Hippocampal Formation Research Articles

Computational cross-species views of the hippocampal formation.

The discovery of place cells and head direction cells in the hippocampal formation of freely foraging rodents has led to an emphasis of its role in encoding allocentric spatial relationships. In contrast, studies in head-fixed primates have additionally found representations of spatial views. We review recent experiments in freely moving monkeys that expand upon these findings and show that postural variables such as eye/head movements strongly influence neural activity in the hippocampal formation, suggesting that the function of the hippocampus depends on where the animal looks. We interpret these results in the light of recent studies in humans performing challenging navigation tasks which suggest that depending on the context, eye/head movements serve one of two roles-gathering information about the structure of the environment (active sensing) or externalizing the contents of internal beliefs/deliberation (embodied cognition). These findings prompt future experimental investigations into the information carried by signals flowing between the hippocampal formation and the brain regions controlling postural variables, and constitute a basis for updating computational theories of the hippocampal system to accommodate the influence of eye/head movements.

Study of the human hippocampal formation: a method for histological and magnetic resonance correlation in perinatal cases.

Little information is available on the magnetic resonance imaging (MRI) determination of the hippocampal formation (HF) during the perinatal period. However, this exploration is increasingly used, which requires defining visible HF landmarks on MRI images, validated through histological analysis. This study aims to provide a protocol to identify HF landmarks on MRI images, followed by histological validation through serial sections of the temporal lobe of the samples examined, to assess the longitudinal extent of the hippocampus during the perinatal period. We examined ex vivo MRI images from nine infant control brain samples. Histological validation of the hippocampal formation MRI images was obtained through serial sectioning and examination of Nissl-stained sections at 250μm intervals along the entire length of the hippocampal formation. Up to six landmarks were identified both in MRI images and the serial histological sections. Proceeding in an anterior to posterior (rostrocaudal) direction, these were as follows: 1) the limen insulae (fronto-temporal junction); 2) the beginning of the amygdaloid complex; 3) the beginning of the lateral ventricle; 4) the caudal limit of the uncus, indicated by the start of the lateral geniculate nucleus (at the level of the gyrus intralimbicus); 5) the end of the lateral geniculate nucleus (beginning of the pulvinar); and 6) the beginning of the fornix. After histological validation of each of these landmarks, the full longitudinal length of the hippocampal formation and distances between landmarks were calculated. No statistically significant differences were found in total length or between landmarks. While the HF is anatomically organized at birth, its annotation is particularly challenging to perform. The histological validation of HF landmarks allows a better understanding of MRI images. The proposed protocol could be useful to assess MRI hippocampal quantification in children and possible variations due to different neurological diseases.

Neonatal exposure to a neuroactive steroid alters low-frequency oscillations in the subiculum.

Preclinical studies have established that neonatal exposure to contemporary sedative/hypnotic drugs causes neurotoxicity in the developing rodent and primate brains. Our group recently reported that novel neuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH) induced effective hypnosis in both neonatal and adult rodents but did not cause significant neurotoxicity in vulnerable brain regions such as subiculum, an output region of hippocampal formation particularly sensitive to commonly used sedatives/hypnotics. Despite significant emphasis on patho-morphological changes, little is known about long-term effects on subicular neurophysiology after neonatal exposure to neuroactive steroids. Hence, we explored the lasting effects of neonatal exposure to 3β-OH on sleep macrostructure as well as subicular neuronal oscillations in vivo and synaptic plasticity ex vivo in adolescent rats. At postnatal day 7, we exposed rat pups to either 10 mg/kg of 3β-OH over a period of 12 h or to volume-matched cyclodextrin vehicle. At weaning age, a cohort of rats was implanted with a cortical electroencephalogram (EEG) and subicular depth electrodes. At postnatal day 30-33, we performed in vivo assessment of sleep macrostructure (divided into wake, non-rapid eye movement, and rapid eye movement sleep) and power spectra in cortex and subiculum. In a second cohort of 3β-OH exposed animals, we conducted ex vivo studies of long-term potentiation (LTP) in adolescent rats. Overall, we found that neonatal exposure to 3β-OH decreased subicular delta and sigma oscillations during non-rapid eye movement sleep without altering sleep macrostructure. Furthermore, we observed no significant changes in subicular synaptic plasticity. Interestingly, our previous study found that neonatal exposure to ketamine increased subicular gamma oscillations during non-rapid eye movement sleep and profoundly suppressed subicular LTP in adolescent rats. Together these results suggest that exposure to different sedative/hypnotic agents during a critical period of brain development may induce distinct functional changes in subiculum circuitry that may persist into adolescent age.

