Radial Water Maze Research Articles

Age‐ and sex‐dependent differences in cognitive decline in rat models of Alzheimer’s disease

AbstractBackgroundMemory loss has been a central focus of Alzheimer’s disease (AD) research but executive dysfunction may be one of the earliest indicators of AD (Baudic et al., 2006). Executive function refers to a group of cognitive processes that are required for goal directed behaviours, such as working memory and cognitive flexibility. Amyloid‐β (Aβ) plaques and neurofibrillary tangles are considered the pathological hallmarks of AD, but evidence suggests that these are not the earliest pathologies to appear in the AD brain (Sperling et al., 2011). This highlights the importance of assessing both the prodromal and more advanced phases of AD in preclinical modelling. This study aimed to characterize age‐ and sex‐related changes in executive function, learning, and memory across normal aging in rats as well as in two aging transgenic rat strains of AD: TgAPP21 (Aβ plaque‐negative) and TgAPP/PS1 (Aβ plaque‐positive).MethodMale and female wildtype Fischer 344, TgAPP21, and TgAPP/PS1 rats were used in this study. The TgAPP21 rat overexpresses the mutant human amyloid precursor protein but does not spontaneously develop Aβ plaques, serving as an important model of prodromal AD. The TgAPP/PS1 rat overexpresses mutant human forms of both the amyloid precursor protein and Presenilin‐1 and does develop age‐dependent Aβ plaques. These strains allowed us to assess cognition under three conditions (i) normal aging, (ii) increased Aβ without plaque deposition, and (iii) age‐dependent Aβ plaque deposition. At 3, 9, or 15 months of age the rats were tested for spatial learning and memory, working memory, and cognitive flexibility using the Morris water maze, the 8‐arm radial water maze, and a T‐maze set‐shifting task.ResultAge‐dependent cognitive decline was observed across all genotypes but was exacerbated in both transgenic models. Effects of age, sex, and genotype varied across the cognitive tasks, emphasizing the importance of assessing multiple cognitive domains.ConclusionThese findings expand our understanding of the roles of sex, age and Aβ plaque‐positive/negative environments in cognitive decline in preclinical rat strains of AD. Overall, this work supports further investigation into the pathologies driving these cognitive changes and potential biomarkers for earlier detection.

A Gad2 specific Slc6a8 deletion recapitulates the contextual and cued freezing deficits seen in Slc6a8-/y mice

The creatine (Cr)-phosphocreatine shuttle is essential for ATP homeostasis. In humans, the absence of brain Cr causes significant intellectual disability, epilepsy, and language delay. Mutations of the creatine transporter (SLC6A8) are the most common cause of Cr deficiency. In rodents, Slc6a8 deletion causes deficits in spatial learning, novel object recognition (NOR), as well as in contextual and cued freezing. The mechanisms that underlie these cognitive deficits are not known. Due to the heterogeneous nature of the brain, it is important to determine which systems are affected by a loss of Cr. In this study, we generated mice lacking Slc6a8 in GABAergic neurons by crossing Slc6a8FL mice with Gad2-Cre mice. These Gad2-specific Slc6a8 knockout (cKO) mice, along with the ubiquitous Slc6a8 KO (Slc6a8-/y), Gad2-Cre+, and wild-type (WT) mice were tested in the Morris water maze, NOR, conditioned freezing, and the radial water maze. Similar to the Slc6a8-/y mice, cKO mice had reduced contextual and cued freezing compared with WT mice. The cKO mice had a mild spatial learning deficit during the reversal phase of the MWM, however they were not as pronounced as in Slc6a8-/y mice. In NOR, the Gad2-Cre mice spent less time with the novel object, similar to the reduced novel time in the cKO mice. There were no changes in radial water maze performance. Slc6a8 deletion in GABAergic neurons is sufficient to recapitulate the conditioned freezing deficits seen in Slc6a8-/y mice.

Cognitive and behavioral effects of whole brain conventional or high dose rate (FLASH) proton irradiation in a neonatal Sprague Dawley rat model.

