Spontaneous Alternation Research Articles

Phoenix dactylifera and polyphenols ameliorated monosodium glutamate toxicity in the dentate gyrus of Wistar rats.

Monosodium glutamate (MSG) has been known to cause neurodegeneration, due to its ability to trigger excitotoxicity, and the hippocampus is one of the most affected regions. Therefore, Phoenix dactylifera (P. dactylifera) and polyphenols was employed in this study to mitigate on the deleterious effect of monosodium glutamate on the dentate gyrus of Wistar rats. Forty-eight male Wistar rats weighing between 120-150g was used for the study. The Wistar rats were grouped into eight, (n=6). Groups 1-8 received 1.6mL/kg normal saline, 4000mg\kg monosodium glutamate for 7-days, 4000mg\kg monosodium glutamate for 7-days and 100mg\kg caffeic-acid for 14-days concurrently, 4000mg\kg monosodium glutamate for 7-days and 100mg\kg Phoenix dactylifera for 14-days concurrently, 4000mg\kg monosodium glutamate for 7-days and 100mg\kg luteolin for 14-days concurrently, 100mg\kg. caffeic-acid for 14-days followed by 4000mg\kg monosodium glutamate for 7-days, 100mg\kg Phoenix dactylifera for 14-days followed by 4000mg\kg monosodium glutamate for 7-days and 100mg\kg luteolin for 14-days followed by 4000mg\kg monosodium glutamate for 7-days respectively. After the treatments, the rats underwent behavioural tests, and subsequently, the brain tissues were processed for histological and biochemical analyses. The activities of P. dactylifera and polyphenols ameliorated the deleterious effect of monosodium glutamate, through increased spontaneous alternation of the experimental animals, dominant matured granule cells of the dentate gyrus and modulated the activities of superoxide dismutase, glutathione peroxidase and malondialdehyde in the of male Wistar rats. Therefore, this study revealed that P. dactylifera and polyphenols ameliorated monosodium glutamate toxicity in the dentate gyrus of Wistar rats.

Ameliorative effects of Albizia adianthifolia aqueous extract against pentylenetetrazole-induced epilepsy and associated memory loss in mice: Role of GABAergic, antioxidant defense and anti-inflammatory systems

Albizia adianthifolia (Schumach.) (Fabaceae) is a medicinal herb used for the treatment of epilepsy and memory impairment. This study aims to investigate the anticonvulsant effects of Albizia adianthifolia aqueous extract against pentylenetetrazole (PTZ)-induced spontaneous convulsions in mice; and determine whether the extract could mitigate memory impairment, oxidative/nitrergic stress, GABA depletion and neuroinflammation. Ultra-high performance liquid chromatography/mass spectrometry analysis was done to identify active compounds from the extract. Mice were injected with PTZ once every 48 h until kindling was developed. Animals received distilled water for the normal group and negative control groups, doses of extract (40, 80, or 160 mg/kg) for the test groups and sodium valproate (300 mg/kg) for the positive control group. Memory was measured using Y maze, novel object recognition (NOR) and open field paradigms, while the oxidative/nitrosative stresses (MDA, GSH, CAT, SOD and NO), GABAergic transmission (GABA, GABA-T and GAD) and neuro-inflammation (TNF-α, IFN-γ, IL- 1β, and IL-6) were determined. Brain photomicrograph was also studied. Apigenin, murrayanine and safranal were identified in the extract. The extract (80–160 mg/kg) significantly protected mice against seizures and mortality induced by PTZ. The extract significantly increased the spontaneous alternation and the discrimination index in the Y maze and NOR tests, respectively. PTZ kindling induced oxidative/nitrosative stress, GABA depletion, neuroinflammation and neuronal cells death was strongly reversed by the extract. The results suggest that the anticonvulsant activity of Albizia adianthifolia extract is accompanied by its anti-amnesic property, and may be supported by the amelioration of oxidative stress, GABAergic transmission and neuroinflammation.

