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Dentate gyrus

The dentate gyrus is a seahorse-shaped cortical structure within the hippocampal formation of the medial , serving as the initial relay station in the that processes sensory inputs from the to support memory formation. It features a distinctive trilaminar , including a cell-sparse molecular layer receiving perforant path afferents, a densely packed layer containing approximately 15 million principal s in humans, and a polymorphic layer with and mossy cells. These granule cells extend axons via mossy fibers to the CA3 subfield of the proper, facilitating the transfer of processed information. Beyond its anatomy, the dentate gyrus is renowned for its capacity for , where new granule cells are continuously generated in the subgranular zone and integrate into existing circuits, enhancing neural plasticity and contributing to . This process, unique among most brain regions in adults, peaks in young adulthood and declines with age, influencing learning and mood regulation. Functionally, the dentate gyrus excels in pattern separation, transforming overlapping entorhinal inputs into orthogonal representations through sparse coding—where only 1-2% of granule cells activate per experience—to minimize memory interference and enable precise episodic encoding. It also supports contextual discrimination, such as in fear conditioning, by binding multimodal sensory details via adult-born neurons that exhibit heightened excitability during a critical 4-6 week integration window. Disruptions in dentate gyrus function, including impaired neurogenesis, are implicated in neurological disorders like , , and , underscoring its broader role in brain health.

Anatomy

Location and Morphology

The dentate gyrus constitutes the innermost component of the hippocampal formation, situated within the medial of the brain, where it wraps around the . It lies adjacent to the CA3 region of the proper and the CA4 area, forming a tightly integrated structural unit. This positioning places it deep within the , contributing to the overall C-shaped configuration of the . In coronal sections, the dentate gyrus displays a distinctive C-shaped or V-shaped morphology, characterized by superior and inferior blades that converge at the of the . Along its septotemporal axis, it adopts a curved, banana-like form, extending from rostral septal areas to caudal temporal regions. These features render it a narrow, crenated band of gray matter, with the molecular layer facing the hippocampal sulcus and the inner aspects bordering the hippocampal . The is covered dorsally by the fimbria of the fornix, separated by the fimbrio-dentate sulcus, and positioned near the , though without direct exposure to the ventricular space. In humans, the dentate gyrus spans approximately 4.5 cm in length along the rostrocaudal axis, with individual variations in thickness ranging from 1.75 to 5.21 mm depending on developmental completeness. Its volume is quantifiable through high-resolution MRI techniques. The morphological organization of the dentate gyrus exhibits strong evolutionary conservation across mammals, featuring the characteristic C- or V-shaped bounded by the hippocampal in most , including monotremes, marsupials, and placentals. However, , particularly humans, display enhanced folding and greater complexity compared to or cetaceans, where the structure may be less convoluted or reduced in relative size, adaptations likely tied to expanded cognitive capacities.

Cellular Layers and Types

The dentate gyrus exhibits a trilaminar histological , consisting of three primary layers: the outer molecular layer, the layer, and the inner polymorphic layer (also referred to as the hilus). These layers are distinguished by their distinct cellular compositions and structural features, which contribute to the region's role as a gateway in hippocampal processing. The outer molecular layer is the most superficial division, adjacent to the hippocampal fissure, and primarily contains the apical dendrites of along with afferent fibers from the perforant pathway originating in the . This layer spans approximately 250 μm in thickness and houses a sparse population of and glial processes, but lacks dense neuronal somata. The granule cell layer forms a compact, V-shaped band of densely packed excitatory neurons known as , which constitute the principal cell type of the dentate gyrus and account for 80-90% of all neurons in the structure. These small, elliptical cells (typically 10-18 μm in size) are tightly arranged, with the layer measuring about 0.1-0.2 mm in thickness and containing approximately 15 million per human . Granule cells are and exhibit uniform morphology, with extensive dendritic arborizations extending into the molecular layer. The inner polymorphic layer, or hilus, lies adjacent to the granule cell layer and contains a more heterogeneous population of cells, including excitatory mossy cells and various inhibitory . Mossy cells are large (25-35 μm), spiny projection neurons that provide excitatory input to the inner molecular layer. Inhibitory interneurons in this layer include cells, which form perisomatic synapses onto s (with a basket-to- ratio of approximately 1:100 to 1:300), hilar perforant path-associated cells (PPAs) that target perforant path terminals, and somatostatin-positive cells that contribute to broader dendritic inhibition. In addition to neurons, glial cells are integral to the dentate gyrus architecture, particularly in the subgranular zone at the border of the and polymorphic layers. provide structural support and trophic factors, while are concentrated in this zone, aiding in cellular maintenance. Radial glia-like s are also present in the subgranular zone, exhibiting stem cell characteristics within the glial framework.

