Subicular neurons represent multiple variables of a hippocampal-dependent task by using theta rhythm.

The subiculum is positioned at a critical juncture at the interface of the hippocampus with the rest of the brain. However, the exact roles of the subiculum in most hippocampal-dependent memory tasks remain largely unknown. One obstacle to make comparisons of neural firing patterns between the subiculum and hippocampus is the broad firing fields of the subicular cells. Here, we used spiking phases in relation to theta rhythm to parse the broad firing field of a subicular neuron into multiple subfields to find the unique functional contribution of the subiculum while male rats performed a hippocampal-dependent visual scene memory task. Some of the broad firing fields of the subicular neurons were successfully divided into multiple subfields similar to those in the CA1 by using the theta phase precession cycle. The new paradigm significantly improved the detection of task-relevant information in subicular cells without affecting the information content represented by CA1 cells. Notably, we found that multiple fields of a single subicular neuron, unlike those in the CA1, carried heterogeneous task-related information such as visual context and choice response. Our findings suggest that the subicular cells integrate multiple task-related factors by using theta rhythm to associate environmental context with action.

Novel characterization of the relationship between verbal list-learning outcomes and hippocampal subfields in healthy adults.

The relationship between hippocampal subfield volumetry and verbal list-learning test outcomes have mostly been studied in clinical and elderly populations, and remain controversial. For the first time, we characterized a relationship between verbal list-learning test outcomes and hippocampal subfield volumetry on two large separate datasets of 447 and 1,442 healthy young and middle-aged adults, and explored the processes that could explain this relationship. We observed a replicable positive linear correlation between verbal list-learning test free recall scores and CA1 volume, specific to verbal list learning as demonstrated by the hippocampal subfield volumetry independence from verbal intelligence. Learning meaningless items was also positively correlated with CA1 volume, pointing to the role of the test design rather than word meaning. Accordingly, we found that association-based mnemonics mediated the relationship between verbal list-learning test outcomes and CA1 volume. This mediation suggests that integrating items into associative representations during verbal list-learning tests explains CA1 volume variations: this new explanation is consistent with the associative functions of the human CA1.

Subiculum as a generator of sharp wave-ripples in the rodent hippocampus.

Sharp wave-ripples (SWRs) represent synchronous discharges of hippocampal neurons and are believed to play a major role in memory consolidation. A large body of evidence suggests that SWRs are exclusively generated in the CA3-CA2 network. In contrast, here, we provide several lines of evidence showing that the subiculum can function as a secondary SWRs generator. SWRs with subicular origin propagate forward into the entorhinal cortex as well as backward into the hippocampus proper. Our findings suggest that the output structures of the hippocampus are not only passively facilitating the transfer of SWRs to the cortex, but they also can actively contribute to the genesis of SWRs. We hypothesize that SWRs with a subicular origin may be important for the consolidation of information conveyed to the hippocampus via the temporoammonic pathway.

Interaction of COMT and KIBRA modulates the association between hippocampal structure and episodic memory performance in healthy young adults.

Genetic variations of COMT and KIBRA, which were reported to be expressed in the hippocampus, have been linked to memory function. However, their interaction on the hippocampal structure remains unknown. This study aimed to explore the interaction effects of COMT rs4680 and KIBRA rs17070145 on the hippocampal subfield volumes and test their associations with hippocampus-memory relationship in 187 healthy young adults. Two-way analysis of covariance was applied to the alterations in hippocampal subfield volumes among COMT and KIBRA genotypes. Significant interaction effects of these two genes were found in the right CA1 and CA3 subfields. Among KIBRA C-allele carriers, COMT Val/Val homozygotes showed greater volume in these regions than COMT Met-allele carriers. Furthermore, the slope of the correlation between right CA1 volume and immediate recall on the California Verbal Learning Test-II (CVLT-II) (F = 4.36, p = 0.041) as well as CVLT-II delayed recall (F = 6.44, p = 0.014) were significantly different between COMT Val/Val homozygotes and Met-allele carriers, which were positive or tend to be positive in COMT Val/Val group (CVLT immediate recall, r = 0.319, p = 0.040; CVLT delayed recall, r = 0.304, p = 0.051), but absent in COMT Met-allele carriers (CVLT immediate recall, r = -0.263, p = 0.205; CVLT delayed recall, r = -0.351, p = 0.086). These findings may provide a novel insight into the genetic effects upon the hippocampal structure and suggest that the conjoint effects of COMT and KIBRA played a modulatory role in the hippocampus-episodic memory correlation.

