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Alzheimer’s disease (AD) is a representative neurodegenerative disease characterized by the structural and functional degeneration of neurons. The present study investigated the neuroprotective effect of Ixeris dentata (ID) extract on trimethyltin (TMT)-induced memory deficit in the rat. Cognitive improving effect and neuronal activity of ID were assessed by using Morris water maze (MWM) test and choline acetyltransferase (ChAT), cAMP-response element-binding protein (CREB) immunohistochemistry. Seven days after TMT injection (8.0 mg/kg, i.p.), each group of rats was administered saline, water extract of ID (WID, 400 or 800 mg/kg, p.o.), ethanol extract of ID (EID, 400 or 800 mg/kg, p.o.), or caffeic acid (CAF, 30 mg/kg, i.p.) daily for fourteen days. Results: Treatment with EID and CAF produced a significant improvement in escape latency time of the acquisition, and retention time in the target area of the MWM task. Additionally, administration of EID or CAF markedly alleviated TMT-induced loss of ChAT- and CREB-immunoreactive cells in the hippocampus. The results demonstrated that EID has a protective effect against TMT-induced memory deficit, partly through increasing the CREB and cholinergic signaling pathway in the hippocampus. These results suggest that ethanol extracts of ID might be useful for improving cognitive functions in neurodegenerative diseases such as Alzheimer’s disease.

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

Circadian rhythms influence virtually all aspects of physiology and behavior. This is problematic when circadian rhythms no longer reliably predict time. Circadian rhythm disruption can impair memory, yet we don't know how this fully works at the systems and molecular level. When trying to determine the root of a memory impairment, assessing neuronal activation with c-FOS is useful. This has yet to be assessed in the hippocampi of circadian rhythm disrupted rats in a hippocampal gold standard task. Rats were trained on the Morris water task (MWT), then received 6 days of a 21-h day (T21), 13 days of a normal light dark cycle, probe trial, and tissue extraction an hour later. Despite having impaired memory in the probe trial, compared to controls there were no differences in c-FOS expression in hippocampal sub regions: CA1; CA3; Dentate gyrus. These data confirm others in hamsters demonstrating that arrhythmicity which produces an impairment in spontaneous alternation does not affect c-FOS in the dentate gyrus. The current study indicates that the memory impairment induced by a lighting manipulation is likely not due to attenuated neuronal activation. Determining how the master clock in the brain communicates with the hippocampus is needed to untangle the relationship between circadian rhythms and memory. [ABSTRACT FROM AUTHOR]

Circadian rhythms influence virtually all aspects of physiology and behavior. This is problematic when circadian rhythms no longer reliably predict time. Circadian rhythm disruption can impair memory, yet we don’t know how this fully works at the systems and molecular level. When trying to determine the root of a memory impairment, assessing neuronal activation with c-FOS is useful. This has yet to be assessed in the hippocampi of circadian rhythm disrupted rats in a hippocampal gold standard task. Rats were trained on the Morris water task (MWT), then received 6 days of a 21-h day (T21), 13 days of a normal light dark cycle, probe trial, and tissue extraction an hour later. Despite having impaired memory in the probe trial, compared to controls there were no differences in c-FOS expression in hippocampal sub regions: CA1; CA3; Dentate gyrus. These data confirm others in hamsters demonstrating that arrhythmicity which produces an impairment in spontaneous alternation does not affect c-FOS in the dentate gyrus. The current study indicates that the memory impairment induced by a lighting manipulation is likely not due to attenuated neuronal activation. Determining how the master clock in the brain communicates with the hippocampus is needed to untangle the relationship between circadian rhythms and memory.

