations to the hippocampus through the perforant path, while deep layers V-VI receive inputs from association cortices such as the retrosplenial and cingulate regions. Layer II projections fan out topographically to the dentate gyrus and CA3, whereas layer III targets CA1 and subiculum, maintaining laminar segregation.^[21] Modulatory inputs further shape EC activity, including cholinergic projections from the basal forebrain that innervate all layers to enhance attention and plasticity.^[20] Dopaminergic afferents from the ventral tegmental area target superficial layers of the LEC, influencing synaptic transmission via D1 receptors.^[23] Serotonergic inputs from the raphe nuclei, acting through 5-HT3a receptors on interneurons in layer II, provide inhibitory modulation across the EC.^[24] These neuromodulatory systems integrate with the core entorhinal-hippocampal loop to regulate signal propagation.^[4]

Function

The entorhinal cortex plays a pivotal role in spatial navigation by providing a metric framework for representing an animal's position in its environment. Within the medial entorhinal cortex (MEC), specialized neurons contribute to this process through distinct firing patterns that encode location, direction, and boundaries, enabling path integration based on self-motion cues such as velocity and heading. These representations form a foundational input to the hippocampus, where they interact with place cells to support more flexible spatial mapping.^[25] Grid cells, a key cell type discovered in layer II of the MEC, fire when an animal traverses specific locations that form a regular hexagonal lattice pattern.^[25] This seminal finding by Hafting et al. in 2005 demonstrated that these neurons activate at vertices of equilateral triangles, creating a honeycomb-like array that tiles the environment with remarkable precision.^[25] In rats, the spacing between firing fields typically ranges from 30 to 70 cm, providing a scalable metric for distance estimation independent of environmental features.^[25] Grid cell firing exhibits organizational principles that enhance navigational robustness, including division into multiple modules characterized by distinct spatial frequencies. These modules, aligned along the dorsoventral axis of the MEC, feature low, intermediate, and high scales, with grid spacing increasing systematically from dorsal to ventral regions, allowing for hierarchical representation of space at varying resolutions.^[26] The hexagonal patterns also display rotational symmetry of 60 degrees and can rotate coherently with environmental cues, maintaining structural invariance while adapting to changes in orientation. Complementing grid cells, border cells and head-direction cells in the MEC further refine spatial coding by signaling environmental boundaries and orientation. Border cells, identified in 2008, discharge selectively near walls or edges, firing at a consistent distance from barriers regardless of their shape or position, thus anchoring the grid to the geometry of the surroundings.^[27] Head-direction cells, recorded concurrently with grid cells, increase firing when the animal faces a preferred direction, integrating angular velocity to track heading stability. Together, these cell types support path integration by combining translational (grid and border) and rotational (head-direction) signals from self-motion, enabling the brain to compute displacement without external landmarks.^[27] A 2025 study revealed that grid cells generate rapid oscillatory sweeps of activity, projecting into potential future positions ahead of the animal at approximately 10 Hz, alternating in direction by 30 degrees. This predictive mechanism enhances the dynamic updating of spatial maps during navigation.^[28] Evidence for analogous grid-like representations in humans comes from functional magnetic resonance imaging (fMRI) studies during virtual navigation tasks. In a landmark 2010 study, Doeller et al. observed periodic spatial modulation in entorhinal cortex activity, resembling the hexagonal firing of rodent grid cells, as participants navigated a controlled environment with rotated landmarks.^[29] This grid-code signature persisted across different spatial contexts, suggesting a conserved mechanism for metric spatial processing in the human brain.^[29]

Memory Processing and Hippocampal Interactions

The entorhinal cortex serves as the primary gateway for cortical information to the hippocampus via the perforant path, which originates from layer II of the entorhinal cortex and projects to the dentate gyrus, CA3, and CA1 regions.^[30] The lateral entorhinal cortex (LEC) conveys non-spatial "what" information, such as object identity and contextual details, through the lateral perforant path, while the medial entorhinal cortex (MEC) transmits spatial "where" information via the medial perforant path, enabling the integration of sensory and environmental cues for memory encoding.^[31] This functional segregation allows the entorhinal-hippocampal circuit to bind contextual and spatial elements into coherent representations.^[31] Within this circuit, the entorhinal cortex contributes to pattern separation in the dentate gyrus, where sparse granule cell activity orthogonalizes similar inputs to prevent memory interference, and pattern completion in CA3, where recurrent collaterals reconstruct full memories from partial cues.^[32] Theta oscillations (4-8 Hz), driven by entorhinal inputs and synchronized across the hippocampal-entorhinal loop, provide temporal windows for these processes, facilitating rapid synaptic plasticity and coordination of neuronal firing during memory formation and retrieval.^[33] For instance, theta phase-locking supports the segregation of weakly correlated patterns in CA3, enhancing the distinctiveness of episodic traces.^[33] The entorhinal cortex is crucial for episodic memory encoding, as evidenced by lesion studies in rodents showing severe anterograde amnesia following ibotenate-induced damage, with impairments in forming new spatial and contextual memories while sparing remote ones in a temporal gradient.^[34] These deficits highlight the circuit's role in consolidating novel experiences into long-term storage.^[34] Neuromodulators like acetylcholine further regulate memory gating in the entorhinal cortex, particularly by suppressing subthreshold oscillations in layer II stellate cells of the MEC, which reduces persistent firing and shifts the network toward encoding new information over retrieval.^[35] This cholinergic modulation enhances the selectivity of inputs to the hippocampus, promoting the transition between memory states essential for episodic processing.^[35]

