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Subiculum

The subiculum is a pivotal cortical structure within the hippocampal formation of the mammalian brain, positioned anatomically between the CA1 field of the hippocampus proper and the entorhinal cortex, forming part of the parahippocampal gyrus in the medial temporal lobe.^[1]^[2] It functions as the principal output gateway of the hippocampus, relaying processed information to diverse targets including limbic cortices, subcortical nuclei, and hypothalamic regions, thereby bridging hippocampal activity with broader neural networks involved in cognition and emotion.^[3]^[1] Anatomically, the subiculum exhibits a trilaminar organization typical of allocortical regions, consisting of a superficial molecular layer, a middle pyramidal cell layer with loosely packed, large excitatory neurons that extend apical dendrites upward and basal dendrites downward, and a deep polymorphic layer containing interneurons and fibers.^[1]^[2] It encompasses several subregions, including the prosubiculum (transitional to CA1), presubiculum, parasubiculum, and postsubiculum, with a topographic gradient: the dorsal subiculum predominantly links to cognitive processes, while the ventral subiculum interfaces more with affective and stress-related systems.^[3]^[2] Principal cell types include regular-spiking and bursting pyramidal neurons, the latter comprising up to twice as many cells as regular types and contributing to rhythmic activity patterns, alongside inhibitory interneurons such as those expressing parvalbumin for local circuit control.^[2] The subiculum receives major monosynaptic inputs from the CA1 pyramidal cells (accounting for 40-60% of its afferents depending on species), as well as from layers II and III of the entorhinal cortex, perirhinal cortex, and prefrontal areas, integrating hippocampal and cortical signals.^[1]^[2] Its efferent projections are extensive and predominantly excitatory, targeting layer V of the entorhinal cortex for re-entrant loops, medial prefrontal cortex, amygdala, nucleus accumbens, lateral septum, and hypothalamic nuclei via the fornix pathway, with the ventral subiculum providing the bulk of hippocampal innervation to stress-regulatory hypothalamic sites.^[3]^[1] This connectivity positions the subiculum as a hub for modulating bidirectional information flow between the hippocampus and extrahippocampal structures.^[2] Physiologically, subicular neurons display distinct properties from upstream CA1 cells, including subthreshold membrane oscillations, burst firing modes, and the ability to generate theta rhythms (4-12 Hz), gamma oscillations (30-100 Hz), and sharp-wave ripples independently, which support synaptic plasticity mechanisms like long-term potentiation (LTP) at CA1-subiculum synapses.^[1]^[2] Functionally, it plays essential roles in spatial navigation—evidenced by place-modulated firing patterns with multiple activity peaks—episodic memory consolidation, contextual fear conditioning, and regulation of the hypothalamic-pituitary-adrenal (HPA) axis during stress, where ventral lesions attenuate cortisol responses.^[3]^[1] Dysfunctions in the subiculum are implicated in neurological disorders, including temporal lobe epilepsy (as a potential seizure onset zone), Alzheimer's disease (due to early tau pathology), and schizophrenia (via altered ventral circuitry).^[3]^[2]

Overview

Definition and location

The subiculum is the primary output structure of the hippocampus, serving as a transitional cortical region that receives major projections from the CA1 field of the cornu ammonis and relays processed information to the entorhinal cortex and other targets.^[1] It forms an integral component of the hippocampal formation, which encompasses the dentate gyrus, hippocampus proper (cornu ammonis fields CA1–CA3), and subiculum, thereby distinguishing the subiculum as the principal efferent pathway in contrast to the dentate gyrus's role in afferent processing.^[4] As part of the broader limbic system, the subiculum contributes to emotional and memory-related functions through its embedded position in the medial temporal lobe.^[5] Anatomically, the subiculum is positioned between the proximal boundary adjacent to CA1 and the distal boundary bordering the presubiculum, with its layers continuous with those of the adjacent hippocampal regions.^[1] It occupies the medial and superior edge of the parahippocampal gyrus, lying within the uncus and adjacent to the hippocampal fissure, which separates it from the dentate gyrus and cornu ammonis.^[4] This placement situates the subiculum adjacent to the CA1 field in the curled structure of the hippocampus, integrating it seamlessly with surrounding mesial temporal lobe components.^[6] In terms of size and orientation, the subiculum extends along the longitudinal axis of the hippocampal formation, which is oriented dorsoventrally in rodents such as mice, spanning several millimeters in length with varying laminar thickness across subregions.^[7] In humans and primates, evolutionary rotation of this axis results in an anteroposterior orientation, rendering the subiculum more elongated—up to approximately 10 mm rostrocaudally in the posterior portion—and folded at the anterior pole near the amygdala.^[7] The subiculum includes proximal and distal subdivisions along its extent, with further details on internal organization addressed elsewhere.^[1]

Etymology and history

The term "subiculum" was coined by the German anatomist Karl Friedrich Burdach in the second volume of his three-volume treatise Vom Bau und Leben des Gehirns, published between 1819 and 1826, with the relevant description appearing in the 1822 volume. Derived from the Latin word for "support" or "foundation," the name reflects the structure's position directly beneath the hippocampus proper, serving as a foundational layer in the hippocampal formation. Historically, the subiculum was classified as the "subiculum cornu ammonis," denoting its transitional role adjacent to the subfields of Ammon's horn (the cornu ammonis, or hippocampus proper). This nomenclature emphasized its integration within the broader hippocampal complex, where the cornu ammonis itself derived from ancient comparisons to the ram's horns of the Egyptian god Ammon, a term popularized in 18th- and 19th-century neuroanatomy.^[8] In the late 19th century, Theodor Meynert advanced descriptions of the hippocampal region's cytoarchitecture, including the subiculum, through his studies on cortical lamination and cellular organization in works such as Der Bau der Grosshirnwindungen des Menschen (1872), highlighting regional variations in neuronal arrangements.^[9] Twentieth-century refinements came from researchers like Max Rose, who in 1927 delineated subregions such as the prosubiculum within the subicular complex using cytoarchitectonic criteria, distinguishing it from adjacent areas. Building on this, Rafael Lorente de Nó's seminal 1934 Golgi-based studies in Journal für Psychologie und Neurologie provided detailed cytoarchitectonic analyses of the subiculum and its subdivisions (prosubiculum, presubiculum, parasubiculum, and postsubiculum), clarifying their laminar organization and transitions from the cornu ammonis; these studies solidified the modern understanding of the subiculum's structural heterogeneity.^[10]^[11]

Anatomy

Gross structure

The subiculum is characterized by a tri-laminar cortical architecture typical of allocortex, comprising a superficial molecular layer, a prominent pyramidal cell layer, and a deep polymorphic layer. The molecular layer receives inputs primarily from the entorhinal cortex and contains apical dendrites of pyramidal neurons, while the pyramidal layer houses the principal output neurons with somata arranged in a relatively loose, irregular fashion compared to the denser packing in CA1. The polymorphic layer, situated deepest, includes multipolar neurons, interneurons, and myelinated fibers, contributing to the subiculum's role as a transitional zone between the hippocampus proper and parahippocampal regions. This layering is conserved across species but exhibits subtle variations in thickness and cell density.^[7]^[12] Along the dorsoventral axis, the subiculum displays a functional gradient, with the dorsal portion predominantly supporting cognitive and spatial processing, such as navigation and memory encoding, while the ventral portion is more engaged in emotional regulation and autonomic responses, including stress integration. This dichotomy mirrors broader hippocampal organization, where dorsal regions emphasize spatial cognition and ventral areas modulate affective behaviors via connections to hypothalamic and limbic targets. The transition is gradual, with overlapping features in intermediate zones, but lesions or imaging studies confirm distinct behavioral impacts from targeting dorsal versus ventral subiculum.^[13]^[14]^[15] The proximodistal axis introduces further heterogeneity in cellular morphology, reflecting adaptations to differing input-output profiles along this gradient. These morphological distinctions correlate with variations in dendritic arborization and synaptic integration, enhancing the subiculum's capacity for diverse information processing.^[12] In comparative terms, the subiculum's gross architecture varies across species, with rodents exhibiting a linear dorsoventral orientation integrated into the hippocampal tail, whereas in primates and humans, it adopts an anterior-posterior alignment with pronounced folding in the anterior (ventral-equivalent) portion, rendering it more compact relative to overall hippocampal volume. Human subiculum volumes are substantially larger in absolute terms (approximately 10–15% of total hippocampal formation), but proportionally similar to rodents when scaled to brain size; however, the pyramidal layer in humans shows greater sublamination and gene expression complexity, particularly posteriorly. Monkeys display an intermediate form, with partial uncus folding akin to humans but less pronounced than in rodents' ventral extensions. These adaptations likely support expanded cognitive demands in higher primates.^[7]^[16]

