Lrp8 knockout mice fed a selenium-replete diet display subtle deficits in their spatial learning and memory function.

Selenium is an essential trace element that is delivered to the brain by the selenium transport protein selenoprotein P (SEPP1), primarily by binding to its receptor low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2 (ApoER2), at the blood-brain barrier. Selenium transport is required for several important brain functions, with transgenic deletion of either Sepp1 or Lrp8 resulting in severe neurological dysfunction and death in mice fed a selenium-deficient diet. Previous studies have reported that although feeding a standard chow diet can prevent these severe deficits, some motor coordination and cognitive dysfunction remain. Importantly, no single study has directly compared the motor and cognitive performance of the Sepp1 and Lrp8 knockout (KO) lines. Here, we report the results of a comprehensive parallel analysis of the motor and spatial learning and memory function of Sepp1 and Lrp8 knockout mice fed a standard mouse chow diet. Our results revealed that Sepp1 knockout mice raised on a selenium-replete diet displayed motor and cognitive function that was indistinguishable from their wild-type littermates. In contrast, we found that although Lrp8-knockout mice fed a selenium-replete diet had normal motor function, their spatial learning and memory showed subtle deficits. We also found that the deficit in baseline adult hippocampal neurogenesis exhibited by Lrp8-deficit mice could not be rescued by dietary selenium supplementation. Taken together, these findings further highlight the importance of selenium transport in maintaining healthy brain function. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Potential Molecular Mechanisms of Electroacupuncture With Spatial Learning and Memory Impairment Induced by Chronic Pain on a Rat Model.

BACKGROUND: It is frequently reported that neuropathic pain is associated with abnormalities in brain function and structure as well as cognitive deficits. However, the contributing mechanisms have remained elusive. OBJECTIVES: We aimed to investigate the systemic ultrastructural changes of the peripheral nervous system (PNS) and central nervous system (CNS) in rats with trigeminal neuralgia (TN) induced by cobra venom, as well as the effects and mechanisms of electroacupuncture (EA) and pregabalin (PGB) on TN. STUDY DESIGN: This study used an experimental design in rats. SETTING: The research took place in the laboratory at the Aviation General Hospital of China Medical University and Beijing Institute of Translational Medicine. METHODS: Male Sprague-Dawley rats were randomly divided into 4 groups (n = 12/group): cobra venom (CV), PGB, EA, and sham-operated (SHAM). The development of pain-related behaviors and spatial learning and memory abilities were measured using video recordings and Morris water maze tests, respectively. The ultrastructural changes of the PNS and CNS were examined using transmission electron microscopy. We also screened the differentially expressed genes and proteins in the prefrontal cortex  and hippocampus using  ribonucleic acid sequencing and isobaric tag for relative and absolute quantitation techniques, respectively. Data for the behavioral tests and molecular biology were analyzed with a one-way analysis of variance. RESULTS: The rats in the CV group exhibited long-lasting pain-like behaviors, cognitive deficits, and systemic ultrastructural changes. Both EA and PGB alleviated the chronic pain syndrome, but EA also inhibited the chronic pain-induced cognitive dysfunction and restored normal cellular structures, while PGB was associated with no improvements. Transcriptomic and proteomic analyses revealed marcks, pak2 and acat1 were altered in rats with TN but were adjusted back to baseline by EA but not by PGB. LIMITATIONS: We examined systemic ultrastructural alterations at different levels of the nervous system; however, the detailed timeline of the damage process was not explicitly delineated.  Moreover, the current study provides only preliminary evidence for the neurobiological mechanisms of cognitive impairment resulting from chronic pain.  Further research is still necessary (using models such as gene knockout rats and cell cultures) before a detailed mechanism can be postulated. CONCLUSIONS: EA treatment may offer significant advantages when compared to PGB for the treatment of cognitive impairment associated with chronic pain. Moreover, marcks, pak2 and acat1 may be the potential therapeutic targets of EA.

Evaluation of the effects of metformin as adenosine monophosphate-activated protein kinase activator on spatial learning and memory in a rat model of multiple sclerosis disease.