Repetitive subconcussive head impact exposure has been associated with clinical and MRI changes in some non-concussed contact sport athletes over the course of a season. However, analysis of human tolerance for repeated head impacts is complicated by concussion and head impact exposure history, genetics, and other personal factors. Therefore, the objective of the current study was to develop a rodent model for repetitive subconcussive head impact exposure that can be used to understand injury mechanisms and tolerance in the human. This study incorporated the Medical College of Wisconsin Rotational Injury Model to expose rats to multiple low-level head accelerations per day over a 4-week period. The peak magnitude of head accelerations were scaled from our prior human studies of contact sport athletes and the number of exposures per day were based on the median (moderate exposure) and 95th percentile (high exposure) number of exposures per day across the human sample. Following the exposure protocol, rats were assessed for cognitive deficits, emotional changes, blood serum levels of axonal injury biomarkers, and histopathological evidence of injury. High exposure rats demonstrated cognitive deficits and evidence of anxiety-like behaviors relative to shams. Moderate exposure rats did not demonstrate either of those behaviors. Similarly, high exposure rats had histopathological evidence of gliosis [i.e., elevated Iba1 intensity and glial fibrillary acidic protein (GFAP) volume relative to shams] in the basolateral amygdala and other areas. Blood serum levels of neurofilament light (NFL) demonstrated a dose response relationship with increasing numbers of low-level head acceleration exposures with a higher week-to-week rate of NFL increase for the high exposure group compared to the moderate exposure group. These findings demonstrate a cumulative effect of repeated low-level head accelerations and provide a model that can be used in future studies to better understand mechanisms and tolerance for brain injury resulting from repeated low-level head accelerations, with scalable biomechanics between the rat and human. [ABSTRACT FROM AUTHOR]

Repetitive subconcussive head impact exposure has been associated with clinical and MRI changes in some non-concussed contact sport athletes over the course of a season. However, analysis of human tolerance for repeated head impacts is complicated by concussion and head impact exposure history, genetics, and other personal factors. Therefore, the objective of the current study was to develop a rodent model for repetitive subconcussive head impact exposure that can be used to understand injury mechanisms and tolerance in the human. This study incorporated the Medical College of Wisconsin Rotational Injury Model to expose rats to multiple low-level head accelerations per day over a 4-week period. The peak magnitude of head accelerations were scaled from our prior human studies of contact sport athletes and the number of exposures per day were based on the median (moderate exposure) and 95th percentile (high exposure) number of exposures per day across the human sample. Following the exposure protocol, rats were assessed for cognitive deficits, emotional changes, blood serum levels of axonal injury biomarkers, and histopathological evidence of injury. High exposure rats demonstrated cognitive deficits and evidence of anxiety-like behaviors relative to shams. Moderate exposure rats did not demonstrate either of those behaviors. Similarly, high exposure rats had histopathological evidence of gliosis [i.e., elevated Iba1 intensity and glial fibrillary acidic protein (GFAP) volume relative to shams] in the basolateral amygdala and other areas. Blood serum levels of neurofilament light (NFL) demonstrated a dose response relationship with increasing numbers of low-level head acceleration exposures with a higher week-to-week rate of NFL increase for the high exposure group compared to the moderate exposure group. These findings demonstrate a cumulative effect of repeated low-level head accelerations and provide a model that can be used in future studies to better understand mechanisms and tolerance for brain injury resulting from repeated low-level head accelerations, with scalable biomechanics between the rat and human.

The present study was aimed at evaluating cognitive changes following neonatal methamphetamine exposure in combination with repeated treatment in adulthood of female Wistar rats. Pregnant dams and their pups were used in this study. One half of the offspring were treated indirectly via the breast milk of injected mothers, and the other half of pups were treated directly by methamphetamine injection. In the group with indirect exposure, mothers received methamphetamine (5 mg/ml/kg) or saline (1 ml/kg) between postnatal days (PD) 1–11. In the group with direct exposure, none of the mothers were treated. Instead, progeny were either: (1) treated with injected methamphetamine (5 mg/ml/kg); or (2) served as controls and received sham injections (no saline, just a needle stick) on PD 1–11. Learning ability and memory consolidation were tested on PD 70–90 in the Morris Water Maze (MWM) using three tests: Place Navigation Test, Probe Test, and Memory Recall Test. Adult female progeny were injected daily, after completion of the last trial of MWM tests, with saline or methamphetamine (1 mg/ml/kg). The effects of indirect/direct neonatal methamphetamine exposure combined with acute adult methamphetamine treatment on cognitive functions in female rats were compared. Statistical analyses showed that neonatal drug exposure worsened spatial learning and the ability to remember the position of a hidden platform. The study also demonstrated that direct methamphetamine exposure has a more significant impact on learning and memory than indirect exposure. The acute dose of the drug did not produce any changes in cognitive ability. Analyses of search strategies (thigmotaxis, scanning) used by females during the Place Navigation Test and Memory Recall Test confirmed all these results. Results from the present study suggested extensive deficits in learning skills and memory of female rats that may be linked to the negative impact of neonatal methamphetamine exposure.

