Pre-operative environmental enrichment does not yield a prophylactic effect against traumatic brain injury-induced neurobehavioral deficits.

The robustness of environmental enrichment (EE) in ameliorating neurobehavioral and cognitive deficits after experimental traumatic brain injury (TBI) is unequivocal. What is equivocal is whether EE can function as a prophylactic to afford resiliency and neuroprotection against TBI. We hypothesized that pre-operative EE would yield a protective effect against TBI-induced motor, cognitive, and coping deficits, and that further improvements would be conferred when EE is provided before and after TBI. To test the hypotheses, adult male rats received either 4 weeks of EE or standard (STD) housing prior to undergoing a controlled cortical impact of moderate severity (2.8 mm deformation at 4 m/s) or sham injury while under anesthesia. After injury, the rats were randomly assigned to post-operative EE or STD housing. Motor ability, spatial learning, and memory retention were assessed by beam-walk and water maze tests, respectively. Active and passive behavioral coping strategies were evaluated with the shock probe defensive burying (SPDB) test. c-Fos and cortical lesion volume were also quantified. The post-TBI enrichment groups (EE + TBI + EE and STD + TBI + EE) did not differ (p > 0.05) and performed better than the post-TBI STD-housed groups (EE + TBI + STD and STD + TBI + STD) on motor and cognition (p < 0.05). The post-TBI STD groups did not differ, regardless of whether in EE or STD living conditions before injury (p > 0.05). Moreover, both post-TBI enrichment groups performed better in the SPDB test relative to the STD + TBI + STD group (p < 0.05). c-Fos + cells were upregulated in the ipsilateral CA1 in both pre-injury EE groups relative to the pre-injury STD groups (p < 0.05). No statistical differences were observed in cortical lesion volume among the groups. Overall, these data do not support the hypothesis as no neuroprotective effect was observed with 4 weeks of pre-operative EE and no additional benefit was achieved in the TBI group receiving both pre-and-post EE relative to the TBI group receiving only post-EE. However, the data do reinforce the consistency of post-TBI EE in producing robust neurobehavioral benefits, which further supports this paradigm as a relevant preclinical model of neurorehabilitation.

Development, Statistical Optimization, and Characterization of Resveratrol-Containing Solid Lipid Nanoparticles (SLNs) and Determination of the Efficacy in Reducing Neurodegenerative Symptoms Related to Alzheimer's Disease: In Vitro and In Vivo Study.

Resveratrol (RSV), as a natural polyphenol exhibiting antioxidative properties, is studied in the treatment of neurodegenerative diseases. However, RSV has low oral bioavailability. In this study and in order to overcome the issue, RSV was encapsulated into the solid lipid nanoparticles (SLNs). In this study, RSV-loaded solid lipid nanoparticles (RSV-SLNs) were prepared by the solvent emulsification-evaporation technique, and their physicochemical properties were optimized using Box-Behnken response surface methodology. The morphology of the particles was evaluated using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The neuroprotective effects of the nanoparticles were investigated in animal models using the Morris water maze (MWM). Then after, the rats were sacrificed, their brains were collected, and the extent of lipid peroxidase (LPO) as well as the level of reduced glutathione (GSH) were determined in the hippocampus section samples. Finally, the collected brain tissues were histologically studied. The particle size, polydispersity index (PDI), zeta potential, entrapment efficiency (EE%), and drug loading (DL%) of the optimized nanoparticles were 104.5 ± 12.3 nm, 0.322 ± 0.11, -3.1 ± 0.15 mV, 72.9 ± 5.31% and 14.6 ± 0.53%, respectively. The microscopic images revealed spherically shaped and nonaggregated nanoparticles. The in vivo studies demonstrated higher efficiency of RSV-SLN in the reduction of escape latency time and improvement in the time spent in the target quadrant compared to free RSV. Moreover, it was demonstrated that RSV-SLN posed a higher potency in the reduction of LPO as well as elevation of the GSH levels in the brain samples. The histological studies revealed a decline in neural degeneration and an improvement in the CA1 pyramidal cell morphology. The obtained data revealed that RSV-SLNs caused more reduction in Alzheimer-related symptoms rather than free RSV.