Connectivity and Circuits

The dentate gyrus serves as the primary entry point for cortical information into the via the , a canonical pathway that facilitates sequential processing across hippocampal subfields. Layer II neurons of the project to dentate cells through the perforant path, which excites cells and initiates the . axons then extend as mossy fibers to onto pyramidal cells in the CA3 region, while CA3 neurons subsequently project to CA1 via Schaffer collaterals, completing the trisynaptic loop. This ensures a unidirectional flow of information, with the dentate gyrus acting as a critical gateway for entorhinal inputs. The perforant path provides the dominant excitatory input to the dentate gyrus, originating from the and terminating selectively within the molecular layer of the dentate. The medial perforant path arises from the medial and targets the middle third of the molecular layer, synapsing onto proximal dendrites of and conveying predominantly spatial representations. In contrast, the lateral perforant path originates from the lateral and innervates the outer third of the molecular layer on distal dendrites, primarily carrying non-spatial, object-related information. Each receives convergent input from approximately 20-50 perforant path fibers, establishing a sparse pattern where only 1-4% of typically activate in response to stimuli, promoting efficient information encoding. Outputs from the dentate gyrus primarily occur via mossy fibers, unmyelinated axons of that traverse the hilus and form large, specialized boutons in the CA3 . These boutons, characterized by multiple active zones and containing 10-20 synaptic vesicles per release site, synapse onto proximal dendrites of CA3 pyramidal cells via thorny excrescences, providing powerful excitatory drive. Mossy fibers also contact hilar and other CA3 , modulating local inhibition. Local circuits within the dentate further refine processing: mossy cells in the hilus receive inputs and provide recurrent excitation back to ipsilaterally and contralaterally, while hilar form inhibitory loops that preferentially target mossy cells, with over 80% of their synapses dedicated to this inhibition for balanced network dynamics. Commissural connections link the dentate gyri of both hemispheres, primarily through the ventral hippocampal commissure, which carries fibers from hilar regions including mossy cells and to the inner molecular layer of the contralateral dentate. These projections, occupying the innermost portion of the molecular layer, enable interhemisphic coordination and constitute a subset of the broader hippocampal commissural system.