Group I mGluRs positive allosteric modulators improved schizophrenia-related behavioral and molecular deficits in the Poly I:C rat model

RationaleMaternal polyinosinic-polycytidylic acid (Poly I:C) exposure leads to an increase in various proinflammatory cytokines and causes schizophrenia-like symptoms in offspring. In recent years, group I metabotropic glutamate receptors (mGluRs) have emerged as a potential target in the pathophysiology of schizophrenia. ObjectivesThe aim of our study was to investigate the behavioral and molecular changes by using the mGlu1 receptor positive allosteric modulator (PAM) agent RO 67-7476, and the negative allosteric modulator (NAM) agent JNJ 16259685 and the mGlu5 receptor PAM agent VU-29, and NAM agent fenobam in the Poly I:C-induced schizophrenia model in rats. MethodsFemale Wistar albino rats were treated with Poly I:C on day 14 of gestation after mating. On the postnatal day (PND) 34-35, 56-57 and 83-84, behavioral tests were performed in the male offspring. On the PND84, brain tissue was collected and the level of proinflammatory cytokines was determined by ELISA method. ResultsPoly I:C caused impairments in all behavioral tests and increased the levels of proinflammatory cytokines. While PAM agents caused significant improvements in prepulse inhibition (PPI), novel object recognition (NOR), spontaneous alternation and reference memory tests, they brought the levels of proinflammatory cytokines closer to the control group. NAM agents were ineffective on behavioral tests. It was observed that PAM agents significantly improved Poly I:C-induced disruption in behavioral and molecular analyses. ConclusionsThese results suggest that PAM agents, particularly the mGlu5 receptor VU-29, are also promising and could be a potential target in schizophrenia.

Chronic nSMase inhibition suppresses neuronal exosome spreading and sex-specifically attenuates amyloid pathology in APP knock-in Alzheimer's disease mice

Female biased pathology and cognitive decline in Alzheimer's disease (AD) have been consistently observed with unclear underlying mechanisms. Although brain sphingolipid ceramide is elevated in AD patients, whether and how ceramide may contribute to sex-specific differences in amyloid pathology is unknown. Here we investigated the sex-specific impact of chronic pharmacological inhibition of neutral sphingomyelinase (nSMase), a key enzyme responsible for ceramide metabolism, on in vivo neuron-derived exosome dynamics, Aβ plaque load, and cognitive function in the APPNL-F/NL-F knock-in (APP NL-F) AD mouse model. Our results found sex-specific increase of cortical C20:0 ceramide and brain exosome levels only in APP NL-F but not in age-matched WT mice. Although nSMase inhibition similarly blocks exosome spreading in male and female mice, significantly reduced amyloid pathology was mostly observed in cortex and hippocampus of female APP NL-F mice with only modest effect found on male APP NL-F mice. Consistently, T maze test to examine spatial working memory revealed a female-specific reduction in spontaneous alternation rate in APP NL-F mice, which was fully reversed with chronic nSMase inhibition. Together, our results suggest that disease induced changes in ceramide and exosome pathways contribute to the progression of female-specific amyloid pathology in APP NL-F AD models.

Jujuboside A ameliorates cognitive deficiency in delirium through promoting hippocampal E4BP4 in mice.

Delirium (acute brain syndrome) is a common and serious neuropsychiatric disorder characterized by an acute decline in cognitive function. However, there is no effective treatment clinically. Here we investigated the potential effect of jujuboside A (JuA, a natural triterpenoid saponin) on cognitive impairment in delirium. Delirium models of mice were established by injecting lipopolysaccharide (LPS) plus midazolam and implementing a jet lag protocol. Novel object recognition test and Y maze test were used to evaluate the effects of JuA on delirium-associated cognitive impairment. The mRNA and protein levels of relevant clock factors and inflammatory factors were measured by qPCR and Western blotting. Hippocampal Iba1+ intensity was determined by immunofluorescence staining. JuA ameliorated delirium (particularly delirium-associated cognitive impairment) in mice, which was proved by the behavioural tests, including a preference for new objects, an increase of spontaneous alternation and improvement of locomotor activity. Furthermore, JuA inhibited the expression of ERK1/2, p-p65, TNFα and IL-1β in hippocampus, and repressed microglial activation in delirious mice. This was attributed to the increased expression of E4BP4 (a negative regulator of ERK1/2 cascade and microglial activation). Moreover, loss of E4bp4 in mice abrogated the effects of JuA on delirium as well as on ERK1/2 cascade and microglial activation in the hippocampus of delirious mice. Additionally, JuA treatment increased the expression of E4BP4 and decreased the expression of p-p65, TNFα and IL-1β in LPS-stimulated BV2 cells, supporting a protective effect of JuA on delirium. JuA protects against delirium-associated cognitive impairment through promoting hippocampal E4BP4 in mice. Our findings are of great significance to the drug development of JuA against delirium and related disorders.