The present study was aimed at evaluating cognitive changes following neonatal methamphetamine exposure in combination with repeated treatment in adulthood of female Wistar rats. Pregnant dams and their pups were used in this study. One half of the offspring were treated indirectly via the breast milk of injected mothers, and the other half of pups were treated directly by methamphetamine injection. In the group with indirect exposure, mothers received methamphetamine (5 mg/ml/kg) or saline (1 ml/kg) between postnatal days (PD) 1–11. In the group with direct exposure, none of the mothers were treated. Instead, progeny were either: (1) treated with injected methamphetamine (5 mg/ml/kg); or (2) served as controls and received sham injections (no saline, just a needle stick) on PD 1–11. Learning ability and memory consolidation were tested on PD 70–90 in the Morris Water Maze (MWM) using three tests: Place Navigation Test, Probe Test, and Memory Recall Test. Adult female progeny were injected daily, after completion of the last trial of MWM tests, with saline or methamphetamine (1 mg/ml/kg). The effects of indirect/direct neonatal methamphetamine exposure combined with acute adult methamphetamine treatment on cognitive functions in female rats were compared. Statistical analyses showed that neonatal drug exposure worsened spatial learning and the ability to remember the position of a hidden platform. The study also demonstrated that direct methamphetamine exposure has a more significant impact on learning and memory than indirect exposure. The acute dose of the drug did not produce any changes in cognitive ability. Analyses of search strategies (thigmotaxis, scanning) used by females during the Place Navigation Test and Memory Recall Test confirmed all these results. Results from the present study suggested extensive deficits in learning skills and memory of female rats that may be linked to the negative impact of neonatal methamphetamine exposure. [ABSTRACT FROM AUTHOR]

The supramammillary area (SUM) of the hypothalamus has wide spread connection with numerous brain structures. It is known that the SUM can control the frequency of the hippocampal theta rhythm, which plays a role in the cognitive functions of the hippocampal formation. In order to examine the role of the specific cells of the SUM in learning and memory, selective cholinergic neurotoxic or excitotoxic lesioned rats of the SUM were tested for spatial memory on the Morris water maze (MWM) test. After the behavior tests, the expression of acetylcholinesterase (AChE) in the hippocampus was studied using the immunohistochemistry. In the MWM test, both lesion of the SUM with 192 IgG-saporin or ibotenic acid produced the impairment of spatial learning and memory. The expression of AChE immunreactive neurons in the hippocampal CA3 region was decreased after injections of 192 IgG-saporin into the SUM. These findings suggest that cholinoceptive cells of the SUM area may play a critical role in the process of learning and memory.

Nigella sativa, a plant widely used in traditional medicine, possesses anti-inflammatory, antioxidant and neuroprotective properties. In the present study, we investigated the effect of hydroalcoholic extract of N. sativa seeds (NSE) and its active constituent, thymoquinone (TQ), on learning and memory deficits, hippocampal acetylcholine esterase (AChE) activity, and markers of redox status, mainly lipid peroxidation and superoxide dismutase (SOD) activity following cerebral hypoperfusion in rats. Cerebral hypoperfusion was induced by permanent occlusion of bilateral common carotid arteries (2VO). Male Wistar rats were administered either a vehicle (sham group: 10 ml/kg/day, ip), NSE (100, 200, and 400 mg/kg/day, ip), TQ (10, 20, and 40 mg/kg/day, ip), or donepezil (5 mg/kg/day, ip) for 10 days (three days before and seven days after ligation). Spatial learning and memory deficits were investigated using the Morris water maze (MWM) task. 2VO produced significant learning and memory deficits as evidenced by increased latency time to reach the hidden platform, increased swimming time, and decreased time spent in the target quadrant in the probe trial in the MWM task. There was also a significant increase in the lipid peroxidation level and AChE activity, and a significant decrease in SOD activity in the hippocampal portion of hypoperfused rats, as compared with the sham group. Treatment with NSE (400 mg/kg/day; p < 0.001) and TQ (40 mg/kg/day; p < 0.001), as well as donepezil significantly prevented learning and memory impairments and alleviated changes in the hippocampal lipid peroxide level and SOD and AChE activities in this model. In conclusion, our data suggest that N. sativa and thymoquinone have a beneficial role in cerebrovascular insufficiency states and dementia. [ABSTRACT FROM AUTHOR]