Development

Embryonic and Postnatal Development

The dentate gyrus originates from the ventricular zone of the medial in the hippocampal neuroepithelium during early embryonic stages. In , this emerges around embryonic day 10 to 12.5 (E10–E12.5), driven by signaling from the cortical hem involving Wnt and pathways that specify progenitor fate. In humans, the dentate becomes histologically identifiable by gestational week 9, arising from the dorsal within the hippocampal formation. Progenitor proliferation begins shortly thereafter, with Ki-67-positive cells detectable from week 9 and peaking at week 14 in the dentate gyrus. Granule cell precursors migrate from the primary matrix zone in the ventricular zone to secondary germinal zones near the hippocampal fissure, establishing the dentate anlage. In rodents, this migration occurs between E14 and E15.5, guided by radial glia scaffolds and chemotactic cues such as SDF1/CXCR4, leading to the formation of a primitive tertiary matrix by E17.5. In humans, analogous migration patterns form the dentate anlage by approximately week 20, with progressive folding of the dentate gyrus and cornu ammonis into the temporal lobe starting around weeks 14–15 and nearing completion by weeks 18–20. Morphogenetic events, including blade folding of the granule cell layer, initiate postnatally in rodents around P0–P5, while vascularization of the developing dentate begins around E15 in mice, supporting progenitor survival and niche formation. Postnatal proliferation significantly expands the population, particularly in where approximately 85% of granule cells are generated between postnatal day 0 and 21 (P0–P21). The hilus emerges by P5 as precursors condense and the granule cell layer organizes. Genetic regulators such as Emx2 and Lhx5 are essential for patterning the hippocampal primordium and dentate formation; Emx2 knockouts in mice result in complete of the dentate gyrus due to impaired cortical hem specification, while Lhx5 deficiency leads to hippocampal by disrupting dorsoventral axis establishment. In humans, in the dentate gyrus peaks at birth and declines rapidly in the first year, but continues at detectable levels through early childhood (up to 2–3 years), establishing the basic structural framework before substantial reduction.

Adult Neurogenesis

Adult neurogenesis in the dentate gyrus occurs primarily in the subgranular zone (SGZ) of the granule cell layer, where type-1 radial glia-like neural stem cells (NSCs) serve as the quiescent progenitors that initiate the process. These type-1 cells, characterized by their radial morphology and expression of markers such as Nestin and , give rise to intermediate progenitor cells through asymmetric division. The process unfolds in distinct stages: proliferation of type-2 progenitor cells, which are transient-amplifying cells marked by markers like Tbr2; differentiation into neuroblasts expressing (DCX); and maturation into functional granule cells that integrate into hippocampal circuits, typically by 4-6 weeks post-birth in . During maturation, new neurons extend dendrites toward the molecular layer and axons via the mossy fiber pathway, acquiring mature electrophysiological properties such as spike frequency adaptation. Regulation of adult neurogenesis involves a balance of promoting and inhibitory factors. (BDNF) and (VEGF) enhance and of progenitors, with BDNF signaling through TrkB receptors to support neuronal . Conversely, inhibit by suppressing progenitor via glucocorticoid receptors in the SGZ. Environmental factors like voluntary exercise and enriched conditions robustly increase neurogenesis rates, up to 2-3-fold in mice, through mechanisms involving increased BDNF expression and enhanced vascular support. In humans, the persistence of adult neurogenesis in the dentate gyrus remains debated, with Boldrini et al. (2018) demonstrating ongoing generation of new neurons up to at least age 70+ using postmortem for DCX and PSA-NCAM. In contrast, Sorrells et al. (2018) reported a sharp decline to negligible levels after , based on similar marker analysis and 14C dating. However, recent studies from 2022-2025, including single-nucleus sequencing and improved detection methods, confirm low-level continuation into adulthood, albeit at reduced rates compared to . For example, a 2025 study using single-nucleus sequencing identified proliferating neural progenitors in the adult , supporting ongoing low-level . Some estimates, based on 2013 14C birth-dating analyses, suggest approximately 700 new neurons are added daily to each dentate gyrus in humans, though this rate is debated and recent studies indicate low-level continuation without specifying exact numbers. This process is supported by a vascular niche in the SGZ, where provides essential nutrients and signaling molecules to neural progenitors, as evidenced by postnatal refinements in the dentate gyrus vasculature that persist into adulthood. Upon integration, new granule cells exhibit initial hyperexcitability, with enhanced synaptic plasticity and lower thresholds for long-term potentiation during a critical 4-6 week window, which contributes to heightened circuit adaptability. This phase gradually resolves as the neurons mature, aligning their activity with the existing granule cell population.

