Behavioral Analysis of NMDAR Function in Rodents: Tests of Long-Term Spatial Memory.

NMDAR-dependent forms of synaptic plasticity in brain regions like the hippocampus are widely believed to provide the neural substrate for long-term associative memory formation. However, the experimental data are equivocal at best and may suggest a more nuanced role for NMDARs and synaptic plasticity in memory. Much of the experimental data available comes from studies in genetically modified mice in which NMDAR subunits have been deleted or mutated in order to disrupt NMDAR function. Behavioral assessment of long-term memory in these mice has involved tests like the Morris watermaze and the radial arm maze. Here we describe these behavioral tests and some of the different testing protocols that can be used to assess memory performance. We discuss the importance of distinguishing selective effects on learning and memory processes from nonspecific effects on sensorimotor or motivational aspects of performance.

Retuning of hippocampal representations during sleep.

Hippocampal representations that underlie spatial memory undergo continuous refinement following formation1. Here, to track the spatial tuning of neurons dynamically during offline states, we used a new Bayesian learning approach based on the spike-triggered average decoded position in ensemble recordings from freely moving rats. Measuring these tunings, we found spatial representations within hippocampal sharp-wave ripples that were stable for hours during sleep and were strongly aligned with place fields initially observed during maze exploration. These representations were explained by a combination of factors that included preconfigured structure before maze exposure and representations that emerged during θ-oscillations and awake sharp-wave ripples while on the maze, revealing the contribution of these events in forming ensembles. Strikingly, the ripple representations during sleep predicted the future place fields of neurons during re-exposure to the maze, even when those fields deviated from previous place preferences. By contrast, we observed tunings with poor alignment to maze place fields during sleep and rest before maze exposure and in the later stages of sleep. In sum, the new decoding approach allowed us to infer and characterize the stability and retuning of place fields during offline periods, revealing the rapid emergence of representations following new exploration and the role of sleep in the representational dynamics of the hippocampus.

Interleukin-33 ameliorates perioperative neurocognitive disorders by modulating microglial state.

Perioperative neurocognitive disorders (PND) are cognitive dysfunctions that usually occur in elderly patients after anesthesia and surgery. Microglial overactivation is a key underlying mechanism. Interleukin-33 (IL-33) is a member of the IL-1 family that orchestrates microglial function. In the present study, we explored how IL-33, which regulates microglia, contributes to cognitive improvement in a male mouse model of PND. An exploratory laparotomy was performed to establish a PND model. The expression levels of IL-33 and its receptor ST2 were evaluated using Western blot. IL-33/ST2 secretion, microglial density, morphology, phagocytosis of synapse, and proliferation, and dystrophic microglia were assessed using immunofluorescence. Synaptic plasticity was measured using Golgi staining and long-term potentiation. The Morris water maze and open field test were used to evaluate cognitive function and anxiety. Hippocampal expression of IL-33 and ST2 were elevated on postoperative day 3. We confirmed that IL-33 was secreted by astrocytes and neurons, whereas ST2 mainly colocalized with microglia. IL-33 treatment induced microgliosis after anesthesia and surgery. These microglia had larger soma sizes and shorter and fragmented branches. Compared to the Surgery group, IL-33 treatment reduced the synaptic phagocytosis of microglia and increased microglial proliferation and dystrophic microglia. IL-33 treatment also reversed the impaired synaptic plasticity and cognitive function caused by anesthesia and surgery. In conclusion, these results indicate that IL-33 plays a key role in regulating microglial state and synaptic phagocytosis in a PND mouse model. IL-33 treatment has a therapeutic potential for improving cognitive dysfunction in PND.

The changing of α5-GABAA receptors expression and distribution participate in sevoflurane-induced learning and memory impairment in young mice.

