Spatial Memory Performance Research Articles

Paw preference is associated with behavioural despair and spatial reference memory in male rats

Paw preference, one of the well-studied behavioural markers of asymmetry, has been associated with affective states and pathologies such as behavioural despair, a rodent model of clinical depression. However, a consistent differential effect of paw preference has not been observed for cognitive functions. In order to investigate the affective properties of paw preference together with its potential cognitive effects, we grouped male Wistar rats as left- or right-pawed, and tested them in the forced swim test and Morris water maze for behavioural despair and spatial memory performance, respectively. We found that left-pawed rats were significantly more susceptible to behavioural despair, while spatial learning performance of the two groups were not different over a five-day Morris water maze task. Left-pawed rats, however, displayed a better reference memory than the right-pawed ones on the subsequent probe trial when the hidden platform of the maze was removed. These findings indicate paw preference as a vulnerability factor for behavioural despair and reveal a previously unknown association between left-paw preference and reference memory performance as assessed in the probe trial of the Morris water maze.

Voluntary exercise enhances hippocampal theta rhythm and cognition in the rat

Regular exercise promotes learning and memory functions. Theta activity is known to relate to various cognitive functions. An increase in theta power may be related to higher cognitive functioning and learning functions. However, evidence is lacking to directly confirm that exercise training can increase the theta activity and promote various cognitive functions simultaneously. We hypothesize that long-term voluntary exercise increases the activity of hippocampal theta rhythm and enhances memory behavior. We used the voluntary wheel running model and a training period of 8 weeks. We started the training when the rats were 12 weeks old. Before and after intervention, we performed a 24 -h electrophysiological recording and 8-arm radial maze test to analyze the hippocampal theta rhythm in awake stage, and spatial memory functions. We discovered that middle to high range frequency (6.5–12 Hz) of theta power was increased after exercise intervention. In addition, the working memory error of 8-arm radial maze test in the exercise group decreased significantly after the 8 weeks of treatment, and these reductions were negatively correlated with hippocampal theta activity. Our results demonstrate that 8-weeks voluntary exercise increases both hippocampal theta amplitude and spatial memory in the rats.

Hippocampal interleukin-33 mediates neuroinflammation-induced cognitive impairments

BackgroundInterleukin (IL)-33 is expressed in a healthy brain and plays a pivotal role in several neuropathologies, as protective or contributing to the development of cerebral diseases associated with cognitive impairments. However, the role of IL-33 in the brain is poorly understood, raising the question of its involvement in immunoregulatory mechanisms.MethodsWe administered recombinant IL-33 (rmIL-33) by intra-hippocampal injection to C57BL/6 J (WT) and IL-1αβ deficient mice. Chronic minocycline administration was performed and cognitive functions were examined trough spatial habituation test. Hippocampal inflammatory responses were investigated by RT-qPCR. The microglia activation was assessed using immunohistological staining and fluorescence-activated cell sorting (FACS).ResultsWe showed that IL-33 administration in mice led to a spatial memory performance defect associated with an increase of inflammatory markers in the hippocampus while minocycline administration limited the inflammatory response. Quantitative assessment of glial cell activation in situ demonstrated an increase of proximal intersections per radius in each part of the hippocampus. Moreover, rmIL-33 significantly promoted the outgrowth of microglial processes. Fluorescence-activated cell sorting analysis on isolated microglia, revealed overexpression of IL-1β, 48 h post-rmIL-33 administration. This microglial reactivity was closely related to the onset of cognitive disturbance. Finally, we demonstrated that IL-1αβ deficient mice were resistant to cognitive disorders after intra-hippocampal IL-33 injection.ConclusionThus, hippocampal IL-33 induced an inflammatory state, including IL-1β overexpression by microglia cells, being causative of the cognitive impairment. These results highlight the pathological role for IL-33 in the central nervous system, independently of a specific neuropathological model.

Oxytocin Reduces Brain Injury and Maintains Blood-Brain Barrier Integrity After Ischemic Stroke in Mice.