Recent studies suggest that ultra-high dose rates of proton radiation (>40 Gy/s; FLASH) confer less toxicity to exposed healthy tissue and reduce cognitive decline compared with conventional radiation dose rates (~1 Gy/s), but further preclinical data are required to demonstrate this sparing effect. In this study, postnatal day 11 (P11) rats were treated with whole brain irradiation with protons at a total dose of 0, 5, or 8 Gy, comparing a conventional dose rate of 1 Gy/s vs. a FLASH dose rate of 100 Gy/s. Beginning on P64, rats were tested for locomotor activity, acoustic and tactile startle responses (ASR, TSR) with or without prepulses, novel object recognition (NOR; 4-object version), striatal dependent egocentric learning ([configuration A] Cincinnati water maze (CWM-A)), prefrontal dependent working memory (radial water maze (RWM)), hippocampal dependent spatial learning (Morris water maze (MWM)), amygdala dependent conditioned freezing, and the mirror image CWM [configuration B (CWM-B)]. All groups had deficits in the CWM-A procedure. Weight reductions, decreased center ambulation in the open-field, increased latency on day-1 of RWM, and deficits in CWM-B were observed in all irradiated groups, except the 5 Gy FLASH group. ASR and TSR were reduced in the 8 Gy FLASH group and day-2 latencies in the RWM were increased in the FLASH groups compared with controls. There were no effects on prepulse trials of ASR or TSR, NOR, MWM, or conditioned freezing. The results suggest striatal and prefrontal cortex are sensitive regions at P11 to proton irradiation, with reduced toxicity from FLASH at 5 Gy.

Latrophilin-3 heterozygous versus homozygous mutations in Sprague Dawley rats: Effects on egocentric and allocentric memory and locomotor activity.

Latrophilin-3 (LPHN3) is a brain specific G-protein coupled receptor associated with increased risk of attention deficit hyperactivity disorder (ADHD) and cognitive deficits. CRISPR/Cas9 was used to generate a constitutive knockout (KO) rat of Lphn3 by deleting exon 3, based on human data that LPHN3 variants are associated with some cases of ADHD. Lphn3 KO rats are hyperactive with an attenuated response to ADHD medication and have cognitive deficits. Here, we tested KO, heterozygous (HET), and wildtype (WT) rats to determine if there was a gene-dosage effect. We tested the rats in home-cage activity starting at postnatal day (P)35 and P50, followed by tests of egocentric learning (Cincinnati water maze [CWM]), spatial learning (Morris water maze [MWM]), working memory (radial water maze [RWM]), incidental learning (novel object recognition [NOR]), acoustic startle response (ASR) habituation, tactile startle response (TSR) habituation, prepulse modification of acoustic startle, shuttle-box passive avoidance, conditioned freezing, and a mirror image version of the CWM. KO and HET rats were hyperactive. KO and HET rats had egocentric (CWM) and spatial deficits (MWM), increased startle response, and KO rats showed less conditioned freezing on contextual and cued memory; there were no effects on working memory (RWM) or passive avoidance. The selective gene-dosage effect in Lphn3 HET rats indicates that Lphn3 exhibits dominate expression on functions where it is most abundantly expressed (striatum, hippocampus) but not on behaviors mediated by regions of low expression. The data add further evidence to the impact of this synaptic protein on brain function and behavior.

Treatment with the BCL-2/BCL-xL inhibitor senolytic drug ABT263/Navitoclax improves functional hyperemia in aged mice.

