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Structural comparison of the mouse and human hippocampus. (a) Three-dimensional representations of the mouse and human hippocampus showing the relative locations of the DG/CA3 (yellow), CA1 (red), and SUB (green); see also Supplementary Movie 1 or use Schol-AR app). The longitudinal hippocampal axis (red in axes chart) in mouse is oriented dorsoventrally, whereas the human longitudinal axis is rotated into the anterior–posterior axis. In addition the anterior/posterior (septo-temporal; blue color) axis in mice is oriented in the superior-inferior direction in humans. (b) Sagittal view of human brain volume representing the spatial location of all in situ hybridization datasets from the Allen Human Brian Atlas (top). Two tissue blocks containing posterior (middle) and anterior (bottom) parts of the hippocampus (white arrows) are shown overlaid on sagittal 3 T structural MRI images. All images in (b) are from www.brain-map.org. Data viewable with Schol-AR augmented reality app, for details visit https://www.ini.usc.edu/scholar/download.html.
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The subiculum is the major output component of the hippocampal formation and one of the major brain structures most affected by Alzheimer’s disease. Our previous work revealed a hidden laminar architecture within the mouse subiculum. However, the rotation of the hippocampal longitudinal axis across species makes it unclear how the laminar organizat...
Citations
... However, the gross morphological and cytoarchitectural organization of the hippocampus is species-speci c, also within the primate order (Rosene and van Hoesen, 1977; Barbas andBlatt, 1995, Ding andVan Hoesen, 2015). Speci cally, differences have been reported in convolutions, relative width of cell layers and dendritic tree organization (Seress, 2007;Strange et al., 2014), as well as boundary de nition between areas (Fernandez-Lamo et al., 2019; Bienkowski et al., 2021). These differences have a bearing, among other factors, on the differential development of learning, perception, and episodic memory (Zeidman and Maguire, 2016; act as Ca2 + binders and aggregate at acidic pH (Yoo and Albanesi 1991;Videen et al., 1992). ...
... Secretagonin (Tapia-González et al., 2020). and neurotensin(Bienkowski et al., 2021) are useful marker to trace the human CA1-subiculum border.4.2. Histological studies using stereotaxic sampling methods are required for adequate hippocampal segmentation Lesions in the hippocampal formation are known to be involved in the pathogenesis of many diseases like epilepsy(Dam, 1980;Mathern et al., 1996;Thom et al., 2005), schizophrenia(Benes et al., 1998), depression and bipolar disorder(Knable et al., 2004). ...
The primate hippocampus includes the dentate gyrus, cornu ammonis (CA), and subiculum. CA is subdivided into four fields (CA1-CA3, plus CA3h/hilus of the dentate gyrus). with specific pyramidal cell morphology and connections. Work in non-human mammals has shown that hippocampal connectivity is precisely patterned both in the laminar and longitudinal axes. One of the main handicaps in the study of neuropathological semiology in the human hippocampus is the lack of clear laminar and longitudinal borders. The aim of this study was to explore a histochemical segmentation of the adult human hippocampus, integrating field (medio-lateral), laminar, and antero-posterior longitudinal patterning. We provide criteria for field parcellation of the human hippocampus based on the use of Rph3a, PCP4, Chromogranin A and RGS-14 immunostaining. We also provide novel histological data about the composition of species-specific regions of the rostral and caudal ends of the human hippocampus. The data are given with stereotaxic coordinates along the longitudinal axis. This study provides novel insights for a detailed region-specific parcellation of the human hippocampus useful for human brain imaging and neuropathology.
... Furthermore, other studies have shown that the molecular layer, the hypointense band containing neuropil between the DG and SUB, undergoes significant age-related changes in cognitively normal controls and patients with MCI (G A and the inclusion of this region will likely alter volumetric estimates of the subiculum. Our recent study using gene expression patterns suggest the SUB may be located more proximally along the hippocampal transverse axis than the ASHS segmentation indicates (Bienkowski et al., 2019). ...