A multi-organ analysis of the role of mTOR in fetal alcohol spectrum disorders.

Alcohol exposure during gestation can lead to fetal alcohol spectrum disorders (FASD), an array of cognitive and physical developmental impairments. Over the past two and a half decades, Mammalian Target of Rapamycin (mTOR) has emerged at the nexus of many fields of study, and has recently been implicated in FASD etiology. mTOR plays an integral role in modulating anabolic and catabolic activities, including protein synthesis and autophagy. These processes are vital for proper development and can have long lasting effects following alcohol exposure, such as impaired hippocampal and synapse formation, reduced brain size, as well as cognitive, behavioral, and memory impairments. We highlight recent advances in the field of FASD, primarily with regard to animal model discoveries and discuss the interaction between alcohol and mTOR in the context of various tissues, including brain, placenta, bone, and muscle, with respect to developmental alcohol exposure paradigms. The current review focuses on novel FASD research within the context of the mTOR signaling and sheds light on mechanistic etiologies at various biological levels including molecular, cellular, and functional, across multiple stages of development and illuminates the dichotomy between the different mTOR complexes and their unique signaling roles.

Standardized extract of Ginkgo biloba enhances memory persistence over time

BackgroundPreviously, our group has shown that treatment with a standardized extract of Ginkgo biloba leaves (EGb) before acquisition/encoding of the conditioned suppression and object recognition task produced recent memory persistence by upregulating CREB-1 and BDNF in the hippocampal formation in a dose-dependent manner. Moreover, memory durability is influenced by processes that occur after encoding. Since the effects of EGb on consolidation processes and memory persistence are unknown, the characterization of these effects will help elucidate both the beneficial and harmful effects of “cognitive enhancers” treatments. MethodsWe investigated the effects of EGb treatment (250, 500 and 1000 mg Kg−1) on consolidation of conditioned lick suppression memory and its persistence, i.e., assessing fear memory retrieval and extinction, 2–4 days (recent long-term memory) or 40–42 days (remote long-term memory) after its acquisition. We also analyzed the compounds in the EGb by UHPLC-HRMS/MS and molecular networking (MN) for dereplication. ResultsWe show, for the first time, that EGb-induced persistence of conditioned suppression. Interestingly, while a higher dose promoted both recent and remote long-term memory persistence without preventing the acquisition of fear extinction memory, the lower dose induced the persistence of original fear remote memory and prevented extinction fear memory formation. The intermediate dose seems to be related to anti-anxiety effects. Furthermore, dereplication of EGb assisted by GNPS detected, besides ginkgolides A, B and D, distinct flavonoids, including quercetin, rutin and nicotiflorin. ConclusionThis study is the first to show that EGb treatment modulates recent and remote fear memory consolidation and its persistence. Additionally, our phytochemical analysis of the EGb corroborates the presence of flavonoids and terpenoids, which may account for the biological effects of EGb on the duration of memory and shed light on its potential as an adjunct to the treatment of memory decline or anxiety disorders.

Differential vulnerability of neuronal subpopulations of the subiculum in a mouse model for mesial temporal lobe epilepsy.

Selective loss of inhibitory interneurons (INs) that promotes a shift toward an excitatory predominance may have a critical impact on the generation of epileptic activity. While research on mesial temporal lobe epilepsy (MTLE) has mostly focused on hippocampal changes, including IN loss, the subiculum as the major output region of the hippocampal formation has received less attention. The subiculum has been shown to occupy a key position in the epileptic network, but data on cellular alterations are controversial. Using the intrahippocampal kainate (KA) mouse model for MTLE, which recapitulates main features of human MTLE such as unilateral hippocampal sclerosis and granule cell dispersion, we identified cell loss in the subiculum and quantified changes in specific IN subpopulations along its dorso-ventral axis. We performed intrahippocampal recordings, FluoroJade C-staining for degenerating neurons shortly after status epilepticus (SE), fluorescence in situ hybridization for glutamic acid decarboxylase (Gad) 67 mRNA and immunohistochemistry for neuronal nuclei (NeuN), parvalbumin (PV), calretinin (CR) and neuropeptide Y (NPY) at 21 days after KA. We observed remarkable cell loss in the ipsilateral subiculum shortly after SE, reflected in lowered density of NeuN+ cells in the chronic stage when epileptic activity occurred in the subiculum concomitantly with the hippocampus. In addition, we show a position-dependent reduction of Gad67-expressing INs by ∼50% (along the dorso-ventral as well as transverse axis of the subiculum). This particularly affected the PV- and to a lesser extent CR-expressing INs. The density of NPY-positive neurons was increased, but the double-labeling for Gad67 mRNA expression revealed that an upregulation or de novo expression of NPY in non-GABAergic cells with a concomitant reduction of NPY-positive INs underlies this observation. Our data suggest a position- and cell type-specific vulnerability of subicular INs in MTLE, which might contribute to hyperexcitability of the subiculum, reflected in epileptic activity.