BACKGROUND: Sevoflurane is a superior agent for maintaining anesthesia during surgical procedures. However, the neurotoxic mechanisms of clinical concentration remain poorly understood. Sevoflurane can interfere with the normal function of neurons and synapses and impair cognitive function by acting on α5-GABAAR. METHODS: Using MWM test, we evaluated cognitive abilities in mice following 1 h of anesthesia with 2.7%-3% sevoflurane. Based on hippocampal transcriptome analysis, we analyzed the differential genes and IL-6 24 h post-anesthesia. Western blot and RT-PCR were performed to measure the levels of α5-GABAAR, Radixin, P-ERM, P-Radixin, Gephyrin, IL-6, and ROCK. The spatial distribution and expression of α5-GABAAR on neuronal somata were analyzed using histological and three-dimensional imaging techniques. RESULTS: MWM test indicated that partial long-term learning and memory impairment. Combining molecular biology and histological analysis, our studies have demonstrated that sevoflurane induces immunosuppression, characterized by reduced IL-6 expression levels, and that enhanced Radixin dephosphorylation undermines the microstructural stability of α5-GABAAR, leading to its dissociation from synaptic exterior and resulting in a disordered distribution in α5-GABAAR expression within neuronal cell bodies. On the synaptic cleft, the expression level of α5-GABAAR remained unchanged, the spatial distribution became more compact, with an increased fluorescence intensity per voxel. On the extra-synaptic space, the expression level of α5-GABAAR decreased within unchanged spatial distribution, accompanied by an increased fluorescence intensity per voxel. CONCLUSION: Dysregulated α5-GABAAR expression and distribution contributes to sevoflurane-induced partial long-term learning and memory impairment, which lays the foundation for elucidating the underlying mechanisms in future studies.

Electroacupuncture regulates Rab5a-mediating NGF transduction to improve learning and memory ability in the early stage of AD mice.

AIMS: Nerve growth factor (NGF) loss is a potential factor for the degeneration of basal forebrain cholinergic neurons (BFCNs) in Alzheimer's disease (AD), and Rab5a is a key regulatory molecule of NGF signaling transduction. Here, we investigated the changes of Rab5a in 5 × FAD mice and further explored the mechanism of Electroacupuncture (EA) treatment in improving cognition in the early stage of AD. METHODS: The total Rab5a and Rab5a-GTP in 5-month-old 5 × FAD mice and wild-type mice were detected using WB and IP technologies. 5 × FAD mice were treated with EA at the Bai hui (DU20) and Shen ting (DU24) acupoints for 4 weeks and CRE/LOXP technology was used to confirm the role of Rab5a in AD mediated by EA stimulation. The Novel Object Recognition and Morris water maze tests were used to evaluate the cognitive function of 5 × FAD mice. The Nissl, immunohistochemistry, and Thioflavin S staining were used to observe pathological morphological changes in the basal forebrain circuit. The Golgi staining was used to investigate the synaptic plasticity of the basal forebrain circuit and WB technology was used to detect the expression levels of cholinergic-related and NGF signal-related proteins. RESULTS: The total Rab5a was unaltered, but Rab5a-GTP increased and the rab5a-positive early endosomes appeared enlarged in the hippocampus of 5 × FAD mice. Notably, EA reduced Rab5a-GTP in the hippocampus in the early stage of 5 × FAD mice. EA could improve object recognition memory and spatial learning memory by reducing Rab5a activity in the early stage of 5 × FAD mice. Moreover, EA could reduce Rab5a activity to increase NGF transduction and increase the levels of phosphorylated TrkA, AKT, and ERK in the basal forebrain and hippocampus, and increase the expression of cholinergic-related proteins, such as ChAT, vAchT, ChT1, m1AchR, and m2AchR in the basal forebrain and ChAT, m1AchR, and m2AchR in the hippocampus, improving synaptic plasticity in the basal forebrain hippocampal circuit in the early stage of 5 × FAD mice. CONCLUSIONS: Rab5a hyperactivation is an early pathological manifestation of 5 × FAD mice. EA could suppress Rab5a-GTP to promote the transduction of NGF signaling, and enhance the synaptic plasticity of the basal forebrain hippocampal circuit improving cognitive impairment in the early stage of 5 × FAD mice.

