Radial Arm Research Articles

Neuroprotective effects of Daphnetin on hippocampal neurons and blood-brain barrier integrity in a mouse model of cerebral ischemia

The purpose of this research was to assess the impact of different doses of Daphnetin (DAP, a natural compound derived from coumarin) on hippocampus neuronal injury, neurobehavioral function, blood-brain barrier (BBB) integrity, expression of claudin-5, brain-derived neurotrophic factor (BDNF), superoxide dismutase (SOD), and inflammatory markers in a mouse model of cerebral ischemia. Cerebral ischemia was induced in mice through 30 minutes of bilateral common carotid occlusion (BCCAO), followed by 48 hours of reperfusion. The viability of hippocampal neurons was assessed using Cresyl violet staining and BBB function was determined by measuring Evans blue (E.B) dye leakage. Spatial memory was tested using the Radial Arm Water Maze (RAWM) task. Claudin-5 and BDNF were measured by immunofluorescence, while SOD, interleukin-1 beta (IL-1β), and nuclear factor-κB (NF-κB) expression were determined through western blotting. Administering DAP significantly increased neuron survival in the hippocampus CA1, CA3, and dentate gyrus (DG) regions and improved spatial memory dose-dependently (P<0.0001). Treatment with DAP (40 mg/kg IP) significantly reduced E.B leakage and brain water content (P<0.001). Furthermore, it increased the claudin-5, BDNF, and SOD levels and diminished NF-κB and IL-1β expression (P<0.0001). The research found that DAP protected neurons in the CA1, CA3, and DG areas of the hippocampus, enhanced behavioral functions, and preserved BBB integrity in a cerebral ischemia model. This positive impact is achieved by increasing the expression of claudin-5, BDNF, and SOD and diminishing neuroinflammation. Further research is required to clarify the mechanisms and possible clinical uses.

Design and synthesis of phyto-Saxagliptin conjugates: Targeting DPP IV, AChE, and β-amyloid in cognitive impairment

Cognitive impairment is a major secondary consequence of Type II diabetes mellitus. The present investigation is designed to enhance the efficacy of an antidiabetic drug (Saxagliptin/SXG) against diabetes-induced cognitive impairment in rats. SXG has limited blood-brain barrier (BBB) permeability due to its hydrophilic nature. Phytochemical-based carboxylic acid conjugates enhance the lipophilicity and anti-oxidant properties of the drugs. Virtually SXG was conjugated with 10 different carboxylic acids and evaluated for drug-likeness, pre-ADMET, Molecular docking, and HUMO-LUMO study. Based on the molecular weight, log P value, docking score, and toxicity profile; three carboxylic acids were selected. Gallic acid (GA), Isonicotinic acid (INA), and Caffeic acid (CA) conjugates of SXG were synthesized and characterized by FTIR, and NMR studies. Diabetes-induced cognitive impairment was induced in the rats by administration of STZ, 45 mg kg-1 i.p. Learning and memory were evaluated by assessing spontaneous alternation behavior (SAB), number of correct responses, and transfer latency using Y-maze, radial arm maze, and elevated plus maze respectively. The antioxidant activity, nitrite levels, acetylcholine esterase level, and Aβ42 content in the rat brain was also evaluated. Histopathology of the hippocampal area was also done. The carboxamides of SXG have improved the efficacy of SXG against diabetes-induced cognitive impairment. This neuroprotective effect of carboxamides of SXG may be attributed to anti-oxidant activity, cholinergic activity, and anti-amyloid β activity.