Functions

Role in Memory and Learning

The dentate gyrus serves as the primary entry point for cortical inputs into the hippocampal trisynaptic circuit, where it plays a crucial role in the formation of episodic memories by detecting novel stimuli and facilitating their encoding. Granule cells in the dentate gyrus receive perforant path projections from the entorhinal cortex and transform these inputs into sparse, orthogonal representations that are relayed to CA3, enabling the initial processing of contextual and event-specific information essential for episodic memory. Memory consolidation in the dentate gyrus involves the stabilization of engrams through (LTP) at perforant path-granule cell synapses, which is reliably induced by high-frequency stimulation and enhances synaptic efficacy for prolonged periods. This LTP mechanism supports the transition from short-term to storage by increasing the information capacity of dentate synapses and promoting the integration of new experiences into existing neural networks. Lesion studies in demonstrate the dentate gyrus's necessity for hippocampus-dependent learning tasks, including trace fear conditioning—where a temporal gap separates the conditioned stimulus from the unconditioned stimulus—and contextual , with targeted ablations causing significant deficits in memory acquisition and retrieval while sparing non-hippocampal tasks. Immature granule cells, arising from , contribute to memory specificity through their hyperexcitable properties, which allow heightened responsiveness to novel inputs and enhance during encoding, as evidenced by optogenetic manipulations showing improved performance when these cells are selectively activated. Age-related reductions in dentate gyrus neurogenesis correlate strongly with memory impairments, as observed in both aged rodents, where decreased progenitor proliferation leads to deficits in spatial and contextual learning, and in humans, where postmortem analyses reveal diminished granule cell renewal associated with cognitive decline. This decline disrupts the circuit's ability to incorporate new neurons for flexible memory updating. Human evidence from patient H.M., whose 1953 bilateral medial temporal lobe resection removed substantial portions of the hippocampus including the dentate gyrus, resulted in profound anterograde amnesia, underscoring the structure's indispensable role in forming new declarative memories while preserving pre-surgical recollections.

Pattern Separation and Sparse Coding

The dentate gyrus (DG) plays a crucial role in pattern separation, a computational process that transforms similar input representations from the into more distinct, orthogonal output patterns in granule cells, thereby minimizing interference between similar experiences and facilitating memory encoding. This transformation is essential for distinguishing subtle contextual differences, such as similar spatial environments, and is achieved through the sparse activation of granule cells, where only a small responds to any given input. Sparse coding in the DG refers to the low overall activation rate of its cells, with approximately 1-4% of the roughly 1 million cells firing in response to a specific event or stimulus, which supports high-dimensional, non-overlapping representations that enhance discriminability. This sparsity arises from the large number of cells relative to incoming entorhinal afferents, ensuring that similar inputs activate non-overlapping ensembles, thus promoting robust separation. Key mechanisms underlying this include mediated by , such as basket cells and hilar perforant path-associated cells, which suppress overlapping activity, and excitatory feedback from mossy cells that indirectly enhances sparsity through disynaptic inhibition. Recent computational models, including a 2025 multiscale simulation of responses to perforant path stimulation, predict that these dynamics generate engram sparsity, with activation thresholds ensuring only selective cells contribute to separated patterns. Behavioral studies provide evidence for the DG's role in pattern separation, as lesions to the DG impair the ability of to distinguish similar spatial contexts in the Morris water maze, leading to reduced performance in tasks requiring differentiation of subtly altered environments. Optogenetic experiments further demonstrate this function; for instance, silencing s during task performance disrupts the separation of similar contextual cues, as shown in seminal recording studies and confirmed in 2023 mouse models where targeted inhibition of adult-born s altered remapping in downstream CA3 regions. in the DG enhances pattern separation by increasing the sparsity of ensembles, with interventions boosting newborn integration yielding improvements in discrimination accuracy in young adult .