Alzheimer-like behavior and synaptic dysfunction in 3 × Tg-AD mice are reversed with calcineurin inhibition.

Alzheimer's disease is a progressive neurodegenerative disorder characterized by impairments in synaptic plasticity and cognitive performance. Current treatments are unable to achieve satisfactory therapeutic effects or reverse the progression of the disease. Calcineurin has been implicated as part of a critical signaling pathway for learning and memory, and neuronal calcineurin may be hyperactivated in AD. To investigate the effects and underlying mechanisms of FK506, a calcineurin inhibitor, on Alzheimer-like behavior and synaptic dysfunction in the 3 × Tg-AD transgenic mouse model of Alzheimer's disease, we investigated the effect of FK506 on cognitive function and synaptic plasticity in the 3 × Tg-AD transgenic mouse model of Alzheimer's disease. The results showed that FK506 treatment ameliorated cognitive deficits, as indicated by the decreased latency in the water maze, and attenuated tau hyperphosphorylation in 3 × Tg-AD mice. Treatment with FK506 also reduced the levels of certain markers of postsynaptic deficits, including PSD-95 and NR2B, and reversed the long-term potentiation deficiency and dendritic spine impairments in 3 × Tg-AD mice. These findings suggest that treatment with calcineurin inhibitors such as FK506 can be an effective therapeutic strategy to rescue synaptic deficit and cognitive impairment in familial Alzheimer's disease and related tauopathies.

Conditional deletion of neurexin-2 impaired behavioral flexibility to alterations in action-outcome contingency.

Neurexins (Nrxns) are critical for synapse organization and their mutations have been documented in autism spectrum disorder, schizophrenia, and epilepsy. We recently reported that conditional deletion of Nrxn2, under the control of Emx1Cre promoter, predominately expressed in the neocortex and hippocampus (Emx1-Nrxn2 cKO mice) induced stereotyped patterns of behavior in mice, suggesting behavioral inflexibility. In this study, we investigated the effects of Nrxn2 deletion through two different conditional approaches targeting presynaptic cortical neurons projecting to dorsomedial striatum on the flexibility between goal-directed and habitual actions in response to devaluation of action-outcome (A-O) contingencies in an instrumental learning paradigm or upon reversal of A-O contingencies in a water T-maze paradigm. Nrxn2 deletion through both the conditional approaches induced an inability of mice to discriminate between goal-directed and habitual action strategies in their response to devaluation of A-O contingency. Emx1-Nrxn2 cKO mice exhibited reversal learning deficits, indicating their inability to adopt new action strategies. Overall, our studies showed that Nrxn2 deletion through two distinct conditional deletion approaches impaired flexibility in response to alterations in A-O contingencies. These investigations can lay the foundation for identification of novel genetic factors underlying behavioral inflexibility.

Changes in the hippocampal level of tau but not beta-amyloid may mediate anxiety-like behavior improvement ensuing from exercise in diabetic female rats.

BACKGROUND: In the present study, we investigated the effect of high-intensity interval training (HIIT) on cognitive behaviors in female rats with a high-fat diet + streptozotocin (STZ)-induced type 2 diabetes. METHODS: Twenty-four female rats were divided into four groups randomly (n = 6): control (C), control + exercise (Co + EX), diabetes mellitus (type 2) (T2D), and diabetes mellitus + exercise (T2D + EX). Diabetes was induced by a two-month high-fat diet and a single dose of STZ (35 mg/kg) in the T2D and T2D + EX groups. The Co + EX and T2D + EX groups performed HIIT for eight weeks (five sessions per week, running on a treadmill at 80-100% of VMax, 4-10 intervals). Elevated plus maze (EPM) and open field test (OFT) were used for assessing anxiety-like behaviors, and passive avoidance test (PAT) and Morris water maze (MWM) were applied for evaluating learning and memory. The hippocampal levels of beta-amyloid (Aß) and Tau were also assessed using Western blot. RESULTS: An increase in fasting blood glucose (FBG), hippocampal level of Tau, and a decrease in the percentage of open arm time (%OAT) as an index of anxiety-like behavior were seen in the female diabetic rats which could be reversed by HIIT. In addition, T2D led to a significant decrease in rearing and grooming in the OFT. No significant difference among groups was seen for the latency time in the PAT and learning and memory in the MWM. CONCLUSIONS: HIIT could improve anxiety-like behavior at least in part through changes in hippocampal levels of Tau.

