Hippocampal Learning Research Articles

Nrf2 improves hippocampal synaptic plasticity, learning and memory through the circ-Vps41/miR-26a-5p/CaMKIV regulatory network

Antioxidant response transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2/Nfe2l2) is a neuroprotective agent in learning and memory impairment. This study provides a new perspective to explore the regulatory mechanisms of Nrf2. Here, we found that Nrf2 regulated circular RNA circ-Vps41 to increase hippocampal synaptic plasticity; Nrf2 bound the Vps41 promoter to activate transcription of the Vps41 gene and promote expression of circ-Vps41; circ-Vps41 positively correlated with Nrf2, synaptic plasticity, and learning and memory but negatively correlated with reactive oxygen species; and Nrf2 promoted CaMKIV expression by increasing levels of circ-Vps41, which can absorb miR-26a-5p that targets CaMKIV. Our findings revealed a new circRNA-based regulatory network regulated by Nrf2 and provided novel insights into the potential mechanism involved in the improvement of learning and memory impairment.

Exposure to polystyrene microplastics impairs hippocampus-dependent learning and memory in mice

Microplastics (MPs) pollution has become a serious environmental issue worldwide, but its potential effects on health remain unknown. The administration of polystyrene MPs (PS-MPs) to mice for eight weeks impaired learning and memory behavior. PS-MPs were detected in the brain especially in the hippocampus of these mice. Concurrently, the hippocampus had decreased levels of immediate-early genes, aberrantly enhanced synaptic glutamate AMPA receptors, and elevated neuroinflammation, all of which are critical for synaptic plasticity and memory. Interestingly, ablation of the vagus nerve, a modulator of the gut-brain axis, improved the memory function of PS-MPs mice. These results indicate that exposure to PS-MPs in mice alters the expression of neuronal activity-dependent genes and synaptic proteins, and increases neuroinflammation in the hippocampus, subsequently causing behavioral changes through the vagus nerve-dependent pathway. Our findings shed light on the adverse impacts of PS-MPs on the brain and hippocampal learning and memory.

Scopolamine-Induced Alzheimer’s Disease in Wistar Rats: Aqueous Talinum Triangulare Potency on the Hippocampal Nissl Bodies and Long-Term Learning and Memory

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Prepubescent female rodents have enhanced hippocampal LTP and learning relative to males, reversing in adulthood as inhibition increases.

Multiple studies indicate that adult male rodents perform better than females on spatial problems and have a lower threshold for long-term potentiation (LTP) of hippocampal CA3-to-CA1 synapses. We report here that, in rodents, prepubescent females rapidly encode spatial information and express low-threshold LTP, whereas age-matched males do not. The loss of low-threshold LTP across female puberty was associated with three inter-related changes: increased densities of α5 subunit-containing GABAARs at inhibitory synapses, greater shunting of burst responses used to induce LTP and a reduction of NMDAR-mediated synaptic responses. A negative allosteric modulator of α5-GABAARs increased burst responses to a greater degree in adult than in juvenile females and markedly enhanced both LTP and spatial memory in adults. The reasons for the gain of functions with male puberty do not involve these mechanisms. In all, puberty has opposite consequences for plasticity in the two sexes, albeit through different routes.

Increasing stimulus similarity drives nonmonotonic representational change in hippocampus.

Studies of hippocampal learning have obtained seemingly contradictory results, with manipulations that increase coactivation of memories sometimes leading to differentiation of these memories, but sometimes not. These results could potentially be reconciled using the nonmonotonic plasticity hypothesis, which posits that representational change (memories moving apart or together) is a U-shaped function of the coactivation of these memories during learning. Testing this hypothesis requires manipulating coactivation over a wide enough range to reveal the full U-shape. To accomplish this, we used a novel neural network image synthesis procedure to create pairs of stimuli that varied parametrically in their similarity in high-level visual regions that provide input to the hippocampus. Sequences of these pairs were shown to human participants during high-resolution fMRI. As predicted, learning changed the representations of paired images in the dentate gyrus as a U-shaped function of image similarity, with neural differentiation occurring only for moderately similar images.

Plasticity impairment exposes CA3 vulnerability in a hippocampal network model of mild traumatic brain injury.