Novel Phenylethanoid Glycosides Improve Hippocampal Synaptic Plasticity via the Cyclic Adenosine Monophosphate-CREB-Brain-Derived Neurotrophic Growth Factor Pathway in APP/PS1 Transgenic Mice

Introduction: Alzheimer’s disease (AD) is a major public health concern worldwide, but there are still no drugs available that treat it effectively. Previous studies have shown that phenylethanoid glycosides have pharmacological effects, which include anti-AD properties, but the underlying mechanisms by which they ameliorate AD symptoms remain unknown. Methods: In this study, we used an APP/PS1 AD mouse model to explore the function and mechanisms underlying savatiside A (SA) and torenoside B (TB) in the treatment of AD. SA or TB (100 mg·kg-1·d-1) was orally administered to 7-month-old APP/PS1 mice for 4 weeks. Cognitive and memory functions were measured using behavioral experiments (including the Morris water maze test and the Y-maze spontaneous alternation test). Molecular biology experiments (including Western blotting, immunofluorescence, and enzyme-linked immunosorbent assays) were used to detect any corresponding changes in signaling pathways. Results: The results showed that SA or TB treatment could significantly reduce cognitive impairment in APP/PS1 mice. We also showed that chronic treatment with SA/TB could prevent spine loss, synaptophysin immunoreactivity, and neuronal loss in mice, thereby improving synaptic plasticity and moderating learning and memory deficits. SA/TB administration also promoted the expression of synaptic proteins in APP/PS1 mouse brains and upregulated phosphorylation of proteins in the cyclic adenosine monophosphate (cAMP)/CREB/brain-derived neurotrophic growth factor (BDNF) pathway that are responsible for synaptic plasticity. Additionally, chronic SA/TB treatment increased the levels of BDNF and nerve growth factor (NGF) in the brains of APP/PS1 mice. Both astrocyte and microglia volumes, as well as the generation of amyloid β, were also decreased in SA/TB-treated APP/PS1 mice compared to control APP/PS1 mice. Conclusion: In summary, SA/TB treatment was associated with activation of the cAMP/CREB/BDNF pathway and increased BDNF and NGF expression, indicating that SA/TB improves cognitive functioning via nerve regeneration. SA/TB is a promising candidate drug for the treatment of AD.

Ameliorative Effects of 5-7, Dihydroxy Flavone (Chrysin) on Hippocampus of Wistar Rats with Doxorubicin-induced Cognitive Impairment

Concern is increasing regarding the effect of chemotherapy induced cognitive impairment on oncology patients. This sought to investigate the effect of 5-7, dihydroxyflavone on the hippocampus of wistar rats with Doxorubicin induced cognitive impairment. 30 male Wistar rats were procured and acclimatized for 14 days with feed and water, they were divided into six (6) experimental groups of five (5) animals each. Group 1 served as normal control. Group 2 was induced with 2mg/kg of DOX and was untreated. Group 3 received 150mg/kg of Chrysin. Groups 4, 5 and 6 were induced with 2mg/kg of doxorubicin and treated with Chrysin at doses of 50mg/kg, 100mg/kg, and 150mg/kg respectively. The study lasted for 21 days. The body weight of the animals were recorded three (3) times before and after induction and then recorded again at the end of the 21 days treatment. At the end of the experiment, there were significantly increase in body weight. The increase was more pronounce in group 1 and group 2. In the oxidative stress analysis and ELISA analysis on the levels of inflammatory cytokines (IL-1 & IL-6), there was a significant increase in the levels compared to the control group 1. In the neurobehavioural test, group 6 had a high spontaneous alternation percentage compared to other groups. The treatment with Chrysin significantly had an ameliorative effect on the treated animal groups and in group 3. The result from this work suggest that Chrysin extract had an ameliorative effect on cognitive impairment of the hippocampus.

Hippocampal BDNF encapsulated cell bio‐delivery improves spontaneous behavioral alternations in the Y‐maze test in AppNL‐G‐F mice.