Peripherally-restricted recurrent infection by engineered E. coli strain modulates hippocampal proteome promoting memory impairments in a rat model

Commensal bacteria that breach endothelial barrier has been reported to induce low grade chronic inflammation producing disease symptoms in major peripheral tissues. In this study, we investigated the role of genetically modified cellular invasive form of commensal E. coli K12 (SK3842) in cognitive impairment. Low-grade systemic infection model was developed using recurring peripheral inoculation of live bacteria in Wistar rats. To examine memory parameters, Novel object recognition test and Radial arm maze test were performed. Differential protein expression profiling of rat hippocampus was carried out using LC-MS/MS and subsequently quantified using SWATH. HBA1/2, NEFH, PFN1 and ATP5d were chosen for validation using quantitative RT-PCR. Results showed drastic decline in Recognition memory of the SK3842 infected rats. Reference and Working Memory of the infected group were also significantly reduced in comparison to control group. Proteome analysis using LC-MS/MS coupled with SWATH revealed differential expression of key proteins that are crucial for the maintenance of various neurological functions. Moreover, expression of NEFH and PFN1transcripts were found to be in line with the proteomics data. Protein interaction network of these validated proteins generated by STRING database converged to RhoA protein. Thus, the present study establishes an association between peripheral infection of a hippocampal protein network dysregulation and overall memory decline.

Melatonin Supplementation Alleviates Impaired Spatial Memory by Influencing Aβ1-42 Metabolism via γ-Secretase in the icvAβ1-42 Rat Model with Pinealectomy

In the search for Alzheimer’s disease (AD) therapies, most animal models focus on familial AD, which accounts for a small fraction of cases. The majority of AD cases arise from stress factors, such as oxidative stress, leading to neurological changes (sporadic AD). Early in AD progression, dysfunction in γ-secretase causes the formation of insoluble Aβ1-42 peptides, which aggregate into senile plaques, triggering neurodegeneration, cognitive decline, and circadian rhythm disturbances. To better model sporadic AD, we used a new AD rat model induced by intracerebroventricular administration of Aβ1-42 oligomers (icvAβ1-42) combined with melatonin deficiency via pinealectomy (pin). We validated this model by assessing spatial memory using the radial arm maze test and measuring Aβ1-42 and γ-secretase levels in the frontal cortex and hippocampus with ELISA. The icvAβ1-42 + pin model experienced impaired spatial memory and increased Aβ1-42 and γ-secretase levels in the frontal cortex and hippocampus, effects not seen with either icvAβ1-42 or the pin alone. Chronic melatonin treatment reversed memory deficits and reduced Aβ1-42 and γ-secretase levels in both structures. Our findings suggest that our icvAβ1-42 + pin model is extremely valuable for future AD research.

Guatemalan beaded lizards (Helodermatidae: Heloderma charlesbogerti) navigate and follow a scent trail in maze tasks.

Maze studies have provided substantial information about nonhuman cognition, such as insights on navigational strategies, spatial memory, and choice discriminations. This knowledge can aid in how we understand the foraging strategies of many animals, particularly understudied and endangered species, such as the Guatemalan beaded lizard (Heloderma charlesbogerti). These actively foraging lizards rely on chemoreception to locate prey, but it is unknown to what extent they engage in olfaction and vomerolfaction to hunt and navigate their environment. We investigated how Guatemalan beaded lizards moved through a physical maze. When navigating an eight-arm radial maze with all arms baited, lizards tended to turn into the immediately adjacent arm in a single direction, similar to other reptiles that have been tested in radial arm mazes. In a T-maze, the lizards had to discriminate between arms that contained scent and no-scent from a distance. They were generally unable to choose the baited (correct) arm at levels greater than chance, indicating an inability for this discrimination. With the addition of a scent trail, however, all lizards chose the baited arm at levels significantly above chance, and this increased accuracy was correlated with increased latency to make the arm choice. The lizards also demonstrated a decreased rate of tongue flicking as proximity to reward increased. Guatemalan beaded lizards can efficiently navigate a radial arm maze and can successfully use vomerolfaction with substrate-borne cues to locate prey, but they appear to have minimal olfaction abilities when sensing from a distance. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Darts fast-learning reduces theta power but is not affected by Hf-tRNS: A behavioral and electrophysiological investigation