Other Physiological Roles

Beyond its established contributions to memory processes, the dentate gyrus (DG) plays key roles in spatial processing, where inputs from the medial perforant path, originating from the medial , encode grid-like spatial representations that are relayed to granule cells. These grid-like maps in the DG help transform entorhinal inputs into more discrete spatial signals, facilitating the formation of place fields in downstream CA3 pyramidal cells. This processing supports the refinement of environmental navigation without directly overlapping with broader mechanisms. The DG also participates in mood regulation, particularly through cholinergic projections from the medial that modulate anxiety-like behaviors. Activation of these septo-DG circuits in the ventral reduces anxiety responses by enhancing release and altering local circuit dynamics. Additionally, exposure increases the intrinsic excitability of DG granule cells, leading to heightened neuronal firing that can exacerbate . Hyperglycemia, as seen in diabetic conditions, impairs (LTP) at synapses in the DG, reducing and neuronal responsiveness to metabolic signals. Circadian rhythms are another domain of DG involvement, with exhibiting oscillatory patterns of intrinsic excitability that align with sleep-wake cycles, peaking during active phases to synchronize hippocampal activity with daily environmental demands. This 24-hour modulation is mediated by G-protein signaling pathways that control membrane currents and spiking probability in these cells. The DG contributes to sensory integration by detecting novelty in non-spatial stimuli, such as odors, where granule cells classify and discriminate olfactory inputs from the lateral to support rapid adaptation to unfamiliar sensory contexts. For instance, adult-born granule cells enhance odor discrimination accuracy by refining cortical representations into distinct ensembles. Evolutionarily, the DG structure is highly conserved across mammals, serving as a critical adaptation for environmental responsiveness through ongoing and circuit that enable flexible behavioral adjustments to changing habitats. This conservation underscores its role in promoting survival by integrating sensory and contextual cues for adaptive .

Clinical Significance

In Epilepsy and Seizures

The dentate gyrus plays a critical role in the of (TLE), particularly through structural and functional changes that contribute to network hyperexcitability and propagation. In TLE, aberrant reorganization of dentate granule cell axons, known as mossy fiber sprouting, occurs prominently, where mossy fibers extend into the inner molecular layer of the dentate gyrus, forming recurrent excitatory loops that enhance synaptic excitation among granule cells. This sprouting is observed in both human TLE patients and animal models, potentially amplifying susceptibility by creating pro-epileptogenic circuits. Hyperexcitability in the dentate gyrus arises partly from reduced following loss of hilar after . Specifically, selective depletion of somatostatin-positive hilar diminishes inhibition onto granule cells, overwhelming the compensatory capacity of surviving and thereby promoting unbalanced excitation in the network. This loss is a hallmark of post- and contributes to the dentate gyrus's failure as a for hippocampal spread. Seizure initiation often involves the perforant path, where entorhinal inputs stimulate the dentate gyrus, triggering dentate —large-amplitude population events characterized by depolarization and hilar activation. These spikes can propagate downstream to the CA3 via the mossy pathway, facilitating ictal and contributing to the spread of epileptiform activity in TLE. In epileptic conditions, such stimulation evokes abnormal multiple population spikes, contrasting with single spikes in controls, underscoring the dentate gyrus's altered gating function. Animal models of TLE, such as pilocarpine-induced , reliably replicate dentate pathology, including mossy fiber sprouting and dispersion, where the layer abnormally widens due to migration defects. In these models, dispersion is frequently observed, correlating with increased frequency and hippocampal cell loss, providing insights into epileptogenic mechanisms. In human TLE, —a common involving neuronal loss and —is present in approximately 60% of surgical cases and frequently includes dentate gyrus detectable via MRI volumetry. This reflects volume reductions in dentate subfields, contributing to the overall mesial temporal structural damage and refractory characteristic of the disorder. Therapeutic strategies targeting dentate pathology show promise; for instance, silencing dentate cells via genetic approaches inhibits mossy sprouting and reduces epileptogenesis in TLE models, highlighting sprouted fibers as a viable target. Recent optogenetic studies further demonstrate that inhibiting aberrant dentate circuits, including those involving sprouted mossy fibers, can attenuate severity, suggesting potential for circuit-specific interventions in management.