Other Cognitive Roles

The lateral entorhinal cortex (LEC) plays a key role in processing non-spatial sensory information, receiving inputs from perirhinal and polymodal association cortices to encode object features and contextual associations independent of spatial location.^[36] In particular, LEC neurons contribute to object-location associations by integrating sensory cues with contextual elements, facilitating recognition memory for objects in specific environments without reliance on allocentric spatial frameworks.^[37] This processing supports associative learning where objects are linked to non-geometric cues, as demonstrated in tasks requiring discrimination of object identities amid varying backgrounds.^[38] Beyond sensory integration, the LEC is involved in temporal sequence learning, where it encodes the order and timing of events to form coherent episodic representations. Neurons in the LEC exhibit activity patterns that track precise temporal intervals, enabling the formation of temporal associations critical for sequence memory.^[39] Human studies further reveal that the anterior LEC represents abstract temporal structures, such as the progression of sequences in non-spatial tasks, through population codes that differentiate event orders.^[40] In primates, the entorhinal cortex supports working memory and decision-making processes, with recordings from macaque monkeys showing sustained activity during delay periods in visual working memory tasks.^[41] Entorhinal neurons also encode reward prediction signals, integrating value-based information with mnemonic representations to guide choices in probabilistic environments.^[42] This activity overlaps briefly with memory pathways but extends to evaluative functions in rhinal-entorhinal circuits during reward-guided selections.^[43] The entorhinal cortex contributes to attention and cognitive flexibility by adapting neural representations under varying demands, as evidenced by increased decoding accuracy for task-relevant features in high-load conditions. A 2025 study using intracranial recordings in humans demonstrated that entorhinal power features enhance residual decoding in the hippocampus during medium-to-high cognitive loads, supporting flexible shifts in attentional focus.^[44] This adaptability aids in reallocating resources for dynamic environments requiring rapid adjustments. Integration with the prefrontal cortex enables goal-directed behavior, where entorhinal outputs modulate prefrontal activity to balance stability and flexibility in action selection. Inhibitory projections from the entorhinal cortex to the medial prefrontal cortex influence cognitive control, allowing adjustments in behavioral strategies based on updated contextual inputs.^[45] This circuit facilitates the alignment of sensory-mnemonic signals with executive demands, promoting efficient pursuit of objectives in complex scenarios.^[46]

Clinical Significance

Alzheimer's Disease

The entorhinal cortex (EC) exhibits early vulnerability to tau pathology in Alzheimer's disease (AD), with neurofibrillary tangles (NFTs) initially accumulating in layer II neurons, often preceding involvement of the hippocampus. This progression aligns with Braak staging, where stages I–II are characterized by tau deposition confined primarily to the transentorhinal and entorhinal regions, marking the onset of AD neuropathology before spreading to limbic structures. Layer II stellate cells, which project via the perforant path to the dentate gyrus, are particularly susceptible, contributing to the disruption of hippocampal input early in the disease course.^[47]^[48]^[49] Entorhinal atrophy strongly correlates with cognitive decline in AD, serving as a predictor of memory impairment independent of hippocampal volume loss. Longitudinal studies show that EC thinning or volume reduction over several years forecasts episodic memory deficits in both preclinical and mild cognitive impairment stages, with greater atrophy linked to faster progression to dementia. In Braak stages I–II, this early EC involvement is associated with isolated memory dysfunction while sparing other cognitive domains, highlighting its role as a harbinger of broader decline. Emerging EC-targeted interventions, such as deep brain stimulation, show promise in slowing tau progression in early AD trials as of 2025.^[50]^[51]^[52]^[53] Several mechanisms underlie EC degeneration in AD, including neuronal hyperexcitability, synaptic loss, and perforant path degeneration. Soluble tau species in the EC induce presynaptic mitochondrial dysfunction and synaptic vesicle depletion, leading to impaired neurotransmission and eventual neuronal death. Hyperexcitability arises from imbalanced excitatory-inhibitory circuits, with increased intrinsic excitability in medial EC neurons exacerbating tau propagation and network instability. Recent evidence suggests structural compression from adjacent tentorial structures contributes to this vulnerability, promoting tau burden through chronic mechanical stress on EC tissue. Perforant path degeneration, stemming from layer II neuron loss, further severs EC-hippocampal connectivity, accelerating memory circuit breakdown.^[54]^[55]^[56]^[57] Imaging biomarkers targeting the EC enable early AD diagnosis, with MRI volumetry quantifying atrophy and tau PET visualizing NFT deposition. Automated MRI-based EC volume measurements detect subtle changes years before clinical symptoms, outperforming global atrophy metrics for predicting conversion from mild cognitive impairment to AD. Tau PET tracers, such as flortaucipir, bind specifically to paired helical filaments in the EC during Braak stages I–II, offering high sensitivity for preclinical detection and monitoring disease progression. Combining these modalities enhances prognostic accuracy, with EC-specific tau uptake correlating strongly with future cognitive trajectories.^[58]^[59]^[60]