Mesenchymal stem cell-derived exosomes improve neurogenesis and cognitive function of mice with methamphetamine addiction: A novel treatment approach.

BACKGROUND: Methamphetamine (METH) is a psychostimulant substance with highly addictive and neurotoxic effects, but no ideal treatment option exists to improve METH-induced neurocognitive deficits. Recently, mesenchymal stem cells (MSCs)-derived exosomes have raised many hopes for treating neurodegenerative sequela of brain disorders. This study aimed to determine the therapeutic potential of MSCs-derived exosomes on cognitive function and neurogenesis of METH-addicted rodents. METHODS: Male BALB/c mice were subjected to chronic METH addiction, followed by intravenous administration of bone marrow MSCs-derived exosomes. Then, the spatial memory and recognition memory of animals were assessed by the Barnes maze and the novel object recognition test (NORT). The neurogenesis-related factors, including NeuN and DCX, and the expression of Iba-1, a microglial activation marker, were assessed in the hippocampus by immunofluorescence staining. Also, the expression of inflammatory cytokines, including TNF-α and NF-κB, were evaluated by western blotting. RESULTS: The results showed that BMSCs-exosomes improved the time spent in the target quadrant and correct-to-wrong relative time in the Barnes maze. Also, NORT's discrimination index (DI) and recognition index (RI) were improved following exosome therapy. Additionally, exosome therapy significantly increased the expression of NeuN and DCX in the hippocampus while decreasing the expression of inflammatory cytokines, including TNF-α and NF-κB. Besides, BMSC-exosomes down-regulated the expression of Iba-1. CONCLUSION: Our findings indicate that BMSC-exosomes mitigated METH-caused cognitive dysfunction by improving neurogenesis and inhibiting neuroinflammation in the hippocampus.

The relationship between object-based spatial ability and virtual navigation performance.

Spatial navigation is a multi-faceted behaviour drawing on many different aspects of cognition. Visuospatial abilities, such as mental rotation and visuospatial working memory, in particular, may be key factors. A range of tests have been developed to assess visuospatial processing and memory, but how such tests relate to navigation ability remains unclear. This understanding is important to advance tests of navigation for disease monitoring in various disorders (e.g., Alzheimer's disease) where spatial impairment is an early symptom. Here, we report the use of an established mobile gaming app, Sea Hero Quest (SHQ), as a measure of navigation ability in a sample of young, predominantly female university students (N = 78; 20; female = 74.3%; mean age = 20.33 years). We used three separate tests of navigation embedded in SHQ: wayfinding, path integration and spatial memory in a radial arm maze. In the same participants, we also collected measures of mental rotation (Mental Rotation Test), visuospatial processing (Design Organization Test) and visuospatial working memory (Digital Corsi). We found few strong correlations across our measures. Being good at wayfinding in a virtual navigation test does not mean an individual will also be good at path integration, have a superior memory in a radial arm maze, or rate themself as having a strong sense of direction. However, we observed that participants who were good in the wayfinding task of SHQ tended to perform well on the three visuospatial tasks examined here, and to also use a landmark strategy in the radial maze task. These findings help clarify the associations between different abilities involved in spatial navigation.

Astrocytic HILPDA promotes lipid droplets generation to drive cognitive dysfunction in mice with sepsis-associated encephalopathy.