Bioactive Properties of Enzymatic Gelatin Hydrolysates Based on In Silico, In Vitro, and In Vivo Studies.

This current study aims to analyze the potential bioactivities possessed by the enzymatic hydrolysates of commercial bovine, porcine, and tilapia gelatins using bioinformatics in combination with in vitro and in vivo studies. The hydrolysate with superior inhibition of angiotensin converting enzyme (ACE) activity was used to treat the D-galactose (DG)-induced amnesic mice. In silico digestion of the gelatins led to the identification of peptide sequences with potential antioxidant, ACE-inhibitory, and anti-amnestic properties. The results of in vitro digestion revealed that the <1 kDa peptide fraction of porcine gelatin hydrolysate obtained after 1 h digestion with papain (PP) (PP1, <1 kDa) potently inhibited ACE, acetylcholinesterase, and prolyl endopeptidase activities at 87.42%, 21.24%, and 48.07%, respectively. Administering the PP1 to DG-induced amnesic mice ameliorated the spatial cognitive impairment and Morris water maze learning abilities. The dentate area morphology in the PP1-treated mice was relatively similar to the control group. In addition, PP1 enhanced the antioxidant capacity in the DG-induced amnesic mice. This study suggests that PP1 could serve as a potential treatment tool against oxidative stress, hypertension, and neurodegenerative diseases.

Adult zebrafish can learn Morris water maze-like tasks in a two-dimensional virtual reality system.

Virtual reality (VR) has emerged as a powerful tool for investigating neural mechanisms of decision-making, spatial cognition, and navigation. In many head-fixed VRs for rodents, animals locomote on spherical treadmills that provide rotation information in two axes to calculate two-dimensional (2D) movement. On the other hand, zebrafish in a submerged head-fixed VR can move their tail to enable movement in 2D VR environment. This motivated us to create a VR system for adult zebrafish to enable 2D movement consisting of forward translation and rotations calculated from tail movement. Besides presenting the VR system, we show that zebrafish can learn a virtual Morris water maze-like (VMWM) task in which finding an invisible safe zone was necessary for the zebrafish to avoid an aversive periodic mild electric shock. Results show high potential for our VR system to be combined with optical imaging for future studies to investigate spatial learning and navigation.

Berberine Hydrochloride Improves Cognitive Function and Hippocampal Antioxidant Status in Subchronic and Chronic Lead Poisoning.

OBJECTIVES: To determine the neuroprotective effects of berberine hydrochloride (BBR) against lead-induced injuries on the hippocampus of rats. METHODS: Wistar rats were exposed orally to doses of 100 and 500 ppm lead acetate for 1 and 2 months to develop subchronic and chronic lead poisening models, respectively. For treatment, BBR (50 mg/kg daily) was injected intraperitoneally to rats poisoned with lead. At the end of the experiment, the spatial learning and memory of rats were assessed using the Morris water maze test. Hippocampal tissue changes were examined by hematoxylin and eosin staining. The activity of antioxidant enzymes catalase, superoxide dismutase, glutathione peroxidase, and malondialdehyde levels as parameters of oxidative stress and antioxidant status of the hippocampus were evaluated. RESULTS: BBR reduced cognitive impairment in rats exposed to lead (P<0.05 or P<0.01). The resulting biochemical changes included a decrease in the activity of antioxidants and an increase in lipid peroxidation of the hippocampus of lead-exposed rats (P<0.05 or P<0.01), which were significantly modified by BBR (P<0.05). BBR also increased the density of healthy cells in the hippocampus of leadexposed rats (P<0.05). Significant changes in tissue morphology and biochemical factors of the hippocampus were observed in rats that received lead for 2 months (P<0.05). Most of these changes were insignificant in rats that received lead for 1 month. CONCLUSION: BBR can improve oxidative tissue changes and hippocampal dysfunction in lead-exposed rats, which may be due to the strong antioxidant potential of BBR.

Chlorogenic acid ameliorates memory dysfunction via attenuating frontal lobe oxidative stress and apoptosis in diabetic rat model.