Moment-to-moment adjustment of regional cerebral blood flow to neuronal activity via neurovascular coupling (NVC or "functional hyperemia") has a critical role in maintenance of healthy cognitive function. Aging-induced impairment of NVC responses importantly contributes to age-related cognitive decline. Advanced aging is associated with increased prevalence of senescent cells in the cerebral microcirculation, but their role in impaired NVC responses remains unexplored. The present study was designed to test the hypothesis that a validated senolytic treatment can improve NVC responses and cognitive performance in aged mice. To achieve this goal, aged (24-month-old) C57BL/6 mice were treated with ABT263/Navitoclax, a potent senolytic agent known to eliminate senescent cells in the aged mouse brain. Mice were behaviorally evaluated (radial arms water maze) and NVC was assessed by measuring CBF responses (laser speckle contrast imaging) in the somatosensory whisker barrel cortex evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. ABT263/Navitoclax treatment improved NVC response, which was associated with significantly improved hippocampal-encoded functions of learning and memory. ABT263/Navitoclax treatment did not significantly affect endothelium-dependent acetylcholine-induced relaxation of aorta rings. Thus, increased presence of senescent cells in the aged brain likely contributes to age-related neurovascular uncoupling, exacerbating cognitive decline. The neurovascular protective effects of ABT263/Navitoclax treatment highlight the preventive and therapeutic potential of senolytic treatments (as monotherapy or as part of combination treatment regimens) as effective interventions in patients at risk for vascular cognitive impairment (VCI).

The study of attenuating effects of quercetin on spatial memory impairment and degenerative changes in hippocampus of lead exposed rats

Lead neurotoxicity has been studied in animal models to induce neurodegeneration. The study was aimed to evaluate the attenuating effects of quercetin on spatial memory impairment and degenerative changes in hippocampus of lead exposed rats. Thirty (30) Wistar rats were randomly divided into six groups of five rats per group (each, n = 5). Groups I (control) and II were administered distilled water and lead, respectively for 42 days. Lead was co-administered with Quercetin and Succimer for Groups III and VI, respectively for 42 days. Groups IV and V were administered lead for 21 days and treated with Quercetin for Group IV and Succimer for Group V for another 21 days. The administration was orally, once per day and lasted for 42 days. Spatial memory was assessed using Eight-arm radial water maze (8-ARWM) test. The rats were anaesthetized with Ketamine at 75 mg/kg intraperitoneally and euthanized. Brain was harvested, processed, Haematoxylin and Eosin stains were used for histo¬logical study of the hippocampus and cells were counted. Results showed spatial memory was impaired and histopatho¬logy such as vacuolation, pyknotic and reduction in pyramidal cells count in CA3 region of hippocampus of lead exposed rats. How¬ever, treat¬ment with quercetin improved spatial memory and histopatho¬logy. Thus, quercetin could be used as an antidote in lead neurotoxicity. Key words: Lead, quercetin, memory, neurodegeneration.

Effects of Juvenile or Adolescent Working Memory Experience and Inter-Alpha Inhibitor Protein Treatment after Neonatal Hypoxia-Ischemia.

Hypoxic-Ischemic (HI) brain injury in the neonate contributes to life-long cognitive impairment. Early diagnosis and therapeutic interventions are critical but limited. We previously reported in a rat model of HI two interventional approaches that improve cognitive and sensory function: administration of Inter-alpha Inhibitor Proteins (IAIPs) and early experience in an eight-arm radial water maze (RWM) task. Here, we expanded these studies to examine the combined effects of IAIPs and multiple weeks of RWM assessment beginning with juvenile or adolescent rats to evaluate optimal age windows for behavioral interventions. Subjects were divided into treatment groups; HI with vehicle, sham surgery with vehicle, and HI with IAIPs, and received either juvenile (P31 initiation) or adolescent (P52 initiation) RWM testing, followed by adult retesting. Error rates on the RWM decreased across weeks for all conditions. Whereas, HI injury impaired global performance as compared to shams. IAIP-treated HI subjects tested as juveniles made fewer errors as compared to their untreated HI counterparts. The juvenile group made significantly fewer errors on moderate demand trials and showed improved retention as compared to the adolescent group during the first week of adult retesting. Together, results support and extend our previous findings that combining behavioral and anti-inflammatory interventions in the presence of HI improves subsequent learning performance. Results further indicate sensitive periods for behavioral interventions to improve cognitive outcomes. Specifically, early life cognitive experience can improve long-term learning performance even in the presence of HI injury. Results from this study provide insight into typical brain development and the impact of developmentally targeted therapeutics and task-specific experience on subsequent cognitive processing.