The use of opioid analgesics to treat non-cancer pain has increased over the years. Many chronic pain patients suffer from numerous adverse effects, such as reduced quality of life, development of dependence, and cognitive impairments. Cognitive processes are regulated by several systems, one of which involves growth hormone (GH) and its secondary mediator insulin-like growth factor-1 (IGF-1), but also glutamatergic transmission, including receptors such as the N -methyl- d -aspartate (NMDA)-receptor complex. In the laboratory, repeated injections are commonly used to establish animal models of long-term or chronic drug exposure. However, in the present study, we aimed to mimic a more human dose regimen using constant drug delivery provided by mini-osmotic pumps implanted subcutaneously in male Sprague Dawley rats. After developing opioid tolerance the cognitive function of rats was studied. Spatial learning and memory capabilities were evaluated using the rat Morris water maze (MWM). Moreover, gene expression related to the GH/IGF-1-axis and the NMDA-receptor system was analyzed using quantitative PCR (qPCR) and plasma levels of IGF-1 were assessed using the ELISA technique. Our results demonstrate that rats exposed to morphine for 27 days display memory impairments in the MWM probe trial. However, the behavioral effects of chronic morphine treatment were not accompanied by any significant differences in terms of mRNA expression or IGF-1 plasma concentration. The animal model used in this study provides a simple and suitable way to investigate the behavioral and neurochemical effects of chronic opioid treatment similar to the exposure seen in human pain patients. [ABSTRACT FROM AUTHOR]

Background: Opioids have been shown to affect learning and memory processes. Different protocols of morphine withdrawal can substantially vary in their success to prevent opioid induced impairments of cognitive performance. In the present study, we report the effects of single and repetitive ultra-rapid detoxification (URD) on spatial learning and memory in morphine addicted rats. Methods: Morphine (10 mg/kg) was intraperitoneally (IP) injected in male rats once a day over one week and after which they were detoxified with naloxone administration under anesthesia. For the repetitive procedure, a second one week morphine treatment with a second subsequent detoxification was performed. Control groups received an equivalent volume of saline injections. Spatial learning and memory was evaluated using the Morris water maze (MWM) task. Findings: Both protocols of morphine administration resulted in a severe spatial memory impairment that could be significantly prevented by both single and repetitive URD. However, memory abilities in animals treated with repetitive URD were still significantly lower than in animals of the corresponding control group. Alterations in motor activity or sensory-motor coordination between morphine treated and control animals could be ruled out by comparing swimming speed and visible platform performances that were not different between groups. Thus, URD and, specifically single URD, can prevent the spatial memory impairments in addicted rats. Conclusion: As opioid addiction is an extending and serious concern in many societies, these findings may have clinical values and therapeutic implications for patients who experience multiple opioid relapses.

The aim of this review is to discuss the research presented in a symposium entitled “Current progress in characterizing therapeutic strategies and challenges in experimental CNS injury” which was presented at the 2016 International Behavioral Neuroscience Society annual meeting. Herein we discuss diffuse and focal traumatic brain injury (TBI) and ensuing chronic behavioral deficits as well as potential rehabilitative approaches. We also discuss the effects of stress on executive function after TBI as well as the response of the endocrine system and regulatory feedback mechanisms. The role of the endocannabinoids after CNS injury is also discussed. Finally, we conclude with a discussion of antipsychotic and antiepileptic drugs, which are provided to control TBI-induced agitation and seizures, respectively. The review consists predominantly of published data. [ABSTRACT FROM AUTHOR]