Hippocampal subfields revealed through unfolding and unsupervised clustering of laminar and morphological features in 3D BigBrain.

The internal structure of the human hippocampus is challenging to map using histology or neuroimaging due to its complex archicortical folding. Here, we aimed to overcome this challenge using a unique combination of three methods. First, we leveraged a histological dataset with unprecedented 3D coverage, BigBrain. Second, we imposed a computational unfolding framework that respects the topological continuity of hippocampal subfields, which are traditionally defined by laminar composition. Third, we adapted neocortical parcellation techniques to map the hippocampus with respect to not only laminar but also morphological features. Unsupervised clustering of these features revealed subdivisions that closely resemble gold standard manual subfield segmentations. Critically, we also show that morphological features alone are sufficient to derive most hippocampal subfield boundaries. Moreover, some features showed differences within subfields along the hippocampal longitudinal axis. Our findings highlight new characteristics of internal hippocampal structure, and offer new avenues for its characterization with in-vivo neuroimaging.

The nucleus reuniens of the thalamus sits at the nexus of a hippocampus and medial prefrontal cortex circuit enabling memory and behavior.

The nucleus reuniens of the thalamus (RE) is a key component of an extensive network of hippocampal and cortical structures and is a fundamental substrate for cognition. A common misconception is that RE is a simple relay structure. Instead, a better conceptualization is that RE is a critical component of a canonical higher-order cortico-thalamo-cortical circuit that supports communication between the medial prefrontal cortex (mPFC) and the hippocampus (HC). RE dysfunction is implicated in several clinical disorders including, but not limited to Alzheimer's disease, schizophrenia, and epilepsy. Here, we review key anatomical and physiological features of the RE based primarily on studies in rodents. We present a conceptual model of RE circuitry within the mPFC-RE-HC system and speculate on the computations RE enables. We review the rapidly growing literature demonstrating that RE is critical to, and its neurons represent, aspects of behavioral tasks that place demands on memory focusing on its role in navigation, spatial working memory, the temporal organization of memory, and executive functions.

Elongation of the CA1 field of the septal hippocampus in ungulates.

It is widely assumed that the hippocampal formation seen in laboratory rodents and in primates is typical of that seen in other mammals. We have tested this assumption by examining sections of brains of 56 mammals from 20 mammalian orders from images on the brainmuseum.org website. We found wide variation in the form of the hippocampal formation, the most extreme examples of which are seen in ungulates, which possess an unusual elongation of the distal CA1 of the septal hippocampus. This phenomenon has not previously been reported. In individual coronal sections of the brains of seven artiodactyl ungulates, the pyramidal layer of CA1 is four times as long as CA2 + CA3. In a perissodactyl ungulate (Burchell's zebra) the distal end of CA1 is so large that it forms a number of folds. A similar but less pronounced CA1 elongation was seen in the brains of 14 carnivores. A modest elongation of CA1 is also present in some other placental mammals, notably the elephant shrew, hyrax, capybara, beaver, and rabbit. The elongation was not present in brains of primates, marsupials, or monotremes. The distal part of CA1 has been shown to play a role in object integration into the spatial map. We hypothesize that the distal CA1 enlargement could serve to enhance the ability to integrate objects into spatial navigation, which would be an advantage for migrating herds of ungulates. We suggest that the remarkable elongation of Q5 CA1 represents a major evolutionary specialization in the ungulates.

Protective Effects of 17ß-Estradiol on Hippocampal Myelinated Fibers in Ovariectomized Middle-aged Rats.