Proper function of the hippocampus is critical for executing cognitive tasks such as learning and memory. Traumatic brain injury (TBI) and other neurological disorders are commonly associated with cognitive deficits and hippocampal dysfunction. Although there are many existing models of individual subregions of the hippocampus, few models attempt to integrate the primary areas into one system. In this work, we developed a computational model of the hippocampus, including the dentate gyrus, CA3, and CA1. The subregions are represented as an interconnected neuronal network, incorporating well-characterized ex vivo slice electrophysiology into the functional neuron models and well-documented anatomical connections into the network structure. In addition, since plasticity is foundational to the role of the hippocampus in learning and memory as well as necessary for studying adaptation to injury, we implemented spike-timing-dependent plasticity among the synaptic connections. Our model mimics key features of hippocampal activity, including signal frequencies in the theta and gamma bands and phase-amplitude coupling in area CA1. We also studied the effects of spike-timing-dependent plasticity impairment, a potential consequence of TBI, in our model and found that impairment decreases broadband power in CA3 and CA1 and reduces phase coherence between these two subregions, yet phase-amplitude coupling in CA1 remains intact. Altogether, our work demonstrates characteristic hippocampal activity with a scaled network model of spiking neurons and reveals the sensitive balance of plasticity mechanisms in the circuit through one manifestation of mild traumatic injury.

Retraction: Impacts of low-protein diet on the hippocampal CA1 neurons and learning deficits in rats

Retraction: Impacts of low-protein diet on the hippocampal CA1 neurons and learning deficits in rats

Supplementation of Carvacrol Attenuates Hippocampal Tumor Necrosis Factor-Alpha Level, Oxidative Stress, and Learning and Memory Dysfunction in Lipopolysaccharide-Exposed Rats

Background:Carvacrol is a natural phenolic monoterpene with anti-inflammatory and antioxidant bioactivities. Neuroinflammatory and oxidative stress responses play a crucial role in the pathogenesis of Alzheimer's disease. The present study examined the effect of carvacrol on brain tumor necrosis factor-alpha (TNF-α) level and oxidative stress as well as spatial learning and memory performances in lipopolysaccharide (LPS)-exposed rats.Materials and Methods:The rats were treated with either carvacrol (25 and 50 mg/kg) or Tween 80 for 2 weeks. Thereafter, LPS (1 mg/kg) or saline was intraperitoneally administered on days 15–19, 2 h before Morris water maze task, and treatments with carvacrol or Tween 80 were performed 30 min prior to behavioral testing. The level of TNF-α, lipid peroxidation, and total thiol concentration were measured in the hippocampus and cerebral cortex at the end of the experiment.Results:It was found that LPS-exposed rats exhibited spatial learning and memory dysfunction, which was accompanied by increased TNF-α level and lipid peroxidation, and decreased total thiol concentration in the hippocampus and/or cortex. Moreover, treatment with carvacrol at a dose of 25 mg/kg attenuated learning and memory impairments, decreased TNF-α and lipid peroxidation level in the hippocampus and cortex, and increased total thiol concentration in the cortex.Conclusion:Carvacrol exerts neuroprotective effects against LPS-induced spatial memory deficits through attenuating hippocampal TNF-α level and oxidative stress in rats.

Hippocampal Sclerosis in Pilocarpine Epilepsy: Survival of Peptide-Containing Neurons and Learning and Memory Disturbances in the Adult NMRI Strain Mouse.

The present experiments reveal the alterations of the hippocampal neuronal populations in chronic epilepsy. The mice were injected with a single dose of pilocarpine. They had status epilepticus and spontaneously recurrent motor seizures. Three months after pilocarpine treatment, the animals were investigated with the Barnes maze to determine their learning and memory capabilities. Their hippocampi were analyzed 2 weeks later (at 3.5 months) with standard immunohistochemical methods and cell counting. Every animal displayed hippocampal sclerosis. The neuronal loss was evaluated with neuronal-N immunostaining, and the activation of the microglia was measured with Iba1 immunohistochemistry. The neuropeptide Y, parvalbumin, and calretinin immunoreactive structures were qualitatively and quantitatively analyzed in the hippocampal formation. The results were compared statistically to the results of the control mice. We detected neuronal loss and strongly activated microglia populations. Neuropeptide Y was significantly upregulated in the sprouting axons. The number of parvalbumin- and calretinin-containing interneurons decreased significantly in the Ammon’s horn and dentate gyrus. The epileptic animals displayed significantly worse learning and memory functions. We concluded that degeneration of the principal neurons, a numerical decrease of PV-containing GABAergic neurons, and strong peptidergic axonal sprouting were responsible for the loss of the hippocampal learning and memory functions.