The supramammillary area (SUM) of the hypothalamus has wide spread connection with numerous brain structures. It is known that the SUM can control the frequency of the hippocampal theta rhythm, which plays a role in the cognitive functions of the hippocampal formation. In order to examine the role of the specific cells of the SUM in learning and memory, selective cholinergic neurotoxic or excitotoxic lesioned rats of the SUM were tested for spatial memory on the Morris water maze (MWM) test. After the behavior tests, the expression of acetylcholinesterase (AChE) in the hippocampus was studied using the immunohistochemistry. In the MWM test, both lesion of the SUM with 192 IgG-saporin or ibotenic acid produced the impairment of spatial learning and memory. The expression of AChE immunreactive neurons in the hippocampal CA3 region was decreased after injections of 192 IgG-saporin into the SUM. These findings suggest that cholinoceptive cells of the SUM area may play a critical role in the process of learning and memory. [ABSTRACT FROM AUTHOR]

Background: Cognitive performance is a complex process influenced by multiple factors. Cognitive assessment in experimental animals is often based on longitudinal datasets analyzed using uni- and multivariate analyses that do not account for the temporal dimension of cognitive performance and also do not adequately quantify the relative contribution of individual factors onto the overall behavioral outcome. To circumvent these limitations, we applied an Autoregressive Latent Trajectory (ALT) to analyze the Morris water maze (MWM) test in a complex experimental design involving four factors: stress, age, sex, and genotype. Outcomes were compared with a traditional Mixed-Design Factorial ANOVA (MDF ANOVA).Results: In both the MDF ANOVA and ALT models, sex and stress had a significant effect on learning throughout the nine days. However, on the ALT approach, the effects of sex were restricted to the learning growth. Unlike the MDF ANOVA, the ALT model revealed the influence of single factors at each specific learning stage and quantified the cross interactions among them. In addition, ALT allows us to consider the influence of baseline performance, a critical and unsolved problem that frequently yields inaccurate interpretations in the classical ANOVA model. Discussion: Our findings suggest the beneficial use of ALT models in the analysis of complex longitudinal datasets offering a better biological interpretation of the interrelationship of the factors that may influence cognitive performance.

The anorectic neuropeptide nesfatin-1 has recently been characterized as a potential mood regulator, but the accurate effect of nesfatin-1 on anxiety and learning and memory behavior and the possible mechanisms remains unknown. In the present study, to test the hypothesis that nesfatin-1 might affect the anxiety-like and learning and memory behaviors in rats via ERK/CREB/BDNF pathway, nesfatin-1 was administered intraperitoneally to rats with the doses (10, 20, 40 μg/kg), and the behavioral performance was tested using the open field task, the Morris water maze (MWM), and the Y maze. Moreover, the protein expression of brain-derived neurotrophic factor (BDNF), total and phosphorylated-ERK in the hippocampus and the prefrontal cortex (PFC) were evaluated. The results showed that chronic administration of nesfatin-1 could decrease the moving distance, the duration in the center, and the frequencies of rearing and grooming in the open field task, decrease the moving distance, frequency, and the preference index of new arm in the Y maze, although there was no significant difference of the performance in the MWM task among groups. Furthermore, 3 weeks’ consecutive administration of nesfatin-1 resulted in the decrease of protein expression of BDNF and phosphorylated-ERK in the hippocampus and the PFC. These results provided evidence that exogenous nesfatin-1 could decrease exploration and induce anxiety-like behavior in rats, the mechanism of which might be related to the reduced protein expression of BDNF and phosphorylated-ERK in the hippocampus and the PFC. [ABSTRACT FROM AUTHOR]

Highlights: [•] MEM treatment increased endogenous NGF level in APP/PS1 mice. [•] NGF/TrkA signaling is activated after MEM treatment, accompanied with the inhibition of p75NTR signaling. [•] Our research revealed a new NGF-related mechanism of MEM for improving cognitive deficits and amyloidosis. [•] The new mechanism suggests that NGF signaling is a potential target of MEM treatment for AD therapy. [Copyright &y& Elsevier]