Background/aim: Diabetes mellitus, characterized by hyperglycemia, causes various complications, one of which is memory dysfunction. The frontal lobe is known to be responsible for impaired memory function due to hyperglycemia and is associated with oxidative stress-mediated neuronal cell apoptosis. Chlorogenic acid (CGA) is reported to have neuroprotective effects. However, its effect on the frontal lobe in diabetes mellitus (DM) rats is not widely known. This research aimed to elucidate the effect of CGA on the mRNA expressions of SOD1, SOD2, p53, and Bcl-2 in the frontal lobe of DM rats. Materials and methods: Thirty male Wistar rats (2-month-old, 150-200 gBW) were randomly divided into six groups: C (control), DM1.5 (1.5-month DM), DM2 (2-month DM), CGA12.5, CGA25 and CGA50 (DM+CGA 12.5, 25, and 50 mg/kgBW, respectively). A single dose of streptozotocin (60 mg/kgBW) was intraperitoneally injected. Intraperitoneal CGA injection was administered daily for DM1.5 rats for 14 days. Path length was measured in the Morris water maze (MWM) probe test. After termination, the frontal lobes were carefully harvested for RNA extraction. Reverse transcriptase PCR was performed to examine the mRNA expression of SOD1, SOD2, p53, and Bcl-2. Results: The DM2 group demonstrated significant shorter path length on the MWM probe test and significantly lower mRNA expression of SOD1 and Bcl-2, compared to the C group. After CGA administration, the CGA25 group showed a significantly shorter path length than the C group. The CGA12.5 and CGA25 groups had significantly higher mRNA expression of SOD1 than the DM1.5 group. Compared to the DM1.5 and DM2 groups, SOD2 mRNA expression of the administration of all three CGA doses increased markedly. Furthermore, Bcl-2 mRNA expression was significantly increased in the CGA12.5 and CGA50 groups, compared with the DM2 group. Conclusion: Chlorogenic acid might improve memory function through upregulation of frontal lobes' SOD1, SOD2, and Bcl-2 mRNA expression in DM rats.

Spatial memory and learning: investigating the role of dynamic visual acuity.

Introduction: The vestibular system's contribution to spatial learning and memory abilities may be clarified using the virtual Morris Water Maze Task (vMWMT). This is important because of the connections between the vestibular system and the hippocampus area. However, there is ongoing debate over the role of the vestibular system in developing spatial abilities. This study aimed to evaluate the relationship between Dynamic Visual Acuity (DVA) across three planes and spatial abilities. Methods: This cross-sectional study was conducted with 50 healthy adults aged 18 to 55 with normal stress levels and mental health and no neurological, audiological, or vestibular complaints. The Trail-Making Test (TMT) Forms A and B for the assessment of executive functions, the DVA test battery for the evaluation of visual motor functions, and the Virtual Morris Water Maze Test (vMWMT) for the assessment of spatial learning and spatial memory were performed. All participants also underwent the Benton Face Recognition Test (BFRT) and Digit Symbol Substitution Tests (DSST) to assess their relation with spatial memory. Results: DVA values in horizontal (H-DVA), vertical (V-DVA), and sagittal (S-DVA) planes ranged from (-0.26) to 0.36 logMAR, (-0.20) to 0.36 logMAR, and (-0.28) to 0.33 logMAR, respectively. The latency of three planes of DVA was affected by vMWMT (Horizontal, Vertical, and Sagittal; Estimate: 22.733, 18.787, 13.341, respectively p < 0.001). Moreover, a moderately significant correlation was also found, with a value of 0.571 between the Virtual MWM test and BFRT and a value of 0.539 between the DSST (p < 0.001). Conclusion: Spatial abilities in healthy adults were significantly influenced by dynamic visual functions across horizontal, vertical, and sagittal planes. These findings are expected to trigger essential discussions about the mechanisms that connect the vestibular-visual system to the hippocampus. The original vMWMT protocol is likely to serve as a model for future studies utilizing this technology.

Effects of high-intensity chronic noise on spatial memory in male versus female rats.