Differential effects of N-methyl-D-aspartate receptor blockade during the second and third postnatal weeks on spatial working and reference memory in adult rats

The present study investigated the effects of chronic NMDA receptor blockade during different developmental age after birth on the performance of two kinds of spatial memory tasks. Rats were chronically treated with MK-801 only during the 2nd or 3rd postnatal week or both, and later they were trained in radial maze and Morris water maze tasks. In radial maze training, MK-801 treatment in the 2nd postnatal week significantly impaired learning as well as the treatment of both the 2nd and 3rd weeks did. On the other hand, in Morris water maze training, MK-801 treatment in the 2nd postnatal week resulted only in mild learning impairment, although the treatment of both the 2nd and 3rd weeks caused severe impairment. MK-801 treatment only during the 3rd postnatal week did not cause any detectable changes in performance of both radial maze and water maze learning. Results suggest the possibility that NMDA receptor blockade during the 2nd postnatal week has a major impact on the development of abilities including spatial working memory required for proper performance in radial maze task, and that NMDA receptor-dependent development of spatial reference memory that is primarily assessed in water maze task persists beyond the 2nd postnatal week.

Impairment of cognitive flexibility in type 2 diabetic db/db mice

Impaired executive function is a major peril for patients with type 2 diabetes, reducing quality of life and ability for diabetes management. Despite the significance of this impairment, few animal models of type 2 diabetes examine domains of executive function such as cognitive flexibility or working memory. Here, we evaluated these executive function domains in db/db mice, an established model of type 2 diabetes, at 10 and 24 weeks of age. The db/db mice showed impaired cognitive flexibility in the Morris water maze reversal phase. However, the db/db mice did not show apparent working memory disturbance in the spatial working memory version of the Morris water maze or in the radial water maze. We also examined axon initial segments (AIS) and nodes of Ranvier, key axonal domains for action potential initiation and propagation. AIS were significantly shortened in medial prefrontal cortex and hippocampus of 26-week-old db/db mice compared with controls, similar to our previous findings in 10-week-old mice. Nodes of Ranvier in corpus callosum, previously shown to be unchanged at 10 weeks, were elongated at 26 weeks, suggesting an important role for this domain in disease progression. Together, the findings help establish db/db mice as a model of impaired cognitive flexibility in type 2 diabetes and advance our understanding of its pathophysiology.

Accelerated Deficits of Spatial Learning and Memory Resulting From Prenatal Inflammatory Insult Are Correlated With Abnormal Phosphorylation and Methylation of Histone 3 in CD-1 Mice.

Gestational infection causes various neurological deficits in offspring, such as age-related spatial learning and memory (SLM) decline. How inflammation causes age-related SLM dysfunction remains unknown. Previous research has indicated that histone modifications, such as phosphorylation of H3S10 (H3S10p) and trimethylation of H3K9 (H3K9me3) may be involved. In our study, pregnant mice received an intraperitoneal injection of lipopolysaccharide (LPS, 50 or 25 μg/kg) or normal saline during gestational days 15–17. After normal parturition, the offspring were randomly separated into 1-, 6-, 12-, 18-, and 22-month-old groups. SLM performance was assessed using a radial six-arm water maze (RAWM). The hippocampal levels of H3S10p and H3K9me3 were detected using an immunohistochemical method. The results indicated that the offspring had significantly impaired SLM, with decreased H3S10p and increased H3K9me3 levels from 12 months onward. Maternal LPS exposure during late gestation significantly and dose-dependently exacerbated the age-related impairment of SLM, with the decrease in H3S10p and increase in H3K9me3 beginning at 12 months in the offspring. The histone modifications (H3S10p and H3K9me3) were significantly correlated with impairment of SLM. Our findings suggest that prenatal exposure to inflammation could exacerbate age-related impairments of SLM and changes in histone modifications in CD-1 mice from 12 months onward, and SLM impairment might be linked to decreased H3S10p and increased H3K9me3.