Highlights: [•] Surgery induces cognitive impairment in aged rats. [•] Surgical trauma activates the renin–angiotensin system (RAS) in aged rat hippocampus. [•] Prophylactic RAS inhibition by candesartan mitigates postoperative cognitive decline. [•] Candesartan improves BBB function and promotes resolution of neuroinflammation. [•] Candesartan may have a therapeutic value for cognitive function in aged brain. [Copyright &y& Elsevier]

Abstract: Patients received cranial-irradiation can be affected with cognitive deficits and decreasing hippocampal neurogenesis. In this work, we characterized the cognitive ability and immune-induced neurogenesis of the pre- and post-treated cranial-irradiated rats with Glatiramer acetate (GA), known as a weak CNS auto-antigen. The GA-treated rats displayed better cognitive abilities in Morris water maze (MWM). The numbers of Iba-I-positive microglia, BrdU+/DCX+ cells and BrdU+/NeuN+ cells in hippocampus increased, which are accompanied with increased IFN-γ and decreased IL-6, IL-4. Furthermore, GA reverted the Th1/Th2 balance. GA treatment can reverse the cognitive deficits caused by cranial irradiation through a mechanism that likely involves immunomodulation. [Copyright &y& Elsevier]

Highlights: [•] We investigated early intervention effects of gastrodin on CUS rats’ behaviour. [•] It reduced depressive-like behaviour and promoted hippocampal and stem cell proliferation. [•] It also inhibited NF-κB protein expression and IL-1β level in the hippocampus. [•] Moreover, it protected the viability of NSCs from IL-1β-induced damage. [•] The findings support gastrodin as a newly antidepressant. [ABSTRACT FROM AUTHOR]

Highlights: [•] CEF reduces the mortality rate and improves the neurological scores after SAH. [•] Neuroprotection of CEF is possibly mediated by increasing EAAT2 expression. [•] CEF modulates EAAT2 expression via PI3K/Akt/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Highlights: [•] 6-OHDA resulted in the impaired long-term memory in PD rats. [•] Simvastatin ameliorated the impaired long-term memory in PD rats. [•] 6-OHDA decreased M1/4 receptor binding in Hip, Me, PMCo, and Pir of PD rat brains. [•] Simvastatin reversed M1/4 receptor binding in the examined brain regions. [•] The altered M1/4 receptor binding was related to the long-term memory in PD rats. [ABSTRACT FROM AUTHOR]

Highlights: [•] Rutin attenuates cognitive impairments in AD transgenic mice. [•] Rutin decreases Aβ oligomer levels in the brains of AD transgenic mice. [•] Rutin reduces oxidative stress, gliosis, and cytokine production in AD mice. [•] Rutin exerts neuro-protective effect on AD transgenic mice. [ABSTRACT FROM AUTHOR]

Highlights: [•] Hippocampal autophagic deficits contribute to age-related cognitive disorder in mice. [•] CR activated hippocampal autophagy and ameliorated age-related cognition deficits. [•] The activity of mTOR and its upstream signaling in hippocampus declines with aging. [ABSTRACT FROM AUTHOR]

Highlights: [•] Can animal models be used for studying affective and cognitive comorbidities of pain? [•] How does pain interact with its comorbidities in the animals? [•] What are the underlying mechanisms of pain comorbidities in the animals? [Copyright &y& Elsevier]