AbstractBackgroundAlzheimer’s disease (AD) is an age‐related disease characterized by synaptic dysfunction, brain inflammation, and neurodegeneration against which there is no effective cure available. Brain‐Derived Neurotrophic Factor (BDNF) is a key molecule involved in the learning and memory process, with a crucial role in synaptic plasticity and neuronal survival. Several findings support that a reduced BDNF expression in the human brain is associated with AD pathogenesis. BDNF has been proposed as a potential therapy for AD, but BDNF has low brain permeability. In this study, we used an innovative encapsulated cell biodelivery (ECB) device containing cells capable of locally delivering BDNF to characterize its neuroprotective effects in the novel AD APP‐knock‐in mouse model AppNL‐G‐F.MethodECB devices with human ARPE‐19 cells modified to release BDNF were surgically bilaterally implanted in the hippocampus of 3‐month‐old AppNL‐G‐F mice. BDNF effects on AD pathology were evaluated after 1, 2, and 3 months of treatment by immunohistochemical and biochemical analysis. In the 3‐month‐treated groups, exploratory and memory performances were also evaluated using Elevated Plus Maze (EPM) and Y‐maze tests.ResultThe ECB implants were well tolerated with no signs of unwanted side effects or weight loss. A high BDNF staining was detected in most of the brains in the area surrounding the devices at 1‐3 months, but retrieved devices showed variability of BDNF release. Interestingly, three months of BDNF treatment significantly improved AppNL‐G‐F mice´s anxiety behavior in EPM and improved the spontaneous behavioral alternations in the Y‐maze test.ConclusionThe results of this study are encouraging and support the BDNF device as a promising approach for treating cognitive AD decline. Optimization of the mouse‐sized devices to reduce the variability of BDNF release is needed for future experiments and translated to larger devices for clinical translation.

Continuous wave 670nm LED light therapy improves short‐ and long‐term object recognition, locomotion, and reduces phosphorylated tau burden in 3xTgAD mice

AbstractBackgroundPhotobiomodulation (PBM) therapy uses 620‐1100nm red to near‐infrared light to modulate biological processes including neuroinflammation, amyloid and tau oligomerization, and apoptosis. We have shown that 670nm light therapy reduces synaptic vulnerability to amyloid‐β oligomers in wild‐type (WT) mice and reduces tau oligomerization in mouse models of tauopathy. Here we sought to determine if 670nm light therapy could rescue cognitive and motor dysfunction and reduce tau hyperphosphorylation in 14‐to‐18‐month‐old 3xTgAD mice.Method14‐to‐18‐month‐old 3xTgAD mice were treated with continuous‐wave 670nm LED light applied directly to the head for 90s per day, 5 days per week for 4 weeks. 3xTgAD sham and WT controls were held under the LED device with the light turned off for the same amount of time. During the fourth week of treatment, spontaneous locomotor behavior was measured by placing animals in an empty chamber for 10 minutes using ANY‐maze software to track mobility data. Animals were then tested for working memory in the Y maze spontaneous alternation task and short‐and long‐term memory in the novel object recognition task. At the completion of behavioral testing on treatment day 20, brains were collected for western blot analysis of total tau and phospho‐tau (pTau).ResultLight‐treated 3xTgAD mice showed increased distance traveled compared to sham (17.43 ± 3.46 vs. 9.97 ± 3.03, one‐way ANOVA p = 0.03), and decreased immobile episodes (4.50 ± 1.92 vs 10.00 ± 1.83, one‐way ANOVA p = 0.02) in the spontaneous locomotor activity test. Light‐treated animals also showed significant object recognition at 2 hours (DI 32.75 ± 7.71, one sample t‐test p<0.001) and 24 hours (DI 44.14 ± 15.73, one sample t‐test p = 0.001) post‐training. Light treatment also reduced the ratio of hippocampal pTau/Tau in 3xTg AD mice as compared to sham (0.11 ± 0.05 vs. 0.32 ± 0.13, one‐way ANOVA p = 0.04).ConclusionHere we show rescue of locomotor behavior and cognitive dysfunction, and reduction of Tau phosphorylation in the hippocampus of 3xTgAD mice using a non‐invasive transcranial treatment with 670nm LED light. Our data suggest that treatment with 670nm red light could significantly improve cognitive function in AD patients and reduce hyperphosphorylation of tau thus possibly preventing further neurodegeneration.