The present study was designed to determine the effect of different doses of oxytocin (OXT) on neuronal injury, spatial memory, blood-brain barrier (BBB) integrity and to explore possible underlying molecular mechanisms in the early stage of stroke in mice. Stroke model was generated by middle cerebral artery occlusion (MCAO) for 60min and 24h reperfusion in mice. OXT at doses of 1, 2, 4 and 8IU/per mouse was administrated intranasally at the beginning of brain ischemia. Brain injury, BBB integrity, and spatial memory were evaluated by standard methods. Changes in the expressionof nuclear factor-kappa B (NF-κB), and TUNEL positive cell were detected by immunohistochemistry. The levels of vascular endothelial growth factor(VEGF), aquaporin-4 (AQP4) and brain-derived neurotrophic factor (BDNF) proteins were determined by western blotting and ELISA methods. OXT at doses of 4 and 8IU/per mouse reduced the infarct size by 42% and 52%, respectively, and improved spatial memory function (p < 0.001). OXT (8IU/per mouse) significantly reduced brain edema, BBB disruption and upregulated the AQP4 expression (p < 0.001). Finally, OXT significantly diminished the number of apoptotic, NF-κB positive cells and enhanced the expression of BDNF and VEGF proteins in the brain tissue (p < 0.001). These findings provide important evidences that OXT significantly suppresses neuronal damage in the early stage of stroke by inhibiting apoptotic and NF-κB signaling pathway, increasing the expression of VEGF, AQP4 and BDNF proteins and reducing the BBB leakage.

Effects of Panax quinquefolius (American ginseng) on the steady state visually evoked potential during cognitive performance.

ObjectiveTo investigate the effects of acute Panax quinquefolius (American ginseng) administration on steady state visually evoked potentials (SSVEPs) during completion of working memory and continuous performance tasks.MethodsA randomised, double‐blind, placebo controlled, balanced, cross‐over trial was conducted in middle‐aged volunteers aged between 40 and 60 years. Participants were administered 200 mg P. quinquefolius and placebo on two separate testing sessions. Six‐h post‐dose participants completed spatial working memory (SWM) and continuous performance (CP) tasks while SSVEP from a diffuse task‐irrelevant 13 Hz flicker was recorded.ResultsDuring SWM retrieval, P. quinquefolius was associated with significantly reduced prefrontal SSVEP latency. There were no significant treatment effects on CP nor behavioural performance of either task.ConclusionsThese findings provide preliminary evidence of increased recruitment of prefrontal brain regions during working memory processing following a single acute dose of P. quinquefolius.

Time-dependent effects of platelet-rich plasma on the memory and hippocampal synaptic plasticity impairment in vascular dementia induced by chronic cerebral hypoperfusion

The present study aimed to investigate the effects of early and late administration of platelet-rich plasma (PRP) on learning-memory and hippocampal synaptic plasticity impairment in rat model of vascular dementia. Sprague-Dawley rats (6–7 weeks) were randomly divided into control, sham, 2VO + V (bilateral carotid vessel occlusion + vehicle), 2VO + E-PRP (early after 2VO), and 2VO + L-PRP (late after 2VO) groups. The injection of PRP started immediately or on the day 20 after 2VO in 2VO + E-PRP and 2VO + L-PRP, respectively, and continued until 28th day (two-time a week).The passive avoidance and Morris water maze tests were used for evaluation of fear and spatial memory formation. The in-vivo long-term potentiation (LTP) was evaluated by field-potential recording, paired-pulse ratio (PPR) and input-output (I/O) curve which were monitored as indexes for evaluation of short-term plasticity (STP) and basal-synaptic transmission (BST), respectively.The 2VO decreased PPR at inter-stimuli interval (ISI) 10 ms and BST, but injection of PRP in both treated groups rescued the PPR and BST depression. In addition, the induction of LTP, fear and spatial memory performance decreased in the 2VO + V group. However, early treatment, but not late, recovered LTP and memory.The PPR and BST improved with early and late treatment; therefore, the number and time of injection seem to be not important for recovery of BST. However, we found that LTP and memory loss rescued only with early administration. Hence, timely injection, before development of the disease, or number of injections could be critical.