In patients with multiple sclerosis (MS) disease, cognitive deficits have been detected because of destruction of hippocampus. Cognitive impairment is one of the common signs in MS. Recent studies showed that metformin (Met) has wide-ranging effects in the treatment of diseases. Here, we have tried to study the preservative effects of Met as adenosine monophosphate-activated protein kinase (AMPK) activator on the hippocampus dentate gyrus (DG) neuronal firing pattern, motor coordination, and learning & memory loss following MS induction. The MS induction was done by local ethidium bromide (EB) injection into the rat hippocampus. Then, rats were treated with Met (200 mg/kg) for two weeks. Spatial memory and learning status were assessed using Morris water maze. A neuronal single-unit recording was measured from hippocampus DG. After decapitation, the bilateral hippocampi separated to measure malondialdehyde (MDA). Treatment with Met ameliorated latency times and path lengths (P < 0.05, P < 0.01, P < 0.001 in 1th, 2th, 3th and 4th days) in the Met + MS group respectively. The percent of total time spent in goal quarter and the average number of spikes/bin were decreased significantly in MS rats compared with the sham group (p < 0.001) but significantly increased in the metformin-treated MS group (Met + MS), (p < 0.01, p < 0.001). Met treatment in rats with MS significantly reduced the concentration of MDA, which is an indicator of lipid peroxidation compared to untreated groups. These observations show that increase of neuronal activity, sensory-motor coordination, and improvement of spatial memory in MS rats treated with Met appears via an increment of AMPK.

Exposure to Short Photoperiod Regime Restores Spatial Cognition in Ventral Subicular Lesioned Rats: Potential Role of Hippocampal Plasticity, Glucocorticoid Receptors, and Neurogenesis.

Ambient light influences our mood, behavior, and cognition. Phototherapy has been considered as an effective non-pharmacological intervention strategy in the restoration of cognitive functions following central nervous system insults. However, the cellular and molecular underpinnings of phototherapy-mediated functional recovery are yet to be studied. The present study examines the effectiveness of short photoperiod regime (SPR; 6:18-h light:dark cycle) in restoring the cognitive functions in ventral subicular lesioned rats. Bilateral ventral subicular lesion (VSL) resulted in significant impairment of spatial navigational abilities when tested in the Morris water maze (MWM) task. Further, VSL resulted in reduced expression of glucocorticoid receptors (GRs) and activity-regulated cytoskeletal (Arc) protein and suppression of neurogenesis in the hippocampus. VSL also suppressed the magnitude of long-term potentiation (LTP) in the hippocampal Schaffer collateral-CA1 synapses. However, exposure to SPR for 21 days showed significant restoration of spatial performance in the MWM task as the ventral subicular lesioned rats could deploy higher cognitive allocentric navigational strategies to reach the hidden platform. Further, SPR resulted in enhanced expression of hippocampal GR and Arc protein and neurogenesis but not hippocampal LTP suggestive of appropriate need-based SPR intervention. In conclusion, the study demonstrates the effectiveness of SPR in establishing functional recovery as well as the possible molecular and cellular basis of cognitive recovery in a rat model of neurodegeneration. Such studies provide a framework in understanding the efficacy of non-pharmacological strategies in establishing functional recovery in neurodegenerative conditions.

Co-treatment of vitamin D supplementation with enriched environment improves synaptic plasticity and spatial learning and memory in aged rats.

RATIONALE AND OBJECTIVE: Environmental enrichment (EE) has been shown in old rats to improve learning and memory. Vitamin D (VitD) has also been shown to modulate age-related, cognitive dysfunction. As both EE and VitD could work to improve cognition via enhancement of neurotrophic factors, their effects might occlude one another. Therefore, a clinically relevant question is whether noted cognition-promoting effects of EE and VitD can co-occur. METHODS: Aged rats were housed for 6 weeks in one of three housing conditions: environmentally enriched (EE), socially enriched (SE), or standard condition (SC). Further, a 4th group was co-treated with VitD supplementation (400 IU kg-1 daily, 6 weeks) under EE conditions (EE + VitD). RESULTS: Treatment with VitD and EE housing were associated with higher score on measures of learning and memory and exhibited lower anxiety scores compared to EE alone, SE or SC as assayed in the elevated plus maze, Morris water maze, passive avoidance, and open field tasks. Additionally, in the EE + VitD group, mRNA expression levels of NGF, TrkA, BDNF, Nrf2, and IGF-1 were significantly higher compared to expression seen in the EE group. Furthermore, field potential recordings showed that EE + VitD resulted in a greater enhancement of hippocampal LTP and neuronal excitability when compared to EE alone. CONCLUSIONS: These findings demonstrate that in aged rats exposure to EE and VitD results in effects on hippocampal cognitive dysfunction and molecular mechanisms which are greater than effects of EE alone, suggesting potential for synergistic therapeutic effects for management of age-related cognitive decline.