Combined molecular, structural and memory data unravel the destructive effect of tramadol on hippocampus

Tramadol is a synthetic analogue of codeine and stimulates neurodegeneration in several parts of the brain that leads to various behavioral impairments. Despite the leading role of hippocampus in learning and memory as well as decreased function of them under influence of tramadol, there are few studies analyzing the effect of tramadol administration on gene expression profiling and structural consequences in hippocampus region. Thus, we sought to determine the effect of tramadol on both PC12 cell line and hippocampal tissue, from gene expression changes to structural alterations. In this respect, we investigated genome‐wide mRNA expression using high throughput RNA-seq technology and confirmatory quantitative real‐time PCR, accompanied by stereological analysis of hippocampus and behavioral assessment following tramadol exposure. At the cellular level, PC12 cells were exposed to 600 μM tramadol for 48 hrs, followed by the assessments of ROS amount and gene expression levels of neurotoxicity associated with neurodegenerative pathways such as apoptosis and autophagy. Moreover, the structural and functional alteration of the hippocampus under chronic exposure to tramadol was also evaluated. In this regard, rats were treated with tramadol at doses of 50 mg/kg for three consecutive weeks. In vitro data revealed that tramadol provoked ROS production and caused the increase in the expression of autophagic and apoptotic genes in PC12 cells. Furthermore, in-vivo results demonstrated that tramadol not only did induce hippocampal atrophy, but it also triggered microgliosis and microglial activation, causing upregulation of apoptotic and inflammatory markers as well as over-activation of neurodegeneration. Tramadol also interrupted spatial learning and memory function along with long-term potentiation (LTP). Taken all together, our data disclosed the neurotoxic effects of tramadol on both in vitro and in-vivo. Moreover, we proposed a potential correlation between disrupted biochemical cascades and memory deficit under tramadol administration.

Noncanonical projections to the hippocampal CA3 regulate spatial learning and memory by modulating the feedforward hippocampal trisynaptic pathway.

The hippocampal formation (HF) is well documented as having a feedforward, unidirectional circuit organization termed the trisynaptic pathway. This circuit organization exists along the septotemporal axis of the HF, but the circuit connectivity across septal to temporal regions is less well described. The emergence of viral genetic mapping techniques enhances our ability to determine the detailed complexity of HF circuitry. In earlier work, we mapped a subiculum (SUB) back projection to CA1 prompted by the discovery of theta wave back propagation from the SUB to CA1 and CA3. We reason that this circuitry may represent multiple extended noncanonical pathways involving the subicular complex and hippocampal subregions CA1 and CA3. In the present study, multiple retrograde viral tracing approaches produced robust mapping results, which supports this prediction. We find significant noncanonical synaptic inputs to dorsal hippocampal CA3 from ventral CA1 (vCA1), perirhinal cortex (Prh), and the subicular complex. Thus, CA1 inputs to CA3 run opposite the trisynaptic pathway and in a temporal to septal direction. Our retrograde viral tracing results are confirmed by anterograde-directed viral mapping of projections from input mapped regions to hippocampal dorsal CA3 (dCA3). We find that genetic inactivation of the projection of vCA1 to dCA3 impairs object-related spatial learning and memory but does not modulate anxiety-related behaviors. Our data provide a circuit foundation to explore novel functional roles contributed by these noncanonical hippocampal circuit connections to hippocampal circuit dynamics and learning and memory behaviors.

RETRACTION NOTE: Effect of curcumin on hippocampus dentate gyrus injury induced by nicotine in rats

This paper was published in the Journal of Herbmed Pharmacology in 2019 (doi: 10.15171/jhp.2019.47) (1). Based on an email received from the team of young researchers recently, we were informed that the results of this article (some figures and diagrams) have been published in several similar articles (2-5), which are considered ethical misconduct. This issue was investigated by the editorial team of the Journal of Herbmed Pharmacology. As a result, based on the Committee on Publication Ethics (COPE) guidelines, the editors decided to retract this paper. The authors were informed and advised on this serious ethical breach. This article has been retracted at the request of the corresponding author. The retracted article will remain online to maintain the scholarly record, but it will be watermarked on each page as ‘retracted’.