Lychee seed polyphenol protects the blood-brain barrier through inhibiting Aβ(25-35)-induced NLRP3 inflammasome activation via the AMPK/mTOR/ULK1-mediated autophagy in bEnd.3 cells and APP/PS1 mice.

Blood-brain barrier (BBB) dysfunction has been implicated in Alzheimer's disease (AD) and is closely linked to the release of proinflammatory cytokines in brain capillary endothelial cells. We have previously reported that lychee seed polyphenols (LSP) exerted anti-neuroinflammatory effect. In this study, we aimed to explore the protective effect of LSP on BBB integrity. The monolayer permeability of bEnd.3 cells, and the mRNA level and protein expression of tight junction proteins (TJs), including Claudin 5, Occludin, and ZO-1, were examined. In addition, the inhibition of Aβ(25-35)-induced NLRP3 inflammasome activation, and the autophagy induced by LSP were investigated by detecting the expression of NLRP3, caspase-1, ASC, LC3, AMPK, mTOR, and ULK1. Furthermore, the cognitive function and the expression of TJs, NLRP3, caspase-1, IL-1β, and p62 were determined in APP/PS1 mice. The results showed that LSP significantly decreased the monolayer permeability and inhibited the NLRP3 inflammasome in Aβ(25-35)-induced bEnd3 cells. In addition, LSP induced autophagy via the AMPK/mTOR/ULK1 pathway in bEnd.3 cells, and improved the spatial learning and memory function, increased the TJs expression, and inhibited the expression of NLRP3, caspase-1, IL-1β, and p62 in APP/PS1 mice. Therefore, LSP protects BBB integrity in AD through inhibiting Aβ(25-35)-induced NLRP3 inflammasome activation via the AMPK/mTOR/ULK1-mediated autophagy.

Protective effects of the traditional herbal formulation on oxidative stress, learning and memory in the animal model of type 2 diabetes

Introduction: Diabetes mellitus (DM) is one of the most frequent metabolic diseases that affect various body systems. Cognitive impairment caused by diabetes is gaining more acceptance and attention. In this study, we have investigated the effects of a traditionally herbal formulation (THF) on oxidative stress (OS) and cognitive deficits in type 2 diabetic rats. Methods: Thirty-six male Wistar rats were divided into six groups: control group, diabetic group, diabetic+100, 200 or 300mg/kg THF, diabetic+glibenclamide (G) 5mg/kg. Streptozotocin-nicotinamide was used to induce type-II diabetes mellitus. Spatial and passive avoidance learning and memory function were evaluated by Morris Water Maze (MWM), novel object recognition test (NORT) and open field test (OFT). The OS biomarkers were also analyzed. The THF was standardized using RP-HPLC according to phenolic and flavonoids compounds. Results: Indicated that in the diabetic treated (300mg/kg THF and G) vs. diabetic groups, body weight and insulin were significantly increased and the levels of fasting blood glucose significantly reduced. OS was improved in the treated (300mg/kg THF) groups. Furthermore, we noticed that diabetic treated groups (300mg/kg THF) vs. diabetes caused in significant decreases of the travelled distance and escape latency to find the hidden platform, also increased in the time spent and travelled distance in the target quadrant in MWM test, exploration time in NORT and total distance moved in OFT. Conclusion: These findings suggest that THF ameliorated learning and memory deficits in type 2 diabetic rats via reducing OS. THF can be used with a caution against human DM.