In Neurodegenerative Disorders

The dentate gyrus exhibits early pathological changes in (AD), particularly involving accumulation that begins in the and propagates trans-synaptically to the dentate gyrus via the perforant path. This tau pathology disrupts entorhinal-dentate synapses, contributing to synaptic degeneration and neuronal loss in the outer molecular layer of the dentate gyrus, as observed in early AD cases. Additionally, amyloid-beta oligomers impair (LTP) in the dentate gyrus, affecting both induction and maintenance phases through calcineurin-dependent mechanisms, which exacerbates memory deficits. Recent studies in AD mouse models have highlighted the role of supramammillary nucleus-dentate gyrus circuits, where segregated projections modulate cognitive function, with disruptions linked to disease progression. Structural imaging reveals significant volume loss in the dentate gyrus during (MCI), a prodromal stage of AD, with atrophy patterns in hippocampal subfields including the dentate gyrus correlating strongly with decline. MRI studies show that this subfield-specific predicts progression to AD and reflects underlying neuronal and synaptic loss. Adult neurogenesis in the dentate gyrus declines markedly in , with reduced proliferation of neural stem cells (NSCs) observed in transgenic mouse models such as APP/PS1, where amyloid-beta pathology impairs survival and differentiation, directly linking to cognitive impairments. This reduction in newborn granule cells disrupts pattern separation and contributes to hippocampal-dependent memory deficits characteristic of the disease. In (), accumulation extends beyond the to the , including the dentate gyrus hilus, where it perturbs modulation of synaptic transmission and . This alters innervation in the hilus, impairing function and contributing to non-motor symptoms like cognitive decline, as evidenced in PD models with hippocampal aggregates. Therapeutic strategies targeting dentate gyrus hold promise for , with enhancers such as non-steroidal drugs (NSAIDs) demonstrating potential to restore neural and function in preclinical models and early clinical trials from 2022 to 2024. These interventions, including ibuprofen, reduce and burden, improving hippocampal and cognitive outcomes in patients with mild impairment. In (), expanded repeats in the gene disrupt dentate gyrus development, leading to impaired migration and resultant of the granule cell layer. This early developmental defect, observed in HD mouse models, contributes to hippocampal and cognitive dysfunction, with somatic CAG expansions accelerating neuronal vulnerability in the dentate gyrus over time.

In Psychiatric Conditions

The dentate gyrus plays a in the pathophysiology of , where chronic stress significantly impairs through elevated levels. Studies in animal models demonstrate that prolonged exposure to like leads to a 30–60% reduction in the and of new granule cells in the dentate gyrus subgranular . This suppression is mediated by activation, which inhibits key neurogenic pathways including BDNF signaling and progenitor cell differentiation. Seminal research established that selective serotonin reuptake inhibitors (SSRIs), such as , counteract this effect by increasing the number of BrdU-labeled cells in the dentate gyrus by up to twofold after chronic administration, thereby restoring and contributing to efficacy. More recent investigations confirm this mechanism in human-relevant models, showing that SSRIs enhance dentate gyrus via serotonin-dependent pathways, with implications for . In , hyperactivity of dentate gyrus granule cells disrupts pattern separation, leading to overgeneralization of threat cues and heightened anxious responses. and electrophysiological studies reveal increased neuronal excitability in the dentate gyrus of anxiety models, correlating with impaired ability to distinguish similar contexts and reduced sparse coding efficiency. This hyperexcitability arises from altered inhibition and enhanced inputs, exacerbating and avoidance behaviors characteristic of the disorder. Post-traumatic stress disorder involves dentate gyrus granule cell hyperexcitability, which impairs contextual fear extinction and promotes fear generalization. Postmortem and animal studies following trauma show enhanced action potential firing and prolonged depolarizations in surviving granule cells, driven by mossy fiber sprouting and reduced inhibitory control from hilar interneurons. This leads to deficits in discriminating safe from dangerous environments, perpetuating intrusive memories and hyperarousal symptoms. In , postmortem examinations reveal significant reductions in dentate gyrus granule cell volume, with effect sizes indicating moderate deficits (Cohen's d ≈ 0.57) that disrupt dopamine-glutamate balance and contribute to cognitive impairments. These volumetric changes, observed across multiple cohorts, are associated with decreased transmission in the mossy fiber pathway, potentially exacerbating positive and negative symptoms through impaired hippocampal input processing. Lithium therapy for promotes dentate gyrus , correlating with mood stabilization and . Human studies demonstrate that lithium increases and generation in hippocampal cultures at therapeutic doses, while clinical shows preserved or increased dentate gyrus volume in treated patients. This effect is linked to GSK-3β inhibition and enhanced BDNF expression, supporting lithium's role in mitigating manic-depressive cycles. Human functional MRI studies indicate altered dentate gyrus activation in , often showing hyperconnectivity with prefrontal regions during emotional processing tasks, which may reflect compensatory mechanisms for deficits. In patients with recurrent , this includes increased signal in the dentate gyrus during retrieval, associated with symptom severity and treatment response.