Prosubiculum

The prosubiculum represents the most proximal segment of the subicular complex, positioned immediately adjacent to the CA1 field of the hippocampus proper, where it functions as a transitional zone between the densely layered cornu ammonis regions and the broader subiculum.^[10] This adjacency facilitates a gradual shift in structural organization, with the pyramidal cell layer expanding to occupy nearly the full width between the molecular layer and the stratum oriens, marking the boundary from CA1.^[17] In this transition, pyramidal cell orientation changes progressively, aligning more parallel to the hippocampal fissure in the superficial aspects while adopting a looser, radially oriented arrangement in deeper layers reminiscent of the subiculum proper.^[18] Cytoarchitectonically, the prosubiculum is distinguished by its two-sublayered pyramidal cell band, comprising a superficial sublayer of densely packed, smaller CA1-like neurons and a deeper sublayer of larger, more sparsely distributed subicular-like neurons, resulting in less distinct overall layering compared to adjacent regions.^[10] Pyramidal cells here are notably smaller, with an average soma width of 14.31 μm (n=400), significantly narrower than those in CA1 (15.57 μm) or the subiculum proper (15.63 μm; Kruskal-Wallis test, p < 0.0001).^[19] Neuronal density is elevated in the superficial sublayer relative to other subicular areas, featuring clustered, lightly stained small neurons intermingled with occasional larger ones, alongside a characteristic cell-sparse zone in the middle of the pyramidal layer that varies in prominence.^[10]^[19] As the primary output gateway relaying signals from CA1 to downstream subicular and extrahippocampal targets, the prosubiculum's pyramidal neurons display specialized dendritic arborization, with apical dendrites predominantly confined to the molecular layer and reduced branching in the proximal apical tuft compared to CA1 counterparts, as evidenced by Scholl analysis in rat models.^[10] This pattern supports efficient integration and projection, with basal dendrites extending into the subicular layers below.

Presubiculum

The presubiculum functions as a key transitional zone within the parahippocampal region, bridging the allocortical organization of the subiculum with the more layered neocortical architecture of the entorhinal cortex.^[20] This periallocortical structure exhibits intermediate laminar complexity, facilitating integration between hippocampal outputs and higher cortical processing.^[20] Designated as Brodmann area 27, it extends along the medial temporal lobe, paralleling the hippocampal formation from its temporal pole to the splenium of the corpus callosum.^[20] In contrast to the subiculum proper, which features a relatively homogeneous three-layered allocortical pattern dominated by a single principal cellular band, the presubiculum displays greater laminar differentiation, particularly in its more granular layer II.^[20] Layer II consists of densely packed, small rounded granular neurons often organized into distinct clumps or islands, enhancing its transitional role toward the entorhinal cortex's clustered cell arrangements.^[20] The overall layering includes a prominent molecular layer I, a superficial lamina cellularis (layers II-III), a cell-sparse lamina dissecans in layer IV that divides the cortex into external and internal halves, and a deeper lamina cellularis (layers V-VI) blending into the white matter.^[20] Cellular organization in the presubiculum reflects this transitional nature, with stellate cells predominating in the superficial layers—especially layer II—characterized by their radiating dendrites and role in local circuitry.^[21] Pyramidal cells, featuring apical and basal dendrites suited for projection functions, are more prevalent in deeper layers such as III and V, providing output pathways that align with entorhinal inputs.^[21] These cell types contribute to the region's modular microcircuitry, supporting its integrative position in the hippocampal-entorhinal network.^[22] The presubiculum is anatomically adjacent to the postsubiculum, which some classifications regard as its dorsal extension (corresponding to Brodmann area 48), with both sharing broadly similar cytoarchitectural profiles including granular superficial layers and pyramidal deep layers.^[23] However, distinctions arise in their precise laminar densities and transitional boundaries, marking the postsubiculum as a related but separable entity in comparative anatomy across primates and rodents.^[24] Along the ventral-dorsal gradient, the presubiculum shows variations in layer thickness that mirror patterns in neighboring subicular regions.^[7]

Parasubiculum

The parasubiculum is located medial to the presubiculum within the subicular complex of the hippocampal formation, occupying the ventral shoulder of the hippocampal fissure and bordering the medial entorhinal cortex laterally.^[25] It exhibits a shorter rostrocaudal extent compared to the presubiculum and is generally smaller in overall dimensions, with a typical width of approximately 0.3 mm in rodents.^[26] This positioning places it as a transitional structure between the presubiculum and entorhinal cortex, contributing to the medial organization of the parahippocampal region. A defining feature of the parasubiculum is its prominent layer II, which contains clustered stellate cells organized into distinct patches, often numbering around 15 in rodents and visible through markers such as parvalbumin and NeuN immunoreactivity.^[26] In humans, layer II consists of more widely spaced pyramidal cells that are larger than the granular neurons found in the presubiculum's layer II, though stellate-like islands may intermingle with adjacent entorhinal regions.^[25] These cellular clusters support the region's role in targeted projections, distinguishing it from the more uniform layering in neighboring subregions. The parasubiculum displays unique differences in myelination and fiber tracts relative to other subicular areas, featuring an ill-defined and discontinuous lamina dissecans as well as long "circumcurrent" axons that span its full length, providing global connectivity not seen in the entorhinal cortex.^[26]^[25] This contrasts with the clearer lamina dissecans in the presubiculum and denser fiber meshes in certain entorhinal subfields, emphasizing the parasubiculum's specialized axonal architecture.^[25] Comparatively, the parasubiculum is more prominent and distinctly delineated in rodents, where it forms a well-defined band, than in primates, including humans, where it appears less extensive and often intermingles with entorhinal cortex islands.^[26]^[25] In nonhuman primates, it maintains a continuous band surrounding the entorhinal cortex caudally, but its overall scale is reduced relative to rodent homologues.^[25]

Postsubiculum

The postsubiculum is situated posterior to the presubiculum within the subicular complex, forming a key extension of the hippocampal formation.^[27] It is commonly classified as part of the broader parahippocampal region, contributing to the transitional cortical architecture between the hippocampus and surrounding association areas.^[28] In comparative neuroanatomy across humans, monkeys, and rodents, the postsubiculum maintains a conserved position, though its extent varies: in primates, it reaches toward the cingulate isthmus, while in rodents, it occupies a more dorsal and caudal location adjacent to visual cortices.^[29] Structurally, the postsubiculum features thinner cortical layers relative to neighboring regions like the presubiculum, with a distinct laminar organization that includes a cell-free lamina dissecans between layers III and IV.^[30] Layer II exhibits increased complexity through modular clusters of principal neurons, including calbindin-positive and calbindin-negative populations whose dendrites bundle into layer I, supporting specialized processing capabilities.^[31] These superficial layer features, combined with subtle vascular variations that enhance superficial perfusion, differentiate the postsubiculum from anterior subicular components and underscore its role in posterior cortical integration.^[27] At its posterior boundaries, the postsubiculum integrates seamlessly with the retrosplenial cortex, particularly in rodents where a triangular transitional zone links it to area 29 of the retrosplenial granular cortex and adjacent visual areas.^[28] This adjacency facilitates structural continuity, with the postsubiculum's cytoarchitecture blending into the retrosplenial region's granular layers. In human cytoarchitectonic mapping, the postsubiculum aligns with the dorsal portion of Brodmann area 27.^[29]