Sports trainers have recently shown increasing interest in innovative methods, including transcranial electric stimulation, to enhance motor performance and boost the acquisition of new skills during training. However, studies on the effectiveness of these tools on fast visuomotor learning and brain activity are still limited. In this randomized single-blind, sham-controlled, between-subjects study, we investigated whether a single training session, either coupled or not with 2 mA online high-frequency transcranial random noise stimulation (hf-tRNS) over the bilateral primary motor cortex (M1), would affect dart-throwing performance (i.e., radial error, arm range of motion, and movement variability) in 37 healthy volunteers. In addition, potential neurophysiological correlates were monitored before and after the training through a 32-electrode portable electroencephalogram (EEG). Results revealed that a single training session improved radial error and arm range of motion during the dart-throwing task, but not movement variability. Furthermore, after the training, resting state-EEG data showed a decrease in theta power. Radial error, arm movement, and EEG were not further modulated by hf-tRNS. This indicates that a single training session, regardless of hf-tRNS administration, improves dart-throwing precision and movement accuracy. However, it does not improve movement variability, which might require multiple training sessions (expertise resulting in slow learning). Theta power decrease could describe a more efficient use of cognitive resources (i.e., attention and visuomotor skills) due to the fast dart-throwing learning. Further research could explore different sports by applying longer stimulation protocols and evaluating other EEG variables to enhance our understanding of the lasting impacts of multi-session hf-tRNS on the sensorimotor cortex within the framework of slow learning and training assistance.

Evaluation of the Effects of Repetitive Anaesthesia Administration on the Brain Tissues and Cognitive Functions of Rats with Experimental Alzheimer's Disease.

Introduction: We evaluated the effects of repeated ketamine, propofol, and ketamine + propofol administration on cognitive functions and brain tissue of elderly rat models with streptozotocin-induced Alzheimer's disease. Materials and Methods: Thirty elderly male Wistar Albino rats were divided into five groups: control (Group C), Alzheimer's (Group A), Alzheimer's + ketamine (Group AK), Alzheimer's + propofol (Group AP), and Alzheimer's + propofol + ketamine (Group APK). Alzheimer's disease was induced in Groups A, AK, AP, and APK via intracerebroventricular streptozotocin. Four weeks after surgery, ketamine, propofol, and ketamine + propofol were administered intraperitoneally for 3 days to Groups AK, AP, and APK, respectively. The radial arm maze test (RAMT) was performed in the initial, 1st, 2nd, 3rd, and 4th weeks after surgery and daily following anaesthesia. Blood and brain tissue samples were obtained. Results: The RAMT results of Groups A, AK, AP, and APK decreased compared to Group C 2 weeks after Alzheimer's disease onset. Compared to Group A, the RAMT results increased in Groups AK and APK after the first anaesthesia, and in Group AP after the second anaesthesia. Brain tissue paraoxonase-1 (PON-1) and catalase (CAT) activities were low, and the thiobarbituric acid reactive substance (TBARS) level was high in Group A compared to Group C. TBARS levels of Groups AP and APK were lower than Group A, while CAT activity was higher. PON-1 activity was higher in Groups AK, AP, and APK than in Group A. Histopathological changes decreased in Groups AP and AK. A decrease in p53 was found in Group C compared to Group A. Ketamine and propofol were found to be effective at Bcl-2 immunoexpression, but a decrease in Caspase-3 was observed in Group APK. GFAP immunoexpression increased in Group A compared to Group C and in Group AP compared to Group AK. Conclusions: Repetitive anaesthesia application was found to positively affect cognitive functions. This was supported by histopathological and biochemical markers.

Cholecalciferol Supplementation Impacts Behavior and Hippocampal Neuroglial Reorganization in Vitamin D-Deficient Rats.