The effect of intracerebroventricular amyloid beta 1-42 application on cognitive functions in aged rats supplemented with taurine and the change of peroxisomal proteins in this process.

OBJECTIVE: The aim of our study is to investigate the change of peroxisomal proteins in the neurodegenerative and oxidative process caused by the neurotoxicity of Aß 1-42 in aged rats supplemented with taurine and to show the possible positive effects of taurine in this process. METHODS: 30 Wistar albino rats were randomly divided into 5 groups as control, sham, Aß 1-42, taurine, and Aß 1-42+taurine. Taurine administration continued for 6 weeks (1000 mg/kg/day with drinking water). Stereotaxic surgery was applied to all groups (intracerebroventricular per lateral ventricle needle only or 5 µl, PBS, or Aß 1-42). Spatial learning and memory performances of the animals were evaluated with Morris water maze and elevated plus maze. The levels of MDA and GSH were measured as oxidative stress parameters in the cerebral cortex and hippocampus. Expressions of CAT, PEX14, PMP70 of peroxisomal membrane proteins were indicated by Western blot analysis. RESULTS: Our results showed that injection of Aß 1-42 decreased the spatial learning and memory performance, cortex CAT and hippocampus PEX14, PMP70 and GSH levels, and increased cortex and hippocampus MDA levels (p < 0.05). Although the administration of taurine partially ameliorated the adverse effects of Aß 1-42 injection, a significant difference was found only at the hippocampus GSH levels (p < 0.05). Also, taurine caused anxiety at this dose (p < 0.05). DISCUSSION: In conclusion, decreased peroxisomal proteins and antioxidant capacity in neurodegenerative and oxidative processes induced by intracerebroventricular Aß 1-42 injection showed that peroxisomes may play a role in this process and taurine supplementation may have positive effects especially in increasing antioxidant capacity.

"Olfactory Three-Needle" Enhances Spatial Learning and Memory Ability in SAMP8 Mice.

As one of the most important therapies in complementary and alternative medicine, acupuncture has been used in the treatment of Alzheimer's disease (AD). Acupuncture of "olfactory three-needle" manipulation can improve the cognitive ability of AD patients. However, the mechanism of "olfactory three-needle" in AD remains largely unknown. Here, we identified that the "olfactory three-needle" therapy and eugenol olfactory stimulation both reduced the deposition of ß-amyloid (Aß) protein and increased the expression of synaptophysin (SYP), but only the "olfactory three-needle" enhanced the spatial learning and memory ability of SAMP8. Remarkably, the "olfactory three-needle" inhibited the phosphorylation of p38MAPK and the excessive activation of microglia (MG) in the hippocampus. Our study demonstrates that the "olfactory three-needle" enhances spatial learning and memory ability by inhibiting the phosphorylation of p38MAPK and the excessive activation of MG to reduce the neuroinflammatory response and neurotoxicity of Aß and promote synaptic regeneration, but it was not completely consistent with the stimulation of the olfactory system.

Role of astaxanthin in the modulation of brain-derived neurotrophic factor and spatial learning behavior in perinatally undernourished Wistar rats.

Objective: Maternal health and nutrition during the perinatal period is the predominant factor influencing the functional development of the brain. Maternal malnutrition during the perinatal period causes retardation of brain development. The current study investigates the role of Astaxanthin (AsX) in spatial learning and memory and BDNF in perinatally undernourished Wistar rats.Methods: The albino wistar rats were perinatally undernourished and administered with different dosages of AsX. The spatial learning and memory performance and BDNF level were assessed. Data were collected and analysed.Results: The % Correct choice during the acquisition phase, performance at the end of the acquisition phase and the mean BDNF level at the Hippocampus, Cerebellum, and Cerebral cortex showed significant decline (P<0.001) in the PUN group and significantly high (P<0.001) in the PUNA2 group compared to the control. However, the mean RME and mean WME during different days of the acquisition phase were significantly high (P<0.001) in the PUN group and insignificant (P>0.05) in PUNA2 compared to the control.Discussion: The results showed that AsX effectively modulated the cognitive deficit that occurred in perinatally undernourished rats. This can be attributed to BDNF upregulation as evidenced by the significant increase of the BDNF level.