The detrimental effects of high-intensity noise on the auditory system and emotional status, including the induction of anxiety, are well documented. Preclinical as well as epidemiological and clinical studies have solidly established differential responses between males and females to various stressful stimuli, including high-intensity white noise (HIWN). However, whether chronic exposure to noise affects cognitive functions and whether this effect is sex dependent has not been adequately addressed. In this study, we used two cognitive test paradigms, such as the Morris water maze (MWM) and the multi-branch maze (MBM), to test the effect of chronic HIWN on indices of spatial learning and memory in both male and female Wistar rats. Our findings indicate that daily (1 h) exposure to 100 dB of noise for 30 consecutive days induces different task-dependent responses in male versus female rats. For example, in the acquisition phase of MWM, female rats exposed to noise outperformed their male counterparts at twice the speed. Similarly, in the MBM test, noise-exposed female rats outperformed the male rats in reaching the nest box. It is clear from these studies that noise impairs cognitive functions twice as negatively in male rats as in female rats. Thus, sex-related differences in spatial learning and memory in response to HIWN must be taken into consideration when investigating the neurobiological components and/or treatment modalities.

Transformation of mulberry polyphenols by Lactobacillus plantarum SC-5: Increasing phenolic acids and enhancement of anti-aging effect.

Fermentation can transform bioactive compounds in food and improve their biological activity. This study aims to explore the transformation of polyphenols in mulberry juice and the improvement of its anti-aging effect. The results demonstrated that Lactobacillus plantarum SC-5 transformed anthocyanin in mulberry juice into more phenolic acids, especially improved 2-hydroxy-3-(4-hydroxyphenyl) propanoic acid from 4.16 ± 0.06 to 10.07 ± 0.03. In the D-gal-induced mouse model, fermented mulberry juice significantly raised the abundance of Bifidobacteriaceae (303.7 %) and Lactobacillaceae (237.2 %) and Short-chain fatty acids (SCFAs) in intestine, further reducing the level of oxidative stress (12.3 %). Meanwhile, the expression of Sirtuin 1 (SIRT1) and Brain-derived neurotrophic factor (BDNF) increased, which protected the integrity of hippocampal tissue. Morris water maze results approved that fermented mulberry juice improved cognitive ability in aging mice (30.3 %). This study provides theoretical support for the view that fermentation is an effective means of developing functional foods.

Cognitive deficits in human ApoE4 knock-in mice: A systematic review and meta-analysis.

Apolipoprotein-E4 (ApoE4) is an important genetic risk factor for Alzheimer's disease. The development of targeted-replacement human ApoE knock-in mice facilitates research into mechanisms by which ApoE4 affects the brain. We performed meta-analyses and meta-regression analyses to examine differences in cognitive performance between ApoE4 and ApoE3 mice. We included 61 studies in which at least one of the following tests was assessed: Morris Water Maze (MWM), novel object location (NL), novel object recognition (NO) and Fear Conditioning (FC) test. ApoE4 vs. ApoE3 mice performed significantly worse on the MWM (several outcomes, 0.17 ≤ g ≤ 0.60), NO (exploration, g=0.33; index, g=0.44) and FC (contextual, g=0.49). ApoE4 vs. ApoE3 differences were not systematically related to sex or age. We conclude that ApoE4 knock-in mice in a non-AD condition show some, but limited cognitive deficits, regardless of sex and age. These effects suggest an intrinsic vulnerability in ApoE4 mice that may become more pronounced under additional brain load, as seen in neurodegenerative diseases.

The effects of estrogens on spatial learning and memory in female rodents - A systematic review and meta-analysis.