Cellular Localization and Distribution of TGF-β1, GDNF and PDGF-BB in the Adult Primate Central Nervous System.

The available data on the localization of transforming growth factor beta1 (TGF-β1), glial cell line-derived neurotrophic factor (GDNF), and platelet-derived growth factor-BB (PDGF-BB) in the adult primate and human central nervous system (CNS) are limited and lack comprehensive and systematic information. This study aimed to investigate the cellular localization and distribution of TGF-β1, GDNF, and PDGF-BB in the CNS of adult rhesus macaque (Macaca mulatta). Seven adult rhesus macaques were included in the study. The protein levels of TGF-β1, PDGF-BB, and GDNF in the cerebral cortex, cerebellum, hippocampus, and spinal cord were analyzed by western blotting. The expression and location of TGF-β1, PDGF-BB, and GDNF in the brain and spinal cord was examined by immunohistochemistry and immunofluorescence staining, respectively. The mRNA expression of TGF-β1, PDGF-BB, and GDNF was detected by in situ hybridization. The molecular weight of TGF-β1, PDGF-BB, and GDNF in the homogenate of spinal cord was 25 KDa, 30 KDa, and 34 KDa, respectively. Immunolabeling revealed GDNF was ubiquitously distributed in the cerebral cortex, hippocampal formation, basal nuclei, thalamus, hypothalamus, brainstem, cerebellum, and spinal cord. TGF-β1 was least distributed and found only in the medulla oblongata and spinal cord, and PDGF-BB expression was also limited and present only in the brainstem and spinal cord. Besides, TGF-β1, PDGF-BB, and GDNF were localized in the astrocytes and microglia of spinal cord and hippocampus, and their expression was mainly found in the cytoplasm and primary dendrites. The mRNA of TGF-β1, PDGF-BB, and GDNF was localized to neuronal subpopulations in the spinal cord and cerebellum. These findings suggest that TGF-β1, GDNF and PDGF-BB may be associated with neuronal survival, neural regeneration and functional recovery in the CNS of adult rhesus macaques, providing the potential insights into the development or refinement of therapies based on these factors.

An integrative view of human hippocampal function: Differences with other species and capacity considerations.

We describe an integrative model that encodes associations between related concepts in the human hippocampal formation, constituting the skeleton of episodic memories. The model, based on partially overlapping assemblies of "concept cells," contrast markedly with the well-established notion of pattern separation, which relies on conjunctive, context dependent single neuron responses, instead of the invariant, context independent responses found in the human hippocampus. We argue that the model of partially overlapping assemblies is better suited to cope with memory capacity limitations, that the finding of different types of neurons and functions in this area is due to a flexible and temporary use of the extraordinary machinery of the hippocampus to deal with the task at hand, and that only information that is relevant and frequently revisited will consolidate into long-term hippocampal representations, using partially overlapping assemblies. Finally, we propose that concept cells are uniquely human and that they may constitute the neuronal underpinnings of cognitive abilities that are much further developed in humans compared to other species.