AIMS: Sepsis-associated encephalopathy (SAE) is manifested as a spectrum of disturbed cerebral function ranging from mild delirium to coma. However, the pathogenesis of SAE has not been clearly elucidated. Astrocytes play important roles in maintaining the function and metabolism of the brain. Most recently, it has been demonstrated that disorders of lipid metabolism, especially lipid droplets (LDs) dyshomeostasis, are involved in a variety of neurodegenerative diseases. The aim of this study was to investigate whether LDs are involved in the underlying mechanism of SAE. METHODS: The open field test, Y-maze test, and contextual fear conditioning test (CFCT) were used to test cognitive function in SAE mice. Lipidomics was utilized to investigate alterations in hippocampal lipid metabolism in SAE mice. Western blotting and immunofluorescence labeling were applied for the observation of related proteins. RESULTS: In the current study, we found that SAE mice showed severe cognitive dysfunction, including spatial working and contextual memory. Meanwhile, we demonstrated that lipid metabolism was widely dysregulated in the hippocampus by using lipidomic analysis. Furthermore, western blotting and immunofluorescence confirmed that LDs accumulation in hippocampal astrocytes was involved in the pathological process of cognitive dysfunction in SAE mice. We verified that LDs can be inhibited by specifically suppress hypoxia-inducible lipid droplet-associated protein (HILPDA) in astrocytes. Meanwhile, cognitive dysfunction in SAE was ameliorated by reducing A1 astrocyte activation and inhibiting presynaptic membrane transmitter release. CONCLUSION: The accumulation of astrocytic lipid droplets plays a crucial role in the pathological process of SAE. HILPDA is an attractive therapeutic target for lipid metabolism regulation and cognitive improvement in septic patients.

Interaction of high-fat diet and brain trauma alters adipose tissue macrophages and brain microglia associated with exacerbated cognitive dysfunction.

Obesity increases the morbidity and mortality of traumatic brain injury (TBI). Detailed analyses of transcriptomic changes in the brain and adipose tissue were performed to elucidate the interactive effects between high-fat diet-induced obesity (DIO) and TBI. Adult male mice were fed a high-fat diet (HFD) for 12 weeks prior to experimental TBI and continuing after injury. High-throughput transcriptomic analysis using Nanostring panels of the total visceral adipose tissue (VAT) and cellular components in the brain, followed by unsupervised clustering, principal component analysis, and IPA pathway analysis were used to determine shifts in gene expression patterns and molecular pathway activity. Cellular populations in the cortex and hippocampus, as well as in VAT, during the chronic phase after combined TBI-HFD showed amplification of central and peripheral microglia/macrophage responses, including superadditive changes in selected gene expression signatures and pathways. Furthermore, combined TBI and HFD caused additive dysfunction in Y-Maze, Novel Object Recognition (NOR), and Morris water maze (MWM) cognitive function tests. These novel data suggest that HFD-induced obesity and TBI can independently prime and support the development of altered states in brain microglia and VAT, including the disease-associated microglia/macrophage (DAM) phenotype observed in neurodegenerative disorders. The interaction between HFD and TBI promotes a shift toward chronic reactive microglia/macrophage transcriptomic signatures and associated pro-inflammatory disease-altered states that may, in part, underlie the exacerbation of cognitive deficits. Thus, targeting of HFD-induced reactive cellular phenotypes, including in peripheral adipose tissue immune cell populations, may serve to reduce microglial maladaptive states after TBI, attenuating post-traumatic neurodegeneration and neurological dysfunction.

Disruption of sphingomyelin synthase 2 gene alleviates cognitive impairment in a mouse model of Alzheimer's disease.