Vitamin D deficiency (VDD) is widespread around the world and has been extensively documented to affect various health conditions, including the cognitive functioning of the brain. Serum 25-hydroxylated forms of vitamin D are traditionally used to determine vitamin D status. However, there is now evidence that cholecalciferol activation can occur and be controlled by locally expressed enzymes in the brain. This study aimed to investigate the effects of cholecalciferol supplementation on cognitive function in rats who underwent transient VDD in adulthood. Thirty-six adult Wistar rats were administered paricalcitol (seven doses of 32 ng injected every other day) along with a "vitamin D-free" diet to induce VDD, which was confirmed using a LC-MS/MS serum analysis of the cholecalciferol and 25-hydroxyvitamin D3 levels. Treatment was performed by including 1000 IU/kg and 10,000 IU/kg cholecalciferol in the diet. Cognitive performance was evaluated using the novel object recognition (NOR), Morris water maze (MWM), and radial arm maze (RAM) tests. An immunohistochemical analysis of the brain regions involved in learning and memory was performed by quantifying the neurons, astrocytes, and microglia labelled with anti-neuronal nuclei (NeuN), glial fibrillary acidic protein (GFAP), and ionized calcium-binding adaptor molecule 1 (Iba-1) antibodies, respectively. The vitamin D deficient group showed the lowest performance in both the MWM and RAM tests. In contrast, the cholecalciferol-treated groups exhibited a faster learning curve. However, no difference was detected between the groups in the NOR test. On the other hand, differences in the cellular organization of the hippocampus and amygdala were observed between the groups. Cholecalciferol supplementation decreased the density of the Iba-1- and GFAP-labeled cells in the hilus and cornu Ammonis 3 (CA3) regions of the hippocampus and in the amygdala. These results support vitamin D's substantial role in learning and memory. They also highlight that subtle changes of cognitive function induced by transient VDD could be reversed by cholecalciferol supplementation. Further studies are needed to better understand VDD and cholecalciferol's effects on the brain structure and function.

Corticosterone disrupts spatial working memory during retention testing when highly taxed, which positively correlates with depressive-like behavior in middle-aged, ovariectomized female rats

Major Depressive Disorder affects 8.4 % of the U.S. population, particularly women during perimenopause. This study implemented a chronic corticosterone manipulation (CORT, a major rodent stress hormone) using middle-aged, ovariectomized female rats to investigate depressive-like behavior, anxiety-like symptoms, and cognitive ability. CORT (400 μg/ml, in drinking water) was administered for four weeks before behavioral testing began and continued throughout all behavioral assessments. Compared to vehicle-treated rats, CORT significantly intensified depressive-like behaviors: CORT decreased sucrose preference, enhanced immobility on the forced swim test, and decreased sociability on a choice task between a novel conspecific female rat and an inanimate object. Moreover, CORT enhanced anxiety-like behavior on a marble bury task by reducing time investigating tabasco-topped marbles. No effects were observed on novelty suppressed feeding or the elevated plus maze. For spatial working memory using an 8-arm radial arm maze, CORT did not alter acquisition but disrupted performance during retention. CORT enhanced the errors committed during the highest working memory load following a delay and during the last trial requiring the most items to remember; this cognitive metric positively correlated with a composite depressive-like score to reveal that as depressive-like symptoms increased, cognitive performance worsened. This protocol allowed for the inclusion of multiple behavioral assessments without stopping the CORT treatment needed to produce a MDD phenotype and to assess a battery of behaviors. Moreover, that when middle-age was targeted, chronic CORT produced a depressive-like phenotype in ovariectomized females, who also comorbidly expressed aspects of anxiety and cognitive dysfunction.

Chronic β3 adrenergic agonist treatment improves brain microvascular endothelial function and cognition in aged mice.