Other Neurological Disorders

The entorhinal cortex plays a critical role in the pathophysiology of temporal lobe epilepsy (TLE), where hyperexcitability in its superficial layers, particularly layer II, contributes to seizure initiation and propagation to the hippocampus.^[61] Abnormal synchronized activity in the entorhinal cortex, often triggered by reduced inhibition among principal neurons, facilitates excessive loop gain in the rhinal-hippocampal circuit, exacerbating seizure spread.^[62] In animal models of TLE, such as those induced by pilocarpine, deep-layer entorhinal neurons exhibit network hyperexcitability that sustains ictal events.^[63] Surgical interventions targeting the entorhinal cortex, typically as part of anterior temporal lobectomy or selective amygdalohippocampectomy, have shown favorable outcomes in drug-resistant TLE. Resection of the medial temporal structures, including the entorhinal cortex, achieves seizure freedom in approximately 60-70% of patients at long-term follow-up, with preoperative entorhinal volume not significantly predicting postoperative success but complete lesion removal enhancing efficacy.^[64] These procedures disrupt hyperexcitable pathways, though risks include verbal memory decline due to the entorhinal's role in hippocampal input.^[65] In major depressive disorder, the entorhinal cortex is implicated through disruptions in the entorhinal-hippocampal circuit that impair adult neurogenesis in the dentate gyrus, contributing to mood dysregulation and cognitive symptoms.^[66] Reduced entorhinal input to the hippocampus correlates with decreased proliferation and survival of new neurons, a process exacerbated by chronic stress and glucocorticoid elevation, as highlighted in reviews from 2021 onward.^[67] This circuitry-dependent neurogenesis deficit underlies persistent anhedonia and rumination, with entorhinal layer II stellate cells particularly vulnerable to inflammatory mediators like interleukin-1β.^[66] Entorhinal cortex thinning is observed in mild cognitive impairment (MCI) and schizophrenia, associating with working memory deficits that impair executive function and daily cognition. In MCI, reduced entorhinal thickness predicts declines in working memory tasks, such as digit span and spatial recall, reflecting early disruptions in grid cell-mediated spatial processing.^[68]^[69] Similarly, in schizophrenia, decreased entorhinal volumes compared to controls correlate with working memory impairments, including deficits in maintenance and manipulation of information, linked to disorganized layer II neuronal clustering.^[70]^[71] These structural changes contribute to broader cognitive disorganization, with entorhinal hypoactivity during encoding tasks exacerbating verbal and visuospatial working memory errors.^[72] Following traumatic brain injury (TBI), the entorhinal cortex demonstrates selective vulnerability due to its high metabolic demand from extensive connectivity and glutamatergic signaling, leading to delayed neurodegeneration. Post-TBI, excitotoxic calcium influx in entorhinal neurons, driven by energy failure in layer III, results in axonal damage and synaptic loss, independent of hippocampal pathology.^[73] This vulnerability manifests as volume reduction in the acute phase, correlating with persistent spatial disorientation and memory lapses, as seen in controlled cortical impact models.^[74] The region's reliance on oxidative metabolism amplifies susceptibility to secondary insults like ischemia, underscoring its role in long-term cognitive sequelae of TBI.^[75]