Blockage of ventrolateral periaqueductal gray matter cannabinoid 1 receptor increases dental pulp pain and pain-related subsequent learning and memory deficits in rats

Cannabinoid 1 receptor (CB1R) signaling has a pivotal role in the modulation of both pain and cognitive responses. This study aims at investigating the role of CB1R in the ventrolateral periaqueductal gray matter (vlPAG) on both pulpal pain and pain-related subsequent changes in learning and memory performances in rats. The adult male Wistar rats were cannulated in the vlPAG. The rats were pretreated by intra-vlPAG administration of selective CB1R antagonist AM-251 (2, 4 and 8 µg/rat) and vehicle dimethylsulfoxide. The drugs were microinjected 20 min before the induction of capsaicin-induced pulpalgia. The nociceptive behaviors were recorded for 40 min. Then, passive avoidance and spatial learning and memory were assessed using the shuttle box and Morris water maze tests, respectively. Following the administration of intradental capsaicin, there was a significant nociceptive response that increased after an induced blockage of CB1R by AM-251 at 4 and 8 µg. In addition, capsaicin impaired passive avoidance and spatial memory performance of rats. Microinjection of AM-251, prior to capsaicin, could dose-dependently exaggerate capsaicin-related learning and memory deficits in both tests. The present data indicated that the vlPAG endocannabinoid system is involved in the modulation of pain signals from dental pulp. It was also accompanied by learning and memory impairments.

Minocycline differentially modulates human spatial memory systems

Microglia play a critical role in many processes fundamental to learning and memory in health and are implicated in Alzheimer’s pathogenesis. Minocycline, a centrally-penetrant tetracycline antibiotic, inhibits microglial activation and enhances long-term potentiation, synaptic plasticity, neurogenesis and hippocampal-dependent spatial memory in rodents, leading to clinical trials in human neurodegenerative diseases. However, the effects of minocycline on human memory have not previously been investigated. Utilising a double-blind, randomised crossover study design, we recruited 20 healthy male participants (mean 24.6 ± 5.0 years) who were each tested in two experimental sessions: once after 3 days of Minocycline 150 mg (twice daily), and once 3 days of placebo (identical administration). During each session, all completed an fMRI task designed to tap boundary- and landmark-based navigation (thought to rely on hippocampal and striatal learning mechanisms respectively). Given the rodent literature, we hypothesised that minocycline would selectively modulate hippocampal learning. In line with this, minocycline biased use of boundary- compared to landmark-based information (t980 = 3.140, p = 0.002). However, though this marginally improved performance for boundary-based objects (t980 = 1.972, p = 0.049), it was outweighed by impaired landmark-based navigation (t980 = 6.374, p < 0.001) resulting in an overall performance decrease (t980 = 3.295, p = 0.001). Furthermore, against expectations, minocycline significantly reduced activity during memory encoding in the right caudate (t977 = 2.992, p = 0.003) and five other cortical regions, with no significant effect in the hippocampus. In summary, minocycline impaired human spatial memory performance, likely through disruption of striatal processing resulting in greater biasing towards reliance on boundary-based navigation.

Nicotianamine-rich foods for improving the learning and memory functions and as an effective preventing agent of hypertension

Hypertension is considered one of the most serious long-term medical conditions. Angiotensin I-converting enzyme (ACE), as one of the most important targets for hypertension drugs. It converts angiotensin I to vasopressor angiotensin II through a catalytic hydrolysis process. ACE has been found in higher amounts in the brain cells of Alzheimer disease patients. Brain-penetrating ACE inhibitors (ACEI) decreased the impact of Alzheimer disease in elderly hypertensive patients. It is expected that the inclusion of ACEI-rich foods has a potential to eliminate these health issues. Therefore, this study explored the occurrence of ACEI in food extracts combining an ACE inhibition assay with LC/ESIMS quantification analysis, showing that naturally occurring nicotianamine (NA), ubiquitously present in higher plants, is an important constituent in ACEI active foods. Furthermore, oral administration of NA and NA-rich food extracts improved spatial learning and memory functions in rats, in addition to hypertensive relief. Thus, NA is suggested to be a brain-penetrating ACEI, while the inclusion of NA-rich foods will contribute to the “quality of life” of patients with Alzheimer disease by relieving hypertension and dementia.

Gadolinium Retention in the Central and Peripheral Nervous System: Implications for Pain, Cognition, and Neurogenesis.