Vertigoheel promotes rodent cognitive performance in multiple memory tests.

Cognitive impairment associated with old age or various brain disorders may be very disabling for affected individuals, placing their carers and public health services under considerable stress. The standard-of-care drugs produce only transient improvement of cognitive impairment in older people, so the search for novel, safe and effective therapeutics that would help to reverse or delay cognitive impairment is warranted. Repurposing pharmacological therapies with well-established safety record for additional indications is a promising recent trend in drug development. Vertigoheel (VH-04), a multicomponent drug made of Ambra grisea, Anamirta cocculus L., Conium maculatum, and Petroleum rectificatum, has been successfully used for several decades in the treatment of vertigo. Here, we investigated effects of VH-04 on cognitive performance in standard behavioral tests assessing different types of memory and explored cellular and molecular underpinnings of VH-04's biological activity. In the majority of behavioral experiments, namely in the spontaneous and rewarded alternation tests, passive avoidance test, contextual/cued fear conditioning, and social transmission of food preference, we examined the ability of single and repeated intraperitoneal administrations of VH-04 to improve cognitive parameters of mice and rats disrupted by the application of the muscarinic antagonist scopolamine. In addition, we also assessed how VH-04 affected novel object recognition and influenced performance of aged animals in Morris water maze. Furthermore, we also studied the effects of VH-04 on primary hippocampal neurons in vitro and mRNA expression of synaptophysin in the hippocampus. Administration of VH-04 positively influenced visual recognition memory in the novel object recognition test and alleviated the impairments in spatial working memory and olfactory memory caused by the muscarinic antagonist scopolamine in the spontaneous alternation and social transmission of food preference tests. In addition, VH-04 improved retention of the spatial orientation memory of old rats in the Morris water maze. In contrast, VH-04 did not have significant effects on scopolamine-induced impairments in tests of fear-aggravated memory or rewarded alternation. Experiments in vitro showed that VH-04 stimulated neurite growth and possibly reversed the age-dependent decrease in hippocampal synaptophysin mRNA expression, which implies that VH-04 may preserve synaptic integrity in the aging brain. Our findings allow a cautious conclusion that in addition to its ability to alleviate manifestations of vertigo, VH-04 may be also used as a cognitive enhancer.

0081 The impact of sleep deficiency on spatial working and long-term memory in different rat models of sleep deprivation

Abstract Introduction A pressing issue in modern society, lack of sleep has detrimental health consequences, among which cognitive dysfunctions attract great attention. Although there is consensus about the harmful effects of insufficient sleep on vigilance and attention, there is still a debate about memory susceptibility to acute and chronic sleep deprivation. Which types of memory are more vulnerable remains unclear. We studied the susceptibility of spatial working and long-term memory to acute and chronic sleep deprivation in rats. Methods Male Wistar rats were deprived of sleep (SD) by placing cages on an orbital shaker. Animals were subjected to three patterns of SD: 1) acute SD (ASD) — continuous SD for 18 hours; 2) short sleep restriction (SSR) —cycles of 3-hour SD followed by 1 hour of sleep opportunity over 24 hours, with a total SD duration of 18 hours; 3) chronic sleep restriction (CSR) — SSR for 5 consecutive days. For each SD protocol, working spatial memory was assessed with the spontaneous alternation test in the Y-maze. Learning and long-term spatial memory were assessed in the Barnes maze test. Results ASD impaired spatial working memory, as assessed by spontaneous alternations in the Y-maze test, and decreased the level of locomotion/exploration (assessed by the number of arm entries). However, in SSR and CSR, 1-hour alternating sleep opportunities allowed for preventing working memory loss. The Barnes maze test demonstrated no changes in learning or spatial long-term memory under any tested SD conditions. Conclusion The results suggest that spatial working memory is the most vulnerable to continuous sleep loss. Even under a 5-day chronic sleep restriction, the negative effect disappears if rats are allowed to sleep during intermittent 1-hour intervals. It indicates the great importance of short sleep intervals that protect memory against sustained sleep restriction. The resilience of long-term memory to any of the tested sleep deprivation conditions implies that short-term and long-term memory systems diverge in their susceptibility to sleep deficiency. Support (if any) State assignment to the Institute of Evolutionary Physiology and Biochemistry; theme reg. no. АААА-А18-118012290427-7.