Glibenclamide Ameliorates the Expression of Neurotrophic Factors in Sevoflurane Anaesthesia-induced Oxidative Stress and Cognitive Impairment in Hippocampal Neurons of Old Rats.

IntroductionSeveral antidiabetic medications have been proposed as prospective treatments for cognitive impairments in type 2 diabetes patients, glibenclamide (GBC) among them. Our research aimed to evaluate the impact of GBC on hippocampal learning memory and inflammation due to enhanced neurotrophic signals induced by inhalation of sevoflurane.Material and MethodsRats (Sprague Dawley, both sexes) were assigned to four groups: a control (vehicle, p.o.), GBC (10 mg/kg b.w.; p.o.), low-dose sevoflurane and low-dose sevoflurane + GBC (10 mg/kg b.w.; p.o.) for 23 days. Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining was performed to analyse the count of apoptotic cells and ELISA was conducted to assess the protein signals. A Western blot, a Y-maze test, and a Morris maze test were performed, and the results analysed. Blood and tissues were collected, and isolation of RNA was performed with qRT-PCR.ResultsThe Morris maze test results revealed an improvement in the length of the escape latency on days 1 (P < 0.05), 2 (P < 0.01), 3, and 4 in the low-dose Sevo group. Time spent in the quadrant and crossing axis and the percentage of spontaneous alterations showed a substantial decrease in the low-dose Sevo group which received GBC at 10 mg/kg b.w. Significant increases were shown in IL-6 and TNF-α levels in the low-dose Sevo group, whereas a decrease was evident in the GBC group.ConclusionOur results indicate that glibenclamide may be a novel drug to prevent sevoflurane inhalation-induced impaired learning and reduce brain-derived neurotrophic factor release, which may be a vital target for the development of potential therapies for cognitive deficits and neurodegeneration.

Hippocampal injury and learning deficits following non-convulsive status epilepticus in periadolescent rats

The effects of non-convulsive status epilepticus (NCSE) on the developing brain remain largely elusive. Here we investigated potential hippocampal injury and learning deficits following one or two episodes of NCSE in periadolescent rats. Non-convulsive status epilepticus was induced with subconvulsive doses of intrahippocampal kainic acid (KA) under continuous EEG monitoring in postnatal day 43 (P43) rats. The RKA group (repeated KA) received intrahippocampal KA at P43 and P44, the SKA group (single KA injection) received KA at P43 and an intrahippocampal saline injection at P44. Controls were sham-treated with saline. The modified two-way active avoidance (MAAV) test was conducted between P45 and P52 to assess learning of context-cued and tone-signaled electrical foot-shock avoidance. Histological analyses were performed at P52 to assess hippocampal neuronal densities, as well as potential reactive astrocytosis and synaptic dysfunction with GFAP (glial fibrillary acidic protein) and synaptophysin (Syp) staining, respectively. Kainic acid injections resulted in electroclinical seizures characterized by behavioral arrest, oromotor automatisms and salivation, without tonic-clonic activity. Compared to controls, both the SKA and RKA groups had lower rates of tone-signaled shock avoidance (p < 0.05). In contextual testing, SKA rats were comparable to controls (p > 0.05), but the RKA group had learning deficits (p < 0.05). Hippocampal neuronal densities were comparable in all groups. Compared to controls, both the SKA and RKA groups had higher hippocampal GFAP levels (p < 0.05). The RKA group also had lower hippocampal Syp levels compared to the SKA and control groups (p < 0.05), which were comparable (p > 0.05). We show that hippocampal NCSE in periadolescent rats results in a seizure burden-dependent hippocampal injury accompanied by cognitive deficits. Our data suggest that the diagnosis and treatment of NCSE should be prompt.