Background Despite the wide use of gadolinium-based contrast agents (GBCAs) for enhanced MRI, their neurochemical and behavioral consequences, if any, remain poorly understood. Purpose To investigate the effect of repeated exposure to a linear or macrocyclic GBCA on gadolinium retention in the central and peripheral nervous system of rats and to assess the functional implications of such retention on hippocampal neurogenesis and sensory and cognitive processing. Materials and Methods Seventy male Sprague-Dawley rats (4 weeks old) received intraperitoneal injections of gadoterate meglumine (0.6 or 2.5 mmol per kilogram of body weight), gadodiamide (0.6 or 2.5 mmol/kg), or saline daily for 20 days (February 2018-March 2019). The 5-bromo-2'-deoxyuridine injections were administered every 3 days to determine the number of proliferating cells and the number of newly maturing neurons in the hippocampus. Sensory and cognitive behavioral tests were performed to assess the effect of GBCAs on pain sensitivity and spatial working memory function, respectively. Finally, inductively coupled plasma mass spectrometry analysis was used to quantify gadolinium retention in the brain, spinal cord, and peripheral nerves 24 hours after the last GBCA administration. One-way and mixed-design analyses of variance were used for statistical analysis. Results All GBCAs resulted in significant gadolinium retention in central and peripheral nervous tissues (1.8-333.2 nmol Gd/g tissue). Pain hypersensitivity to thermal and mechanical stimuli (P < .001) was observed after gadodiamide exposure in rats but not after gadoterate meglumine exposure. Rats injected with both GBCAs showed no changes in spatial working memory or in hippocampal cell proliferation and maturation. Conclusion Gadolinium was retained in the spinal cord and peripheral nerves in rats exposed to multiple administrations of linear and macrocyclic contrast agents. Gadodiamide (linear contrast agent) but not gadoterate meglumine (macrocyclic contrast agent) led to pain hypersensitivity, but neither affected spatial working memory performance, hippocampal cellular proliferation, or hippocampal neurogenesis. © RSNA, 2020 See also the editorial by Radbruch in this issue.

Allocentric Spatial Memory Performance in a Virtual Reality-Based Task is Conditioned by Visuospatial Working Memory Capacity

Traditionally, the medial temporal lobe has been considered a key brain region for spatial memory. Nevertheless, executive functions, such as working memory, also play an important role in complex behaviors, such as spatial navigation. Thus, the main goal of this study is to clarify the relationship between working memory capacity and spatial memory performance. Spatial memory was assessed using a virtual reality-based procedure, the Boxes Room task, and the visual working memory with the computer-based Change Localization Task. One hundred and twenty-three (n = 123) participants took part in this study. Analysis of Covariance (ANCOVA) revealed a statistically significant relationship between working memory capacity and spatial abilities. Thereafter, two subgroups n = 60, were formed according to their performance in the working memory task (1st and 4th quartiles, n = 30 each). Results demonstrate that participants with high working memory capacity committed fewer mistakes in the spatial task compared to the low working memory capacity group. Both groups improved their performance through repeated trials of the spatial task, thus showing that they could learn spatial layouts independent of their working memory capacity. In conclusion, these findings support that spatial memory performance is directly related to working memory skills. This could be relevant for spatial memory assessment in brain lesioned patients.

Abstract 5750: The antidepressant vortioxetine reverses cognitive deficits associated with androgen deprivation therapy for the treatment of prostate cancer in healthy rats