Neuroprotective Effect of White Nelumbo nucifera Gaertn. Petal Tea in Rats Poisoned with Mancozeb.

Nelumbo nucifera Gaertn. (N. nucifera) tea is used as food and folk medicine to reduce toxicity in Southeast Asia. Mancozeb (Mz) is used for controlling fungi in agriculture and contains heavy metals. This study aimed to examine the effect of white N. nucifera petal tea on cognitive behavior, hippocampus histology, oxidative stress, and amino acid metabolism in rats poisoned with mancozeb. Seventy-two male Wistar rats were divided into nine groups (n = 8 in each). Y-maze spontaneous alternation test was used to assess cognitive behavior, and amino acid metabolism was investigated by nuclear magnetic resonance spectroscopy (1H-NMR) from blood. There was a significant increase in relative brain weight in the Mz co-administered with the highest dose (2.20 mg/kg bw) of white N. nucifera group. The levels of tryptophan, kynurenine, picolinic acid, and serotonin in blood showed a significant decrease in the Mz group and a significant increase in the Mz co-administered with low dose (0.55 mg/kg bw) of white N. nucifera group. However, there was no significant difference in cognitive behavior, hippocampus histology, oxidative stress, and corticosterone. This study demonstrated that a low dose of white N. nucifera petal tea has a neuroprotective effect against mancozeb.

Lantana camara leaf extract ameliorates memory deficit and the neuroinflammation associated with scopolamine-induced Alzheimer’s-like cognitive impairment in zebrafish and mice

Context Lantana camara Linn. (Verbenaceae) is used for improving memory in certain African societies. Objective This study investigated the effect of prophylactic treatment with hydroethanolic leaf extract of Lantana camara (LCE) on short-term memory deficit and neuroinflammation induced with scopolamine in zebrafish and mice. Materials and methods Zebrafish (AB strain) and mice (ICR) were given donepezil (0.65 mg/kg, oral) and LCE (10, 30, 100 mg/kg, oral) for 7, and 10 days, respectively, before induction of cognitive impairment with scopolamine immersion (200 µM) and intraperitoneal injection (2 mg/kg), respectively. Spatial short-term memory was assessed in zebrafish using both Y- and T-mazes, whereas Y-maze was used in mice. Mice hippocampal and cortical tissues were analyzed for mRNA expression of proinflammatory genes (IL-1β, IL-6, TNF-α, COX-2) using qRT-PCR. Results In the zebrafish Y-maze, LCE (10 and 100 mg/kg) increased time spent in the novel arm by 55.89 ± 5.70%, and 68.21 ± 2.75%, respectively, but not at 30 mg/kg. In the zebrafish T-maze, there was an increase in time spent in the food-containing arm at 30 (44.23 ± 2.13) and 100 mg/kg (52.30 ± 1.94). In the mouse Y-maze, spontaneous alternation increased by 52.89 ± 4.98% at only 10 mg/kg. LCE (10, 30, 100 mg/kg) inhibited proinflammatory gene (IL-1β, IL-6, TNF-α, COX-2) mRNA expression, with the highest inhibitory effect on IL-6 in both the hippocampus (83.27 ± 2.49%; 100 mg/kg) and the cortex (98.74 ± 0.11%; 10 mg/kg). Discussion and conclusion LCE ameliorated scopolamine-induced AD in both zebrafish and mice.

Mid-Adulthood Cognitive Training Improves Performance in a Spatial Task but Does Not Ameliorate Hippocampal Pathology in a Mouse Model of Alzheimer's Disease.