Estrogen replacement therapy (ERT) improves hippocampus-dependent cognition. This study investigated the impact of estrogen on hippocampal volume, CA1 subfield volume and myelinated fibers in the CA1 subfield of middle-aged ovariectomized rats. Ten-month-old bilaterally ovariectomized (OVX) female rats were randomly divided into OVX + E2 and OVX + Veh groups. After four weeks of subcutaneous injection with 17ß-estradiol or a placebo, the OVX + E2 rats exhibited significantly short mean escape latency in a spatial learning task than that in the OVX + Veh rats. Using stereological methods, we did not observe significant differences in the volumes of the hippocampus and CA1 subfields between the two groups. However, using stereological methods and electron microscopy techniques, the total length of myelinated fibers and the total volumes of myelinated fibers, myelin sheaths and myelinated axons in the CA1 subfields of OVX + E2 rats were significantly 38.1%, 34.2%, 36.1% and 32.5%, respectively, higher than those in the OVX + Veh rats. After the parameters were calculated according to different diameter ranges, the estrogen replacement-induced remodeling of myelinated fibers in CA1 was mainly manifested in the myelinated fibers with a diameter of <1.0 µm. Therefore, four weeks of continuous E2 replacement improved the spatial learning capabilities of middle-aged ovariectomized rats. The E2 replacement-induced protection of spatial learning abilities might be associated with the beneficial effects of estrogen on myelinated fibers, particularly those with the diameters less than 1.0 µm, in the hippocampal CA1 region of middle-aged ovariectomized rats.

Manual segmentation of the fornix, fimbria, and alveus on high-resolution 3T MRI: Application via fully-automated mapping of the human memory circuit white and grey matter in healthy and pathological aging.

Recently, much attention has been focused on the definition and structure of the hippocampus and its subfields, while the projections from the hippocampus have been relatively understudied. Here, we derive a reliable protocol for manual segmentation of hippocampal white matter regions (alveus, fimbria, and fornix) using high-resolution magnetic resonance images that are complementary to our previous definitions of the hippocampal subfields, both of which are freely available at https://github.com/cobralab/atlases. Our segmentation methods demonstrated high inter- and intra-rater reliability, were validated as inputs in automated segmentation, and were used to analyze the trajectory of these regions in both healthy aging (OASIS), and Alzheimer's disease (AD) and mild cognitive impairment (MCI; using ADNI). We observed significant bilateral decreases in the fornix in healthy aging while the alveus and cornu ammonis (CA) 1 were well preserved (all p's<0.006). MCI and AD demonstrated significant decreases in fimbriae and fornices. Many hippocampal subfields exhibited decreased volume in both MCI and AD, yet no significant differences were found between MCI and AD cohorts themselves. Our results suggest a neuroprotective or compensatory role for the alveus and CA1 in healthy aging and suggest that an improved understanding of the volumetric trajectories of these structures is required.

Environmental Geometry Aligns the Hippocampal Map during Spatial Reorientation.

When a navigator's internal sense of direction is disrupted, she must rely on external cues to regain her bearings, a process termed spatial reorientation. Extensive research has demonstrated that the geometric shape of the environment exerts powerful control over reorientation behavior, but the neural and cognitive mechanisms underlying this phenomenon are not well understood. Whereas some theories claim that geometry controls behavior through an allocentric mechanism potentially tied to the hippocampus, others postulate that disoriented navigators reach their goals by using an egocentric view-matching strategy. To resolve this debate, we characterized hippocampal representations during reorientation. We first recorded from CA1 cells as disoriented mice foraged in chambers of various shapes. We found that the alignment of the recovered hippocampal map was determined by the geometry of the chamber, but not by nongeometric cues, even when these cues could be used to disambiguate geometric ambiguities. We then recorded hippocampal activity as disoriented mice performed a classical goal-directed spatial memory task in a rectangular chamber. Again, we found that the recovered hippocampal map aligned solely to the chamber geometry. Critically, we also found a strong correspondence between the hippocampal map alignment and the animal's behavior, making it possible to predict the search location of the animal from neural responses on a trial-by-trial basis. Together, these results demonstrate that spatial reorientation involves the alignment of the hippocampal map to local geometry. We hypothesize that geometry may be an especially salient cue for reorientation because it is an inherently stable aspect of the environment.