Connectivity

The subiculum receives its primary afferent inputs from the CA1 field of the hippocampus, where pyramidal neurons project directly to the subiculum, forming a key link in the hippocampal trisynaptic circuit. These CA1 projections are topographically organized, with proximal CA1 targeting the distal subiculum, mid-CA1 innervating the middle portion, and distal CA1 connecting to the proximal subiculum. Additionally, the entorhinal cortex provides substantial direct inputs to the subiculum's molecular layer, distinct from the perforant path's primary termination in the dentate gyrus; the lateral entorhinal cortex (LEC) projects preferentially to the proximal subiculum, while the medial entorhinal cortex (MEC) targets the distal subiculum. Modest commissural afferents arise from the contralateral subiculum, facilitating bilateral integration via fibers that cross the midline. Efferent projections from the subiculum are diverse and extensive, distributing processed hippocampal information to both cortical and subcortical targets. Key efferents include projections to the nucleus accumbens, where proximal dorsal subiculum targets the rostrolateral portion and proximal ventral subiculum innervates the caudomedial region; the prefrontal cortex, particularly the prelimbic and medial orbital areas from the proximal subiculum; the amygdala, with ventral subiculum connecting to the posterior basomedial and basolateral nuclei; the hypothalamus, via ventral subiculum inputs to the ventromedial nucleus through multiple pathways; and the mammillary bodies, where proximal dorsal subiculum projects to the rostral medial nucleus and distal dorsal to the caudal medial nucleus.^[32] Dorsoventral gradients in connectivity underscore the subiculum's functional specialization, with dorsal regions primarily projecting to cortical structures like the prefrontal cortex and cingulate gyrus, as well as to the nucleus accumbens and mammillary bodies, while ventral regions target subcortical limbic areas including the amygdala and hypothalamus.^[32] This organization supports the subiculum's role as a gateway for hippocampal output, with dorsal pathways emphasizing cognitive domains and ventral ones linking to emotional and homeostatic circuits.^[33] Recent tract-tracing studies in mice have refined these mappings, confirming the subiculum's completion of the trisynaptic circuit through integrated CA1 and entorhinal inputs, while highlighting subregional distinctions such as stronger MEC afferents to the subiculum compared to the prosubiculum's amygdala and LEC dominance.^[34] These findings, using viral vectors and transcriptomic boundaries, emphasize topographic precision in efferents, with dorsal subiculum favoring spatial-related targets like the anteroventral thalamus and ventral areas connecting to reward structures.^[34]

Cellular and molecular features

Neuron types

The subiculum primarily consists of glutamatergic pyramidal neurons, which form the principal output cells of the hippocampal formation. These neurons exhibit a characteristic morphology with a large, polygonal soma from which an apical dendrite extends toward the superficial molecular layer, often branching into tufts, while basal dendrites radiate into the deeper pyramidal cell layer.^[35] This dendritic organization allows pyramidal neurons to integrate inputs from the CA1 region and entorhinal cortex, facilitating their role as projection cells. Approximately 80-90% of subicular neurons are pyramidal, with the remainder comprising local circuit interneurons.^[36] GABAergic interneurons in the subiculum constitute a smaller population and provide inhibitory control over pyramidal cell activity. Key types include basket cells, which are parvalbumin-positive (PV+) and form perisomatic synapses on pyramidal somata and proximal dendrites; chandelier cells, also PV+, that specifically target the axon initial segments of pyramidal neurons; and oriens lacunosum-moleculare (OLM) interneurons, which are somatostatin-positive (SST+) and innervate distal dendrites in the outer molecular layer.^[37] These interneurons are predominantly local, with limited projections outside the subiculum, contrasting with the extensive extrinsic connectivity of pyramidal neurons. Pyramidal cells are distributed across the subicular layers, with their somata concentrated in the pyramidal layer as described in gross structural analyses. Species differences in subicular neuron composition are notable, particularly in interneuron diversity. While rodents exhibit a relatively uniform set of interneurons dominated by PV+ and SST+ types, primates display greater heterogeneity, including expanded populations of VIP+ and other subtypes in association areas like the subiculum, reflecting evolutionary adaptations for complex cognition. This increased diversity in primates may enhance fine-tuned inhibition within hippocampal output pathways.

Firing patterns and electrophysiology

Pyramidal neurons in the subiculum exhibit distinct firing patterns, primarily characterized by bursting and regular spiking modes, which differ from those in the upstream CA1 region. In vitro studies using rat hippocampal slices reveal that approximately 68% of subicular pyramidal neurons display intrinsic bursting behavior upon depolarization, including strong bursting (51%) with multiple high-frequency spike bursts (>200 Hz) and weak bursting (17%) with a single initial burst followed by regular spiking, while 32% fire regular spikes without bursts.^[38] These patterns are driven by a calcium tail current activated after each action potential, which depolarizes the membrane to initiate subsequent spikes within the burst.^[39] Unlike CA1 pyramidal neurons, which predominantly show regular spiking, subicular bursting is modulated by intrinsic conductances such as D-type potassium currents, and blocking these with 4-aminopyridine converts regular-spiking cells to bursting modes.^[38] The transition between bursting and single-spiking modes in subicular pyramidal neurons is strongly influenced by membrane potential. At hyperpolarized levels (around -70 to -80 mV), these neurons fire bursts of 2-5 action potentials, but as the membrane is depolarized (to -60 mV or higher), bursts diminish in amplitude and frequency, eventually giving way to non-adapting tonic single spikes.^[40] This voltage-dependent switching is observed in slice preparations and contributes to the functional diversity of subicular output, with burst-firing cells comprising the majority (up to 80% in some classifications).^[41] Intrinsic properties, such as a prominent afterhyperpolarization (AHP) following bursts—lasting tens of milliseconds and mediated by calcium-activated potassium channels—help regulate spike frequency and prevent excessive firing, with subicular neurons showing faster AHP recovery compared to CA1 (half-width ~0.8 ms for first spike).^[38] In vivo extracellular recordings confirm these modes, with subicular cells often transitioning based on behavioral state and synaptic input.^[42] Subicular neurons, particularly in specific subregions, entrain to hippocampal theta rhythms (4-12 Hz) and exhibit phase precession, where spike timing advances relative to the theta cycle during movement, mirroring patterns in CA1 place cells. In freely moving rats, subicular principal cells fire at progressively earlier theta phases as the animal traverses preferred locations, with phase shifts of up to 360° across a theta cycle, facilitating temporal coding of spatial sequences.^[43] This entrainment is prominent in proximal subiculum and supports coordinated oscillatory activity across the hippocampal formation. In the postsubiculum, head direction cells fire selectively based on the animal's azimuthal orientation, with peak rates (up to 30 Hz) tuned to a preferred direction and broader tuning widths (~90°) compared to entorhinal counterparts, as recorded in vivo during open-field exploration.^[44] Similarly, in the parasubiculum, grid-like cells display periodic firing with hexagonal symmetry (spacing 30-60 cm), representing precursors to medial entorhinal grid cells, with firing rates modulated at theta frequencies during navigation. These electrophysiological signatures highlight the subiculum's role in transforming hippocampal signals into directionally and periodically tuned outputs.

Molecular markers

The subiculum exhibits distinct expression patterns of calcium-binding proteins that contribute to its neuronal identity and functional specialization. Calbindin-D28k is predominantly expressed in pyramidal cells, particularly those clustered in the superficial layer of the proximal subiculum, where it modulates intracellular calcium dynamics and supports synaptic plasticity.^[45] In contrast, parvalbumin is primarily found in a subset of GABAergic interneurons, aiding in the fast regulation of calcium transients and contributing to the precise timing of inhibitory networks within the subiculum.^[46] These proteins not only serve as markers for principal excitatory versus inhibitory neuron populations but also correlate with biophysical properties, such as high-frequency firing in parvalbumin-positive cells.31103-2) Glutamatergic signaling in the subiculum is characterized by a high density of ionotropic receptors, particularly AMPA and NMDA subtypes, which underpin its role as a major output gateway from the hippocampus. AMPA receptors, including GluR1 subunits, show elevated expression at subicular synapses, facilitating rapid excitatory transmission and long-term potentiation.^[47] NMDA receptors, with prominent NR2B subunits, exhibit comparable high densities in subicular regions, enabling calcium influx critical for activity-dependent modifications.^[48] Additionally, the subiculum expresses opioid receptors, notably mu-opioid receptors co-localized with parvalbumin in developing and adult neurons, which modulate inhibitory tone and synaptic efficacy.^[49] Cannabinoid receptors, primarily CB1, are present at very high densities in the subiculum, influencing presynaptic inhibition of glutamate release and contributing to endocannabinoid-mediated plasticity.^[50] Among immediate early genes, Zif268 (also known as Egr1) serves as a key marker for activity-dependent plasticity in the subiculum, with its expression rapidly induced by synaptic activation to orchestrate downstream transcriptional changes supporting memory consolidation.^[51] Recent advances in single-cell RNA sequencing have provided transcriptomic profiles that further delineate molecular markers across subicular subregions. Studies from 2020 identified 27 distinct transcriptomic cell types in the subiculum and prosubiculum, highlighting region-specific expression of genes like those encoding calcium-binding proteins and glutamate receptor subunits, which distinguish proximal from distal subicular identities.^[52] Subsequent work in 2023 and 2025, using single-nucleus approaches on human and mouse hippocampus, revealed enriched markers such as Necab1 in subicular interneurons and upregulated plasticity-related transcripts in principal cells, underscoring subregional heterogeneity in receptor and ion channel profiles.^[53]^[54] These datasets emphasize the subiculum's molecular diversity, with implications for targeted circuit analysis.