Alzheimer's disease pathology leads to neurodegeneration within the memory-related structures of the medial temporal cortex and hippocampus. Neurodegeneration also occurs as a part of normative aging and it is unclear whether medial temporal lobe subregions are selectively intact in older adults with preserved cognitive function in comparison to adults who are cognitively impaired. In this study, we used T1-weighted and high-resolution T2-weighted magnetic resonance images to assess age-related volumetric changes to medial temporal lobe regions, including the hippocampal formation and rhinal cortex, in patients with mild cognitive impairment and cognitively normal controls in two independent cohorts. Our results show age was significantly associated with regional atrophy in the hippocampus, but not the rhinal cortex. Additionally, variability in regional medial temporal lobe volume was associated with tau uptake in the rhinal cortex, but not the hippocampus. Together, these results suggest that the rhinal cortex may be more indicative of Alzheimer's disease pathology and can help differentiate from age-related neurodegeneration.
... Ces similitudes entre les mécanismes observés chez les patients atteints de schizophrénie et les souris MAP6 KO sont un argument important soutenant l'idée que l'étude des mécanismes régissant le développement du fornix chez la souris présente une piste de travail intéressante pour la compréhension de l'apparition de défauts de connectivité chez l'homme. De plus une étude datant de cette année a montré des homologies de structure et d'organisation très fortes entre le subiculum de la souris et celui de l'être humain, renforçant le fait qu'il est possible d'effectuer un parallèle entre ces structures au cours du développement chez ces deux espèces (Bienkowski et al., 2021). lorsqu'ils commencent leur migration hors de la zone ventriculaire vers la plaque corticale en développement (Minturn et al., 1995). ...
L'un des objectifs des neurosciences est d'élucider les mécanismes moléculaires impliqués dans la morphogenèse neuronale et conduisant à la mise en place de réseaux neuronaux. Au cours du développement embryonnaire, les neurones établissent entre eux des milliards de connexions via l’émission de dendrites et d’axones qui vont croitre rapidement grâce au cône de croissance situé à leur extrémité. Cette croissance est finement régulée, par les molécules de guidage rencontrées par le cône de croissance, mais dépend également du type de récepteurs pour ces molécules et des effecteurs intracellulaires propres au neurone. Notre laboratoire s’est intéressé à la post-commissure du fornix, un tract composé d’un ensemble d’axones de neurones du subiculum, appartenant à la formation hippocampique, et qui projettent dans les corps mamillaires de l’hypothalamus. La post-commissure du fornix appartient au système limbique et est impliqué dans la mémoire, la gestion des émotions et la navigation. L’altération de l’intégrité de cette post-commissure a été associée à des troubles psychiatriques ainsi qu’à des maladies neurodégénératives. Le développement de la post-commissure est sous le contrôle de la sémaphorine 3E (Sema3E), une molécule de guidage exerçant un effet attractif sur les neurones du subiculum via un complexe de récepteurs constitué de la plexine D1 (PlxD1), de la neuropiline 1 (Nrp1) et du VEGFR2. La liaison de la Sema3E sur la PlxD1 et la transduction du signal via le VEGFR2 induit le recrutement de la voie PI3K/Akt/GSK3β. Cependant les acteurs responsables, in fine, du remodelage du cytosquelette, essentiel pour permettre la croissance axonale, restaient à identifier. Les CRMP1, 2 et 4 ont été caractérisées au départ comme des acteurs de la signalisation sémaphorine 3A, dans laquelle elles régulent, entre autres, la croissance neuritique à travers leur capacité à agir sur le cytosquelette. Ces protéines peuvent en effet se lier avec l’actine et modulent également la dynamique des microtubules via leur déphosphorylation/phosphorylation par GSK3β dont elles sont un substrat. Ces différents éléments tendaient à faire des CRMP des candidats intéressants dont l’implication potentielle dans la signalisation Séma3E méritait d’être étudiée. Parmi ces trois CRMP, seule l’absence de CRMP4 dans des neurones issus du subiculum en culture bloque leur capacité à voir leur croissance axonale stimulée en présence de Séma3E. De plus l’analyse de la neuroanatomie d’embryons de souris CRMP4 révèle que ces animaux présentent à la naissance un développement anormal de la post-commissure du fornix et qui perdure à l’âge adulte. Une altération similaire de ce tract est présente chez des souris double hétérozygote CRMP4/Sema3E, montrant une interaction entre ces deux gènes et entérinant le lien entre CRMP4 et Sema3E in vivo. De manière surprenante, CRMP4 interagit avec le complexe de récepteurs de PlxD1/Nrp1/VEGFR2 seulement à l’intérieur de microdomaines membranaires ayant une composition lipidique particulière et déjà caractérisés dans des mécanismes de guidage, les DRM (detergent resistant membrane). L’ajout de Sema3E sur des neurones du subiculum en culture a permis de mettre en évidence l’inhibition de la phosphorylation de CRMP4, en aval de la voie Akt/GSK3β. De plus nous avons montré que l’intégrité des DRM de même que le domaine de liaison de CRMP4 au cytosquelette étaient nécessaires à l'activité stimulatrice de croissance de la Sema3E, suggérant un rôle pour CRMP4 à l'interface entre les récepteurs de la Sema3E membranaires et le réseau du cytosquelette. Ces différents résultats mettent en évidence le rôle essentiel de CRMP4 dans la signalisation Sema3E conduisant au développement du fornix et contribue à apporter une meilleure compréhension des mécanismes moléculaires impliqués dans l'établissement spécifique des connexions neuronales au cours de la mise en place en place du cerveau.