Emerging Research Areas

Recent studies have elucidated the role of the vascular niche in postnatal dentate gyrus (DG) development, demonstrating that angiogenesis continues to refine the neurogenic environment beyond early postnatal stages. A 2025 investigation revealed that the positioning of quiescent neural stem cells (NSCs), marked by GFAP+ SOX2+ MCM2- expression, shifts toward the granule cell layer (GCL) over postnatal development, supported by evolving vascular structures that maintain NSC quiescence while enabling proliferation in response to niche signals. This dynamic vascular remodeling suggests potential therapeutic targets for enhancing adult neurogenesis by modulating angiogenic factors in the DG. Cholinergic projections from the to the DG have emerged as key regulators of NSC and function, particularly under conditions. Research published in 2024 showed that septo-DG cholinergic circuits influence adult NSC and via intermediary cells, with disruptions in models leading to impaired DG organization and reduced neurogenic output. These findings highlight cholinergic modulation as a bridge between environmental stressors and DG plasticity, offering insights into -related cognitive vulnerabilities. Links between DG development and disorders () have been strengthened by genetic studies, notably involving the . A 2024 study demonstrated that conditional deletion of Trio in s results in postnatal DG , characterized by a zigzagged suprapyramidal blade and reduced density, which correlates with deficits in social novelty recognition and other ASD-like behaviors in mice. This implicates Trio-mediated cytoskeletal regulation in DG morphogenesis as a critical factor in circuits. Computational models are advancing understanding of activation within the DG's () context for engram formation. A 2025 Frontiers in study introduced a multiscale model predicting hippocampal responses, including DG firing patterns modulated by stiffness and , which influences engram stability during encoding. Such models provide a framework for simulating how alterations might disrupt sparse coding in pathological states. A spatiotemporal transcriptomic atlas of the DG, published in in 2025, has uncovered layer-specific profiles associated with mood regulation and learning processes. This atlas maps transcriptome-wide changes across the lifespan, identifying distinct transcripts in the GCL and hilus that correlate with synaptic maturation and neuroinflammatory markers, potentially linking DG heterogeneity to affective disorders and cognitive decline. These layer-resolved insights enable targeted exploration of gene-environment interactions in DG function. In (AD) research, segregated circuits from the supramammillary nucleus to the DG are gaining attention for their differential roles in . A 2025 Neuron study optogenetically dissected these inputs, revealing that distinct supramammillary projections to DG subpopulations enhance in healthy mice but fail to compensate for amyloid-induced impairments in AD models, underscoring circuit-specific vulnerabilities. This work points to neuromodulatory interventions targeting these pathways as promising for mitigating AD-related cognitive deficits. Debates on adult human neurogenesis in the DG persist, with single-nucleus RNA-sequencing (snRNA-seq) providing mounting evidence from 2023 to 2025. Integrated snRNA-seq and analyses have identified rare NSC-like populations in the adult DG, though their proliferative capacity remains contentious compared to , with age-related declines in neurogenic markers complicating resolution. Ongoing refinements in sequencing resolution are expected to clarify the extent and functional relevance of DG neurogenesis.