The contributions of spatial context and imagery to the recollection of single words.

A number of theories of hippocampal function have placed spatial context at the center of richly recollected memories, but the subjective and objective ways that spatial context underlies the recollection of single words has been largely overlooked and underexplained. In this study, we conducted three experiments to investigate the involvement of spatial context in the recollection of single words. In all three experiments, participants encoded single words with varying features such as location and color. The subjective experience of recollection was measured using remember/know judgments and participant self-report of the types of information they recollected about the words. Objectively, recollection was measured using source memory judgments for both spatial and non-spatial features associated with the words. Our results provide evidence that spatial context frequently accompanies the recollection of single, isolated words, reviving discussions on the role of the hippocampus in spatial and detailed recollection.

Subchronic use of rivastigmine increases procognitive flexibility across multimodal behavioral tasks in healthy male rats.

Rivastigmine (RVT) is a reversible inhibitor of cholinesterase approved worldwide for the treatment of cognitive dysfunctions, especially in Alzheimer's disease. Most previous pre-clinical studies have examined the effects of RVT treatment in a wide variety of pathological research models. Nonetheless, the effects of this drug on sensorimotor gating, memory, and learning tasks in healthy subjects remains unclear. In this study, we investigate the procognitive effects of RVT treatment in healthy rats through sensorimotor gating evaluations (measured as prepulse inhibition of the acoustic startle reflex), active avoidance learning, and spatial memory learning in a radial maze. There is an increase in the amplitude of the startle reflex in RVT-treated rats compared to the control groups, whereas the latency remained constant. Sensorimotor gating values were also incremented compared to those values from controls. In active avoidance, rats treated with RVT learned faster to successfully perform the task compared to controls, but afterwards all groups exhibited virtually identical results. During the sessions in the radial maze, RVT-treated rats committed fewer errors in both the working and reference memory compared to controls. All in all, our results support the hypothesis that RVT treatment may entail procognitive effects in healthy subjects.

Interactions between egocentric and allocentric spatial coding of sounds revealed by a multisensory learning paradigm.

Although sound position is initially head-centred (egocentric coordinates), our brain can also represent sounds relative to one another (allocentric coordinates). Whether reference frames for spatial hearing are independent or interact remained largely unexplored. Here we developed a new allocentric spatial-hearing training and tested whether it can improve egocentric sound-localisation performance in normal-hearing adults listening with one ear plugged. Two groups of participants (N = 15 each) performed an egocentric sound-localisation task (point to a syllable), in monaural listening, before and after 4-days of multisensory training on triplets of white-noise bursts paired with occasional visual feedback. Critically, one group performed an allocentric task (auditory bisection task), whereas the other processed the same stimuli to perform an egocentric task (pointing to a designated sound of the triplet). Unlike most previous works, we tested also a no training group (N = 15). Egocentric sound-localisation abilities in the horizontal plane improved for all groups in the space ipsilateral to the ear-plug. This unexpected finding highlights the importance of including a no training group when studying sound localisation re-learning. Yet, performance changes were qualitatively different in trained compared to untrained participants, providing initial evidence that allocentric and multisensory procedures may prove useful when aiming to promote sound localisation re-learning.

Paeoniflorin attenuates impairment of spatial learning and hippocampal long-term potentiation in mice subjected to chronic unpredictable mild stress.

RATIONALE AND OBJECTIVE: Paeoniflorin has been reported to exhibit antidepressant-like effects in several animal model depression; and it also exerts a neuroprotective effect. In the present study, we investigated the effects of paeoniflorin administration on depression-like behaviors and cognitive abilities in mice subjected to chronic unpredictable mild stress (CUMS), an animal model associated with depressive disorders and cognitive deficits. METHODS: We administered paeoniflorin (20 mg/kg), which is the main active constituent extracted from Paeonia lactiflora Pall. and exerts multiple pharmacological actions, to CUMS mice. Subsequently, animals were subjected to tests of depression-like behavior including the sucrose preference test, the forced swimming test and the tail suspension test. The Morris water maze (MWM) task was applied to evaluate learning and memory capacity. Hippocampal CA1 long-term potentiation (LTP) was recorded. Dendritic spine density and the expression levels of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95) in the hippocampus were also investigated. RESULTS: The administration of paeoniflorin protected against CUMS-induced depression-like behavior. Paeoniflorin also improved the performance of CUMS mice in the MWM. The impairment of hippocampal CA1 LTP caused by CUMS was also reversed. Furthermore, paeoniflorin administration prevented decreases in dendritic spine density and in the expression of BDNF and PSD95 in the hippocampus of CUMS mice. CONCLUSION: Our observations suggest that paeoniflorin is a potential antidepressant that protects against cognitive impairment in depression.