... As such, specific functional attributes of prosubicular cells and the network connectivity of prosubiculum are not well understood. Prosubiculum has, however, been distinguished from subiculum in rodent brain using transcriptomics [55] and in situ hybridization data [56], and mouse and human may be more similar than they first appear [28,56]. ...
... As such, specific functional attributes of prosubicular cells and the network connectivity of prosubiculum are not well understood. Prosubiculum has, however, been distinguished from subiculum in rodent brain using transcriptomics [55] and in situ hybridization data [56], and mouse and human may be more similar than they first appear [28,56]. ...
As the average human lifespan lengthens, the impact of neurodegenerative disease increases, both on the individual suffering neurodegeneration and on the community that supports those individuals. Studies aimed at understanding the mechanisms of neurodegeneration have relied heavily on observational studies of humans and experimental studies in animals, such as mice, in which aspects of brain structure and function can be manipulated to target mechanistic steps. An animal model whose brain is structurally closer to the human brain, that lives much longer than rodents, and whose husbandry is practical may be valuable for mechanistic studies that cannot readily be conducted in rodents. To demonstrate that the long-lived Seba’s short-tailed fruit bat, Carollia perspicillata, may fit this role, we used immunohistochemical labeling for NeuN and three calcium-binding proteins, calretinin, parvalbumin, and calbindin, to define hippocampal formation anatomy. Our findings demonstrate patterns of principal neuron organization that resemble primate and human hippocampal formation and patterns of calcium-binding protein distribution that help to define subregional boundaries. Importantly, we present evidence for a clear prosubiculum in the bat brain that resembles primate prosubiculum. Based on the similarities between bat and human hippocampal formation anatomy, we suggest that Carollia has unique advantages for the study of brain aging and neurodegeneration. A captive colony of Carollia allows age tracking, diet and environment control, pharmacological manipulation, and access to behavioral, physiological, anatomical, and molecular evaluation.
The circuitry underlying the initiation, maintenance, and coordination of wakefulness, rapid eye movement sleep, and non‐rapid eye movement sleep is not thoroughly understood. Sleep is thought to arise due to decreased activity in the ascending reticular arousal system, which originates in the brainstem and awakens the thalamus and cortex during wakefulness. Despite the conventional association of sleep–wake states with hippocampal rhythms, the mutual influence of the hippocampal formation in regulating vigilance states has been largely neglected. Here, we focus on the subiculum, the main output region of the hippocampal formation. The subiculum, particulary the ventral part, sends extensive monosynaptic projections to crucial regions implicated in sleep–wake regulation, including the thalamus, lateral hypothalamus, tuberomammillary nucleus, basal forebrain, ventrolateral preoptic nucleus, ventrolateral tegmental area, and suprachiasmatic nucleus. Additionally, second‐order projections from the subiculum are received by the laterodorsal tegmental nucleus, locus coeruleus, and median raphe nucleus, suggesting the potential involvement of the subiculum in the regulation of the sleep–wake cycle. We also discuss alterations in the subiculum observed in individuals with sleep disorders and in sleep‐deprived mice, underscoring the significance of investigating neuronal communication between the subiculum and pathways promoting both sleep and wakefulness.