Cell assemblies at multiple time scales with arbitrary lag constellations.

Hebb's idea of a cell assembly as the fundamental unit of neural information processing has dominated neuroscience like no other theoretical concept within the past 60 years. A range of different physiological phenomena, from precisely synchronized spiking to broadly simultaneous rate increases, has been subsumed under this term. Yet progress in this area is hampered by the lack of statistical tools that would enable to extract assemblies with arbitrary constellations of time lags, and at multiple temporal scales, partly due to the severe computational burden. Here we present such a unifying methodological and conceptual framework which detects assembly structure at many different time scales, levels of precision, and with arbitrary internal organization. Applying this methodology to multiple single unit recordings from various cortical areas, we find that there is no universal cortical coding scheme, but that assembly structure and precision significantly depends on the brain area recorded and ongoing task demands.

Sublayer-Specific Coding Dynamics during Spatial Navigation and Learning in Hippocampal Area CA1.

The mammalian hippocampus is critical for spatial information processing and episodic memory. Its primary output cells, CA1 pyramidal cells (CA1 PCs), vary in genetics, morphology, connectivity, and electrophysiological properties. It is therefore possible that distinct CA1 PC subpopulations encode different features of the environment and differentially contribute to learning. To test this hypothesis, we optically monitored activity in deep and superficial CA1 PCs segregated along the radial axis of the mouse hippocampus and assessed the relationship between sublayer dynamics and learning. Superficial place maps were more stable than deep during head-fixed exploration. Deep maps, however, were preferentially stabilized during goal-oriented learning, and representation of the reward zone by deep cells predicted task performance. These findings demonstrate that superficial CA1 PCs provide a more stable map of an environment, while their counterparts in the deep sublayer provide a more flexible representation that is shaped by learning about salient features in the environment. VIDEO ABSTRACT.

Noncanonical connections between the subiculum and hippocampal CA1.

The hippocampal formation is traditionally viewed as having a feedforward, unidirectional circuit organization that promotes propagation of excitatory processes. While the substantial forward projection from hippocampal CA1 to the subiculum has been very well established, accumulating evidence supports the existence of a significant backprojection pathway comprised of both excitatory and inhibitory elements from the subiculum to CA1. Based on these recently updated anatomical connections, such a backprojection could serve to modulate information processing in hippocampal CA1. Here we review the published anatomical and physiological studies on the subiculum to CA1 backprojection, and present recent conclusive anatomical evidence for the presence of noncanonical subicular projections to CA1. New insights into this understudied pathway will improve our understanding of reciprocal CA1-subicular connections and guide future studies on how the subiculum interacts with CA1 to regulate hippocampal circuit activity and learning and memory behaviors. J. Comp. Neurol. 524:3666-3673, 2016. © 2016 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.

Age differences in hippocampal subfield volumes from childhood to late adulthood.

The hippocampus is composed of distinct subfields: the four cornu ammonis areas (CA1-CA4), dentate gyrus (DG), and subiculum. The few in vivo studies of human hippocampal subfields suggest that the extent of age differences in volume varies across subfields during healthy childhood development and aging. However, the associations between age and subfield volumes across the entire lifespan are unknown. Here, we used a high-resolution imaging technique and manually measured hippocampal subfield and entorhinal cortex volumes in a healthy lifespan sample (N = 202), ages 8-82 yrs. The magnitude of age differences in volume varied among the regions. Combined CA1-2 volume evidenced a negative linear association with age. In contrast, the associations between age and volumes of CA3-DG and the entorhinal cortex were negative in mid-childhood and attenuated in later adulthood. Volume of the subiculum was unrelated to age. The different magnitudes and patterns of age differences in subfield volumes may reflect dynamic microstructural factors and have implications for cognitive functions across the lifespan. © 2015 Wiley Periodicals, Inc.