Estrogens have inconsistent effects on learning and memory in both the clinical and preclinical literature. Preclinical literature has the advantage of investigating an array of potentially important factors contributing to the varied effects of estrogens on learning and memory, with stringently controlled studies. This study set out to identify specific factors in the animal literature that influence the effects of estrogens on cognition, for possible translation back to clinical practice. The literature was screened and studies meeting strict inclusion criteria were included in the analysis. Eligible studies included female ovariectomized rodents with an adequate vehicle for the estrogen treatment, with an outcome of spatial learning and memory in the Morris water maze. Training days of the Morris water maze were used to assess acquisition of spatial learning, and the probe trial was used to evaluate spatial memory recall. Continuous outcomes were pooled using a random effects inverse variance method and reported as standardized mean differences with 95 % confidence intervals. Subgroup analyses were developed a priori to assess important factors. The overall analysis favoured treatment for the later stages of training and for the probe trial. Factors including the type of estrogen, route, schedule of administration, age of animals, timing relative to ovariectomy, and duration of treatment were all found to be important. The subgroup analyses showed that chronic treatment with 17ß-estradiol, either cyclically or continuously, to young animals improved spatial recall. These results, observed in animals, can inform and guide further clinical research on hormone replacement therapy for cognitive benefits.

Exploratory assessment of the effect of systemic administration of soluble glycoprotein 130 on cognitive performance and chemokine levels in a mouse model of experimental traumatic brain injury.

Uncontrolled neuroinflammation mediates traumatic brain injury (TBI) pathology and impairs recovery. Interleukin-6 (IL-6), a pleiotropic inflammatory regulator, is associated with poor clinical TBI outcomes. IL-6 operates via classical-signaling through membrane-bound IL-6 receptor (IL-6R) and trans-signaling through soluble IL-6 receptor (s)IL-6R. IL-6 trans-signaling specifically contributes to neuropathology, making it a potential precision therapeutic TBI target. Soluble glycoprotein 130 (sgp130) prevents IL-6 trans-signaling, sparing classical signaling, thus is a possible treatment. Mice received either controlled cortical impact (CCI) (6.0 ± 0.2 m/s; 2 mm; 50-60ms) or sham procedures. Vehicle (VEH) or sgp130-Fc was subcutaneously administered to sham (VEH or 1 µg) and CCI (VEH, 0.25 µg or 1 µg) mice on days 1, 4, 7, 10 and 13 post-surgery to assess effects on cognition [Morris Water Maze (MWM)] and ipsilateral hemisphere IL-6 related biomarkers (day 21 post-surgery). CCI + sgp130-Fc groups (0.25 µg and 1 µg) were combined for analysis given similar behavior/biomarker outcomes. CCI + VEH mice had longer latencies and path lengths to the platform and increased peripheral zone time versus Sham + VEH and Sham + sgp130-Fc mice, suggesting injury-induced impairments in learning and anxiety. CCI + sgp130-Fc mice had shorter platform latencies and path lengths and had decreased peripheral zone time, indicating a therapeutic benefit of sgp130-Fc after injury on learning and anxiety. Interestingly, Sham + sgp130-Fc mice had shorter platform latencies, path lengths and peripheral zone times than Sham + VEH mice, suggesting a beneficial effect of sgp130-Fc, independent of injury. CCI + VEH mice had increased brain IL-6 and decreased sgp130 levels versus Sham + VEH and Sham + sgp130-Fc mice. There was no treatment effect on IL-6, sIL6-R or sgp130 in Sham + VEH versus Sham + sgp130-Fc mice. There was also no treatment effect on IL-6 in CCI + VEH versus CCI + sgp130-Fc mice. However, CCI + sgp130-Fc mice had increased sIL-6R and sgp130 versus CCI + VEH mice, demonstrating sgp130-Fc treatment effects on brain biomarkers. Inflammatory chemokines (MIP-1ß, IP-10, MIG) were increased in CCI + VEH mice versus Sham + VEH and Sham + sgp130-Fc mice. However, CCI + sgp130-Fc mice had decreased chemokine levels versus CCI + VEH mice. IL-6 positively correlated, while sgp130 negatively correlated, with chemokine levels. Overall, we found that systemic sgp130-Fc treatment after CCI improved learning, decreased anxiety and reduced CCI-induced brain chemokines. Future studies will explore sex-specific dosing and treatment mechanisms for sgp130-Fc therapy.

Memory enhancing and neuroprotective effects of apomorphine in a rat model of dementia.