Identification of the pathogenesis features of various phenotypes of multiple sclerosis based on the study of the morphological functional connectivity of subcortical gray matter structures

Objective. The aim of study: to investigate the functional changes in the thalamus, amygdala, and hippocampal region using functional MRI at rest and determine their clinical significance in various types of MS.Materials and methods. 68 patients with a diagnosis of multiple sclerosis (MS) were examined: 40 patients with a relapsing-remitting MS (RRMS) in remission and 28 patients with secondary progressive MS without signs of activity and progression (SPMS). The control group consisted of 10 healthy people of the appropriate age and gender without neurological and somatic diseases. All patients and controls underwent MRI of the brain on a Siemens Tim Trio tomograph with a magnetic field induction of 3.0 TL, using contrast enhancement, T1 gradient echo protocols, REST-BOLD, and subsequent processing of the data obtained using CONN 19с software.Results and conclusion. In the course of the study, various patterns of changes in functional connections were found: in patients with RRMS, there is a decrease in the intensity of connections of the thalamus with other brain structures and a decrease in their number. In patients with RRMS, a greater number and intensity of connections within the thalamus and other structures of the brain were detected compared to SPMS. In patients with RRMS, there is a significant decrease in the connectivity parameters of the hippocampal formation, which is expressed on the left, and in the case of the amygdala complex – on the right, this is manifested in a total decrease in the intensity of connections with other brain structures and a decrease in their number. Thus, the method of functional MRI at rest makes an additional contribution to the understanding of neurodegenerative processes in various phenotypes of multiple sclerosis.

Cannabinoid regulation of neurons in the dentate gyrus during epileptogenesis: Role of CB1R-associated proteins and downstream pathways.

The hippocampal formation plays a central role in the development of temporal lobe epilepsy (TLE), a disease characterized by recurrent, unprovoked epileptic discharges. TLE is a neurologic disorder characterized by acute long-lasting seizures (i.e., abnormal electrical activity in the brain) or seizures that occur in close proximity without recovery, typically after a brain injury or status epilepticus. After status epilepticus, epileptogenic hyperexcitability develops gradually over the following months to years, resulting in the emergence of chronic, recurrent seizures. Acting as a filter or gate, the hippocampal dentate gyrus (DG) normally prevents excessive excitation from propagating through the hippocampus, and is considered a critical region in the progression of epileptogenesis in pathological conditions. Importantly, lipid-derived endogenous cannabinoids (endocannabinoids), which are produced on demand as retrograde messengers, are central regulators of neuronal activity in the DG circuit. In this review, we summarize recent findings concerning the role of the DG in controlling hyperexcitability and propose how DG regulation by cannabinoids (CBs) could provide avenues for therapeutic interventions. We also highlight possible pathways and manipulations that could be relevant for the control of hyperexcitation. The use of CB compounds to treat epilepsies is controversial, as anecdotal evidence is not always validated by clinical trials. Recent publications shed light on the importance of the DG as a region regulating incoming hippocampal excitability during epileptogenesis. We review recent findings concerning the modulation of the hippocampal DG circuitry by CBs and discuss putative underlying pathways. A better understanding of the mechanisms by which CBs exert their action during seizures may be useful to improve therapies.

Silencing hippocampal CA2 reduces behavioral flexibility in spatial learning.

The hippocampus is a key structure involved in learning and remembering spatial information. However, the extent to which hippocampal region CA2 is involved in these processes remains unclear. Here, we show that chronically silencing dorsal CA2 impairs reversal learning in the Morris water maze. After platform relocation, CA2-silenced mice spent more time in the vicinity of the old platform location and less time in the new target quadrant. Accordingly, behavioral strategy analysis revealed increased perseverance in navigating to the old location during the first day and an increased use of non-spatial strategies during the second day of reversal learning. Confirming previous indirect indications, these results demonstrate that CA2 is recruited when mice must flexibly adapt their behavior as task contingencies change. We discuss how these findings can be explained by recent theories of CA2 function and outline testable predictions to understand the underlying neural mechanisms. Demonstrating a direct involvement of CA2 in spatial learning, this work lends further support to the notion that CA2 plays a fundamental role in hippocampal information processing.