Prior experience in early life has been shown to improve performance in aging and mice with Alzheimer's disease (AD) pathology. However, whether cognitive training at a later life stage would benefit subsequent cognition and reduce pathology in AD mice needs to be better understood. This study aimed to verify if behavioral training in mid-adulthood would improve subsequent cognition and reduce AD pathology and astrogliosis. Mixed-sex APP/PS1 and wildtype littermate mice received a battery of behavioral training, composed of spontaneous alternation in the Y-maze, novel object recognition and location tasks, and spatial training in the water maze, or handling only at 7 months of age. The impact of AD genotype and prior training on subsequent learning and memory of aforementioned tasks were assessed at 9 months. APP/PS1 mice made more errors than wildtype littermates in the radial-arm water maze (RAWM) task. Prior training prevented this impairment in APP/PS1 mice. Prior training also contributed to better efficiency in finding the escape platform in both APP/PS1 mice and wildtype littermates. Short-term and long-term memory of this RAWM task, of a reversal task, and of a transfer task were comparable among APP/PS1 and wildtype mice, with or without prior training. Amyloid pathology and astrogliosis in the hippocampus were also comparable between the APP/PS1 groups. These data suggest that cognitive training in mid-adulthood improves subsequent accuracy in AD mice and efficiency in all mice in the spatial task. Cognitive training in mid-adulthood provides no clear benefit on memory or on amyloid pathology in midlife.

Dapagliflozin Ameliorates Cognitive Impairment in Aluminum-Chloride-Induced Alzheimer's Disease via Modulation of AMPK/mTOR, Oxidative Stress and Glucose Metabolism.

Alzheimer's disease (AD) is a progressive neurological illness characterized by memory loss and cognitive deterioration. Dapagliflozin was suggested to attenuate the memory impairment associated with AD; however, its mechanisms were not fully elucidated. This study aims to examine the possible mechanisms of the neuroprotective effects of dapagliflozin against aluminum chloride (AlCl3)-induced AD. Rats were distributed into four groups: group 1 received saline, group 2 received AlCl3 (70 mg/kg) daily for 9 weeks, and groups 3 and 4 were administered AlCl3 (70 mg/kg) daily for 5 weeks. Dapagliflozin (1 mg/kg) and dapagliflozin (5 mg/kg) were then given daily with AlCl3 for another 4 weeks. Two behavioral experiments were performed: the Morris Water Maze (MWM) and the Y-maze spontaneous alternation (Y-maze) task. Histopathological alterations in the brain, as well as changes in acetylcholinesterase (AChE) and amyloid β (Aβ) peptide activities and oxidative stress (OS) markers, were all evaluated. A western blot analysis was used for the detection of phosphorylated 5' AMP-activated protein kinase (p-AMPK), phosphorylated mammalian target of Rapamycin (p-mTOR) and heme oxygenase-1 (HO-1). Tissue samples were collected for the isolation of glucose transporters (GLUTs) and glycolytic enzymes using PCR analysis, and brain glucose levels were also measured. The current data demonstrate that dapagliflozin represents a possible approach to combat AlCl3-induced AD in rats through inhibiting oxidative stress, enhancing glucose metabolism and activating AMPK signaling.

Intergenerational consequences of adolescent morphine exposure on learning and memory

Drug addiction is a worldwide social and medical disorder. More than 50 percent of drug abusers start their substance abuse in adolescence between the ages of 15–19. Adolescence is a sensitive and crucial period for the development and maturity of the brain. Chronic exposure to morphine, particularly during this period, lead to long-lasting effects, including effects that extend to the next generation. The current study examined the intergenerational effects of paternal morphine exposure during adolescence on learning and memory.In this study, male Wistar rats were exposed to increasing doses of morphine (5–25 mg/kg, s.c.) or saline for 10 days at postnatal days (PND) 30–39 during adolescence. Following a 20-day drug-free period, the treated male rats were mated with naïve females. Adult male offspring (PND 60–80) were tested for working memory, novel object recognition memory, spatial memory, and passive avoidance memory using the Y-Maze, novel object recognition, Morris water maze, and shuttle box tests, respectively.The spontaneous alternation (as measured in the Y-Maze test) was significantly less in the morphine-sired group compared to the saline-sired one. The offspring showed significantly less discrimination index in the novel object recognition test when compared to the control group. Morphine-sired offspring tended to spend significantly more time in the target quadrant and less escape latency in the Morris water maze on probe day when compared to the saline-sired ones. The offspring showed significantly less step-through latency to enter the dark compartment compared to the control group when measured in the shuttle box test.Paternal exposure to morphine during adolescence impaired working, novel object recognition, and passive avoidance memory in male offspring. Spatial memory changed in the morphine-sired group compared to the saline-sired one.