Microvascular endothelial dysfunction, characterized by impaired neurovascular coupling, reduced glucose uptake, blood-brain barrier disruption, and microvascular rarefaction, plays a critical role in the pathogenesis of age-related vascular cognitive impairment (VCI). Emerging evidence points to non-cell autonomous mechanisms mediated by adverse circulating milieu (an increased ratio of pro-geronic to anti-geronic circulating factors) in the pathogenesis of endothelial dysfunction leading to impaired cerebral blood flow and cognitive decline in the aging population. In particular, age-related adipose dysfunction contributes, at least in part, to an unfavorable systemic milieu characterized by chronic hyperglycemia, hyperinsulinemia, dyslipidemia, and altered adipokine profile, which together contribute to microvascular endothelial dysfunction. Hence, in the present study, we aimed to test whether thermogenic stimulation, an intervention known to improve adipose and systemic metabolism by increasing cellular energy expenditure, could mitigate brain endothelial dysfunction and improve cognition in the aging population. Eighteen-month-old old C57BL/6J mice were treated with saline or CL (β3-adrenergic agonist) for 6 weeks followed by functional analysis to assess endothelial function and cognition. CL treatment improved neurovascular coupling responses and rescued brain glucose uptake in aged animals. In addition, CL treatment also attenuated blood-brain barrier leakage and associated neuroinflammation in the cortex of aged animals. More importantly, these beneficial changes in microvascular function translated to improved cognitive performance in radial arm water maze and Y-maze tests. Our results suggest that β3-adrenergic agonist treatment improves multiple aspects of brain microvascular endothelial function and can be potentially repurposed for treating age-associated cognitive decline.

Age-Related Effects of AT1 Receptor Antagonist Losartan on Cognitive Decline in Spontaneously Hypertensive Rats.

Both hypertension and aging are known to increase the vulnerability of the brain to neurovascular damage, resulting in cognitive impairment. The present study investigated the efficacy of the antihypertensive drug losartan on age- and hypertension-associated cognitive decline and the possible mechanism underlying its effect in spontaneously hypertensive rats (SHRs). Losartan was administered (10 mg/kg, i.p. for 19 days) to 3- and 14-month-old SHRs. Age-matched Wistar rats were used as controls. Working memory, short-term object recognition, and spatial memory were assessed using the Y-maze, object recognition test (ORT) and radial arm maze (RAM) test. The expression of markers associated with aging, oxidative stress, and memory-related signaling was assessed in the frontal cortex (FC) and hippocampus. Motor activity measured over 24 h was not different between groups. Middle-aged vehicle-treated SHRs showed poorer performance in spontaneous alternation behavior (SAB) and activity in the first Y-maze test than their younger counterparts, suggesting age-related reduced "decision making" and reactivity in a novel environment. Losartan improved the age- and hypertension-induced decline in short-term recognition and spatial memory measured in the ORT and the second Y-maze test, particularly in the middle-aged rats, but was ineffective in the young adult rats. Changes in memory and age-related markers such as cAMP response element-binding protein (CREB) and amyloid-β1-42 (Aβ1-42) and increased oxidative stress were observed in the hippocampus but not in the FC between young adult and middle-aged vehicle-treated SHRs. Losartan increased CREB expression while reducing Aβ1-42 levels and concomitant oxidative stress in middle-aged SHRs compared with vehicle-treated SHRs. In conclusion, our study highlights the complex interplay between hypertension, aging, and cognitive impairment. It suggests that there is a critical time window for therapeutic intervention with angiotensin II type 1 receptor blockers.

Effects of agmatine on radial-arm maze memory performance and autistic-like behaviors in a male rat model of autism.

Autism spectrum disorder (ASD) is the fastest-growing child neuropsychiatric condition. Cognitive dysfunctions such as memory impairments are experienced by patients along with social disturbances and repetitive/stereotypic movements. We have used the radial arm maze (RAM), for measurement of working and reference memory errors in an animal model of autism. In addition, the potential effects of agmatine, an endogenous NMDA antagonist, on RAM performance and autistic-like behaviors were assessed. Autism was modeled by valproic acid (VPA) administration at gestational Day 12.5. Autism-associated behaviors in male offspring were examined in an open field test (OFT) and three-chambered test (TCT) on postnatal days 50-51. Thereafter, the animals were trained in the RAM (PND 55) until they attained the criteria of 80% correct choices during five consecutive trials. Forty-eight hours after the acquisition of criteria, agmatine was injected 30 min before subsequent behavioral testing, which included the retention phase of the RAM, OFT, and TCT. VPA-treated and intact rats showed the same performance in RAM, and acute injection of agmatine rescued social and anxiety-like behavior induced by VPA without the effect on RAM. In a rat model of autism, spatial learning, and memory did not change. Agmatine rescued social and anxiety-like behavior in autistic animals.