Development

Embryonic development

The subiculum originates from the telencephalic neuroepithelium during early embryonic stages, as part of the broader hippocampal primordium that emerges from the medial wall of the developing forebrain. In humans, this derivation begins around the 9th gestational week, when the hippocampal formation first becomes distinguishable from adjacent structures within the dorsal telencephalon.^[55] In rodents, the homologous process occurs earlier, with the hippocampal primordium forming by embryonic day 12.5 (E12.5) in mice, marking the initial specification of this region including subicular precursors within the hippocampal primordium.^[56] This timeline reflects conserved ontogenetic patterns across mammals, including primates, where the subiculum's precursors arise from proliferative zones in the neuroepithelium prior to more differentiated hippocampal fields. Patterning of the subicular anlage and surrounding hippocampal primordium relies on key transcription factors that establish regional identity and guide cellular differentiation. Emx2, a homeobox gene expressed in the dorsal telencephalon, plays a critical role in promoting hippocampal growth and maturation without directly specifying subicular field identity; its absence leads to reduced hippocampal size and disrupted lamination. Similarly, Lhx5, a LIM-homeodomain transcription factor specifically expressed in the hippocampal primordium, is essential for morphogenesis, ensuring proper formation of subicular and other hippocampal structures through regulation of neuronal precursor specification and organization. These factors act combinatorially with others, such as Lhx2, to delineate the boundaries between the subiculum and neocortical regions during early patterning.^[57] Following specification, subicular progenitors undergo radial migration guided by radial glia, which serve as scaffolds extending from the ventricular zone to the pial surface. This glia-guided movement allows postmitotic neurons to reach their laminar positions in the subicular anlage, establishing the foundational cytoarchitecture by late embryogenesis in both rodents (around E16-E18) and humans (by gestational week 12-14).^[58] Disruptions in this migration, often linked to radial glia integrity, can alter subicular positioning relative to adjacent hippocampal fields.^[59]

Postnatal maturation

In rodents, synaptogenesis in the hippocampal formation, including the subiculum, peaks during the second postnatal week (approximately P7–P14), with a broader critical period spanning the first three weeks after birth, during which synaptic density rapidly increases to support circuit refinement.^[60] This process involves sequential formation of GABAergic and glutamatergic synapses on subicular pyramidal neurons, enabling early bursting activity patterns essential for output integration.^[61] In humans, synaptogenesis in the hippocampus and subiculum extends into adolescence, coinciding with a second surge of synaptic formation that refines connectivity for advanced cognitive functions.^[62] Following the synaptogenesis peak, postnatal pruning eliminates excess connections in the subiculum, with developmental apoptosis peaking around P4 in adjacent hippocampal regions and continuing into the second postnatal week in rodents to sculpt functional circuits.^[61] Myelination in the subiculum and hippocampal efferents begins postnatally in rodents, advancing rapidly during weeks 2–3 to enhance signal transmission efficiency.^[63] In humans, this process is protracted, with significant myelination of hippocampal pathways, including subicular outputs, occurring throughout childhood and into early adulthood (up to age 25), supporting prolonged structural maturation.^[63] Environmental factors, such as enriched rearing conditions, influence subicular development by promoting dendritic growth and branching in the hippocampal formation; for instance, short-term exposure to enriched environments enhances dendritic arborization in hippocampal neurons following subicular lesions, indicating compensatory plasticity.^[64] Recent studies (2016–2023) highlight the role of brain-derived neurotrophic factor (BDNF) in subicular plasticity during critical postnatal periods, where BDNF modulates excitability and long-term potentiation in burst-firing subicular neurons around P20–P28 in rodents.^[65] Recent transcriptomic analyses (as of 2023) have further elucidated the microstructural development of subicular subfields in humans using advanced imaging techniques.^[66]

Functions

The dorsal subiculum contains place cells that fire selectively at specific locations during spatial navigation, similar to those in the CA1 region of the hippocampus from which it receives direct monosynaptic inputs.^[67] These place cells integrate spatial signals from CA1, resulting in firing patterns that are more stable and less fragmented than in CA1, enabling robust representation of an animal's position in the environment.^[68] Additionally, subpopulations of neurons in the dorsal subiculum exhibit grid-like spatial periodicity, reflecting integration of inputs from grid cells in the medial entorhinal cortex alongside CA1 place cell activity.^[69] The subiculum contributes to path integration, the process of updating an internal sense of position based on self-motion cues without external landmarks, by transforming and relaying hippocampal spatial representations to form a cognitive map of the environment. Optogenetic studies in rodents during the 2010s demonstrated that activating or silencing subicular projections modulates path integration accuracy and goal-directed navigation, highlighting its role in bridging hippocampal computations with downstream cortical areas for flexible spatial decision-making.^[67] For instance, optogenetic identification of subicular output neurons during free exploration tasks revealed that these cells maintain consistent spatial tuning, supporting the updating of cognitive maps as animals integrate velocity and directional signals. In memory retrieval, the subiculum acts as a gatekeeper, selectively filtering and directing hippocampal outputs to the entorhinal and prefrontal cortices.^[70] This gating mechanism ensures that relevant spatial contexts are prioritized, with subicular neurons modulating the flow of information based on behavioral relevance during navigation-associated learning. Recent functional magnetic resonance imaging (fMRI) studies in humans (2020–2025) have shown subicular activation during virtual navigation tasks, particularly when processing environmental boundaries and self-guided path choices, corroborating its conserved role in translating allocentric spatial representations into navigational behavior.^[71] These findings indicate that subicular engagement scales with task demands, such as integrating visual cues for route planning in simulated environments. A 2025 study in mice provided evidence of spatial periodic firing in subicular pyramidal neurons, supporting their role in integrating grid-like patterns for spatial coding.^[69]

Emotional regulation and stress response

The ventral subiculum (vSub), a primary output region of the ventral hippocampus, sends direct projections to the basolateral amygdala and hypothalamus, thereby modulating fear and anxiety responses. These projections facilitate the integration of contextual information with emotional processing, where vSub neurons encode threat-related cues and influence amygdala activity to regulate conditioned fear expression. For instance, chemogenetic activation of vSub inputs to the bed nucleus of the stria terminalis (BNST), a key anxiety hub connected to the amygdala, reduces context-dependent fear without affecting cued fear, highlighting its role in anxiety-like behaviors.^[72] Similarly, vSub projections to the anterior hypothalamic nucleus drive defensive responses during anxiety-provoking stimuli, such as predator exposure, by coordinating autonomic arousal and behavioral inhibition.^[73] The subiculum plays a critical role in regulating the hypothalamic-pituitary-adrenal (HPA) axis, particularly during chronic stress, by providing inhibitory feedback to glucocorticoid release. Lesions of the vSub enhance HPA axis activation in response to psychogenic stressors, leading to prolonged cortisol elevation, whereas systemic stressors remain unaffected, indicating a selective modulatory function. Under chronic stress conditions, vSub activation promotes dendritic remodeling and altered neuronal excitability, which sustains HPA hyperactivity and contributes to stress adaptation or maladaptation. This regulation occurs via monosynaptic projections from vSub to the paraventricular nucleus of the hypothalamus, suppressing corticotropin-releasing hormone neurons and thereby buffering excessive stress responses. Recent studies confirm that chronic stress induces burst firing in vSub neurons, amplifying HPA output and linking prolonged stress to physiological dysregulation.^[15]^[74]^[75]^[76] In mood disorders, such as depression and anxiety, vSub dysfunction disrupts corticosteroid negative feedback, exacerbating HPA axis hyperactivity. Ventral subicular lesions impair glucocorticoid-mediated inhibition of the HPA axis, resulting in elevated basal corticosterone levels and heightened stress sensitivity, which mirrors symptoms in major depressive disorder. This feedback alteration stems from vSub's role in glucocorticoid receptor signaling, where chronic stress reduces receptor density in vSub neurons, diminishing their inhibitory control over hypothalamic activity. Consequently, patients with mood disorders exhibit vSub atrophy and impaired corticosteroid regulation, contributing to persistent emotional dysregulation.^[77]^[15]^[74] Circuit tracing studies up to 2025 have elucidated the vSub's connections to the nucleus accumbens (NAc), revealing its involvement in balancing reward and stress processing. Monosynaptic rabies virus tracing demonstrates that vSub projections to the NAc medial shell integrate stress signals with reward valuation, where stress-susceptible states enhance vSub-NAc excitability, tipping the balance toward aversion over reward seeking. In 2024 findings, acute stress induces sex-dependent plasticity in these circuits, with males showing reduced vSub-NAc inhibition and females exhibiting heightened sensitivity, influencing stress-reward interactions. These circuits underscore the vSub's pivotal role in maintaining emotional homeostasis amid conflicting stress and motivational demands.^[78]^[76]