Hippocampal Noradrenaline Is a Positive Regulator of Spatial Working Memory and Neurogenesis in the Rat

Loss of noradrenaline (NA)-rich afferents from the Locus Coeruleus (LC) ascending to the hippocampal formation has been reported to dramatically affect distinct aspects of cognitive function, in addition to reducing the proliferation of neural progenitors in the dentate gyrus. Here, the hypothesis that reinstating hippocampal noradrenergic neurotransmission with transplanted LC-derived neuroblasts would concurrently normalize both cognitive performance and adult hippocampal neurogenesis was investigated. Post-natal day (PD) 4 rats underwent selective immunolesioning of hippocampal noradrenergic afferents followed, 4 days later, by the bilateral intrahippocampal implantation of LC noradrenergic-rich or control cerebellar (CBL) neuroblasts. Starting from 4 weeks and up to about 9 months post-surgery, sensory-motor and spatial navigation abilities were evaluated, followed by post-mortem semiquantitative tissue analyses. All animals in the Control, Lesion, Noradrenergic Transplant and Control CBL Transplant groups exhibited normal sensory-motor function and were equally efficient in the reference memory version of the water maze task. By contrast, working memory abilities were seen to be consistently impaired in the Lesion-only and Control CBL-Transplanted rats, which also exhibited a virtually complete noradrenergic fiber depletion and a significant 62-65% reduction in proliferating 5-bromo-2'deoxyuridine (BrdU)-positive progenitors in the dentate gyrus. Notably, the noradrenergic reinnervation promoted by the grafted LC, but not cerebellar neuroblasts, significantly ameliorated working memory performance and reinstated a fairly normal density of proliferating progenitors. Thus, LC-derived noradrenergic inputs may act as positive regulators of hippocampus-dependent spatial working memory possibly via the concurrent maintenance of normal progenitor proliferation in the dentate gyrus.

Purpose in life promotes resilience to age-related brain burden in middle-aged adults

BackgroundDisease-modifying agents to counteract cognitive impairment in older age remain elusive. Hence, identifying modifiable factors promoting resilience, as the capacity of the brain to maintain cognition and function with aging and disease, is paramount. In Alzheimer’s disease (AD), education and occupation are typical cognitive reserve proxies. However, the importance of psychological factors is being increasingly recognized, as their operating biological mechanisms are elucidated. Purpose in life (PiL), one of the pillars of psychological well-being, has previously been found to reduce the deleterious effects of AD-related pathological changes on cognition. However, whether PiL operates as a resilience factor in middle-aged individuals and what are the underlying neural mechanisms remain unknown.MethodsData was obtained from 624 middle-aged adults (mean age 53.71 ± 6.9; 303 women) from the Barcelona Brain Health Initiative cohort. Individuals with lower (LP; N = 146) and higher (HP; N = 100) PiL rates, according to the division of this variable into quintiles, were compared in terms of cognitive status, a measure reflecting brain burden (white matter lesions; WMLs), and resting-state functional connectivity, examining system segregation (SyS) parameters using 14 common brain circuits.ResultsNeuropsychological status and WMLs burden did not differ between the PiL groups. However, in the LP group, greater WMLs entailed a negative impact on executive functions. Subjects in the HP group showed lower SyS of the dorsal default-mode network (dDMN), indicating lesser segregation of this network from other brain circuits. Specifically, HP individuals had greater inter-network connectivity between specific dDMN nodes, including the frontal cortex, the hippocampal formation, the midcingulate region, and the rest of the brain. Greater functional connectivity in some of these nodes positively correlated with cognitive performance.ConclusionExpanding previous findings on AD pathology and advanced age, the present results suggest that higher rates of PiL may promote resilience against brain changes already observable in middle age. Furthermore, having a purposeful life implies larger functional integration of the dDMN, which may potentially reflect greater brain reserve associated to better cognitive function.

Neural mechanisms for spatial cognition across vertebrates

The ability to navigate the world is a critical cognitive skill that most animals use to find food, shelter, and mates. Understanding the neural basis of navigation requires probing how the brain encodes spatial information through the study of the activity of single neurons and neuronal populations. Classically in vertebrates, studies have centered on the rodent hippocampal formation, which led to the discovery of place, grid, head direction and other cell types. However, since navigation skills are essential to almost all vertebrates, spatial cognition in different species also needs to be explored. In recent years, as a result of advances in technology, new data have emerged on the ways in which space is represented during navigation in the brains of vertebrates other than rodents, including teleost fish, birds, and other mammal species. Here, we review the state of the art on the neural representation of an animal’s position and motion across vertebrates at the level of single neurons. We argue that it is time to pool information across vertebrates to identify the underlying algorithms that lead to successful navigation. Although rodent-based data are important, findings in rodents are unlikely to cover the full spectrum of neural computations supporting navigation strategies in the vertebrate kingdom. Studying other species can shed light on length scales such as in large environments, and different scenarios such as naturalistic environments that are hard to carry out in rodents. In addition, a rodent-centric view may neglect the fact that different species are likely to represent positions in the world in ways that do not exist in mammals. Finally, we provide an outlook for the future which includes prediction about findings in unexplored species, and the opportunities for discoveries and understanding in this field.