Impact of nutrition on inflammation, tauopathy, and behavioral outcomes from chronic traumatic encephalopathy.

BACKGROUND: Repetitive mild traumatic brain injuries (rmTBI) are associated with cognitive deficits, inflammation, and stress-related events. We tested the effect of nutrient intake on the impact of rmTBI in an animal model of chronic traumatic encephalopathy (CTE) to study the pathophysiological mechanisms underlying this model. We used a between group design rmTBI closed head injuries in mice, compared to a control and nutrient-treated groups. METHODS: Our model allows for controlled, repetitive closed head impacts to mice. Briefly, 24-week-old mice were divided into five groups: control, rmTBI, and rmTBI with nutrients (2% of NF-216, NF-316 and NF-416). rmTBI mice received four concussive impacts over 7 days. Mice were treated with NutriFusion diets for 2 months prior to the rmTBI and until euthanasia (6 months). Mice were then subsequently euthanized for macro- and micro-histopathologic analysis for various times up to 6 months after the last TBI received. Animals were examined behaviorally, and brain sections were immunostained for glial fibrillary acidic protein (GFAP) for astrocytes, iba-1 for activated microglia, and AT8 for phosphorylated tau protein. RESULTS: Animals on nutrient diets showed attenuated behavioral changes. The brains from all mice lacked macroscopic tissue damage at all time points. The rmTBI resulted in a marked neuroinflammatory response, with persistent and widespread astrogliosis and microglial activation, as well as significantly elevated phospho-tau immunoreactivity to 6 months. Mice treated with diets had significantly reduced inflammation and phospho-tau staining. CONCLUSIONS: The neuropathological findings in the rmTBI mice showed histopathological hallmarks of CTE, including increased astrogliosis, microglial activation, and hyperphosphorylated tau protein accumulation, while mice treated with diets had attenuated disease process. These studies demonstrate that consumption of nutrient-rich diets reduced disease progression.

Thalamic Proteome Changes and Behavioral Impairments in Thiamine-deficient Rats.

Thiamine deficiency (TD) has been used as an experimental model in rodents to study the molecular mechanisms of neurodegeneration and its association with behavioral changes. The aims of the present study were to investigate the spatial cognitive performance of pyrithiamine-induced thiamine deficiency (PTD) in adult male rats and disclose the thalamic proteome alterations caused by a severe TD episode. After the onset of the neurological signs, such as seizure and/or loss of righting reflex, the TD treatment was interrupted. Following 15 days of recovery, all rats were submitted to the spatial cognitive tasks in the Morris Water Maze (MWM). The results show that the PTD rats exhibited deficits during the learning process, which was reverted by repeated training. However, despite the spatial cognitive recovery, some protein changes were not reversible. The proteomic analysis, using label-free quantification, revealed deregulation of 183 thalamic proteins. Using bioinformatic tools, these proteins were categorized according to Gene Ontology functional annotation and metabolic pathways. We show that a severe TD affects proteins involved in different biological processes, such as, oxidative stress, neurotransmitter synthesis and synaptic vesicle cycle. These could explain the outcome in neurotransmitter release changes caused by TD, previously observed by our group and by other authors. These findings disclose the role of key proteins and metabolic pathways probably involved in the neurodegeneration process induced by TD. These proteins represent relevant molecular targets for future studies focusing also on the molecular basis of selective vulnerability of some brain areas to TD insult.

[Impairment of spatial learning and memory and changes of oxidative stress in hippocampus from Type 1 diabetic mice].