Learning exceptions to the rule in human and model via hippocampal encoding

Category learning helps us process the influx of information we experience daily. A common category structure is “rule-plus-exceptions,” in which most items follow a general rule, but exceptions violate this rule. People are worse at learning to categorize exceptions than rule-following items, but improved exception categorization has been positively associated with hippocampal function. In light of model-based predictions that the nature of existing memories of related experiences impacts memory formation, here we use behavioural and computational modelling data to explore how learning sequence impacts performance in rule-plus-exception categorization. Our behavioural results indicate that exception categorization accuracy improves when exceptions are introduced later in learning, after exposure to rule-followers. To explore whether hippocampal learning systems also benefit from this manipulation, we simulate our task using a computational model of hippocampus. The model successful replicates our behavioural findings related to exception learning, and representational similarity analysis of the model’s hidden layers suggests that model representations are impacted by trial sequence: delaying the introduction of an exception shifts its representation closer to its own category members. Our results provide novel computational evidence of how hippocampal learning systems can be targeted by learning sequence and bolster extant evidence of hippocampus’s role in category learning.

A Proinflammatory Stimulus Disrupts Hippocampal Plasticity and Learning via Microglial Activation and 25-Hydroxycholesterol.

Inflammatory cells, including macrophages and microglia, synthesize and release the oxysterol 25-hydroxycholesterol (25HC), which has antiviral and immunomodulatory properties. Here, we examined the effects of lipopolysaccharide (LPS), an activator of innate immunity, on 25HC production in microglia, and the effects of LPS and 25HC on CA1 hippocampal synaptic plasticity and learning. In primary microglia, LPS markedly increases the expression of cholesterol 25-hydroxylase (Ch25h), the key enzyme involved in 25HC synthesis, and increases the levels of secreted 25HC. Wild-type microglia produced higher levels of 25HC than Ch25h knock-out (KO) microglia with or without LPS. LPS treatment also disrupts long-term potentiation (LTP) in hippocampal slices via induction of a form of NMDA receptor-dependent metaplasticity. The inhibitory effects of LPS on LTP were mimicked by exogenous 25HC, and were not observed in slices from Ch25h KO mice. In vivo, LPS treatment also disrupts LTP and inhibits one-trial learning in wild-type mice, but not Ch25h KO mice. These results demonstrate that the oxysterol 25HC is a key modulator of synaptic plasticity and memory under proinflammatory stimuli.SIGNIFICANCE STATEMENT Neuroinflammation is thought to contribute to cognitive impairment in multiple neuropsychiatric illnesses. In this study, we found that a proinflammatory stimulus, LPS, disrupts hippocampal LTP via a metaplastic mechanism. The effects of LPS on LTP are mimicked by the oxysterol 25-hydroxycholesterol (25HC), an immune mediator synthesized in brain microglia. Effects of LPS on both synaptic plasticity and one-trial inhibitory avoidance learning are eliminated in mice deficient in Ch25h (cholesterol 25-hydroxylase), the primary enzyme responsible for endogenous 25HC synthesis. Thus, these results indicate that 25HC is a key mediator of the effects of an inflammatory stimulus on hippocampal function and open new potential avenues to overcome the effects of neuroinflammation on brain function.

Microglia control glutamatergic synapses in the adult mouse hippocampus.

Microglia cells are active players in regulating synaptic development and plasticity in the brain. However, how they influence the normal functioning of synapses is largely unknown. In this study, we characterized the effects of pharmacological microglia depletion, achieved by administration of PLX5622, on hippocampal CA3‐CA1 synapses of adult wild type mice. Following microglial depletion, we observed a reduction of spontaneous and evoked glutamatergic activity associated with a decrease of dendritic spine density. We also observed the appearance of immature synaptic features and higher levels of plasticity. Microglia depleted mice showed a deficit in the acquisition of the Novel Object Recognition task. These events were accompanied by hippocampal astrogliosis, although in the absence ofneuroinflammatory condition. PLX‐induced synaptic changes were absent in Cx3cr1 −/− mice, highlighting the role of CX3CL1/CX3CR1 axis in microglia control of synaptic functioning. Remarkably, microglia repopulation after PLX5622 withdrawal was associated with the recovery of hippocampal synapses and learning functions. Altogether, these data demonstrate that microglia contribute to normal synaptic functioning in the adult brain and that their removal induces reversible changes in organization and activity of glutamatergic synapses.

Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice

In humans, loss-of-function mutations in the UBE3A gene lead to the neurodevelopmental disorder Angelman syndrome (AS). AS patients have severe impairments in speech, learning and memory, and motor coordination, for which there is currently no treatment. In addition, UBE3A is duplicated in > 1–2% of patients with autism spectrum disorders—a further indication of the significant role it plays in brain development. Altered expression of UBE3A, an E3 ubiquitin ligase, is hypothesized to lead to impaired levels of its target proteins, but identifying the contribution of individual UBE3A targets to UBE3A-dependent deficits remains of critical importance. Ephexin5 is a putative UBE3A substrate that has restricted expression early in development, regulates synapse formation during hippocampal development, and is abnormally elevated in AS mice, modeled by maternally-derived Ube3a gene deletion. Here, we report that Ephexin5 can be directly ubiquitylated by UBE3A. Furthermore, removing Ephexin5 from AS mice specifically rescued hippocampus-dependent behaviors, CA1 physiology, and deficits in dendritic spine number. Our findings identify Ephexin5 as a key driver of hippocampal dysfunction and related behavioral deficits in AS mouse models. These results demonstrate the exciting potential of targeting Ephexin5, and possibly other UBE3A substrates, to improve symptoms of AS and other UBE3A-related developmental disorders.

Mathematics Disability vs. Learning Disability: A 360 Degree Analysis.

A fundamental issue for research in mathematics disability (MD) and reading disability (RD) is: If these disabilities are clearly distinct, why is there so high a level of comorbidity, together with the converse; if these disabilities are so similar, why are there clear differences in underlying causes and aetiology? In order to address this puzzle, we introduce the “360 degree analysis” (360DA) framework and apply it to the overlap between RD and MD. The 360DA process starts by analyzing the issue from four perspectives: theoretical, developmental, affective, and pedagogical. Under 360DA, these analyses are then integrated to provide insights for theory, and for individual assessment and support, together with directions for future progress. The analyses confirm extensive similarities between arithmetic and reading development in terms of rote learning, executive function (EF), and affective trauma, but also major differences in terms of the conceptual needs, the motor coordination needs, and the methods of scaffolding. In terms of theory, commonalities are interpreted naturally in terms of initial general developmental delay followed by domain-independent affective trauma following school failure. Dissociations are interpreted in terms of cerebellar vs. hippocampal learning networks, sequential vs. spatial processing, and language vs. spatial scaffolding, with a further dimension of the need for accurate fixation for reading. The framework has significant theoretical and applied implications.

IL-1\u03b2 and HMGB1 are anti-neurogenic to endogenous neural stem cells in the sclerotic epileptic human hippocampus

BackgroundThe dentate gyrus exhibits life-long neurogenesis of granule-cell neurons, supporting hippocampal dependent learning and memory. Both temporal lobe epilepsy patients and animal models frequently have hippocampal-dependent learning and memory difficulties and show evidence of reduced neurogenesis. Animal and human temporal lobe epilepsy studies have also shown strong innate immune system activation, which in animal models reduces hippocampal neurogenesis. We sought to determine if and how neuroinflammation signals reduced neurogenesis in the epileptic human hippocampus and its potential reversibility.MethodsWe isolated endogenous neural stem cells from surgically resected hippocampal tissue in 15 patients with unilateral hippocampal sclerosis. We examined resultant neurogenesis after growing them either as neurospheres in an ideal environment, in 3D cultures which preserved the inflammatory microenvironment and/or in 2D cultures which mimicked it.Results3D human hippocampal cultures largely replicated the cellular composition and inflammatory environment of the epileptic hippocampus. The microenvironment of sclerotic human epileptic hippocampal tissue is strongly anti-neurogenic, with sustained release of the proinflammatory proteins HMGB1 and IL-1β. IL-1β and HMGB1 significantly reduce human hippocampal neurogenesis and blockade of their IL-1R and TLR 2/4 receptors by IL1Ra and Box-A respectively, significantly restores neurogenesis in 2D and 3D culture.ConclusionOur results demonstrate a HMGB1 and IL-1β-mediated environmental anti-neurogenic effect in human TLE, identifying both the IL-1R and TLR 2/4 receptors as potential drug targets for restoring human hippocampal neurogenesis in temporal lobe epilepsy.