Research and Development

Historical Discoveries

The entorhinal cortex was first described histologically in the late 19th and early 20th centuries through pioneering work on neural pathways in the medial temporal lobe. In 1911, Santiago Ramón y Cajal provided detailed illustrations of the perforant path, identifying it as a key projection from the entorhinal cortex that perforates the subiculum to innervate the dentate gyrus and hippocampus proper, based on Golgi-stained preparations of mammalian brains.^[76] This discovery laid the groundwork for understanding the entorhinal cortex's role as a major gateway to the hippocampal formation. Building on such histological insights, Korbinian Brodmann in 1909 delineated the entorhinal cortex as area 28 based on cytoarchitectonic features, including its granular layer II and agranular layers III-VI, while area 35 was defined adjacent to it as part of the perirhinal cortex within the parahippocampal region.^[30] These classifications, derived from comparative studies of human and primate brains, established the entorhinal cortex's distinct laminar organization and its position in Brodmann's areal map of the cerebral cortex.^[77] The functional significance of the entorhinal cortex in memory emerged prominently in the mid-20th century through clinical case studies of amnesia following medial temporal lobe resections for epilepsy. In 1953, patient H.M. (Henry Molaison) underwent bilateral removal of the anterior two-thirds of the hippocampus, amygdala, and surrounding structures, resulting in profound anterograde amnesia that spared other cognitive functions. Subsequent neuropsychological assessments in the 1950s and 1960s, including those by Brenda Milner and William Scoville, demonstrated that H.M.'s deficits were linked to disruption of declarative memory formation, implicating the medial temporal lobe circuit. Post-mortem examination following H.M.'s death in 2008, with detailed analyses published in the 2010s, confirmed extensive bilateral damage to the entorhinal cortex, with nearly complete removal on both sides and sparing of posterior portions, reinforcing its critical role as the primary interface for cortical inputs to the hippocampus during the era of memory research.^[78] Initial functional mappings of the entorhinal cortex in humans were advanced in the 1980s through intraoperative electrical stimulation in epilepsy patients undergoing temporal lobe surgery. Researchers applied low-intensity currents to subcortical sites, including the entorhinal region, to localize seizure foci and probe cognitive functions, revealing activations associated with memory recall and spatial processing without eliciting seizures in many cases.^[79] These studies, building on earlier cortical mapping techniques, provided early evidence of the entorhinal cortex's involvement in experiential phenomena, such as fragmented autobiographical memories, during controlled stimulations proximal to the hippocampus.^[79] A major breakthrough in entorhinal function occurred in 2005 with the discovery of grid cells, neurons in the medial entorhinal cortex that fire in a hexagonal lattice pattern as rats navigate environments, providing a metric for self-position independent of landmarks. This finding, reported by Torkel Hafting, Marianne Fyhn, Sturla Molden, May-Britt Moser, and Edvard I. Moser using single-unit recordings in freely moving rats, complemented John O'Keefe's earlier identification of place cells in the hippocampus. The work culminated in the 2014 Nobel Prize in Physiology or Medicine, awarded jointly to O'Keefe, May-Britt Moser, and Edvard I. Moser for elucidating neural representations of space within the entorhinal-hippocampal network.^[80]

Recent Advances and Models

Recent research has elucidated the role of neuromodulators in modulating entorhinal-hippocampal (EC-HC) connectivity during healthy cognitive processes, particularly in memory formation and consolidation. A 2024 review highlights that acetylcholine and dopamine enhance synaptic plasticity between EC layers and hippocampal regions, facilitating adaptive encoding of episodic memories by gating excitatory inputs and stabilizing network oscillations.^[81] Similarly, a 2025 eLife preprint demonstrates spatially periodic computation in the EC-HC circuit during navigation in perceptual spaces, where EC exhibits hexagonal (6-fold) periodicity akin to grid patterns, while the hippocampus shows triangular (3-fold) alignment, supporting flexible cognitive mapping of abstract features like object similarities.^[82] Computational models have advanced understanding of grid cell function in the entorhinal cortex, emphasizing mechanisms for stability and error correction in spatial processing. Attractor network models propose that recurrent excitatory-inhibitory interactions in EC layer II generate stable hexagonal firing patterns, with a geometric organization enabling self-organization of multiple grid modules across scales for robust path integration.^[83] Bayesian integration frameworks further explain how EC grid cells mitigate path integration errors by optimally combining self-motion cues with landmark inputs, decomposing errors into components like velocity noise (50-55% contribution) and bias, as validated in human behavioral tasks.^[84] Advances in optogenetics and calcium imaging have revealed layer-specific dynamics in the entorhinal cortex of freely moving rodents, uncovering distinct roles in spatial coding. Two-photon calcium imaging in medial EC layers during locomotion shows that superficial layer II grid cells maintain stable periodic firing, while deeper layer V neurons exhibit transient bursts correlated with hippocampal theta rhythms, enabling coordinated circuit updates without disrupting ongoing navigation.^[85] In humans, functional MRI studies in 2025 have decoded adaptive responses in the entorhinal cortex to varying cognitive loads, revealing enhanced representational flexibility. During working memory tasks, EC activity patterns showed superior decoding accuracy for medium-to-high loads compared to hippocampal or temporal regions, with power features generalizing across conditions to support load-dependent remapping of cognitive maps.^[86]