Other roles

The subiculum contributes to drug addiction through its glutamatergic projections to the nucleus accumbens (NAc), where it modulates dopamine release and promotes reinstatement of drug-seeking behaviors. Specifically, activation of the ventral subiculum (vSub) drives excitatory input to the NAc shell, disinhibiting dopaminergic neurons in the ventral tegmental area and facilitating context-induced relapse in animal models of addiction.^[79] This pathway is critical for the motivational aspects of addiction, as optogenetic stimulation of vSub-NAc projections enhances behavioral sensitization to psychostimulants.^[80] The subiculum supports working memory via its direct projections to the prefrontal cortex (PFC), facilitating the encoding and integration of spatial information. These vSub-to-PFC afferents are essential for short-term maintenance of task-relevant cues, as disruptions impair performance in spatial working memory tasks without affecting long-term storage.^[81] Projections from the ventral subiculum and CA1 to the medial PFC enable theta-rhythmic synchronization that underlies working memory processes.^[82] Recent computational models (2020–2025) highlight emerging roles for the subiculum in decision-making and sensory integration, where it processes mixed selectivity signals to combine environmental context with behavioral outputs. For instance, subicular neurons exhibit task-dependent mixed selectivity, integrating sensory inputs and action values in a manner consistent with Bayesian inference models of decision-making.^[83] Dorsal subiculum circuits further support robust information routing for value-based choices, as simulated in network models that emphasize theta-phase coding for multisensory convergence.^[84] These findings suggest the subiculum acts as a computational hub for adaptive behavior beyond traditional memory functions.^[85]

Clinical significance

Alzheimer's disease

The subiculum exhibits early accumulation of tau pathology in Alzheimer's disease (AD), often following its initial spread from the entorhinal cortex via trans-synaptic mechanisms.^[86] In postmortem analyses, phosphorylated tau burden is significantly elevated in the subiculum and prosubiculum compared to other hippocampal regions, with this pathology preceding widespread neuronal loss.^[87] Amyloid-beta (Aβ) accumulation also occurs early in the subiculum, particularly in mouse models where it correlates with neuronal and presynaptic damage, and in human cases where fibrillar Aβ deposits trigger local neuroinflammation.^[88]^[89] These changes in the subiculum follow entorhinal involvement, as tau aggregates propagate along connected circuits, with subicular neurons showing increased vulnerability due to their role as an output gateway from the hippocampus.^[90] Lesion studies in rodent models demonstrate that disrupting subicular connectivity reduces Aβ propagation to interconnected regions, such as the entorhinal cortex and nucleus accumbens, thereby limiting plaque spread in AD-like pathology.^[91] This 2014 finding has been corroborated and extended by 2020s human imaging, including positron emission tomography (PET) scans showing subicular tau and Aβ signals as early indicators of disease progression, with flortaucipir PET revealing circuit-specific tau deposition patterns.^[92] In mild cognitive impairment (MCI) and AD patients, magnetic resonance imaging (MRI) reveals pronounced volumetric atrophy in the subiculum, often the earliest detectable change among hippocampal subfields, with faster loss rates in MCI converters to AD.^[93]^[94] This atrophy is linked to cognitive decline, particularly memory impairment, and is more severe in the posterior subiculum.^[95] Recent advances highlight the subiculum as a potential biomarker in anti-amyloid clinical trials, where its volume reductions on high-resolution MRI correlate with CSF Aβ levels and predict progression in early AD stages.^[96]^[97] In trials evaluating anti-Aβ therapies, subicular atrophy serves as a sensitive endpoint for assessing treatment effects on hippocampal integrity.^[96] Additionally, subicular circuit hyperexcitability, driven by amyloid pathology and hyperactivity of parvalbumin interneurons, contributes to early Aβ buildup and network dysfunction in AD models, suggesting targeted modulation as a therapeutic strategy.^[98]^[99] These insights underscore the subiculum's role in AD pathogenesis and its utility for monitoring disease-modifying interventions.

Epilepsy and other disorders

The subiculum exhibits hyperexcitability in temporal lobe epilepsy (TLE), where it frequently serves as the seizure-onset zone due to altered neuronal firing patterns, including bursting activity that propagates epileptiform discharges to downstream structures like the entorhinal cortex.^[2] This hyperexcitability arises from pro-excitatory changes in sodium channel function, particularly Nav1.6, which lowers the threshold for action potential generation in subicular pyramidal neurons, contributing to the initiation and synchronization of seizures in both human patients and animal models of TLE.^[100] In vivo recordings from rodent models of spontaneous seizures confirm that subicular neurons activate early during ictal events, mirroring patterns observed in human TLE where the subiculum's role in epileptogenesis involves reduced inhibition and enhanced excitatory drive.^[101] Seminal studies highlight that position- and cell type-specific vulnerability of subicular interneurons in mesial TLE further exacerbates this network hyperexcitability, leading to impaired seizure termination.^[102] Surgical interventions targeting the subiculum, such as lesioning or resection as part of selective amygdalohippocampectomy, have demonstrated improved seizure control in refractory TLE patients.^[103] In procedures like subtemporal multiple hippocampal transection that spare non-epileptogenic subicular regions, patients exhibit favorable outcomes, including high rates of Engel class I seizure freedom in reported cases, preserving cognitive function while disrupting hyperexcitable circuits.^[104] These resections are particularly effective in cases with unilateral mesial temporal sclerosis, where subicular involvement correlates with reduced secondary epileptogenesis and better post-operative seizure reduction compared to non-targeted approaches.^[105] Beyond epilepsy, subicular hyperactivity contributes to addiction disorders through its projections to the nucleus accumbens, where ventral subiculum stimulation induces persistent dopamine neuron activity in the ventral tegmental area, promoting cocaine-seeking behavior and reinstatement of drug use in rodent models.^[80] This pathway facilitates substance use disorders by enhancing glutamatergic input to the nucleus accumbens medial shell, driving compulsive behaviors during withdrawal and cue-induced relapse, as evidenced by optogenetic studies showing circuit-specific hyperactivity in alcohol and psychostimulant addiction.^[106] Dysfunction in the subiculum is also implicated in schizophrenia, particularly through alterations in ventral subicular circuitry that lead to hippocampal hyperactivity and dysregulation of dopamine systems. Structural imaging studies reveal reduced volumes in subicular and other hippocampal subfields in patients with schizophrenia, with these changes present in early stages and associated with psychotic symptoms. Animal models support a role for ventral subicular overdrive in contributing to positive symptoms like hallucinations and delusions via disrupted interneuronal regulation. Recent reviews highlight the subiculum's involvement in the corticolimbic circuitry underlying schizophrenia, positioning it as a potential target for neuromodulation therapies.^[107]^[79] Recent advancements in neuromodulation, including deep brain stimulation (DBS) of the subiculum, offer promising outcomes for refractory TLE as of 2024-2025, with chronic low-frequency stimulation reducing seizure frequency by approximately 67% over 20 months in patients with hippocampal sclerosis, without significant cognitive side effects.^[108] Ongoing clinical trials evaluating subiculum-targeted DBS in drug-resistant epilepsy report preliminary efficacy in suppressing hypersynchronous activity, positioning it as a reversible alternative to resection for cases where traditional surgery risks broader network disruption.^[109] These techniques leverage the subiculum's role as a gatekeeper in limbic seizure propagation, achieving sustained seizure reduction through modulation of its bursting patterns.^[110]