The membrane raft accommodates the key enzymes synthesizing amyloid ß (Aß). One of the two characteristic components of the membrane raft, cholesterol, is well known to promote the key enzymes that produce amyloid-ß (Aß) and exacerbate Alzheimer's disease (AD) pathogenesis. Given that the raft is a physicochemical platform for the sound functioning of embedded bioactive proteins, the other major lipid component sphingomyelin may also be involved in AD. Here we knocked out the sphingomyelin synthase 2 gene (SMS2) in 3xTg AD model mice by hybridization, yielding SMS2KO mice (4S mice). The novel object recognition test in 9/10-month-old 4S mice showed that cognitive impairment in 3xTg mice was alleviated by SMS2KO, though performance in the Morris water maze (MWM) was not improved. The tail suspension test detected a depressive trait in 4S mice, which may have hindered the manifestation of performance in the wet, stressful environment of MWM. In the hippocampal CA1, hyperexcitability in 3xTg was also found alleviated by SMS2KO. In the hippocampal dentate gyrus of 4S mice, the number of neurons positive with intracellular Aß or its precursor proteins, the hallmark of young 3xTg mice, is reduced to one-third, suggesting an SMS2KO-led suppression of syntheses of those peptides in the dentate gyrus. Although we previously reported that large-conductance calcium-activated potassium (BK) channels are suppressed in 3xTg mice and their recovery relates to cognitive amelioration, no changes occurred by hybridization. Sphingomyelin in the membrane raft may serve as a novel target for AD drugs.

Effects of sensory overstimulation in postpartum rats.

Research in rodents has shown that exposure to excessive early life audiovisual stimulation leads to altered anxiety-like behaviors and cognitive deficits. Since this period of stimulation typically begins prior to weaning, newborn rodents receive sensory overstimulation (SOS) as a litter within their home cage while the dam is present. However, the effects of SOS during the postpartum period remain unexplored. To this end, we adapted an SOS paradigm for use in rats and exposed rat dams and their litters from postpartum days (PD) 10-23. Maternal observations were conducted to determine whether SOS produced changes in positive and/or negative maternal behaviors. Next, we assessed changes in anxiety-like behavior and cognition by testing dams in the elevated zero maze, open field, and novel object recognition tests. To assess potential effects on HPA-axis function, levels of the stress hormone corticosterone (CORT) were measured approximately 1-week after the cessation of SOS exposure. Our results indicate increased nursing and licking in SOS dams compared to controls, although SOS dams also exhibited significant increases in pup dragging. Moreover, SOS dams exhibited reduced self-care behaviors and nest-building compared to control dams. No differences were found for anxiety-like behaviors, object recognition memory, or CORT levels. This study is the first to assess the impact of postpartum SOS exposure in rat dams. Our findings suggest an SOS-induced enhancement in positive caregiving, but limited impact in all other measures.

A shift to a standard diet after exposure to a high-fat, high-sucrose diet from gestation to weaning restores brain metabolism and behavioral flexibility in adult rats.

Prolonged consumption of diets high in saturated fat and sugar has been related to obesity and overweight, which in turn are linked to cognitive impairment in both humans and rodents. This has become a current issue, especially in children and adolescents, because these stages are crucial to neurodevelopmental processes and programming of adult behavior. To evaluate the effects of gestational and early exposure to an obesogenic diet, three groups with different dietary patterns were established: high-fat and high-sucrose diet (HFS), standard diet (SD), and a dietary shift from a high-fat, high-sucrose diet to a standard diet after weaning (R). Spatial learning and behavioral flexibility in adult male and female Wistar rats were evaluated using the Morris water maze (MWM) at PND 60. Furthermore, regional brain oxidative metabolism was assessed in the prefrontal cortex and the hippocampus. Contrary to our hypothesis, the HFS diet groups showed similar performance on the spatial learning task as the other groups, although they showed impaired cognitive flexibility. The HFS group had increased brain metabolic capacity compared to that of animals fed the standard diet. Shifting from the HFS diet to the SD diet after weaning restored the brain metabolic capacity in both sexes to levels similar to those observed in animals fed the SD diet. In addition, animals in the R group performed similarly to those fed the SD diet in the Morris water maze in both tasks. However, dietary shift from HFS diet to standard diet after weaning had only moderate sex-dependent effects on body weight and fat distribution. In conclusion, switching from an HFS diet to a balanced diet after weaning would have beneficial effects on behavioral flexibility and brain metabolism, without significant sex differences.