Executive function and spatial abilities in physically active children: an explorative study

BackgroundRegular physical activity has consistently shown promise in improving cognitive functioning among children. However, there is a shortage of comprehensive studies that delve into these benefits across various cognitive domains. This preliminary investigation aimed to discern potential disparities in cognitive performance between active and sedentary children, with a specific focus on inhibitory control, cognitive flexibility, and visuo-spatial working memory abilities.MethodsThe study employed a cross-sectional design encompassing 26 children (mean age 9.53 ± 2.20 years), categorized into two groups: Active and Sedentary. Executive functions were assessed using the NEPSY-II, while visuo-spatial working memory abilities were evaluated through the table version of the Radial Arm Maze (table-RAM) task. All outputs were analyzed with One-way ANOVAS or Kruskal–Wallis Tests to assess differences between Active and Sedentary children in both executive functioning and visuo-spatial working memory processes.ResultsThe findings revealed that the Active group outperformed the sedentary group in inhibitory control (F1,23 = 4.99, p = 0.03*), cognitive flexibility (F1,23 = 5.77, p = 0.02*), spatial span (F1,23 = 4.40, p = 0.04*), and working memory errors (F1,23 = 8.59, p = 0.01**). Both spatial span and working memory errors are parameters closely associated with visuo-spatial working memory abilities.ConclusionsAlthough preliminary, these results offer evidence of a positive link between physical activity and cognitive functioning in children. This indicates the importance of promoting active behaviors, especially within educational environments.

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

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

Memory protective effect of Phyllanthus emblica against scopolamine induced spatial memory loss in male Long Evan Rats tested by Radial Arm Maze

Background: Dementia is the commonest problem of middle aged and elderly subjects due to age related changes and oxidative stress. Many traditional herbal agents including Emblica Officinalis (Phyllantus Emblica) demonstrated its benefit against memory loss. Objective: To investigate the protective effect of Ethanolic extract of Phyllantus Emblica (EEPE) or Emblica Officinalis in scopolamine induced memory impaired male Long Evan rats. Methods: This animal behavioral study was carried out on total 18 male long Evan rats weighing 300-400gm. According to treatment they were divided into NS (control) group (n=6, normal saline 5ml/kg) Sco(n=6; Scopolamine 2mg/kg) and PE(n=6; EEPE 400mg/kg+ Scopolamine 2mg/kg).This experiment was conducted for total 33 days. After 7 days acclimatization NS group and PE rats were treated with normal saline and EEPE respectively for consecutive 26 days. Scopolamine was given to sco group and PE group from day 22 to 26 (5 days during acquisition phase. Spatial memory (working and reference memory error) was assessed by 8 arm radial arm maze (RAM). Statistical analysis was done by ANOVA followed by Bonferroni’s post hoc test. Result: Working memory error (WME) as well as reference memory error (RME) was found significantly higher in scopolamine treated rats compared to normal memory as well as PE pretreated rats whereas no significant difference was found in WME and RME between normal memory rats and PE pre- treated rats. Conclusion: Phyllanthus Emblica can prevent memory impairment in scopolamine induced memory loss in Long Evan rats. J Bangladesh Soc Physiol 2022;17(2): 101-110

Brain Endothelial Senescence and Vascular Density in Mid-Life Obesity: Exploring Neurovascular Dysfunction and Cognitive Impairment