Oxidative stress from generation of increased reactive oxygen species or has been reported to play an important role in dementia. Oxidative stress due to free radicals of oxygen or reactive oxygen species could be precipitating factors in the etiology of dementia. Apomorphine has been reported to have neuroprotective effects. To monitor memory enhancing and neuroprotective effects of apomorphine, we determined the antioxidant enzymes activities, lipid peroxidation, acetylcholine esterase (AChE) activity in brain and plasma, following repetitive administration of apomorphine in rat model of dementia. Biogenic amine levels were also monitored in hippocampus. Repeated administration of scopolamine was taken as an animal model of dementia. Decreased glutathione peroxidase, superoxide dismutase and catalase activities were observed in these animal models of dementia. While increased lipid peroxidation was also observed in the brain and plasma samples. The results showed significant effects of apomorphine. The activities of antioxidant enzymes displayed increased activities in both brain and plasma. Glutathione peroxidase and catalase activities were found to be significantly higher in brain and plasma of apomorphine treated rats. Superoxide dismutase (SOD) was significantly decreased in plasma of scopolamine injected rats; and a decreased tendency (non-significant) of SOD in brain was also observed. AChE activity in brain and plasma was significantly decreased in scopolamine treated rats. Learning and memory of rats in the present study was assessed by Morris Water Maze (MWM). Short-term memory and long-term memory was impaired significantly in scopolamine treated rats, which was prevented by apomorphine. Moreover, a marked decrease in biogenic amines was also found in the brain of scopolamine treated rats and was reverted in apomorphine treated rats. Results showed that scopolamine-treatment induced memory impairment and induced oxidative stress in rats as compared to saline-treated controls. These impairments were significantly restored by apomorphine administration. In conclusion, our data suggests that apomorphine at the dose of 1 mg/kg could be a potential therapeutic agent to treat dementia and related disorders.

Behavioural interference at event boundaries reduces long-term memory performance in the virtual water maze task without affecting working memory performance.

Narrative episodic memory of movie clips can be retroactively impaired by presenting unrelated stimuli coinciding with event boundaries. This effect has been linked with rapid hippocampal processes triggered by the offset of the event, that are alternatively related either to memory consolidation or with working memory processes. Here we tested whether this effect extended to spatial memory, the temporal specificity and extent of the interference, and its effect on working- vs long-term memory. In three computerized adaptations of the Morris Water Maze, participants learned the location of an invisible target over three trials each. A second spatial navigation task was presented either immediately after finding the target, after a 10-s delay, or no second task was presented (control condition). A recall session, in which participants indicated the learned target location with 10 'pin-drop' trials for each condition, was performed after a 1-h or a 24-h break. Spatial memory was measured by the mean distance between pins and the true location. Results indicated that the immediate presentation of the second task led to worse memory performance, for both break durations, compared to the delayed condition. There was no difference in performance between the delayed presentation and the control condition. Despite this long-term memory effect, we found no difference in the rate of performance improvement during the learning session, indicating no effect of the second task on working memory. Our findings are in line with a rapid process, linked to the offset of an event, that is involved in the early stages of memory consolidation.

Intranasal insulin treatment ameliorates spatial memory, muscular strength, and frailty deficits in 5xFAD mice.

The 5xFAD mouse model shows age-related weight loss as well as cognitive and motor deficits. Metabolic dysregulation, especially impaired insulin signaling, is also present in AD. This study examined whether intranasal delivery of insulin (INI) at low (0.875 U) or high (1.750 U) doses would ameliorate these deficits compared to saline in 10-month-old female 5xFAD and B6SJL wildtype (WT) mice. INI increased forelimb grip strength in the wire hang test in 5xFAD mice in a dose-dependent manner but did not improve the performance of 5xFAD mice on the balance beam. High INI doses reduced frailty scores in 5xFAD mice and improved spatial memory in both acquisition and reversal probe trials in the Morris water maze. INI increased swim speed in 5xFAD mice but had no effect on object recognition memory or working memory in the spontaneous alternation task, nor did it improve memory in the contextual or cued fear memory tasks. High doses of insulin increased the liver, spleen, and kidney weights and reduced brown adipose tissue weights. P-Akt signaling in the hippocampus was increased by insulin in a dose-dependent manner. Altogether, INI increased strength, reduced frailty scores, and improved visual spatial memory. Hypoglycemia was not present after INI, however alterations in tissue and organ weights were present. These results are novel and important as they indicate that intra-nasal insulin can reverse cognitive, motor and frailty deficits found in this mouse model of AD.