Organization of projections from the entorhinal cortex to the hippocampal formation of the Egyptian fruit bat Rousettus aegyptiacus.

The hippocampal formation and entorhinal cortex are crucially involved in learning and memory as well as in spatial navigation. The conservation of these structures across the entire mammalian lineage demonstrates their importance. Information on a diverse set of spatially tuned neurons has become available, but we only have a rudimentary understanding of how anatomical network structure affects functional tuning. Bats are the only order of mammals that have evolved true flight, and with this specialization comes the need to navigate and behave in a three dimensional (3D) environment. Spatial tuning of cells in the entorhinal-hippocampal network of bats has been studied for some time, but whether the reported tuning in 3D is associated with changes in the entorhinal-hippocampal network is not known. Here we investigated the entorhinal-hippocampal projections in the Egyptian fruit bat (Rousettus aegyptiacus), by injecting chemical anterograde tracers in the entorhinal cortex. Detailed analyses of the terminations of these projections in the hippocampus showed that both the medial and lateral entorhinal cortex sent projections to the molecular layer of all subfields of the hippocampal formation. Our analyses showed that the terminal distributions of entorhinal fibers in the hippocampal formation of Egyptian fruit bats-including the proximo-distal and longitudinal topography and the layer-specificity-are similar to what has been described in other mammalian species such as rodents and primates. The major difference in entorhinal-hippocampal projections that was described to date between rodents and primates is in the terminal distribution of the DG projection. We found that bats have entorhinal-DG projections that seem more like those in primates than in rodents. It is likely that the latter projection in bats is specialized to the behavioral needs of this species, including 3D flight and long-distance navigation.

Differential effects of emotional valence on mnemonic performance with greater hippocampal maturity.

The hippocampal formation (HF) facilitates declarative memory, with subfields providing unique contributions to memory performance. Maturational differences across subfields facilitate a shift toward increased memory specificity, with peripuberty sitting at the inflection point. Peripuberty is also a sensitive period in the development of anxiety disorders. We believe HF development during puberty is critical to negative overgeneralization, a common feature of anxiety disorders. To investigate this claim, we examined the relationship between mnemonic generalization and a cross-sectional pubertal maturity index (PMI) derived from partial least squares correlation (PLSC) analyses of subfield volumes and structural connectivity from T1-weighted and diffusion-weighted scans, respectively. Participants aged 9-14 yr, from clinical and community sources, performed a recognition task with emotionally valent (positive, negative, and neutral) images. HF volumetric PMI was positively associated with generalization for negative images. Hippocampal-medial prefrontal cortex connectivity PMI evidenced a behavioral relationship similar to that of the HF volumetric approach. These findings reflect a novel developmentally related balance between generalization behavior supported by the hippocampus and its connections with other regions, with maturational differences in this balance potentially contributing to negative overgeneralization during peripuberty.

Moderate Copper Deprivation during Gestation and Lactation Affects Dentate Gyrus and Hippocampal Maturation in Immature Male Rats

The hippocampal formation (HF) is involved in higher brain functions including learning and declarative memory. The possibility that dietary copper has a role in the morphological development, and therefore the function of the HF, has received little attention. A rat model of tiered copper deficiency, initiated during gestation, was employed to determine the susceptibility of the HF, regions of which develop postnatally, to copper deficiency. At postnatal 23, pups whose dams had received either 1.8 or 1.4 mg Cu/kg diet during both gestation and lactation, compared with offspring of a group that had received 4.3 mg Cu/kg diet during both periods had, significantly more cell nuclei in the infrapyrimidal arm of the dentate gyrus. Offspring of rats fed 1.4 mg Cu/kg diet, but not those fed 1.8 mg/kg, compared with those fed 4.3 mg/kg, exhibited smaller, shorter, and narrower cell nuclei in the infrapyrimidal and suprapyrimidal arms of the dentate gyrus and smaller cell nuclei in region CA3c of the hippocampus. A fourth group (gestation, 1.8 mg Cu/kg diet; lactation, 0.9 mg Cu/kg diet) exhibited alterations less marked than those exhibited by the group fed 1.4 mg Cu/kg diet. All alterations in the groups fed low copper diets were consistent with slowed cell nuclear maturation. The findings indicate that copper is required for maturation of the dentate gyrus and hippocampus. Also, copper supplied at or below 1.8 mg/kg is insufficient for morphological maturation of the dentate gyrus and hippocampus. Because the HF is important for higher brain functions, further research is needed to determine whether the copper deficiency-induced alterations in dentate gyrus and hippocampus development are transient or permanent.