Comparative Anatomy

In Rodents

The entorhinal cortex in rodents, such as rats and mice, is notably compact and significantly smaller than in larger mammals, with a volume of approximately 19 mm³ in rats. This structure is clearly subdivided into the medial entorhinal cortex (MEC) and lateral entorhinal cortex (LEC), a distinction that facilitates targeted neurophysiological studies. Layer II of the MEC is particularly characterized by prominent stellate cells, which are large multipolar excitatory neurons that contribute to the region's modular organization and are interspersed with pyramidal neurons. These stellate cells form clusters or "islands" that support the cortex's role in spatial processing, as identified through detailed histological analyses.^[87]^[4]^[88] In the MEC of rodents, grid cells dominate the functional landscape during open-field navigation, with approximately 60% of recorded neurons exhibiting periodic firing patterns that form hexagonal lattices across the environment. These cells, primarily in layer II, provide a metric representation of space, enabling precise path integration in tasks like foraging. The perforant path, originating from layer II of the entorhinal cortex, forms strong, topographically organized projections to the dentate gyrus of the hippocampus, serving as the primary cortical input pathway. This connectivity has been extensively exploited in maze-based behavioral studies, such as the Morris water maze, to probe spatial learning and memory formation.^[89] Rodents offer substantial advantages for entorhinal cortex research due to their genetic manipulability, allowing precise interventions like optogenetic silencing or Cre-lox mediated knockouts targeted to specific cell types, such as stellate cells. Behavioral assays in these models, including open-field exploration and virtual reality setups, have revealed prominent theta-rhythmic activity (4-12 Hz) in the entorhinal cortex, which synchronizes with hippocampal oscillations to support navigation and memory encoding. These features have made rodents the cornerstone for dissecting entorhinal-hippocampal circuits, yielding insights into neural computations underlying cognition.^[30]^[90]

In Primates and Humans

In primates, the entorhinal cortex exhibits notable evolutionary expansions compared to rodents, particularly in the relative size and functional emphasis of its lateral (LEC) and medial (MEC) divisions. The LEC is proportionally larger in primates, reflecting an adaptation for processing complex object-based and associative information, while the MEC remains more specialized for spatial representations akin to those observed in rodents. This shift supports advanced cognitive integration, with the LEC receiving denser inputs from perirhinal and temporal association areas. Layer III pyramidal cells are particularly increased in density and extent within the primate entorhinal cortex, facilitating broader projections to the hippocampus via the perforant path and enabling the formation of intricate relational associations essential for higher-order memory.^[91]^[92]^[93] In humans, the entorhinal cortex displays further specializations, with a substantially greater overall volume—approximately 3,300 mm³ (bilateral)—compared to ~19 mm³ in rats, accommodating expanded neural circuitry for abstract processing. Functional magnetic resonance imaging (fMRI) studies reveal evidence of grid-like neural codes in the human entorhinal cortex extending beyond spatial navigation to non-spatial tasks, such as decision-making in abstract value spaces and semantic comparisons of word meanings. These codes manifest as hexadirectional modulation patterns, indicating a flexible representational framework that integrates relational information across cognitive domains. Building on foundational grid cell discoveries in rodents, this human adaptation underscores the entorhinal cortex's role in generalizing spatial metrics to conceptual structures.^[94]^[95]^[96] Connectivity patterns in the human and primate entorhinal cortex show enhanced inputs from prefrontal regions, particularly the orbitofrontal cortex and anterior cingulate, which synapse predominantly in layers I–III to support executive integration of sensory and mnemonic signals. These projections, more prominent in primates than in rodents, enable the coordination of goal-directed behavior with memory retrieval, as detailed in reviews from 2020 to 2024. Evolutionarily, this entorhinal expansion is closely linked to the development of advanced episodic memory, allowing for the binding of contextual "where" and item-specific "what" details into coherent event representations that enhance adaptive foresight. Aging in primates and humans is associated with specific atrophy patterns in the entorhinal cortex, including cortical thinning and reduced cholinergic inputs from the basal forebrain, which precede broader memory declines without substantial neuronal loss in the cortex itself.^[91]^[81]^[97]^[98]