Molecular development for industrial biotechnology using data analysis, protein structures and small leaps of faith

The aim of this study was to evaluate etazolate against depression-like behavior and, learning and memory impairment induced by 6- hydroxydopamine (6-OHDA) rat model of Parkinson’s disease (PD). This aim was achieved through comparing 6-OHDA lesioned rats in the presence and absence of etazolate. The 6-OHDA was used to induce lesion as a model of PD. Etazolate was administered at a dose of 1 mg/kg/day for 14 days, starting 7 days after lesion induction. Apomorphine-induced rotation test was used to evaluate 6-OHDA-induced motor deficits, tail suspension test was used to assess depression-like symptoms, and the radial arms water maze (RAWM) was used to evaluate special learning and memory functions. Antioxidant biomarkers and BDNF protein levels were assessed in the hippocampus. Results revealed that etazolate administration significantly improved 6-OHDA-induced PD related symptoms including motor deficits, depression-like behavior and impairment of both short- and long- term memory. Moreover, etazolate significantly prevented 6-OHDA-induced reduction in oxidative stress biomarkers (GSH/GSSG ratio, GPx) and BDNF levels. In conclusion, motor dysfunction, depressive- like behavior, and learning and memory deficits in the 6-OHDA rat model of PD can be significantly prevented by etazolate. This prevention could be attributed to etazolate’s ability to prevent reduction in antioxidative stress biomarkers and BDNF levels.

Environmental Enrichment Results in Both Brain Connectivity Efficiency and Selective Improvement in Different Behavioral Tasks

Exposure to environmental enrichment (EE) has been a useful model for studying the effects of experience on brain plasticity, but to date, few is known about the impact of this condition on the brain functional networks that probably underlies the multiple behavioral improvements. Hence, we assessed the effect of an EE protocol in adult Wistar rats on the performance in several behavioral tasks testing different domains (Open field (OP): locomotor activity; Elevated-zero maze (EZM): anxiety-related behaviors; 5-choice serial reaction time task (5-CSRTT): attentional processes; 4-arm radial water maze (4-RAWM): spatial memory) in order to check its effectiveness in a wide range of functions. After this, we analyzed the functional brain connectivity underlying each experimental condition through cytochrome C oxidase (COx) histochemistry. Our EE protocol reduced both locomotor activity in the OP and anxiety-related behaviors in the EZM. On the other hand, enriched rats showed more accuracy in the 4-RAWM, whereas 5-CSRTT performance was not significantly ameliorated by EE condition. In relation to COx functional connectivity, we found that EE reduced the number of strong positive correlations both in basal and training conditions, suggesting a modulating effect on specific brain connections. Our results suggest that EE seems to have a selective effect on specific brain regions, such as prefrontal cortex and hippocampus, leading to a more efficient brain connectivity.

Beneficial effect of etazolate on depression-like behavior and, learning, and memory impairment in a model of Parkinson’s disease

The aim of this study was to evaluate etazolate against depression-like behavior and, learning and memory impairment induced by 6- hydroxydopamine (6-OHDA) rat model of Parkinson’s disease (PD). This aim was achieved through comparing 6-OHDA lesioned rats in the presence and absence of etazolate. The 6-OHDA was used to induce lesion as a model of PD. Etazolate was administered at a dose of 1 mg/kg/day for 14 days, starting 7 days after lesion induction. Apomorphine-induced rotation test was used to evaluate 6-OHDA-induced motor deficits, tail suspension test was used to assess depression-like symptoms, and the radial arms water maze (RAWM) was used to evaluate special learning and memory functions. Antioxidant biomarkers and BDNF protein levels were assessed in the hippocampus. Results revealed that etazolate administration significantly improved 6-OHDA-induced PD related symptoms including motor deficits, depression-like behavior and impairment of both short- and long- term memory. Moreover, etazolate significantly prevented 6-OHDA-induced reduction in oxidative stress biomarkers (GSH/GSSG ratio, GPx) and BDNF levels. In conclusion, motor dysfunction, depressive- like behavior, and learning and memory deficits in the 6-OHDA rat model of PD can be significantly prevented by etazolate. This prevention could be attributed to etazolate’s ability to prevent reduction in antioxidative stress biomarkers and BDNF levels.