Use of Ordered Beta Regression Unveils Cognitive Flexibility Index and Longitudinal Cognitive Training Signatures in Normal and Alzheimer's Disease Pathological Aging.

Generalized linear mixed models (GLMMs) are a cornerstone data analysis strategy in behavioral research because of their robustness in handling non-normally distributed variables. Recently, their integration with ordered beta regression (OBR), a novel statistical tool for managing percentage data, has opened new avenues for analyzing continuous response data. Here, we applied this combined approach to investigate nuanced differences between the 3xTg-AD model of Alzheimer's disease (AD) and their C57BL/6 non-transgenic (NTg) counterparts with normal aging in a 5-day Morris Water Maze (MWM) test protocol. Our longitudinal study included 22 3xTg-AD mice and 15 NTg mice (both male and female) assessed at 12 and 16 months of age. By identifying and analyzing multiple swimming strategies during three different paradigms (cue, place task, and removal), we uncovered genotypic differences in all paradigms. Thus, the NTg group exhibited a higher percentage of direct search behaviors, while an association between circling episodes and 3xTg-AD animals was found. Furthermore, we also propose a novel metric-the "Cognitive Flexibility Index"-which proved sensitive in detecting sex-related differences. Overall, our integrated GLMMs-OBR approach provides a comprehensive insight into mouse behavior in the MWM test, shedding light on the effects of aging and AD pathology.

Neuroprotective effects of Anshen Bunao Syrup on cognitive dysfunction in Alzheimer's disease rat models.

Alzheimer's disease (AD) presents a significant challenge due to its prevalence and lack of cure, driving the quest for effective treatments. Anshen Bunao Syrup, a traditional Chinese medicine known for its neuroprotective properties, shows promise in addressing this need. However, understanding its precise mechanisms in AD remains elusive. This study aimed to investigate Anshen Bunao Syrup's therapeutic potential in AD treatment using a scopolamine-induced AD rat model. Assessments included novel-object recognition and Morris water maze tasks to evaluate spatial learning and memory, alongside Nissl staining and ELISA analyses for neuronal damage and biomarker levels. Results demonstrated that Anshen Bunao Syrup effectively mitigated cognitive dysfunction by inhibiting amyloid-ß and phosphorylation Tau aggregation, thereby reducing neuronal damage. Metabolomics profiling of rats cortex revealed alterations in key metabolites implicated in tryptophan and fatty acid metabolism pathways, suggesting a role in the therapeutic effects of Anshen Bunao Syrup. Additionally, ELISA and correlation analyses indicated attenuation of oxidative stress and immune response through metabolic remodeling. In conclusion, this study provides compelling evidence for the neuroprotective effects of Anshen Bunao Syrup in AD models, shedding light on its potential as a therapeutic agent for AD prevention and treatment.

Involvement of relaxin-family peptide-3 receptor (RXFP3) in the ventral dentate gyrus of the hippocampus in spatial and fear memory in rats.

The neuropeptide relaxin-3 and its cognate receptor, relaxin family peptide-3 receptors (RXFP3), have been implicated in modulating learning and memory processes, but their specific roles remain unclear. This study utilized behavioral and molecular approaches to investigate the effects of putatively reversible blockade of RXFP3 in the ventral dentate gyrus (vDG) of the hippocampus on spatial and fear memory formation in rats. Male Wistar rats received bilateral vDG cannula implantation and injections of the RXFP3 antagonist, R3(BΔ23-27)R/I5 (400 ng/0.5 µL per side), or vehicle at specific time points before acquisition, consolidation, or retrieval phases of the Morris water maze and passive avoidance learning tasks. RXFP3 inhibition impaired acquisition in the passive avoidance task but not the spatial learning task. However, both memory consolidation and retrieval were disrupted in both tasks following RXFP3 antagonism. Ventral hippocampal levels of the consolidation-related kinase p70-S6 kinase (p70S6K) were reduced RXFP3 blockade. These findings highlight a key role for ventral hippocampal RXFP3 signaling in the acquisition, consolidation, and retrieval of spatial and emotional memories, extending previous work implicating this neuropeptide system in hippocampal memory processing.