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Excitatory Postrhinal Projections to Principal Cells in the Medial ...
Dec 2, 2015 · The postrhinal cortex (POR) provides substantial input to the entorhinal cortex, mainly targeting superficial layers of the medial ...
[22]
Dopaminergic Regulation of Neuronal Excitability through ...
Mar 22, 2006 · The entorhinal cortex (EC) is a significant component of the systems that underlie certain forms of memory formation and recall.
[23]
Serotonergic modulation of Neural activities in the entorhinal cortex
The cerebral cortices including the EC receive prominent serotonergic innervations from the raphe nuclei which are clustered along the midline of the brainstem.
[24]
Microstructure of a spatial map in the entorhinal cortex - Nature
Jun 19, 2005 · Here we show that the dorsocaudal medial entorhinal cortex (dMEC) contains a directionally oriented, topographically organized neural map of the spatial ...
[25]
Representation of Geometric Borders in the Entorhinal Cortex
Dec 19, 2008 · We report the existence of an entorhinal cell type that fires when an animal is close to the borders of the proximal environment.
[26]
Evidence for grid cells in a human memory network - Nature
Jan 20, 2010 · Our results provide evidence for grid-cell-like representations in humans, and implicate a specific type of neural representation in a network of regions.
[27]
Architecture of the Entorhinal Cortex A Review of ... - Frontiers
The entorhinal cortex (EC) is the major input and output structure of the hippocampal formation, forming the nodal point in cortico-hippocampal circuits.
[28]
Functional correlates of the lateral and medial entorhinal cortex - NIH
It is commonly believed that the MEC provides spatial input to the hippocampus, whereas the LEC provides non-spatial input.
[29]
The mechanisms for pattern completion and pattern separation in ...
The aim of this paper is to describe some of the different types of pattern separation and pattern completion in the hippocampal system, and the mechanisms ...
[30]
Review Theta Oscillations in the Hippocampus - ScienceDirect.com
Theta oscillations represent the “on-line” state of the hippocampus. The extracellular currents underlying theta waves are generated mainly by the entorhinal ...Main Text · Hippocampal Plasticity... · Acknowledgements
[31]
Extended temporal gradient for the retrograde and anterograde amnesia produced by ibotenate entorhinal cortex lesions in mice
**Summary of Findings on Entorhinal Cortex Lesions and Amnesia:**
[32]
Effects of acetylcholine on neuronal properties in entorhinal cortex
This review focuses on intrinsic cellular properties of neurons in EC that may underlie functions such as working memory, spatial processing, and episodic ...
[33]
Representation of Non-Spatial and Spatial Information in the Lateral ...
Oct 28, 2011 · The hippocampus receives cortical input from two major pathways: the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC).Missing: associations | Show results with:associations
[34]
Lateral entorhinal cortex is necessary for associative but not ... - NIH
The lateral entorhinal cortex (LEC) provides one of the two major input pathways to the hippocampus and has been suggested to process the nonspatial contextual ...
[35]
Lateral entorhinal neurons are not spatially selective in cue-rich ...
The lateral entorhinal cortex (LEC) receives major input from the perirhinal cortex, which is connected with unimodal sensory areas and appears to be involved ...
[36]
Precise temporal memories are supported by the lateral entorhinal ...
Jan 14, 2019 · Abstract. There is accumulating evidence that the entorhinal-hippocampal network is important for temporal memory.
[37]
Mapping sequence structure in the human lateral entorhinal cortex
Our findings demonstrate representations of temporal structure in the alEC; dovetailing with temporal information carried by population signals.
[38]
Functional role of entorhinal cortex in working memory processing
Most studies of the physiological basis of working memory have been done in prefrontal cortex (PFC) of primates performing a so-called delayed match-to-sample ( ...
[39]
Intersection of Reward and Memory in Monkey Rhinal Cortex
May 16, 2012 · (1993) The dopaminergic innervation of monkey entorhinal cortex. ... (1999) Relative reward preference in primate orbitofrontal cortex.
[40]
https://pmc.ncbi.nlm.nih.gov/articles/PMC6684227/
[41]
Enhanced role of the entorhinal cortex in adapting to increased ...
Jul 1, 2025 · Further analysis revealed that removing EC-related information significantly reduced residual decoding accuracy in the hippocampus and LTC.
[42]
Entorhinal Cortex Inhibits Medial Prefrontal Cortex and Modulates ...
The prefrontal cortex receives multiple inputs from the hippocampal complex, which are thought to drive memory-guided behavior.
[43]
A Prefrontal-Hippocampal Comparator for Goal-Directed Behavior
They suggest that prefrontal inputs to entorhinal cortex and hippocampus mediate the prospective coding. Ferbinteanu and Shapiro (2003), recording from CA1 ...
[44]
Propagation of tau pathology in a model of early Alzheimer's disease
Neurofibrillary tangles advance from layer II of the entorhinal cortex (EC-II) toward limbic and association cortices as Alzheimer disease (AD) evolves.
[45]
Propagation of Tau Pathology in a Model of Early Alzheimer's Disease
Feb 23, 2012 · Neurofibrillary tangles advance from layer II of the entorhinal cortex (EC-II) toward limbic and association cortices as Alzheimer's disease ...
[46]
Biomarker modeling of Alzheimer's disease using PET-based Braak ...
Apr 25, 2022 · Early Braak stages were associated with isolated memory impairment and sparing of other cognitive domains, whereas later Braak stages were ...