Objectives: Cognitive deficit is considered to be a characteristic feature of schizophrenia disorder. A similar cognitive dysfunction was demonstrated in animal models of schizophrenia. However, the poor comparability of methods used to assess cognition in animals and humans could be responsible for low predictive validity of current animal models. In order to assess spatial abilities in schizophrenia and compare our results with the data obtained in animal models, we designed a virtual analog of the Morris water maze (MWM), the virtual Four Goals Navigation (vFGN) task. Methods: Twenty-nine patients after the first psychotic episode with schizophrenia symptoms and a matched group of healthy volunteers performed the vFGN task. They were required to find and remember four hidden goal positions in an enclosed virtual arena. The task consisted of two parts. The Reference memory (RM) session with a stable goal position was designed to test spatial learning. The Delayed-matching-to-place (DMP) session presented a modified working memory protocol designed to test the ability to remember a sequence of three hidden goal positions. Results: Data obtained in the RM session show impaired spatial learning in schizophrenia patients compared to the healthy controls in pointing and navigation accuracy. The DMP session showed impaired spatial memory in schizophrenia during the recall of spatial sequence and a similar deficit in spatial bias in the probe trials. The pointing accuracy and the quadrant preference showed higher sensitivity toward the cognitive deficit than the navigation accuracy. Direct navigation to the goal was affected by sex and age of the tested subjects. The age affected spatial performance only in healthy controls. Conclusions: Despite some limitations of the study, our results correspond well with the previous studies in animal models of schizophrenia and support the decline of spatial cognition in schizophrenia, indicating the usefulness of the vFGN task in comparative research. [ABSTRACT FROM AUTHOR]

Highlights: [•] IL-10 mediated the neuroprotection of HBO in TBI. [•] HBO suppressed neuroinflammation after TBI via an IL-10-dependent mechanism. [•] HBO inhibited apoptosis after TBI via an IL-10-dependent mechanism. [•] HBO restored BBB permeability after TBI via an IL-10-dependent mechanism. [Copyright &y& Elsevier]

Abstract: Introduction: Early life or prenatal stress induces many lifelong, mostly cognitive, homeostatic alterations in the behavior of the offspring. Purpose: We investigated the effect of heterogeneous sequential stress (HSS) at three separate periods, before and during the first and second half of pregnancies on spatial learning and memory retrieval of adult male offspring. Method: HSS is composed of several stressors, each in a day, during nine consecutive days including; restraint, swimming, isolation, and water and food deprivation on Wistar rats. The offspring were studied in a Morris water maze (MWM) apparatus to explore the latency, distance, proximity and target to opposite area as measures of learning and memory. Serum corticosterone was measured as a criterion of stress application. Results: HSS increased blood corticosterone in dams of PS2 (Pregnancy Stress second half), and also in adult male offspring from BPS (Before Pregnancy Stress) and PS1 (Pregnancy Stress first half) groups. The weight of the offspring decreased in the PS1 and PS2 groups. While distance traveled and latency to locate the hidden platform were increased in BPS and PS1 acquisition trials, swimming speed was unchanged during the acquisition and retrieval tests. Moreover, time to platform location was increased in BPS and PS1 during retention tests. While control rats spent more time in the target quadrant, stressed animals spent a longer duration in the opposite quadrant. Furthermore, proximity measure was increased in all stress treated rats. Conclusion: It is concluded that prenatal stress, around the beginning of the pregnancy, increases corticosterone in adult male offspring, which might be the basis for spatial learning and memory retrieval deficits in this study. [Copyright &y& Elsevier]

Abstract: Myelination failure is associated with perinatal cerebral hypoxia-ischemia (PHI) induced brain injury in premature infants. How to efficiently promote remyelination is crucial for improving cognitive deficits caused by brain injury. Here, we demonstrated that quercetin (Que), a kind of flavonoids, significantly improved cognitive deficits and the behavior of PHI-rat in Morris water maze and open field tasks. After administration of Que to PHI-rat, the number of neogenetic Olig2+ oligodendrocyte progenitor cells (OPCs) was evidently increased in the subventricular zone. Additionally, in corpus callosum (CC), the expression of MBP (myelin basic protein) was increased, and the myelin sheaths reached normal level at 30 days with more compact while less damaged myelin sheaths and more mature oligodendrocytes (OLs) repopulating the CC compared with PHI groups. In a word, our findings indicated that Que could remarkably improve both cognition performance and myelination in the context of PHI-induced brain injury by promoting the proliferation of OPCs and strengthening survival of OLs in vivo. [Copyright &y& Elsevier]