Efecto de la tibolona en la densidad de las espinas dendríticas en el hipocampo de la rata / Effect of tibolone on dendritic spine density in the rat hippocampus

Introducción: El hipoestrogenismo produce estrés oxidativo (EO) y cambios en las neuronas del hipocampo (H) y reduce la densidad de las espinas dendríticas (ED). Estas alteraciones repercuten en la respuesta plástica del H. La terapia de sustitución intraperitoneal con estrógenos revierte estos efectos, pero no se sabe si ocurre lo mismo con la tibolona (TB). El objetivo fue comprobar los efectos neuroprotectivos de la TB administrada por vía oral a largo plazo y su capacidad para revertir la poda de ED de las neuronas piramidales (NP) del CA1 del H. Métodos: Ratas Sprague Dawley jóvenes: distribuidas en 3 grupos: control en proestro (Pro) y 2 grupos ovariectomizados (Ovx), uno suplementado con dosis diaria de TB (1 mg/kg), OvxTB, y otro con vehículo (OvxV), por 40 días. Se analizaron la peroxidación de lípidos y la densidad de las ED en 3 segmentos de la dendrita apical de las NP del CA1 del H. Resultados: La TB no redujo la peroxidación de lípidos en el H, pero recuperó la poda de espinas en las NP del CA1 del H, producida por la ovariectomía. Conclusiones: La terapia de sustitución estrogénica en el hipoestrogenismo por ovariectomía tiene un efecto protector

Introduction: Oestrogen deficiency produces oxidative stress (OS) and changes in hippocampal neurons and also reduces the density of dendritic spines (DS). These alterations affect the plastic response of the hippocampus. Oestrogen replacement therapy reverses these effects, but it remains to be seen whether the same changes are produced by tibolone (TB). The aim of this study was to test the neuroprotective effects of long-term oral TB treatment and its ability to reverse DS pruning in pyramidal neurons (PN) of hippocampal area CA1. Methods: Young Sprague Dawley rats were distributed in 3 groups: a control group in proestrus (Pro) and two ovariectomised groups (Ovx), of which one was provided with a daily TB dose (1 mg/kg), OvxTB and the other with vehicle (OvxV), for 40 days in both cases. We analysed lipid peroxidation and DS density in 3 segments of apical dendrites from PNs in hippocampal area CA1. Results: TB did not reduce lipid peroxidation but it did reverse the spine pruning in CA1 pyramidal neurons of the hippocampus which had been caused by ovariectomy. Conclusions: Oestrogen replacement therapy for ovariectomy-induced oestrogen deficiency has a protective effect on synaptic plasticity in the hippocampus

Differential associations of age with volume and microstructure of hippocampal subfields in healthy older adults.

Hippocampal atrophy in advanced healthy aging has frequently been reported. However, the vulnerability of different hippocampal subfields to age-related atrophy is still a source of debate. Moreover, the association of age with the microstructural integrity of subfields is largely unknown. In this study, we investigated the associations between age and volume as well as microstructural integrity of hippocampal subfields using a three-dimensional (3D) surface mapping approach. Forty-three healthy older adults spanning the age range from 60 to 85 years underwent T1-weighted and diffusion-tensor imaging. Analyses demonstrated an association of age with hippocampal volume predominantly in the most anterior part of the hippocampal head, mainly corresponding to the subiculum. In contrast, the association of age with hippocampal microstructural integrity was mainly confined to regions located in the hippocampal body and tail, corresponding to the subiculum and CA1. Results indicate that age-related volumetric and microstructural alterations within hippocampal subfields provide complementary information and reflect different age-related processes. Potential mechanisms underlying the differential associations of age with volume and microstructure of hippocampal subfields are discussed.

Ultra-high resolution in-vivo 7.0T structural imaging of the human hippocampus reveals the endfolial pathway.