High-frequency rTMS alleviates cognitive impairment and regulates synaptic plasticity in the hippocampus of rats with cerebral ischemia.

Poststroke cognitive impairment (PSCI) is a common complication of stroke, but effective treatments are currently lacking. Repetitive transcranial magnetic stimulation (rTMS) is gradually being applied to treat PSCI, but there is limited evidence of its efficacy. To determine rTMS effects on PSCI, we constructed a transient middle cerebral artery occlusion (tMCAO) rat model. Rats were then grouped by random digital table method: the sham group (n = 10), tMCAO group (n = 10) and rTMS group (n = 10). The shuttle box and Morris water maze (MWM) tests were conducted to detect the cognitive functions of the rats. In addition, synaptic density and synaptic ultrastructural parameters, including the active zone length, synaptic cleft width, and postsynaptic density (PSD) thickness, were quantified and analyzed using an electron microscope. What's more, synaptic associated proteins, including PSD95, SYN, and BDNF were detected by western blot. According to the shuttle box and MWM tests, rTMS improved tMCAO rats' cognitive functions, including spatial learning and memory and decision-making abilities. Electron microscopy revealed that rTMS significantly increased the synaptic density, synaptic active zone length and PSD thickness and decreased the synaptic cleft width. The western blot results showed that the expression of PSD95, SYN, and BDNF was markedly increased after rTMS stimulation. Based on these results, we propose that 20 Hz rTMS can significantly alleviate cognitive impairment after stroke. The underlying mechanism might be modulating the synaptic plasticity and up-regulating the expression PSD95, SYN, and BDNF in the hippocampus.

GADD45B in the ventral hippocampal CA1 modulates aversive memory acquisition and spatial cognition.

AIMS: This study was designed to investigate the role of growth arrest and DNA damage-inducible ß (GADD45B) in modulating fear memory acquisition and elucidate its underlying mechanisms. MAIN METHODS: Adeno-associated virus (AAV) that knockdown or overexpression GADD45B were injected into ventral hippocampal CA1 (vCA1) by stereotactic, and verified by fluorescence and Western blot. The contextual fear conditioning paradigm was employed to examine the involvement of GADD45B in modulating aversive memory acquisition. The Y-maze and novel location recognition (NLR) tests were used to examine non-aversive cognition. The synaptic plasticity and electrophysiological properties of neurons were measured by slice patch clamp. KEY FINDINGS: Knockdown of GADD45B in the vCA1 significantly enhanced fear memory acquisition, accompanied by an upregulation of long-term potentiation (LTP) expression and intrinsic excitability of vCA1 pyramidal neurons (PNs). Conversely, overexpression of GADD45B produced the opposite effects. Notably, silencing the activity of vCA1 neurons abolished the impact of GADD45B knockdown on fear memory development. Moreover, mice with vCA1 GADD45B overexpression exhibited impaired spatial cognition, whereas mice with GADD45B knockdown did not display such impairment. SIGNIFICANCE: These results provided compelling evidence for the crucial involvement of GADD45B in the formation of aversive memory and spatial cognition.

Landmark use by ghost crab (Ocypode quadrata) during wayfinding in a complex maze.