References

[1]
The subiculum: what it does, what it might do, and what ... - NIH
The subiculum is a pivotal but under-investigated structure positioned between the hippocampus proper and entorhinal and other cortices, as well as a range ...
[2]
Role of the Subiculum in Focal Epilepsy - NCBI - NIH
The subiculum is therefore considered as a bridge, or a relay station, between the hippocampus and parahippocampal cortices, and more widely with several limbic ...Subiculum: Anatomy, Local... · Subiculum Substructures · Subiculum Physiology: More...
[3]
Subiculum - an overview | ScienceDirect Topics
The subiculum is a pivotal structure that controls the output and input activity to the hippocampus. An accumulating body of evidence now suggests that this ...Missing: anatomy | Show results with:anatomy
[4]
a pictorial essay on anatomy and pathology of the hippocampus
Jan 20, 2017 · Normal hippocampal anatomy. The hippocampus is a bilaminar gray matter structure located medially in the temporal lobe that protrudes over the ...<|control11|><|separator|>
[5]
Limbic System: Hippocampus (Section 4, Chapter 5) Neuroscience ...
The subiculum is the transition layer from the hippocampus to the parahippocampal gyrus and changes gradually from three to six layers. The hippocampus ...Missing: boundaries | Show results with:boundaries
[6]
The Anatomy of the Hippocampus - Cerebral Ischemia - NCBI - NIH
The subiculum is continuous with the six-layered neocortex (para-hippocampal gyrus). During development, cornu ammonis and dentate gyrus are folded into the ...
[7]
Homologous laminar organization of the mouse and human subiculum
Feb 12, 2021 · The subiculum (SUB) is a stratified cortical region that is anatomically-positioned as the major output of the hippocampal formation. The SUB ...
[8]
Hippocampus and cornu ammonis: mythonyms that prevail in ...
Apr 3, 2025 · Years later, French anatomists called the structure ram's horns, and a decade later, it was named cornu ammonis. Although both concepts were ...
[9]
Theodor Meynert - Hektoen International
Nov 18, 2021 · Theodor Meynert (1833-1892) (Fig 1) was an eminent if eccentric neuropathologist and psychiatrist. His original work had an impact not just on medicine but on ...Missing: subiculum | Show results with:subiculum
[10]
Multimodal mapping and analysis of the cyto - PubMed Central - NIH
Jan 18, 2020 · For example, whereas Lorente de Nó (1934) identified three subfields within CA1, Vogt and Vogt (1919) described the existence of six subfields.
[11]
Chapter 4 The subiculum: cytoarchitectonically a simple structure ...
The subiculum gives rise to the majority of hippocampal projections to various telencephalic and diencephalic structures.
[12]
The subiculum: Unique hippocampal hub and more - ScienceDirect
The subiculum innervates various downstream regions as a hippocampal output structure. •. The subiculum has unique behavioral and physiological properties. •.Perspective · Synaptic Plasticity · Neural Oscillations<|control11|><|separator|>
[13]
[Morphology of neurons of human subiculum proper] - PubMed
The subiculum has three layers: molecular, pyramidal and polymorphic layer. The dominant cell type in the pyramidal layer was the pyramidal neurons, which ...
[14]
Aversive contexts reduce activity in the ventral subiculum-BNST ...
The dorsal part contains navigation-specific cells (O'Mara et al., 2009) whereas the ventral part of the subiculum (vSUB) is involved in mediating stress and ...
[15]
Are The Dorsal and Ventral Hippocampus functionally distinct ... - PMC
One can interpret these data as being consistent with the dorsal/spatial memory and ventral/emotion distinction. If DH lesions cause a loss of spatial ...Missing: dorsoventral gradient
[16]
Role of the ventral subiculum in stress integration - ScienceDirect
The actions of the ventral and dorsal subiculum on the HPA axis differ in character; the ventral subiculum is critical for stress responsiveness, whereas the.
[17]
Comparative anatomy of the prosubiculum, subiculum, presubiculum, postsubiculum, and parasubiculum in human, monkey, and rodent
### Summary of Gross Structure of Subiculum in Human, Monkey, Rodent
[18]
Cytoarchitecture of the hippocampal head and adjacent subicular...
... cytoarchitectonic and... | Hippocampus, Autoradiography and Dentate ... 2020; Rose 1927;Rosenblum et al. 2024;von Economo and Koskinas 1925;Witter ...
[19]
Hippocampus | Neuroscience Journal | Wiley Online Library
Oct 26, 2017 · Identify the CA1/subiculum boundary based on a change in the density and direction of the pyramidal cell dendrites. Extend the line along ...
[20]
The prosubiculum in the human hippocampus: A rostrocaudal ...
Lorente de Nó (1934) reported that ProS was divided into three subparts, “a,” “b,” and “c.” Rosene and Van Hoesen (1987) described ProS in the monkey and human ...
[21]
The Human Periallocortex: Layer Pattern in Presubiculum ... - Frontiers
Oct 3, 2017 · The presence of this cell free layer “splits” the thickness of the cortex into approximately equal halves. For this reason, Rose (1927) ...
[22]
Presubicular and Parasubicular Cortical Neurons of the Rat - PubMed
Pyramidal cells were recorded in layers III and V of presubiculum and layers II and V of parasubiculum. Superficial layer cells had spiny dendrites that were ...Missing: deeper | Show results with:deeper
[23]
Modular microcircuit organization of the presubicular head-direction ...
Apr 12, 2022 · We find that the mouse dorsal presubiculum (PreS), a key structure in the cortical representation of HD, displays a modular “patch-matrix” organization.
[24]
Subiculum - an overview | ScienceDirect Topics
... Rose, 1929). The subiculum shares the typical cytoarchitectonic characteristics of allocortex with the other hippocampal subfields, i.e., three layers.
[25]
Comparative Anatomy of the Prosubiculum, Subiculum ...
Aug 6, 2025 · These differences clearly mark the postsubiculum, the presubiculum, and the parasubiculum as distinct regions within the subicular cortex and ...
[26]
https://doi.org/10.1523/JNEUROSCI.3749-15.2016
[27]
https://doi.org/10.1016/0006-8993(90)90824-U
[28]
https://onlinelibrary.wiley.com/doi/full/10.1002/cne.23416
[29]
https://pubmed.ncbi.nlm.nih.gov/23839777/
[30]
Comparative anatomy of the prosubiculum, subiculum ... - PubMed
Dec 15, 2013 · This review is an attempt to discuss equivalencies and extent of the five subicular components in human, monkey, and rodent based on available information.Missing: volume shape
[31]
Head-Direction Cells Recorded from the Postsubiculum in Freely ...
Like all 6 layered cortex in the hippo- campal formation, the postsubiculum has a distinctly cell-free lamina dissecans between layers III and IV. Almost ...
[32]
Anatomical organization of presubicular head-direction circuits - PMC
Here we explored the cellular basis of head-direction coding in the rat dorsal presubiculum (PreS). We found that layer2 is composed of two principal cell ...
[33]
https://doi.org/10.1016/S0301-0082(00)00054-X
[34]
https://doi.org/10.1016/j.celrep.2020.107648
[35]
https://pmc.ncbi.nlm.nih.gov/articles/PMC1592135/
[36]
https://journals.physiology.org/doi/10.1152/physrev.00007.2017
[37]
Intrinsic Connectivity of the Rat Subiculum: I. Dendritic Morphology ...
Apical dendritic spines are shown in parts 1 and 2 of each set; basal dendrites are shown in parts 3 and 4 of each set. The most proximal portion of the apical ...
[38]
Hippocampal GABAergic Inhibitory Interneurons
Sep 27, 2017 · In the hippocampus GABAergic local circuit inhibitory interneurons represent only ~10–15% of the total neuronal population.
[39]
10 Role of the Subiculum in Focal Epilepsy - Oxford Academic
As a result, the subiculum is an important limbic structure involved in spatial location and memory. ... Synchronous GABA-mediated potentials and epileptiform ...Subiculum: Anatomy, Local... · Subiculum Substructures · Subiculum Physiology: More...<|control11|><|separator|>
[40]
Resting and Active Properties of Pyramidal Neurons in Subiculum and CA1 of Rat Hippocampus | Journal of Neurophysiology | American Physiological Society
### Summary of Firing Patterns and Intrinsic Properties of Subicular Pyramidal Neurons
[41]
Action Potential Bursting in Subicular Pyramidal Neurons Is Driven ...