[47]
Shrinkage of the Entorhinal Cortex over Five Years Predicts Memory ...
The main finding in this study is that, in healthy and educated elderly, longitudinal shrinkage of the entorhinal cortex is associated with reduced memory ...
[48]
Entorhinal cortex thickness predicts cognitive decline in Alzheimer's ...
These data indicate that AD subjects with thinner ERC had lower baseline cognitive scores, higher disease severity, and predicted greater subsequent cognitive ...
[49]
Vulnerability of the entorhinal cortex II to neurodegeneration in ...
Feb 26, 2025 · The entorhinal cortex is an area involved in the cognitive function of memory formation. Braak and Braak stages evidenced a specific sequence of ...
[50]
Soluble pathological tau in the entorhinal cortex leads to presynaptic ...
Nov 24, 2013 · Here we investigate if soluble pathological tau, specifically directed to the entorhinal cortex (EC), can cause behavioral or synaptic deficits.
[51]
Progressive Excitability Changes in the Medial Entorhinal Cortex in ...
Nov 1, 2023 · This observed combination of increased intrinsic and synaptic hyperexcitability suggests a breakdown in homeostatic mechanisms specifically in ...
[52]
Entorhinal cortex dysfunction in Alzheimer's disease - PMC - NIH
Feb 1, 2023 · This review will focus on recent findings on EC dysfunction in AD, and discuss the potential pathways for mitigating AD progression by protecting the EC.
[53]
Structural Compression and Entorhinal Vulnerability - bioRxiv
Sep 4, 2025 · In this study, we are the first to directly evaluate the contribution of chronic mechanical stress to tau burden in the entorhinal cortex and ...
[54]
Combination of automated brain volumetry on MRI and quantitative ...
May 14, 2021 · While tau PET reflects the underlying pathophysiologic hallmark of AD, MRI demonstrates regional atrophy with automated brain volumetry ...
[55]
Tau PET imaging in aging and early Alzheimer's disease - PMC - NIH
Detection of focal brain tau deposition during life could greatly facilitate accurate diagnosis of Alzheimer's disease (AD), staging and monitoring of disease ...
[56]
Tau PET Imaging in Neurodegenerative Disorders
Jun 1, 2022 · The entorhinal or transentorhinal cortex is usually considered the earliest region in which tau PET tracers can detect tau pathology and is ...
[57]
Reduced Inhibition and Increased Output of Layer II Neurons in the ...
Sep 17, 2003 · It has been proposed that in models of temporal lobe epilepsy the layer II neurons of the medial entorhinal cortex become hyperexcitable ...
[58]
The piriform, perirhinal, and entorhinal cortex in seizure generation
Abnormal activity from these regions is hypothesized to cause hyperexcitability and excessive propagation associated with temporal lobe epilepsy along with ...
[59]
Network-Hyperexcitability-in-the-Deep-Layers-of-the-Pilocarpine ...
Dec 1, 2006 · While both of these structures have been implicated in mesial temporal lobe epilepsy, surgical removal of the EC can control seizure activity.Missing: resection | Show results with:resection
[60]
Improving Seizure Outcomes After Epilepsy Surgery - PubMed Central
A complete resection of an epileptic lesion, such as a tumor or a cortical malformation, increases the chance of postoperative freedom from seizure.Missing: hyperexcitability propagation
[61]
One-year neuropsychological outcome after temporal lobe epilepsy ...
Jun 17, 2022 · We studied postoperative neuropsychological changes and factors contributing to worse memory outcomes in patients who experienced a significant decline.
[62]
The Entorhinal Cortex and Adult Neurogenesis in Major Depression
This review focuses on recent reports that support the biological association between the entorhinal–hippocampal circuitry and adult neurogenesis in the ...
[63]
The Entorhinal Cortex and Adult Neurogenesis in Major Depression
Oct 29, 2021 · This review highlights recent findings suggesting neural circuitry-regulated neurogenesis, with a focus on the potential role of the entorhinal cortex in ...Missing: 2021-2025 | Show results with:2021-2025
[64]
Thickness in Entorhinal and Subicular Cortex Predicts Episodic ...
Thickness in Entorhinal and Subicular Cortex Predicts Episodic Memory Decline in Mild Cognitive Impairment ... Classic MCI symptoms include deficits in the memory ...
[65]
Entorhinal cortical thinning affects perceptual and cognitive ...
Conclusions. Entorhinal cortical thinning is related with low IQ and reduced perceptual and executive functions in VLBW adolescents.
[66]
Decreased entorhinal cortex volumes in schizophrenia - ScienceDirect
Our study confirmed the presence of abnormally decreased entorhinal volumes, particularly on the right side, in a large number of patients with schizophrenia.
[67]
The quantitative neuropathology of schizophrenia - SpringerLink
Feb 27, 2009 · Comparable changes have been reported in the entorhinal cortex with abnormalities in neuronal distribution within the layer II clusters, as well ...<|separator|>
[68]
Brain-Performance Correlates of Working Memory Retrieval in ...
Nov 20, 2008 · The results show at both cognitive and neural levels that disordered memory scanning contributes to deficient SIRP performance among ...
[69]
Pathophysiological Findings of Selective Vulnerability in the ...
In this article, we review the clinical and experimental evidence of hippocampal damage after TBI. Recent data suggesting that TBI may be both an inflammatory ...Missing: entorhinal demand
[70]
Selective Neuronal Vulnerability in the Hippocampus: Relationship ...
In terms of input to the hippocampal formation, the entorhinal cortex is of particular importance in both normal functional connectivity to the hippocampus and ...
[71]
Assessing Metabolism and Injury in Acute Human Traumatic Brain ...