Age- and Gender-Based Differences in Nest-Building Behavior and Learning and Memory Performance Measured Using a Radial Six-Armed Water Maze in C57BL/6 Mice.

Background Understanding age-based and gender-based behavioral changes is becoming more important as a greater percentage of people lives longer worldwide. In this study, a C57BL/6 mouse animal model was used to study age-based and gender-based behavioral differences using nest building and radial six-armed water maze (RAWM) testing. Methods In C57BL/6 mice, nest-building behavior was recorded as nesting scores, while spatial learning and memory behaviors were assessed using RAWM platform search errors and latencies. Results In the nest-building test, nest building significantly declined in nineteen 25-month-old mice compared to that of twenty-three 7-month-old mice. Meanwhile, nest building in 25-month-old mice was lower for eight male mice than for eleven female mice, while no significant gender differences were observed in nest building of 7-month-old mice. RAWM performance also declined in aged versus nonaged adult mice, while no significant gender differences were observed in average RAWM performance regardless of age. Conclusions In adult C57BL/6 mice, nest building is a sensitive indicator for detecting both age- and gender-based behavioral declines, while RAWM performance, an assessment of spatial learning and memory behaviors, is not sensitive to gender but significantly declines with aging. Therefore, for a C57BL/6 mouse model of aging, both nest building and RAWM should be useful to further study mechanisms involved in behavioral decline with aging.

Neuroprotective Effect of Pedalium murex Linn. Leaf against Lipopolysaccharide Induced Behavioural Disorders in Rats

Introduction: Effective treatment is necessary to minimize the neuronal damage and oxidative stress. Traditional medicines offer potent pharmacological activity with minimal side effects compared to synthetic drugs to treat such chronic disorders. There is no renowned remedy for arrest or rescuing infection or inflammation-induced brain damage. The present study was aimed to evaluate the neuroprotective effect of ethanol extract of Pedalium murex Linn. (EEPM) leaves against lipopolysaccharide (LPS)-induced endotoxemia. Methods: Neurodegeneration was induced in rats with a single intraperitoneal injection of LPS (1 mg/kg). The induced endotoxemia constantly linked with battery of behavioural tests viz., choice reaction time task (CRT), 8-arm radial maze (RAM) and water maze test (WMT). At the end of the study, rats were sacrificed, brain hippocampal region was removed and biochemical parameters were measured. Results: In WMT swimming length (cm) was increased in LPS-treated rats when compared to control animals, the swimming length (EEPM; 400 mg/kg) was found to be significant; in RAM, different doses of EEPM at 100, 200 and 400 mg/kg decreased the number of errors in entry 4.00±0.36, 4.16±0.16and 3.33±2.79 respectively when compared with control animals (2.66± 0.21). EEPM at 400 mg/kg showed significant activity, in CRT apparatus increased incorrect lever pressing was observed in LPS-treated rats when compared to control animals. Incorrect lever pressing was minimized by EEPM at 400 mg/kg (43.5±2.40). Conclusions: Our results showed that EEPM is a hopeful aspirant for hindrance of infection and inflammation induced brain damage by LPS.

Learning and memory effects of neonatal methamphetamine exposure in rats: Role of reactive oxygen species and age at assessment.