Abstract First-line treatment for prostate cancer includes androgen deprivation therapy (ADT). However, this intervention can induce severe cognitive impairments in more than half of patients and increases the likelihood of dementia or Alzheimer's disease. Long-term occurrence of these impairments can significantly reduce quality of life for cancer survivors and ultimately impacts their families and caregivers. Thus, it is important to improve the cognitive side effects of ADT, as 45% of prostate cancer patients will undergo ADT, and the five-year relative survival rate is greater than 99%. The clinical literature indicates that ADT-induced impairments typically occur in the cognitive domains of spatial memory and executive function, which are associated with function of the hippocampus (Hipp) and medial prefrontal cortex (mPFC), respectively. The cognitive symptoms that develop can also increase in severity with duration of treatment, suggesting that it may be possible to slow or reverse the impairment. To address the mechanisms underlying these effects, we used the Attentional Set-shifting Test (AST) and the Novel Object Location (NOL) Test to assess cognitive function after surgical castration as a rodent model of ADT. ADT induced impairments in cognitive flexibility on the AST (p&amp;lt;0.001, n=10-12) and visuospatial memory on the NOL task (p&amp;lt;0.05, n=8-11) in male Sprague Dawley rats. These deficits were reversed by chronic administration of a multimodal antidepressant drug, vortioxetine (28 mg/kg/day for 2 weeks). Vortioxetine is FDA-approved for the treatment of Major Depressive Disorder, and it has been shown to improve cognitive impairment associated with depression. Our data indicate that vortioxetine may also represent a novel therapeutic approach to alleviate ADT-induced cognitive impairments. To increase the translational relevance our rodent model of ADT, we are investigating potential cognitive impairments induced by chemical castration with degarelix, a gonadotropin releasing hormone antagonist. Experiments are underway to test the hypothesis that vortioxetine will also reverse cognitive impairments induced by androgen depletion with degarelix. The results of this study will be compared to those obtained with surgical castration. In sum, these studies aim to identify possible therapeutic interventions by which cognitive impairment induced by ADT as a treatment for prostate cancer can be reversed or prevented. This research was funded by the Cancer Prevention &amp; Research Institute of Texas grant RP180055, and by NIH grant R01 CA224672. Citation Format: Alexandra M. Vaiana, Jonathan Gelfond, Teresa Johnson-Pais, Robin Leach, Michael Liss, Anna Sullivan, Ian Thompson, David A. Morilak. The antidepressant vortioxetine reverses cognitive deficits associated with androgen deprivation therapy for the treatment of prostate cancer in healthy rats [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5750.

Effects of Hibiscus sabdariffa calyces on spatial memory and hippocampal expression of BDNF in ovariectomized rats

ABSTRACT Ovarian hypofunction is characterized by decay in brain-derived neurotrophic factor (BDNF), a neurotrophin associated with cognitive and memory function. Hormone replacement therapy is the most common treatment to counteract the negative effects of ovarian insufficiency; however, this therapy may increase the odds of endometrial cancer, blood clots, stroke, and breast cancer. Therefore, a safer alternative to synthetic estrogens is needed. One possible candidate may be phytoestrogens. Hibiscus sabdariffa L. (Malvaceae) is a source of natural food colorants; the calyces and leaves of the plant are consumed in drinks and culinary preparations and are recognized for several health benefits related to their high content of anthocyanins. In the present study, we used an ovariectomized rat model to assess the phytoestrogenic effect of H. sabdariffa, and evaluated spatial memory and BDNF expression. Ninety-day-old female Wistar rats were randomly separated into six groups. Rats from four groups were ovariectomized and injected with a physiological dose of estradiol, or given, in drinking water, an extract prepared from calyces of H. sabdariffa at doses of 50 or 100 mg/kg body weight. Both Intact and Sham groups were included as controls. At day 42, short- and long-term memories were assessed by the Barnes maze test, and hippocampal BDNF expression was evaluated by RT-qPCR and Western blot. Ovariectomy significantly decreased memory performance and BDNF expression, compared with controls. However, administration of H. sabdariffa extract reversed the negative effect of ovariectomy on short- and long-term memory parameters and BDNF expression. A stronger effect was observed at a lower dose of the extract. In conclusion, the extract from H. sabdariffa acted as a phytoestrogen in ovariectomized rats, improving spatial memory performance and hippocampal BDNF expression. Based on these promising results, further clinical experimentation is recommended to study the benefits of H. sabdariffa as an alternative hormonal therapy in patients with ovarian hypofunction.