May 15, 2001 · A majority of subicular pyramidal neurons communicate via bursts of action potentials, a mode of signaling that may enhance the fidelity of ...<|separator|>
[42]
Repetitive firing and oscillatory activity of pyramidal-like bursting ...
Our findings demonstrate that pyramidal-like subicular neurons generate both bursting and non-adapting tonic firing, depending upon their membrane potential.
[43]
Electrophysiological Characterization of Regular and Burst Firing ...
Aug 25, 2021 · Earlier studies in the subiculum have reported three distinct subtypes of PNs classified as strong bursting (SB), weak bursting (WB), and ...
[44]
Functional Diversity of Subicular Principal Cells during Hippocampal ...
Oct 7, 2015 · Indeed, the membrane potential modulation was negative for all regular firing ... bursting and regular firing neurons in the subiculum (Fig. 5A) ...
[45]
Distributed Spatial Coding and Phase Precession in the Subiculum
Aug 22, 2012 · Hippocampal place cells convey spatial information through a combination of spatially selective firing and theta phase precession.Missing: entrainment | Show results with:entrainment
[46]
Head-direction cells recorded from the postsubiculum in freely moving rats. I. Description and quantitative analysis
**Summary of Key Findings on Head Direction Cells in Postsubiculum:**
[47]
Distribution of the calcium binding proteins, calbindin D-28K and ...
In the subiculum most of calbindin-IR neurons were pyramidal cells which were clustered in the superficial half of the cell layer in the proximal subiculum and ...Missing: molecular markers
[48]
Distribution of neurofilament protein and calcium-binding ... - PubMed
Neurofilament protein and calcium-binding proteins parvalbumin, calbindin, and calretinin are present in morphologically distinct neuronal subpopulations in ...
[49]
Distinct neurexin-cerebellin complexes control AMPA- and NMDA ...
Oct 7, 2022 · At CA1→subiculum synapses, alternatively spliced neurexin-1 (Nrxn1SS4+) and neurexin-3 (Nrxn3SS4+) enhance NMDA-receptors and suppress ...
[50]
Regional changes in the hippocampal density of AMPA and NMDA ...
We found an age-related decline in the number of NMDA receptors in the CA1, CA3 and subicular cell regions of the hippocampus, but not in the FD/hilar region, ...
[51]
Vicia villosa agglutinin labels a subset of neurons coexpressing both ...
Research report. Vicia villosa agglutinin labels a subset of neurons coexpressing both the mu opioid receptor and parvalbumin in the developing rat subiculum.
[52]
Cannabinoid receptors in the human brain: a detailed anatomical ...
The allocortex contained very high concentrations of cannabinoid receptor binding sites in the dentate gyrus, Ammons's horn and subiculum of the hippocampal ...
[53]
Induction of the learning and plasticity‐associated gene Zif268 ...
May 14, 2003 · We investigated whether the expression of the plasticity-associated gene, zif268, was associated with memories retrieved by exposure to a ...
[54]
Distinct Transcriptomic Cell Types and Neural Circuits of the ...
May 19, 2020 · The subicular subfields mainly include the prosubiculum (PS), subiculum proper (Sub), presubiculum (PrS, including postsubiculum [PoS], i.e., ...Missing: cytoarchitecture | Show results with:cytoarchitecture
[55]
NECAB1-3, parvalbumin, calbindin, and calretinin in the ... - Frontiers
Sep 3, 2024 · Among them, calbindin, calretinin, and parvalbumin are extensively used as markers due to their relation to functionally defined neuronal ...
[56]
An integrated single-nucleus and spatial transcriptomics atlas ... - PMC
Jul 30, 2025 · To molecularly define the organization of the subicular complex, we leverage cross-species neuronal circuit data and anatomical insights from ...
[57]
Asymmetric Development of the Hippocampal Region Is Common
Mar 1, 2012 · Hippocampal development begins at GW 8, and the hippocampal sulcus becomes visible at GW 10 as a shallow groove on the medial side of the ...
[58]
Zbtb20 is essential for the specification of CA1 field identity ... - PNAS
Mar 22, 2010 · In summary, Zbtb20 transcripts are detected in the hippocampal primordium as early as E12.5, and thereafter Zbtb20 is expressed specifically in ...Missing: timeline | Show results with:timeline
[59]
The differentiation and integration of the hippocampal dorsoventral ...
May 10, 2023 · It has been demonstrated that both extrinsic signals, such as Wnts and Bmps, and intrinsic factors, including Emx1, Emx2, Lef1, Lhx2, and Lhx5, ...
[60]
Ariadne's Thread in the Developing Cerebral Cortex: Mechanisms ...
Dec 22, 2020 · Radial glia not only generate neurons and glial cells through cell division, they also guide neurons migrating radially from their birthplace to ...Missing: subiculum | Show results with:subiculum
[61]
Extracellular Control of Radial Glia Proliferation and Scaffolding ...
During the development of the cortex, newly generated neurons migrate long-distances in the expanding tissue to reach their final positions.Missing: subiculum | Show results with:subiculum
[62]
Brain development in rodents and humans - PMC - NIH
In rodents, the critical period of synaptogenesis occurs during the first three postnatal weeks of life, peaking during week 2.
[63]
How development sculpts hippocampal circuits and function
In mammals, the selective transformation of transient experience into stored memory occurs in the hippocampus, which develops representations of specific ...
[64]
Maturation of the adolescent brain - PMC - PubMed Central - NIH
The second surge of synaptogenesis occurs in the brain during the adolescent years. Hence, adolescence is one of the most dynamic events of human growth and ...
[65]
Comparative Milestones in Rodent and Human Postnatal Central ...
Sep 26, 2021 · In the rat hippocampus, the majority of granule cell development in the dentate gyrus occurs between birth and PND 21 and continues throughout ...
[66]
Short-term Exposure to an Enriched Environment ... - PubMed
We have evaluated the efficacy of enriched environment on the dendritic morphology and brain-derived neurotrophic factor (BDNF) expression in the hippocampus of ...
[67]
Brain-derived neurotrophic factor differentially modulates excitability ...
We present new data that BDNF regulates neuronal excitability and cellular plasticity in a much more complex manner than previously suggested. Subicular ...
[68]
Robust information routing by dorsal subiculum neurons - Science
Mar 10, 2021 · Subicular neurons demonstrated a noise-resistant representation of place, speed, and trajectory, which was as accurate as or even more accurate ...
[69]
Subicular neurons represent multiple variables of a hippocampal ...
Our findings suggest that the subicular cells integrate multiple task-related factors by using theta rhythm to associate environmental context with action.
[70]
Memory Retrieval: Taking the Route via Subiculum - ScienceDirect
Nov 20, 2017 · The hippocampal formation is crucially involved in memory formation, consolidation and retrieval. · On a broader scale, the subiculum has been ...Missing: gating | Show results with:gating
[71]
Altered Coding of Environmental Boundaries in Human Aging
Oct 16, 2025 · To gain further insight into boundary use during navigation in aging, we re-analyzed data from a self-guided virtual object location memory task ...
[72]
Chemogenetic activation of the ventral subiculum–BNST pathway ...
Aug 3, 2023 · Activation of the vSUB–BNST pathway reduced context but not cued fear expression. These data suggest that the vSUB–BNST pathway contributes to ...
[73]
A circuit from the ventral subiculum to anterior hypothalamic nucleus ...
Dec 3, 2022 · Here we examine the role of the anterior hypothalamic nucleus (AHN), a node in the predator defense network, in anxiety-like behaviors.
[74]
Neural regulation of the stress response: glucocorticoid feedback ...
Lesion studies indicate that destruction of the hippocampus (particularly its primary ventral output, the ventral subiculum) prolongs HPA axis responses to ...
[75]
Neural control of chronic stress adaptation - Frontiers
Aug 7, 2013 · Finally, unpredictable or severe stress exposure may cause long-term and lasting dysregulation of the HPA axis, likely due to altered limbic ...
[76]