The obesity epidemic is a major health challenge in the United States, with more than 42% of American adults being obese. Growing evidence shows that mid-life obesity has detrimental effects on cerebrovasculature, and it compromises cerebral blood flow (CBF) regulation and promotes the pathogenesis of vascular cognitive impairment and dementia (VCID). The cerebral microcirculation and the "neurovascular unit" (NVU) play a key role in maintaining healthy brain function. Our previous studies have shown that obesity-induced NVU dysfunction impairs endothelium-mediated neurovascular coupling (NVC) and contributes to VCID. Although great advances have been made in the last decade, the cellular mechanisms underlying NVU dysfunction, CBF dysregulation and NVC impairment remain not clear and there are no available treatments. Cellular senescence is a typical cellular response that occurs in physiological and pathological conditions. In this context, we found that middle-life obesity promotes cellular senescence in the brain and in the vasculature. Moreover, senescence of cells within the NVU has been linked to cognitive impairment and neuro-vascular dysfunction. To provide proof-of-concept for our studies on obesity induced NVU senescence, we used the novel transgenic mouse model (p16-3MR mouse), which allows the visualization and selective elimination of senescent cells. We evaluated senescence through the expression of RFP (senescent marker) with flow cytometry and through the analysis of single cell transcriptomic. NVC and vascular density was measured with functional ultrasound imaging (ICONEUS) and cognitive function was tested with radial arm water maze test (RAWM). We found increased senescence in endothelial cells in high fat diet-fed (HFD; 60% kcal from fat) mice compared to ones fed with standard diet (SD; 10% kcal from fat). Moreover, we demonstrated the functional significance of senescent cells by treating older HFD-fed obese mice with the well-characterized, potent senolytic compound Navitoclax/ABT263, which selectively kills senescent cells. We found that in obese older mice NVC responses were significantly impaired and were rescued by senolytic treatment. HFD-fed mice had impaired learning plasticity in RAWM. Restoration of NVC responses by ABT263 treatment associated with significant cognitive benefit. Overall, our work is novel in that it will be the first to demonstrate that obesity-induced senescence is a critical contributing factor to the pathogenesis of VCID, providing insights into potential therapeutic interventions. NIH R03AG070479, K01AG073614, R21AG080775, American Heart Association, Hevolution/AFAR. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Chronic high-dose testosterone impairs economic decision making, but has no effect on memory in male rats

The goal is to understand consequences of anabolic-androgenic steroid (AAS) abuse on cognitive function, using rats as a model. Economic decision making was evaluated in an operant test of effort value discounting, where subjects choose between 2 levers that deliver large and small rewards differing in maximum value and reward contrast. The hypothesis is that chronic high-dose testosterone increases preference for large rewards. Male rats were treated chronically with testosterone (7.5 mg/kg) or vehicle. Initially, all rats preferred the large reward lever when large and small rewards remained fixed at 3 and 1 sugar pellets, respectively. When different reward values were introduced, and with increasing response requirements, testosterone-treated rats made fewer responses for the large reward, and increased omissions. They earned fewer rewards overall. To determine if testosterone impairs memory, rats were tested for recognition memory with the novel object recognition and social transmission of food preference tasks, and for spatial memory with the radial arm maze and Morris water maze. There was not effect of chronic high-dose testosterone on any memory task. These results suggest that testosterone shifts economic decision making towards larger rewards even when they are disadvantageous, but does not alter memory in rats.

Astaxanthin and DHA Supplementation Modulates the Maternal Undernutrition-induced Impairment of Cognitive Behavior and Synaptic Plasticity in Adult Life of Offspring's -Exploring the Molecular Mechanism.