In utero methamphetamine (MA) exposure leads to a range of adverse effects, such as decreased attention, reduced working-memory capability, behavioral dysregulation, and spatial memory impairments in exposed children. In the current experiment, preweaning Sprague-Dawley rats-as a model of third trimester human exposure-were administered the spin trapping agent, N-tert-butyl-α-phenylnitrone (PBN), daily prior to MA. Rats were given 0 (SAL) or 40 mg/kg PBN prior to each MA dose (10 mg/kg, 4× per day) from postnatal day (P) 6-15. Littermates underwent Cincinnati water maze, Morris water maze, and radial water maze assessment beginning on P30 (males) or P60 (females). Males were also tested for conditioned contextual and cued freezing, while females were trained in passive avoidance. Findings show that, regardless of age/sex, neonatal MA induced deficits in all tests, except passive avoidance. PBN did not ameliorate these effects, but had a few minor effects. Taken together, MA induced learning deficits emerge early and persist, but the mechanism remains unknown.

Chronic low-level exposure to the common seafood toxin domoic acid causes cognitive deficits in mice

The consumption of one meal of seafood containing domoic acid (DA) at levels high enough to induce seizures can cause gross histopathological lesions in hippocampal regions of the brain and permanent memory loss in humans and marine mammals. Seafood regulatory limits have been set at 20mgDA/kg shellfish to protect human consumers from symptomatic acute exposure, but the effects of repetitive low-level asymptomatic exposure remain a critical knowledge gap. Recreational and Tribal-subsistence shellfish harvesters are known to regularly consume low levels of DA. The aim of this study was to determine if chronic low-level DA exposure, at doses below those that cause overt signs of neurotoxicity, has quantifiable impacts on cognitive function. To this end, female C57BL/6NJ mice were exposed to asymptomatic doses of DA (≈0.75mg/kg) or vehicle once a week for several months. Spatial learning and memory were tested in a radial water maze paradigm at one, six and 25 weeks of exposure, after a nine-week recovery period following cessation of exposure, and at three old age time points (18, 24 and 28 months old). Mice from select time points were also tested for activity levels in a novel cage environment using a photobeam activity system. Chronic low-level DA exposure caused significant spatial learning impairment and hyperactivity after 25 weeks of exposure in the absence of visible histopathological lesions in hippocampal regions of the brain. These cognitive effects were reversible after a nine-week recovery period with no toxin exposure and recovery was sustained into old age. These findings identify a new potential health risk of chronic low-level exposure in a mammalian model. Unlike the permanent cognitive impacts of acute exposure, the chronic low-level effects observed in this study were reversible suggesting that these deficits could potentially be managed through cessation of exposure if they also occur in human seafood consumers.

Reducing Peripheral Inflammation with Infliximab Reduces Neuroinflammation and Improves Cognition in Rats with Hepatic Encephalopathy.

Inflammation contributes to cognitive impairment in patients with hepatic encephalopathy (HE). However, the process by which peripheral inflammation results in cognitive impairment remains unclear. In animal models, neuroinflammation and altered neurotransmission mediate cognitive impairment. Taking into account these data, we hypothesized that in rats with HE: (1) peripheral inflammation is a main contributor to neuroinflammation; (2) neuroinflammation in hippocampus impairs spatial learning by altering AMPA and/or NMDA receptors membrane expression; (3) reducing peripheral inflammation with infliximab (anti-TNF-a) would improve spatial learning; (4) this would be associated with reduced neuroinflammation and normalization of the membrane expression of glutamate receptors. The aims of this work were to assess these hypotheses. We analyzed in rats with portacaval shunt (PCS) and control rats, treated or not with infliximab: (a) peripheral inflammation by measuring prostaglandin E2, IL10, IL-17, and IL-6; (b) neuroinflammation in hippocampus by analyzing microglial activation and the content of TNF-a and IL-1b; (c) AMPA and NMDA receptors membrane expression in hippocampus; and (d) spatial learning in the Radial and Morris water mazes. We assessed the effects of treatment with infliximab on peripheral inflammation, on neuroinflammation and AMPA and NMDA receptors membrane expression in hippocampus and on spatial learning and memory. PCS rats show increased serum prostaglandin E2, IL-17, and IL-6 and reduced IL-10 levels, indicating increased peripheral inflammation. PCS rats also show microglial activation and increased nuclear NF-kB and expression of TNF-a and IL-1b in hippocampus. This was associated with altered AMPA and NMDA receptors membrane expression in hippocampus and impaired spatial learning and memory in the radial and Morris water maze. Treatment with infliximab reduces peripheral inflammation in PCS rats, normalizing prostaglandin E2, IL-17, IL-6, and IL-10 levels in serum. Infliximab also prevents neuroinflammation, reduces microglial activation, translocates NF-kB into nucleoli and normalizes TNF-a and IL-1b content in hippocampus. This was associated with normalization of AMPA receptors membrane expression in hippocampus and of spatial learning and memory. The results suggest that peripheral inflammation contributes to spatial learning impairment in PCS rats. Treatment with anti-TNF-a could be a new therapeutic approach to improve cognitive function in patients with HE.