Full-scale scaffold model of the human hippocampus CA1 area

The increasing availability of quantitative data on the human brain is opening new avenues to study neural function and dysfunction, thus bringing us closer and closer to the implementation of digital twin applications for personalized medicine. Here we provide a resource to the neuroscience community: a computational method to generate full-scale scaffold model of human brain regions starting from microscopy images. We have benchmarked the method to reconstruct the CA1 region of a right human hippocampus, which accounts for about half of the entire right hippocampal formation. Together with 3D soma positioning we provide a connectivity matrix generated using a morpho-anatomical connection strategy based on axonal and dendritic probability density functions accounting for morphological properties of hippocampal neurons. The data and algorithms are supplied in a ready-to-use format, suited to implement computational models at different scales and detail.

Memantine/Aripiprazole Combination Alleviates Cognitive Dysfunction in Valproic Acid Rat Model of Autism: Hippocampal CREB/BDNF Signaling and Glutamate Homeostasis

SummarySignificant efforts are increasingly directed towards identifying novel therapeutic targets for autism spectrum disorder (ASD) with a rising role of aberrant glutamatergic transmission in the pathogenesis of ASD-associated cellular and behavioral deficits. This study aimed at investigating the role of chronic memantine (20 mg/kg/day) and aripiprazole (3 mg/kg/day) combination therapy in the management of prenatal sodium valproate (VPA)-induced autistic-like/cognitive deficits in male Wistar rats. Pregnant female rats received a single intraperitoneal injection of VPA (600 mg/kg) to induce autistic-like behaviors in their offspring. Prenatal VPA induced autistic-like symptoms (decreased social interaction and the appearance of stereotyped behavior) with deficits in spatial learning (in Morris water maze) and cognitive flexibility (in the attentional set-shifting task) in addition to decreased hippocampal protein levels of phosphorylated cAMP response element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and gene expression of glutamate transporter-1 (Glt-1) with a decline in GABA/glutamate ratio (both measured by HPLC). These were accompanied by the appearance of numerous neurofibrillary tangles (NFTs) with enhanced apoptosis in hippocampal sections. Memantine/aripiprazole combination increased the protein levels of p-CREB, BDNF, and Glt-1 gene expression with restoration of GABA/glutamate balance, attenuation of VPA-induced neurodegenerative changes and autistic-like symptoms, and improvement of cognitive performance. This study draws attention to the favorable cognitive effects of memantine/aripiprazole combination in autistic subjects which could be mediated via enhancing CREB/BDNF signaling with increased expression of astrocytic Glt-1 and restoration of GABA/glutamate balance, leading to inhibition of hippocampal NFTs formation and neuronal apoptosis.

Reelin and APP Cooperatively Modulate Dendritic Spine Formation In Vitro and In Vivo

Amyloid precursor protein (APP) plays an important role in the pathogenesis of Alzheimer's disease (AD), but the normal function of APP at synapses is poorly understood. We and others have found that APP interacts with Reelin and that each protein is individually important for dendritic spine formation, which is associated with learning and memory, in vitro. However, whether Reelin acts through APP to modulate dendritic spine formation or synaptic function remains unknown. In the present study, we found that Reelin treatment significantly increased dendritic spine density and PSD-95 puncta number in primary hippocampal neurons. An examination of the molecular mechanisms by which Reelin regulates dendritic spinogenesis revealed that Reelin enhanced hippocampal dendritic spine formation in a Ras/ERK/CREB signaling-dependent manner. Interestingly, Reelin did not increase dendritic spine number in primary hippocampal neurons when APP expression was reduced or in vivo in APP knockout (KO) mice. Taken together, our data are the first to demonstrate that Reelin acts cooperatively with APP to modulate dendritic spine formation and suggest that normal APP function is critical for Reelin-mediated dendritic spinogenesis at synapses.