Maternal nutrition was recognized as a significant part of brain growth and maturation in most mammalian species. Timely intervention with suitable nutraceuticals would provide long-term health benefits. We aim to unravel the molecular mechanisms of perinatal undernutrition-induced impairments in cognition and synaptic plasticity, employing animal model based on dietary nutraceutical supplementation. We treated undernourished dams at their gestational, lactational, and at both the time point with Astaxanthin (AsX) and Docosahexaenoic acid (DHA), and their pups were used as experimental animals. We evaluated the cognitive function by subjecting the pups to behavioral tests in their adult life. In addition, we assessed the expression of genes in the hippocampus related to cognitive function and synaptic plasticity. Our results showed downregulation of Brain-derived neurotrophic factor (BDNF), Neurotrophin-3 (NT-3), cAMP response-element-binding protein (CREB), and uncoupling protein-2 (UCP2) gene expression in pups born to undernourished dams in their adult life, which AsX and DHA modulated. Maternal AsX and DHA supplementation ameliorated the undernutrition-induced learning impairment in novel object recognition (NOR) tests and partially baited radial arm maze (RAM) tasks in offspring's. The expressions of Synapsin-1 and PSD-95 decreased in perinatally undernourished groups compared to control and AsX-DHA treated groups at CA1, CA2, CA3, and DG. AsX and DHA supplementation upregulated BDNF, NT-3, CREB, and UCP2 gene expressions in perinatally undernourished rats, which are involved in intracellular signaling cascades like Ras, PI3K, and PLC. The results of our study give new insights into neuronal differentiation, survival, and plasticity, indicating that the perinatal period is the critical time for reversing maternal undernutrition-induced cognitive impairment in offspring's.

Neuroprotective impact of Ximenia americana aqueous bark extract on Diazepam-induced memory impairment in mice via its antioxidant potential

In traditional medicine, Ximenia americana (XA) is used to treat mental disorders, and headaches. The current study aimed to show the preventive and biochemical impacts of XA aqueou’s extract on diazepam-induced amnesia. Mice were randomized as follows: distilled water (10 mL/kg); diazepam (3 mg/kg); piracetam (PIR) (150 mg/kg); and XA experimental groups (25, 50 and 75 mg/kg). Mice were then treated in groups, 14 straight days. Radial arm maze (RAM) and T-maze were employed to assess different behaviours 30 min after each treatment. After the test was completed, the brains were isolated for histological and biochemical examinations. The results obtained showed that XA extract seriously (p &lt; 0.001) reversed mistakes in working remembrance in the radial arm maze test contrasted to the normal control factions. In the T-maze test, pretreatment of mice with XA extract seriously (p &lt; 0.001) expanded the time spent in the preferred arm when contrasted to the DZP-only treated faction. The XA-treated DZP groups showed subsequent (p &lt; 0.001) improvement in catalase (CAT) and reduced glutathione (GHS). A diminish in malondialdehyde (MDA) level was observed in brain homogenates of mice treated with the extract contrasted with the DZP- group. These few results regarding the neuroprotective and antioxidant effects of XA extract at least partially demonstrate its empirical use in the treatment of certain pathologies.

Impaired Response to Mismatch Novelty in the Li2+-Pilocarpine Rat Model of TLE: Correlation with Hippocampal Monoaminergic Inputs.

Novelty detection, crucial to episodic memory formation, is impaired in epileptic patients with mesial temporal lobe resection. Mismatch novelty detection, that activates the hippocampal CA1 area in humans and is vital for memory reformulation and reconsolidation, is also impaired in patients with hippocampal lesions. In this work, we investigated the response to mismatch novelty, as occurs with the new location of known objects in a familiar environment, in the Li2+-pilocarpine rat model of TLE and its correlation with hippocampal monoaminergic markers. Animals showing spontaneous recurrent seizures (SRSs) for at least 4 weeks at the time of behavioural testing showed impaired spatial learning in the radial arm maze, as described. Concurrently, SRS rats displayed impaired exploratory responses to mismatch novelty, yet novel object recognition was not significantly affected in SRS rats. While the levels of serotonin and dopamine transporters were mildly decreased in hippocampal membranes from SRS rats, the levels on the norepinephrine transporter, tyrosine hydroxylase and dopamine-β-hydroxylase were enhanced, hinting for an augmentation, rather than an impairment in noradrenergic function in SRS animals. Altogether, this reveals that mismatch novelty detection is particularly affected by hippocampal damage associated to the Li2+-pilocarpine model of epilepsy 4-8 weeks after the onset of SRSs and suggests that deficits in mismatch novelty detection may substantially contribute to cognitive impairment in MTLE. As such, behavioural tasks based on these aspects of mismatch novelty may prove useful in the development of cognitive therapy strategies aiming to rescue cognitive deficits observed in epilepsy.