Cognitive function and brain plasticity in a rat model of shift work: role of daily rhythms, sleep and glucocorticoids

Many occupations require operations during the night-time when the internal circadian clock promotes sleep, in many cases resulting in impairments in cognitive performance and brain functioning. Here, we use a rat model to attempt to identify the biological mechanisms underlying such impaired performance. Rats were exposed to forced activity, either in their rest-phase (simulating night-shift work; rest work) or in their active-phase (simulating day-shift work; active work). Sleep, wakefulness and body temperature rhythm were monitored throughout. Following three work shifts, spatial memory performance was tested on the Morris Water Maze task. After 4 weeks washout, the work protocol was repeated, and blood and brain tissue collected. Simulated night-shift work impaired spatial memory and altered biochemical markers of cerebral cortical protein synthesis. Measures of daily rhythm strength were blunted, and sleep drive increased. Individual variation in the data suggested differences in shift work tolerance. Hierarchical regression analyses revealed that type of work, changes in daily rhythmicity and changes in sleep drive predict spatial memory performance and expression of brain protein synthesis regulators. Moreover, serum corticosterone levels predicted expression of brain protein synthesis regulators. These findings open new research avenues into the biological mechanisms that underlie individual variation in shift work tolerance.

Neural Working Memory Changes During a Spaceflight Analog With Elevated Carbon Dioxide: A Pilot Study.

Spaceflight missions to the International Space Station (ISS) expose astronauts to microgravity, radiation, isolation, and elevated carbon dioxide (CO2), among other factors. Head down tilt bed rest (HDBR) is an Earth-based analog for spaceflight used to study body unloading, fluid shifts, and other factors unrelated to gravitational changes. While in space, astronauts need to use mental rotation strategies to facilitate their adaptation to the ISS environment. Therefore, spatial working memory is essential for crewmember performance. Although the effects of HDBR on spatial working memory have recently been studied, the results are still inconclusive. Here, we expand upon past work and examine the effects of HDBR with elevated CO2 (HDBR + CO2) on brain activation patterns during spatial working memory performance. In addition, we compare brain activation between 30 days of HDBR + CO2 and 70 days of HDBR to test the isolated effect of CO2. Eleven subjects (6 males, 5 females; mean age = 34 ± 8 years) underwent six functional magnetic resonance imaging (fMRI) sessions pre-, during, and post-HDBR + CO2. During the HDBR + CO2 intervention, we observed decreasing activation in the right middle frontal gyrus and left regions of the cerebellum, followed by post-intervention recovery. We detected several correlations between brain and behavioral slopes of change with the HDBR + CO2 intervention. For example, greater increases in activation in frontal, temporal and parietal regions were associated with larger spatial working memory improvements. Comparing the HDBR + CO2 group to data from our previous 70-day HDBR study, we found greater decreases in activation in the right hippocampus and left inferior temporal gyrus for the HDBR + CO2 group over the course of the intervention. Together, these findings increase our understanding of the neural mechanisms of HDBR, elevated levels of CO2 and spaceflight-related changes in spatial working memory performance.

Naringenin alleviates cognition deficits in high-fat diet-fed SAMP8 mice.

Naringenin is a natural dihydro flavonoid that is abundant in grapefruit. Previous studies suggested the cognition protective effect of naringenin in various cognitive deficits models, such as type 2 diabetic rat model and chemicals (e.g., lipopolysaccharide, scopolamine) treated rodents. However, the effects of naringenin on aging animals and the potential mechanisms are still unclear. In this study, we investigated the influence of naringenin administration on learning deficits in aging mice. High-fat diet-fed SAMP8 mice were employed as an age-related model of Alzheimer's disease. Dietary administration of 0.2% naringenin for 12weeks significantly improved the spatial learning and memory performance of the high-fat diet-fed SAMP8 mice in both Barnes Maze test and Morris Water Maze test. Further mechanism research indicated that naringenin reduced Aβ production, tau-hyperphosphorylation, oxidative stress, and neuroinflammation in the brain. This research provides further evidence for the treatment effect of naringenin on Alzheimer's disease. PRACTICAL APPLICATIONS: Naringenin, also known as 4',5,7-thrihydroxyflflavanone, is a natural dihydro flavonoid that is abundant in grapefruit and other citrus fruits. The current study first demonstrated the improvement effect of naringenin on cognition deficits in HFD-fed SAMP8 mice, an aging mouse model. Potential mechanisms were also systematically explained by exploring the amyloid-β (Aβ) accumulation, tau hyperphosphorylation, oxidative stress, and neuroinflammation in the brain of mice. This study provides further evidence for the utilization of naringenin as an effective treatment agent for Alzheimer's disease.