Dihydroergotamine Increases Histamine Brain Levels and Improves Memory in a Scopolamine-Induced Amnesia Model.

The beneficial effects of increasing histamine levels on memory have acquired special interest due to their applicability to psychiatric conditions that cause memory impairments. In addition, by employing drug repurposing approaches, it was demonstrated that dihydroergotamine (DHE), an FDA drug approved to treat migraines, inhibits Histamine N Methyl Transferase (HNMT), the enzyme responsible for the inactivation of histamine in the brain. For this reason, in the present work, the effect of DHE on histamine levels in the hippocampus and its effects on memory was evaluated, employing the scopolamine-induced amnesia model, the Novel Object Recognition (NOR) paradigm, and the Morris Water Maze (MWM). Furthermore, the role of histamine 1 receptor (H1R) and histamine 2 receptor (H2R) antagonists in the improvement in memory produced by DHE in the scopolamine-induced amnesia model was evaluated. Results showed that the rats that received DHE (10 mg/kg, i.p.) showed increased histamine levels in the hippocampus after 1 h of administration but not after 5 h. In behavioral assays, it was shown that DHE (1 mg/kg, i.p.) administered 20 min before the training reversed the memory impairment produced by the administration of scopolamine (2 mg/kg, i.p.) immediately after the training in the NOR paradigm and MWM. Additionally, the effects in memory produced by DHE were blocked by pre-treatment with pyrilamine (20 mg/kg, i.p.) administered 30 min before the training in the NOR paradigm and MWM. These findings allow us to demonstrate that DHE improves memory in a scopolamine-induced amnesia model through increasing histamine levels at the hippocampus due to its activity as an HNMT inhibitor.

Doxycycline cotherapy with albendazole relieves neural function damage in C57BL/6 and BALB/c mice infected with Angiostrongylus cantonensis.

BACKGROUND: We investigated the effects of combination therapy albendazole and doxycycline in Angiostrongylus cantonensis-infected mice during early and late treatment. MATERIALS AND METHODS: C57BL/6 and BALB/c mice were divided into five groups: (i) uninfected, (ii) infected with A. cantonensis, (iii) infected + 10 mg/kg albendazole, (iv) infected + 25mg/kg doxycycline, and (v) infected + 10 mg/kg albendazole + 25 mg/kg doxycycline. We administered drugs in both early treatments started at 7-day post infections (dpi) and late treatments (14 dpi) to A. cantonensis-infected C57BL/6 and BALB/c mice. To assess the impact of these treatments, we employed the Morris water maze test to evaluate spatial learning and memory abilities, and the rotarod test to measure motor coordination and balance in C57BL/6 mice. Additionally, we monitored the expression of the cytokine IL-33 and GFAP in the brain of these mice using western blot analysis. RESULTS: In this study, A. cantonensis infection was observed to cause extensive cerebral angiostrongyliasis in C57BL/6 mice. This condition significantly affected their spatial learning and memory abilities, as assessed by the Morris water maze test, as well as their motor coordination, which was evaluated using the rotarod test. Early treatment with albendazole led to favorable recovery outcomes. Both C57BL/6 and BALB/c mice express IL-33 and GFAP after co-therapy. The differences of levels and patterns of IL-33 and GFAP expression in mice may be influenced by the balance between pro-inflammatory and anti-inflammatory signals within the immune system. CONCLUSIONS: Combination therapy with anthelmintics and antibiotics in the early stage of A. cantonensis infection, in C57BL/6 and BALB/c mice resulted in the death of parasites in the brain and reduced the subsequent neural function damage and slowed brain damage and neurobehavior impairment. This study suggests a more effective and novel treatment, and drug delivery method for brain lesions that can decrease the neurological damage of angiostrongyliasis patients.