Accelerated reduction of serum thyroxine and hippocampal histone acetylation links to exacerbation of spatial memory impairment in aged CD-1 mice pubertally exposed to bisphenol-a.

Age-related cognitive decline has been associated with changes in endogenous hormones and epigenetic modification of chromatin, including histone acetylation. Developmental exposure to endocrine disrupting chemicals, such as bisphenol-A (BPA) that produces endocrine disruption and epigenetic changes, may be a risk factor for accelerating cognitive deficits during aging. Thus, we exposed CD-1 mice to BPA (0, 1, and 100mg/l BPA in the drinking water) orally during puberty (from postnatal days 28 to 56) and investigated whether pubertal BPA exposure exacerbates the age-related impairment of spatial cognition in old age (18months old) and whether serum sex and thyroid hormones or hippocampal histone acetylation (H3K9ac and H4K8ac) are associated with cognitive effects. A young control group (6months old) was added to analyze the age effect. Results showed untreated aged mice had marked decline of spatial learning and memory in the novel location recognition and radial six-arm water maze tasks, with decreased levels of these hormones and hippocampal H3K9ac and H4K8ac compared to young controls. The BPA treatment exacerbated age-related spatial cognitive impairment and accelerated the reduction of free thyroxine (FT4), H3K9ac, and H4K8ac, and the 100mg/l BPA group showed more significant impact. Additionally, correlation analyses revealed that lower levels of FT4, H3K9ac, and H4K8ac were accompanied by decreased spatial memory abilities. We concluded that accelerated reduction of serum FT4 and hippocampal H3K9ac and H4K8ac might be linked to exacerbation of age-related spatial cognitive impairment due to pubertal BPA exposure.

Studies on cerebral protection of digoxin against hypoxic-ischemic brain damage in neonatal rats.

Hypoxic-ischemic brain damage (HIBD) is a major cause of neonatal acute deaths and chronic nervous system damage. Our present study was designed to investigate the possible neuroprotective effect of digoxin-induced pharmacological preconditioning after hypoxia-ischemia and underlying mechanisms. Neonatal rats were assigned randomly to control, HIBD, or HIBD+digoxin groups. Pharmacological preconditioning was induced by administration of digoxin 72 h before inducing HIBD by carotid occlusion+hypoxia. Behavioral assays, and neuropathological and apoptotic assessments were performed to examine the effects; the expression of Na/K ATPase was also assessed. Rats in the HIBD group showed deficiencies on the T-maze, radial water maze, and postural reflex tests, whereas the HIBD+digoxin group showed significant improvements on all behavioral tests. The rats treated with digoxin showed recovery of pathological conditions, increased number of neural cells and proliferative cells, and decreased number of apoptotic cells. Meanwhile, an increased expression level of Na/K ATPase was observed after digoxin preconditioning treatment. The preconditioning treatment of digoxin contributed toward an improved functional recovery and exerted a marked neuroprotective effect including promotion of cell proliferation and reduction of apoptosis after HIBD, and the neuroprotective action was likely associated with increased expression of Na/K ATPase.