A regulatable adenovector system for GDNF and GFP delivery in the rat hippocampus

Spatial memory performance declines in both normal aging and Alzheimer's disease. This cognitive deficit is related to hippocampus dysfunction. Gene therapy using neurotrophic factors like Glial cell line-derived neurotrophic factor (GDNF) emerges as a promising approach to ameliorate age-related cognitive deficits. We constructed a two vector regulatable system (2VRS) which consists of a recombinant adenoviral vector (RAd) harboring a Tet-Off bidirectional promoter flanked by GDNF and Green Fluorescent Protein (GFP) genes. A second adenovector, RAd-tTA, constitutively expresses the regulatory protein tTA. When cells are cotransduced by the 2VRS, tTA activates the bidirectional promoter and both transgenes are expressed. In the presence of the antibiotic doxycycline (DOX) transgene expression is silenced. We tested the 2VRS in CHO-K1 cells where we observed a dose-dependent GFP expression that was completely inhibited by DOX (1 mg/ml). The 2VRS injected in the hippocampal CA1 region transduced both neurons and astrocytes and was efficiently inhibited by DOX added to the drinking water. In order to assess GDNF biological activity we injected 2VRS and its Control (CTRL) vector in the hypothalamus and monitored body weight for one month. The results showed that GDNF retards weight recovery 6 days more than CTRL. In conclusion, our 2VRS demonstrated optimal GFP expression and showed a bioactive effect of transgenic GDNF in the brain.

Gene-modified Exosomes Protect the Brain Against Prolonged Deep Hypothermic Circulatory Arrest

Neurologic deficit remains a major complication after cardiovascular surgeries with deep hypothermic circulatory arrest (DHCA). We hypothesized that exosomes derived from bone marrow mesenchymal stem cells (MSCs) may conduct cerebral protection against prolonged DHCA in rats, and overexpressing microRNA-214 (miR-214) may further enhance the neuroprotection. Cultured MSCs were transfected with lentivirus vectors containing pre-miR-214 or control vectors. Exosomes were isolated by centrifugation. The DHCA was conducted for 60 minutes when the pericranial temperature was cooled to 18°C. Exosomes from MSCs, MSCs transfected with control vectors, or pre-miR-214 were administered by intracerebroventricular injection 1 day before DHCA. Transfection of pre-miR-214 significantly enhanced the miR-214 expression in exosomes from MSCs. All exosome-pretreating groups exhibited lower levels of interleukin-1β and tumor necrosis factor-α, higher capillary density, more significant neurogenesis and angiogenesis, and more normal neurons in the hippocampus than those of the control group. Exosome pretreatment markedly improved the spatial learning and memory function and vestibulomotor function. Compared with exosomes from MSCs or MSCs transfected with control vectors, miR-214-enriched exosomes remarkably enhanced the miR-214 level and expressions of phosphor-protein kinase B and Bcl-2, inhibited expressions of phosphate and tension homology, Bcl-2 interacting mediator of cell death, Bcl-2-associated X protein, and cleaved Caspase-3, and increased the number of survival neurons. Significantly better neurologic functions were also detected in rats pretreated with miR-214-enriched exosomes. Exosomes from MSCs conduct powerful neuroprotection against cerebral injury induced by DHCA, which can be further enhanced by genetic modification of the exosomes to overexpress miR-214.