Sep 12, 2017 · Traumatic brain injury (TBI) triggers a series of complex pathophysiological processes. These include abnormalities in brain energy metabolism; ...
[72]
The dentate gyrus: fundamental neuroanatomical organization ...
The dentate gyrus receives its major input from the entorhinal cortex, via the so-called perforant pathway (Ramón y Cajal, 1893). The projection to the ...
[73]
Entorhinal Cortex - an overview | ScienceDirect Topics
The term “entorhinal cortex” was coined by Brodmann (1909) as a synonym for his area 28. More than any other hippocampal field, the entorhinal cortex has ...
[74]
H. M.'s Medial Temporal Lobe Lesion: Findings from Magnetic ...
May 15, 1997 · Virtually all of the entorhinal cortex, bilaterally, was either removed or damaged extensively.
[75]
Memory scrutinized through electrical brain stimulation: A review of ...
Electrical brain stimulations (EBS) sometimes induce reminiscences, but it is largely unknown what type of memories they can trigger. We reviewed 80 years ...
[76]
The Nobel Prize in Physiology or Medicine 2014 - Press release
Oct 6, 2014 · They identified another type of nerve cell, which they called “grid cells ... The discoveries of John O'Keefe, May-Britt Moser and Edvard Moser ...
[77]
Entorhinal cortex–hippocampal circuit connectivity in health and ...
In this review, we focus on the role of neuromodulators in entorhinal cortex–hippocampal functional connectivity during the encoding and consolidation of ...Missing: efferents | Show results with:efferents
[78]
Spatially Periodic Computation in the Entorhinal-Hippocampal ...
Sep 15, 2025 · This study provides valuable results on how entorhinal and hippocampal activity may support human thinking in perceptual spaces. ... © 2025 eLife ...
[79]
A geometric attractor mechanism for self-organization of entorhinal ...
Aug 2, 2019 · The hierarchy of entorhinal grid cell modules with constant scale ratios can self-organize through a new geometrically organized attractor ...
[80]
Path integration impairments reveal early cognitive changes in ...
Sep 3, 2025 · We developed a Bayesian computational model to decompose path integration errors into distinct components. ... Grid cells and the wider entorhinal ...
[81]
Large-scale two-photon calcium imaging in freely moving mice
Sep 21, 2021 · Large-scale proof-of-principle data were obtained from cell populations in visual cortex, medial entorhinal cortex, and hippocampus, revealing ...
[82]
Dissecting cell‐type‐specific pathways in medial entorhinal cortical ...
May 30, 2023 · In this review, we will comprehensively examine the complementary roles of superficial layers of neurons (II and III) and the roles of deeper layers (V and VI) ...
[83]
Enhanced role of the entorhinal cortex in adapting to increased ...
Jul 1, 2025 · The authors show that entorhinal cortex power features contributed more under medium-to-high loads than hippocampus and lateral temporal cortex.
[84]
Entorhinal Cortex - an overview | ScienceDirect Topics
The entorhinal cortex is an important source of neocortical input to the hippocampus and provides most of the neocortical input to the hippocampus in rodents.
[85]
What Does the Anatomical Organization of the Entorhinal Cortex Tell ...
Amygdala input terminates primarily in layer III of the entorhinal cortex, and the return projection originates predominantly from cells in layer V. The ...
[86]
projections from the entorhinal cortex to the dentate gyrus - PubMed
This paper provides a comprehensive description of the organization of projections from the entorhinal cortex to the dentate gyrus.<|control11|><|separator|>
[87]
Generation of theta rhythm in medial entorhinal cortex of ... - PubMed
A regular slow wave theta rhythm can be recorded in the medial entorhinal cortex (MEC) of freely moving rats during voluntary behaviors and paradoxical sleep.Missing: advantages genetic manipulation
[88]
[PDF] Anatomy and Function of the Primate Entorhinal Cortex - Buffalo Lab
Jun 24, 2020 · In this review, we highlight the significance of the EC as a major player in mem- ory processing, along with other associated structures in the ...
[89]
The evolution of episodic memory | PNAS
The “what” pathway, composed of the perirhinal and lateral entorhinal cortex, is important for processing and representing features of specific objects or items ...<|separator|>
[90]
Laminar Organization of the Entorhinal Cortex in Macaque Monkeys ...
To bridge the gap between rodents and primates, here we provide the first cell-type-based global map of EC in macaque monkeys. The laminar organization of the ...
[91]
Connectomic comparison of mouse and human cortex - Science
Jun 23, 2022 · The human cerebral cortex houses 1000 times more neurons than that of the cerebral cortex of a mouse, but the possible differences in synaptic ...
[92]
Grid-like entorhinal representation of an abstract value space during ...
Feb 9, 2024 · In this fMRI study, participants predicted changing values of choice options in a sequence, forming a trajectory through an abstract two-dimensional value ...
[93]
Grid-like and distance codes for representing word meaning in the ...
May 15, 2021 · Here we use fMRI to show that when humans compare newly learnt words, they recruit a grid-like and a distance code, the same types of neural ...
[94]
The evolution of episodic memory - PMC - PubMed Central
We propose that episodic memory capacity depends on a fundamental neural circuit that is similar across mammalian and avian species.
[95]
Age-associated neuronal atrophy occurs in the primate brain and is ...
The effects of normal aging on the primate brain are incompletely understood. Although both human and nonhuman primates demonstrate clear functional declines in ...