Species of crab have been shown to spatially track and navigate to consequential locations through different processes, such as path integration and landmark orienting. Few investigations examine their ability to wayfind in complex environments, like mazes, with multiple intersections and how they may utilize specific features to benefit this process. Spatial learning potentially would lend a fitness advantage to animals living in complicated habitats, and ghost crab (Ocypode quadrata) is a semiterrestrial species that typically occupies extensive beach environments, which present many navigational challenges. Despite their potential, there are currently no studies that investigate forms of spatial cognition in these animals. To better diversify our knowledge of this trait, the current research exposed ghost crab to a maze with seven intersections. Animals were given multiple trials to learn the location of a reward destination to a specific criterion proficiency. In one condition several landmarks were distributed throughout the maze, and in another the environment was completely empty. Results showed that ghost crab in the landmark present group were able to learn the maze faster, they required significantly fewer trials to reach the learning criterion than those in the landmark absent group. However, only approximately half of the total sample met the learning criterion, indicating the maze was rather difficult. These findings are interpreted through theories of route learning that suggest animals may navigate by establishing landmark-turn associations. Such processes have implications for the cognitive ability of ghost crab, and spatial learning in this species may support the notion of convergent evolution for this trait.

Transcranial direct current stimulation combined with swimming exercise improves the learning and memory abilities of vascular dementia rats by regulating microglia through miR-223-3p/PRMT8.

BACKGROUND: Vascular dementia (VD) is the second most common type of dementia worldwide. Previous studies have proven that transcranial direct current stimulation (tDCS) has potential applications in relieving cognitive impairment in VD animal models. The purpose of this study was to probe the mechanism by which tDCS combined with swimming exercise improves the learning and memory abilities of VD model rats. METHOD: The VD rat model was induced using the permanent bilateral common carotid artery occlusion (2-VO) method; tDCS was applied to the rats and then they took part in swimming exercises. Rat memory, platform crossing time, and platform crossing frequency were analyzed via a water maze experiment. Nerve damage in the cortex and hippocampal CA1 area of the rats was observed using Nissl staining. Western blotting, immunohistochemistry, immunofluorescence staining and reverse transcription quantitative polymerase chain reaction (RT - qPCR) were used to determine the expression of related proteins and genes. The levels of oxidative stress were detected by kits. RESULTS: We demonstrated that VD model rats treated with tDCS combined with swimming exercise exhibited significant improvement in memory, and VD model rats exhibited significantly reduced neuronal loss in the hippocampus, and reduced microglial activation and M1 polarization. tDCS combined with swimming exercise protects VD model rats from oxidative stress through the miR-223-3p/protein arginine methyltransferase 8 (PRMT8) axis and inhibits the activation of the TLR4/NF-κB signaling pathway. CONCLUSION: Our results suggest that tDCS combined with swimming exercise improved the learning and memory ability of VD model rats by regulating the expression of PRMT8 through miR-223-3p to affect microglial activation and M1 polarization.

Anxiety in Alzheimer's disease rats is independent of memory and impacted by genotype, age, sex, and exercise.

INTRODUCTION: Alzheimer's disease (AD) is characterized by cognitive impairments; however, heightened anxiety often accompanies and, in some cases, exacerbates cognitive its. The present study aims to understand the influence of multiple variables on anxiety-like behavior in TgF344-AD rats and determine whether anxiety impacts memory performance. METHODS: An elevated plus maze was used to assess anxiety-like behavior in the established colony (n = 107). Influences of age, sex, genotype, and exercise on anxiety were evaluated via multiple linear regression. Correlation analysis evaluated the relationship between anxiety and memory performance. RESULTS: Age (P < 0.05) and AD genotype (P < 0.001) were associated with increasing anxiety, while exercise (P < 0.05) was associated with decreasing anxiety. Female AD animals displayed more anxiety-like behavior versus wild-type female (P < 0.001) and AD male (P < 0.05) littermates. DISCUSSION: Concluding that while factors such as age, sex, AD genotype, and training status can impact anxiety levels in the TgF344-AD model, anxiety level did not impact memory performance. HIGHLIGHTS: Increased anxiety-like behavior in TgF344-AD rats does not correlate with declines in memory performance. Predictors of higher anxiety-like behaviors in the TgF344-AD rat include age, Alzheimer's disease (AD) genotype, and sex with female AD animals experiencing greater anxiety compared to female wild-type or male AD. Exercise training leads to decreased anxiety-like behaviors in the TgF344-AD rat.