The primate hippocampus includes the dentate gyrus, cornu ammonis (CA), and subiculum. CA is subdivided into four fields (CA1-CA3, plus CA3h/hilus of the dentate gyrus) with specific pyramidal cell morphology and connections. Work in non-human mammals has shown that hippocampal connectivity is precisely patterned both in the laminar and longitudinal axes. One of the main handicaps in the study of neuropathological semiology in the human hippocampus is the lack of clear laminar and longitudinal borders. The aim of this study was to explore a histochemical segmentation of the adult human hippocampus, integrating field (medio-lateral), laminar, and anteroposterior longitudinal patterning. We provide criteria for head-body-tail field and subfield parcellation of the human hippocampus based on immunodetection of Rabphilin3a (Rph3a), Purkinje-cell protein 4 (PCP4), Chromogranin A and Regulation of G protein signaling-14 (RGS-14). Notably, Rph3a and PCP4 allow to identify the border between CA3 and CA2, while Chromogranin A and RGS-14 give specific staining of CA2. We also provide novel histological data about the composition of human-specific regions of the anterior and posterior hippocampus. The data are given with stereotaxic coordinates along the longitudinal axis. This study provides novel insights for a detailed region-specific parcellation of the human hippocampus useful for human brain imaging and neuropathology.
Over the last two decades, the definition of hippocampal area CA2 has evolved from Lorente de Nó's original Golgi-based morphological description with the discovery of specific CA2 gene expression markers. Exploiting the specificity of these molecules has allowed for the genetic dissection of CA2 structure and function in transgenic mice. With this change in criteria, the anatomical boundaries of the CA2 have expanded across the hippocampal axis but the CA2's full rostrocaudal extent is not consistently delineated across atlases. The Hippocampus Gene Expression Atlas (HGEA) provides a comprehensive map of 20 gene expression domains across the entire mouse hippocampus including the CA2. In this commentary, I will review the consensus gene expression patterns that demarcate the expanded CA2 boundaries in the HGEA. Using DropViz single-cell transcriptomics and Mouse Connectome Project connectomics data, I will then suggest potential differences in CA2 cell type heterogeneity and connectivity that may identify and characterize further CA2 subregions.
The medial temporal lobe (MTL) is a complex anatomic region encompassing the hippocampal formation, parahippocampal region, and amygdaloid complex. To enable the reader to understand the well-studied regional anatomic relationships and cytoarchitecture that form the basis of functional connectivity, the authors have created a detailed yet approachable anatomic reference for clinicians and scientists, with special attention to MR imaging. They have focused primarily on the hippocampal formation, discussing its gross structural features, anatomic relationships, and subfield anatomy and further discuss hippocampal terminology and development, hippocampal connectivity, normal anatomic variants, clinically relevant disease processes, and automated hippocampal segmentation software.
Many anxiety disorders can be characterized by abnormalities in detecting and learning about threats, and the inability to reduce fear responses in non-threatening environments. PTSD may be the most representative of context processing pathology, as intrusive memories are experienced in “safe” contexts. The ventral subiculum (vSUB), the main output of the ventral hippocampus, encodes environmental cues and is critical for context processing. The bed nucleus of the stria terminalis (BNST) contributes to anxiety-like behaviors as well as context fear conditioning. Given the important roles of the BNST and the vSUB in these anxiety and fear-related behaviors, and the anatomical connections between the two brain regions, the major aims of this study were to characterize the anatomy and function of the vSUB-BNST pathway. First, using the retrograde tracer cholera toxin, we mapped the topographical arrangement of the vSUB-BNST pathway. Dual retrograde tracing experiments revealed neurons projecting to the BNST and those projecting to the basolateral amygdala are distinct populations. Second, we assessed whether activity in this pathway, as indexed by FOS immunohistochemistry, was modulated by context fear conditioning. Our data reveal less activation of the vSUB-BNST pathway in both males and females in aversive contexts and the greatest activation when animals explored a neutral familiar context. In addition, the vSUB of females contained fewer GABAergic neurons compared to males. These findings suggest that the vSUB-BNST pathway is involved in eliciting appropriate responses to contexts.