OBJECTIVE: To investigate the relevance between spatial learning and memory impairment and the changes of inducible nitric oxide synthase (iNOS) activity, superoxide dismutase (SOD) activity and malondiadehyde (MDA) content in hippocampus from Type 1 diabetic mice.
 Methods: Sixty male mice were randomly assigned into a control group (NC group, 20 mice) and a Type 1 diabetic group (DM group, 40 mice). Type 1 diabetic mouse models were established by a large dose intraperitoneal injection of streptozotocin (100 mg/kg). The spatial learning and memory abilities of mice were assessed by Morris water maze (MWM) test. After MWM test, we chose 20 mice (diabetic encephalopathy mice) with the worst spatial learning and memory abilities from diabetic model group, and detected the iNOS activity, SOD activity and MDA content in hippocampus in both groups.
 Results: Compared with the NC group, the escape latency was significantly extended and platform crossings were significantly declined in diabetic mice (P<0.01). Furthermore, the activity of iNOS and the content of MDA were markedly increased, and the activity of SOD was significantly decreased in hippocampus of diabetic encephalopathy mice (P<0.01).
 Conclusion: The established Type 1 diabetic mice show symptoms of cognitive dysfunction, which might be related to the increase of oxidative stress in hippocampus.

Cognitive Control Structures in the Imitation Learning of Spatial Sequences and Rhythms-An fMRI Study.

Imitation learning involves the acquisition of novel motor patterns based on action observation (AO). We used event-related functional magnetic resonance imaging to study the imitation learning of spatial sequences and rhythms during AO, motor imagery (MI), and imitative execution in nonmusicians and musicians. While both tasks engaged the fronto-parietal mirror circuit, the spatial sequence task recruited posterior parietal and dorsal premotor regions more strongly. The rhythm task involved an additional network for auditory working memory. This partial dissociation supports the concept of task-specific mirror mechanisms. Two regions of cognitive control were identified: 1) dorsolateral prefrontal cortex (DLPFC) was found to be more strongly activated during MI of novel spatial sequences, which allowed us to extend the 2-level model of imitation learning by Buccino et al. (2004) to spatial sequences. 2) During imitative execution of both tasks, the posterior medial frontal cortex was robustly activated, along with the DLPFC, which suggests that both regions are involved in the cognitive control of imitation learning. The musicians' selective behavioral advantage for rhythm imitation was reflected cortically in enhanced sensory-motor processing during AO and by the absence of practice-related activation differences in DLPFC during rhythm execution.

Deep Brain Magnetic Stimulation Promotes Neurogenesis and Restores Cholinergic Activity in a Transgenic Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by progressive decline of memory and cognitive functions. Deep magnetic stimulation (DMS), a noninvasive and nonpharmacological brain stimulation, has been reported to alleviate stress-related cognitive impairment in neuropsychiatric disorders. Our previous study also discovered the preventive effect of DMS on cognitive decline in an AD mouse model. However, the underlying mechanism must be explored further. In this study, we investigated the effect of DMS on spatial learning and memory functions, neurogenesis in the dentate gyrus (DG), as well as expression and activity of the cholinergic system in a transgenic mouse model of AD (5XFAD). Administration of DMS effectively improved performance in spatial learning and memory of 5XFAD mice. Furthermore, neurogenesis in the hippocampal DG of DMS-treated 5XFAD mice was clearly enhanced. In addition, DMS significantly raised the level of acetylcholine and prevented the increase in acetylcholinesterase activity as well as the decrease in acetyltransferase activity in the hippocampus of 5XFAD mice. These findings indicate that DMS may be a promising noninvasive tool for treatment and prevention of AD cognitive impairment by promoting neurogenesis and enhancing cholinergic system function.

Electroacupuncture ameliorates spatial learning and memory impairment via attenuating NOX2-related oxidative stress in a rat model of Alzheimer's disease induced by Aß1-42.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive deterioration of cognition and memory, in which oxidative stress has been played a crucial role in the pathology of AD. Electroacupuncture (EA) is a widely used therapy based on traditional acupuncture combined with modern electrotherapy in Asia. The present study aimed to determine the effects of EA treatment on spatial learning and memory impairment, and to elucidate the status of NOX2-related oxidative stress in a rat model of Alzheimer's disease induced by Beta-amyloid1-42 (Aß1-42). Fifty-six adult female Sprague-Dawley (SD) rats were randomly divided into four groups: sham, sham+EA, AD and AD+EA. The rats in Sham+EA and AD+EA groups were respectively administrated EA treatment at Baihui and yongquan acupoints, once a day for 30 min, lasting for 28 days. The spatial learning and memory functions were assessed by Morris water maze (MWM) test. The activities of total antioxidant capacity (T-AOC), reactive oxygen species (ROS), malondialdehyde (MDA) and 8-hydroxy-2-deoxyguanosine (8-OH-dG) were evaluated. Moreover, the neuronal injury was detected by Nissl staining. Meanwhile, the NeuN expression was examined in the hippocampus, the expression levels of Nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase2(NOX2) was detected by immunofluorescence staining and western blot. The results showed that EA treatment significantly improved spatial learning and memory impairment in rats induced by Aß1-42. Concomitantly, EA treatment markedly restored T-AOC and attenuated the abnormal increase in levels of ROS, MDA and 8-OH-dG in the hippocampus of the AD rats. More notably, EA treatment also effectively ameliorated neuronal injury and counteracted the aberrant increase of NOX2 levels in the hippocampus of AD rats. Our findings suggested that EA is a potential strategy for the treatment of AD, and the possible mechanism is associated with the alleviation of neuronal injury and inhibition of NOX2-related oxidative stress.