https://pmc.ncbi.nlm.nih.gov/articles/PMC11312572/
[77]
Hippocampal Remodeling and Damage by Corticosteroids - Nature
Oct 1, 1999 · This review examines data on the role of corticosteroids in hippocampal remodeling and atrophy in patients with mood disorders.
[78]
Ventral Subiculum Inputs to Nucleus Accumbens Medial Shell ... - NIH
Ventral subiculum (vSUB) is the major output region of ventral hippocampus (vHIPP) and sends major projections to nucleus accumbens medial shell (NAcMS).
[79]
Reward integration in prefrontal-cortical and ventral-hippocampal ...
Apr 15, 2025 · We identify a common neural motif integrating reward history in medial prefrontal cortex and ventral hippocampus inputs.
[80]
Dopamine System Dysregulation by the Ventral Subiculum as the ...
Thus, the ventral subiculum will adjust the responsivity of the dopamine system based on the needs of the organism and the characteristics of the environment.
[81]
Ventral Subiculum Stimulation Promotes Persistent Hyperactivity of ...
Dec 15, 2015 · To test whether NMDA receptor activity in the amBNST in response to HFSvSUB gates the hyperactivity of the tonic firing parameters of the VTA ...<|separator|>
[82]
Pro-excitatory alterations in sodium channel activity facilitate ...
In TLE, subiculum neurons are largely spared, become hyperexcitable and show spontaneous epileptiform activity. The basis for this hyperexcitability is unclear, ...Subiculum Bursting Neurons... · Figure 1. Subiculum Neurons... · Subiculum Bursting Tle...
[83]
Hippocampal-prefrontal input supports spatial encoding in working ...
Here, we find that direct hippocampal-prefrontal afferents are critical for encoding, but not for maintenance or retrieval, of spatial cues.
[84]
Interactions between the Medial Prefrontal Cortex and Hippocampus
Apr 18, 2017 · This review will examine both spatial working memory and long-term memory interactions between the mPFC and HC, concentrating on whether these processes are ...
[85]
Task-dependent mixed selectivity in the subiculum - PubMed Central
May 25, 2021 · The subiculum (SUB) has an important anatomical ... Neural mechanisms of visual working memory in prefrontal cortex of the macaque.<|separator|>
[86]
Robust information routing by dorsal subiculum neurons - PMC
Mar 10, 2021 · We investigated this by identifying axonal projections using optogenetics during large-scale recordings from the rat subiculum, the major ...
[87]
Subicular neurons represent multiple variables of a hippocampal ...
Subicular cells were found along the entire proximodistal axis, whereas CA1 cells were mainly recorded from the intermediate to proximal portions of the CA1. ...
[88]
Trans-synaptic spread of tau pathology in vivo - PubMed - NIH
Feb 1, 2012 · Tauopathy in the brain of patients with Alzheimer's disease starts in the entorhinal cortex (EC) and spreads anatomically in a defined pattern.
[89]
Co-pathologies modify hippocampal protein accumulation patterns ...
Dec 23, 2024 · Alzheimer's disease-related phosphorylated tau predominates in the prosubiculum. Amyloid beta predominates in the CA1 and Lewy body-related ...
[90]
Early neuronal loss and axonal/presynaptic damage is ... - PubMed
Early neuronal loss and axonal/presynaptic damage is associated with accelerated amyloid-β accumulation in AβPP/PS1 Alzheimer's disease mice subiculum. J ...
[91]
Fibrillar Amyloid-β Accumulation Triggers an Inflammatory ... - PubMed
Our results indicate that the presence of fibrillar Aβ deposits correlates with a significant activation of astrocytes and microglia in subiculum and CA1 ...
[92]
Atrophy associated with tau pathology precedes overt cell death in a ...
Oct 16, 2020 · Tau pathology in Alzheimer's disease (AD) first develops in the entorhinal cortex (EC), then spreads to the hippocampus, followed by the ...
[93]
Lesion of the subiculum reduces the spread of amyloid beta ...
Feb 11, 2014 · Lesion of the subiculum reduces the spread of amyloid beta pathology to interconnected brain regions in a mouse model of Alzheimer's disease.
[94]
Lesion of the subiculum reduces the spread of amyloid beta ...
Feb 14, 2024 · Correction: Lesion of the subiculum reduces the spread of amyloid beta pathology to interconnected brain regions in a mouse model of Alzheimer's
[95]
Atrophy of presubiculum and subiculum is the earliest hippocampal ...
Mar 29, 2015 · Atrophy of presubiculum and subiculum is the earliest hippocampal anatomical marker of Alzheimer's disease ... In the MCI group, only the ...
[96]
Distinct Atrophy Pattern of Hippocampal Subfields in Patients with ...
Nov 21, 2020 · Conclusion: The faster volume loss in subiculum and ML suggest a higher risk of disease progression in MCI patients. The hippocampal asymmetry ...
[97]
Atrophy of the Posterior Subiculum Is Associated with Memory ...
Sep 20, 2017 · Both SCD and MCI patients with elevated P-tau or low Aβ42 levels displayed predominantly posterior subicular atrophy in comparisons to control ...
[98]
The Hippocampal Subfield Volume Reduction and Plasma ...
The subiculum-body may be the most clinically meaningful hippocampal subfield, which could be an effective target region for assessing disease progression.Missing: trials | Show results with:trials
[99]
Combined cognitive assessment and automated MRI volumetry ...
Jan 10, 2025 · Combined cognitive assessment and automated MRI volumetry improves the diagnostic accuracy of detecting MCI due to Alzheimer's disease · Authors.<|control11|><|separator|>
[100]
Amyloid pathology-produced unexpected modifications of calcium ...
Alzheimer's disease (AD) is linked to neuronal calcium dyshomeostasis, which is associated with network hyperexcitability. ... The subiculum is affected ...
[101]
Hyperactivity of subicular parvalbumin interneurons drives early ...
Sep 6, 2025 · In this study, using the 5×FAD mouse model, we identified significant amyloid-beta (Aβ) accumulation in the subiculum during the early stages of ...
[102]
Pro-excitatory alterations in sodium channel activity facilitate ...
These findings support an important role of sodium channels, particularly Na v 1.6, in facilitating subiculum neuron hyperexcitability in TLE.
[103]
Early Activation of Ventral Hippocampus and Subiculum during ...
Jul 3, 2013 · The results of the present study reveal similarities in onset sites of spontaneous seizures in patients with temporal lobe epilepsy and ...
[104]
Differential vulnerability of neuronal subpopulations of the ... - Frontiers
Mar 28, 2023 · Regarding the dorsal level, a reduced density of NeuN+ cells was visible in proximal and distal parts of the subiculum (Figure 1J) in comparison ...<|control11|><|separator|>
[105]
Long-Term Seizure Outcome following Resective Surgery for Epilepsy
In this study, we showed that long-term favorable outcome of seizure control following resection surgery can be achieved in more than half of the patients.
[106]
Subtemporal Multiple Hippocampal Transection with/without CA1 ...
These techniques might be useful to obtain good neuropsychological functions and good seizure control for language-dominant temporal lobe epilepsy. Further ...
[107]
Low-frequency Stimulation at the Subiculum Prevents Extensive ...
Jan 20, 2024 · Secondary epileptogenesis is highly associated with poor treatment outcomes including poor seizure control, pharmacoresistance, failure of ...
[108]
Ventral Subiculum Inputs to Nucleus Accumbens Medial Shell ...
Feb 15, 2023 · Ventral subiculum (vSUB) provides robust synaptic input to nucleus accumbens medial shell (NAcMS) and activity of this circuit is linked to substance use ...
[109]
Deep brain stimulation of the subiculum in the treatment for ...
The subiculum may be a target for treating drug-resistant epilepsy. Subicular stimulation reduced seizures by 67 % in our patient over 20 months.
[110]
Subiculum Electrical Stimulation for Temporal Lobe Epilepsy With ...
Device : Subiculum-DBS ON. The surgical intervention named deep brain stimulation is a well-established neurosurgical treatment for drug-resistant epilepsy.
[111]
Subicular circuit in epilepsy: deconstruct heterogeneity for precise ...
Their results showed that ANT-projecting subicular pyramidal neurons are defined as an “amplifier” for controlling the generation of hippocampal seizures via ...