Chronic corticosterone improves perseverative behavior in mice during sequential reversal learning

BackgroundStressful life events can both trigger development of psychiatric disorders and promote positive behavioral changes in response to adversities. The relationship between stress and cognitive flexibility is complex, and conflicting effects of stress manifest in both humans and laboratory animals. ObjectiveTo mirror the clinical situation where stressful life events impair mental health or promote behavioral change, we examined the post-exposure effects of stress on cognitive flexibility in mice. MethodsWe tested female C57BL/6JOlaHsd mice in the touchscreen-based sequential reversal learning test. Corticosterone (CORT) was used as a model of stress and was administered in the drinking water for two weeks before reversal learning. Control animals received drinking water without CORT. Behaviors in supplementary tests were included to exclude non-specific confounding effects of CORT and improve interpretation of the results. ResultsCORT-treated mice were similar to controls on all touchscreen parameters before reversal. During the low accuracy phase of reversal learning, CORT reduced perseveration index, a measure of perseverative responding, but did not affect acquisition of the new reward contingency. This effect was not related to non-specific deficits in chamber activity. CORT increased anxiety-like behavior in the elevated zero maze test and repetitive digging in the marble burying test, reduced locomotor activity, but did not affect spontaneous alternation behavior. ConclusionCORT improved cognitive flexibility in the reversal learning test by extinguishing prepotent responses that were no longer rewarded, an effect possibly related to a stress-mediated increase in sensitivity to negative feedback that should be confirmed in a larger study.

Specifics of Experimental Modeling 8-OH-DPAT-Induced Perseverative Behavior in Mice.

The effect of 5-HT1A receptor agonist 8-OH-DPAT (intraperitoneal injection in doses of 1, 2, and 4 mg/kg) on spontaneous alternation behavior of mice in Y-maze was studied without and with habituation procedure and food reward. In the first case, 8-OH-DPAT administration led to a decrease in spontaneous alternation and locomotor activity in mice. At the same time, 8-OH-DPAT treatment after habituation and food deprivation increased repeated choices of goal arms without affecting locomotor activity, which was consistent with perseverative behavior. 8-OH-DPAT-induced decrease in spontaneous alternation behavior in Y-maze in mice with habituation and food reward is the most suitable procedure for experimental modeling of the perseverative behavior and studying the anticompulsive activity of new substances.

Urethane provides an unparalleled anaesthetic model for natural sleep: Commentary on Mondino et al., 2022.

Urethane provides an unparalleled anaesthetic model for natural sleep: Commentary on Mondino et al., 2022.

Tramadol and Coffee Synergy Triggered Oxidative Stress, Altered Cerebellar Histomorphology and Behaviour in Rats

Tramadol intoxication with other substances has recently raised neurological concerns especially among youths in the society. The effects of tramadol and coffee on the cerebellum of Wistar rats were studied. Thirty adult Wistar rats (average weight of 180 g) were randomly assigned into six groups (n=6) as follows: Control, coffee (72.46 mg/kg), coffee (108.69 mg/kg), tramadol (2.86 mg/kg), tramadol (5.71 mg/kg) and coffee (72.46 mg/kg) + tramadol (2.86 mg/kg). The administrations were orally, and done once daily for twenty-eight consecutive days. On day 29, spontane-ous alternation in the T-maze was carried out, and the rats anaesthetized with ketamine hydrochloride (50 mg/kg intraperitoneally). Their blood were assayed for antioxidant, while the 10 % buffered formalin perfused brains were routinely processed with haematoxylin and eosin technique. Behavioural study showed significantly (p<0.05) increased spontaneous alternation in coffee (108.69 mg/kg), tramadol (5.71 mg/kg), and coffee (72.46 mg/kg) + tramadol (2.86 mg/kg) groups compared to the control. Catalase, superoxide dismutase and reduced glutathione levels were not different (p>0.05), while the malondialdehyde level was significantly (p<0.05) higher in the coffee (72.46 mg/kg) + tramadol (2.86 mg/kg) group compared to the control. Histological observations showed cerebellar cytoarchitectural alterations, including atrophy of the Purkinje cells in the coffee (108.69 mg/kg), tramadol (5.71 mg/kg), and coffee (72.46 mg/kg) + tramadol (2.86 mg/kg) groups compared to the control. In conclusion, co-administration of tramadol and coffee triggered free radicals, damaged the cerebellar tissues and caused a more deleterious effect on memory function than individual doses.