The hippocampus is a very important structure in memory formation and retrieval, as well as in various neurological disorders such as Alzheimer's disease, epilepsy and depression. It is composed of many intricate subregions making it difficult to study the anatomical changes that take place during disease. The hippocampal hilus may have a unique neuroanatomy in humans compared to that in monkeys and rodents, with field CA3h greatly enlarged in humans compared to that in rodents, and a white-matter pathway, called the endfolial pathway, possibly only present in humans. In this study we have used newly developed 7.0T whole brain imaging sequence, balanced steady-state free precession (bSSFP) that can achieve 0.4mm isotropic images to study, in vivo, the anatomy of the hippocampal hilus. A detailed hippocampal subregional segmentation was performed according to anatomic atlases segmenting the following regions: CA4, CA3, CA2, CA1, SRLM (stratum radiatum lacunosum moleculare), alveus, fornix, and subiculum along with its molecular layer. We also segmented a hypointense structure centrally within the hilus that resembled the endfolial pathway. To validate that this hypointense signal represented the endfolial pathway, we acquired 0.1mm isotropic 8-phase cycle bSSFP on an excised specimen, and then sectioned and stained the specimen for myelin using an anti-myelin basic protein antibody (SMI 94). A structure tensor analysis was calculated on the myelin-stained section to show directionality of the underlying fibers. The endfolial pathway was consistently visualized within the hippocampal body in vivo in all subjects. It is a central pathway in the hippocampus, with unknown relevance in neurodegenerative disorders, but now that it can be visualized noninvasively, we can study its function and alterations in neurodegeneration.

Role of hippocampal CA1 area gap junction channels on morphine state-dependent learning.

Morphine produces a state dependent learning. The hippocampus is involved in this kind of learning. Gap junctions (GJs) are involved in some of the effects of morphine and exist in different areas of the hippocampus. We investigated the effects of blocking GJ channels of the hippocampal CA1 area, by means of pre-test bilateral injection of carbenoxolone (CBX), on morphine state dependent learning, using a passive avoidance task. Post-training subcutaneous administrations of morphine (0.5, 2.5, 5 and 7.5 mg/kg) dose-dependently impaired memory retrieval. Pre-test administration of morphine (0.5, 2.5, 5 and 7.5 mg/kg) induced a state-dependent retrieval of the memory acquired under post-training morphine influence. Pre-test injections of CBX (25, 75 and 150 nM) dose dependently prevented memory retrieval by post-training (7.5 mg/kg) and pre-test (0.5, 2.5, 5, 7.5 mg/kg) injections of morphine. The results suggest that intercellular coupling via GJ channels of the hippocampal CA1 area modulates morphine state dependent learning.

An analysis of entorhinal cortex projections to the dentate gyrus, hippocampus, and subiculum of the neonatal macaque monkey.

The entorhinal cortex is the primary interface between the hippocampal formation and neocortical sources of sensory information. Although much is known about the cells of origin, termination patterns, and topography of the entorhinal projections to other fields of the adult hippocampal formation, very little is known about the development of these pathways, particularly in the human or nonhuman primate. We have carried out experiments in which the anterograde tracers (3) H-amino acids, biotinylated dextran amine, and Phaseolus vulgaris leucoagglutinin were injected into the entorhinal cortex in 2-week-old rhesus monkeys (Macaca mulatta). We found that the three fiber bundles originating from the entorhinal cortex (the perforant path, the alvear pathway, and the commissural connection) are all established by 2 weeks of age. Fundamental features of the laminar and topographic distribution of these pathways are also similar to those in adults. There is evidence, however, that some of these projections may be more extensive in the neonate than in the mature brain. The homotopic commissural projections from the entorhinal cortex, for example, originate from a larger region within the entorhinal cortex and terminate much more densely in layer I of the contralateral entorhinal cortex than in the adult. These findings indicate that the overall topographical organization of the main cortical afferent pathways to the dentate gyrus and hippocampus are established by birth. These findings add to the growing body of literature on the development of the primate hippocampal formation and will facilitate further investigations on the development of episodic memory.