Multitarget Therapeutic Effect of Fasudil in APP/PS1transgenic Mice.

INTRODUCTION: Therapeutic strategies targeting Alzheimer's disease-related molecule ß- amyloid (Aß), Tau protein and ß-site amyloid precursor protein cleaving enzyme (BACE) have been recently explored. However, the treatment effect for single target is not ideal. Based on multiaspect roles of Rho kinase inhibitor Fasudil on neuroprotection, neurorepair and immunomodulation, we observed therapeutic potential of Fasudil and explored possible mechanisms in amyloid precursor protein/ presenilin-1 transgenic (APP/PS1 Tg) mice, an animal model of Alzheimer's disease. METHODS: APP/PS1 Tg mice were treated with Fasudil (25 mg/kg/day) for 2 months by intraperitoneal injection. Mouse behavior tests were recorded every day. The expression of Aß deposition, Tau protein phosphorylation, BACE and postsynaptic density 95 (PSD-95) in hippocampus was assayed. The levels in the brain of Toll-like receptors (TLRs)-nuclear factor kappa B/p65（NF-κB/p65)- myeloid differentiation primary response gene 88 (MyD88) inflammatory cytokine axis were measured. RESULTS: Fasudil treatment ameliorated learning and memory deficits, accompanied by reduced Aß deposition, Tau protein phosphorylation, and BACE expression, as well as increased PSD-95 expression in hippocampus. Fasudil intervention also inhibited TLR-2/4, p-NF-κB/p65, MyD88, interleukin-1beta, interleukin-6 and tumor necrosis factor-α for TLRs-NF-κB-MyD88 inflammatory cytokine axis and the induction of interleukin-10. CONCLUSION: Fasudil exhibited multitarget therapeutic effect in APP/PS1 Tg mice. The study provides preclinical evidence that Fasudil treatment ameliorated memory deficits in APP/PS1 Tg mice, accompanied by the reduction of Aß deposition and Tau protein phosphorylation, the decrease of BACE and the increase of PSD-95, as well as inhibition of TLRs-NF-κB-MyD88 inflammatory cytokine axis. However, these results still need to be repeated and confirmed before clinical application.

Effects of thalamic hemorrhagic lesions on explicit and implicit learning during the acquisition and retrieval phases in an animal model of central post-stroke pain.

Hemorrhagic stroke has many symptoms, including central pain, learning and memory impairments, motor deficits, language problems, emotional disturbances, and social maladjustment. Lesions of the ventral basal complex (VBC) of the thalamus elicit thermal and mechanical hyperalgesia, forming an animal model of central post-stroke pain (CPSP). However, no research has yet examined the involvement of learning and memory in CPSP using an animal model. The present study examined whether VBC lesions affect motor function, conditioned place preference (CPP; implicit memory), and spatial learning (explicit memory) in the acquisition and retrieval phases. The results showed that rats with VBC lesions exhibited thermal hyperalgesia in the acquisition and retrieval phases, indicating that these lesions can induce CPSP. During these phases, the rats with VBC lesions exhibited enhanced (morphine-induced) CPP learning. These lesions did not affect the rats' total distance travelled, time spent, or velocity in the spatial learning tasks. The lesions also did not affect motor function in the rotarod task. Altogether, VBC lesions resulted in CPSP and facilitated CPP (implicit memory). However, the lesions did not affect spatial learning (explicit memory) or motor function. The relationship between CPSP and learning and memory is important for patients who suffer from such central pain. The implications of the present study may provide insights into helping reduce CPSP and its associated symptoms.