Abstract: Tropisetron was identified in a screen for candidates that increase the ratio of the trophic, neurite-extending peptide sAPPα to the anti-trophic, neurite-retractive peptide Aβ, thus reversing this imbalance in Alzheimer's disease (AD). We describe here a hierarchical screening approach to identify such drug candidates, moving from cell lines to primary mouse hippocampal neuronal cultures to in vivo studies. By screening a clinical compound library in the primary assay using CHO-7W cells stably transfected with human APPwt, we identified tropisetron as a candidate that consistently increased sAPPα. Secondary assay testing in neuronal cultures from J20 (PDAPP, huAPPSwe/Ind) mice showed that tropisetron consistently increased the sAPPα/Aβ 1-42 ratio. In in vivo studies in J20 mice, tropisetron improved the sAPPα/Aβ ratio along with spatial and working memory in mice, and was effective both during the symptomatic, pre-plaque phase (5–6 months) and in the late plaque phase (14 months). This ameliorative effect occurred at a dose of 0.5mg/kg/d (mkd), translating to a human-equivalent dose of 5mg/day, the current dose for treatment of postoperative nausea and vomiting (PONV). Although tropisetron is a 5-HT3 receptor antagonist and an α7nAChR partial agonist, we found that it also binds to the ectodomain of APP. Direct comparison of tropisetron to the current AD therapeutics memantine (Namenda) and donepezil (Aricept), using similar doses for each, revealed that tropisetron induced greater improvements in memory and the sAPPα/Aβ1-42 ratio. The improvements observed with tropisetron in the J20 AD mouse model, and its known safety profile, suggest that it may be suitable for transition to human trials as a candidate therapeutic for mild cognitive impairment (MCI) and AD, and therefore it has been approved for testing in clinical trials beginning in 2014. [Copyright &y& Elsevier]

Abstract: Depression is one of the most common neuropsychiatric disorders and has been associated with impaired cognition, as well as causing neuroendocrine systems and brain proteins alterations. Resveratrol is a natural polyphenol enriched in polygonum cuspidatum and has diverse biological activities, including potent antidepressant-like effects. The aim of this study was to determine whether resveratrol administration influences chronic unpredictable mild stress (CUMS)-induced cognitive deficits and explores underlying mechanisms. The results showed that CUMS (5weeks) was effective in producing cognitive deficits in rats as indicated by Morris water maze and novel object recognition task. Additionally, CUMS exposure significantly elevated serum corticosterone levels and decreased BDNF levels in the prefrontal cortex (PFC) and hippocampus, accompanied by decreased phosphorylation of extracellular signal-regulated kinase (pERK) and cAMP response element-binding protein (pCREB). Chronic administration of resveratrol (80mg/kg, i.p., 5weeks) significantly prevented all these CUMS-induced behavioral and biochemical alterations. In conclusion, our study shows that resveratrol may be an effective therapeutic agent for cognitive disturbances as was seen within the stress model and its neuroprotective effect was mediated in part by normalizing serum corticosterone levels, up-regulating of the BDNF, pCREB and pERK levels. [Copyright &y& Elsevier]

Highlights: [•] 3-Nitropropionic acid (3-NPA) has induced dementia and Huntington's disease (HD). [•] 3-NPA has impaired brain AChE, MDA, SOD, CAT, mitochondrial enzymes. [•] Modulation of I1 receptor and NF-κB has attenuated 3-NPA induced dementia & HD. [•] I1 receptor and NF-κB modulator have attenuated 3-NPA induced biochemical changes. [•] I1 receptor and NF-κB modulator may be explored further for benefits in HD. [Copyright &y& Elsevier]

Highlights: [•] The medial prefrontal cortex is required for spatial memory extinction. [•] The amygdala complex was activated after spatial memory extinction. [•] The lateral mammillary nucleus is involved in spatial memory extinction. [ABSTRACT FROM AUTHOR]

Abstract: Aberrant CDK5 activity is implicated in a number of neurodegenerative disorders. Isoflurane exposure leads to neuronal apoptosis, and subsequent learning and memory defects in the developing brain. The present study was designed to examine whether and how CDK5 activity plays a role in developmental isoflurane neurotoxicity. Rat pups and hippocampal neuronal cultures were exposed to 1.5% isoflurane for 4 h. The protein and mRNA levels of CDK5, p35 and p25 were detected by western blot and QReal-Time PCR. CDK5 activity was evaluated in vitro using Histone H1 as a substrate. Roscovitine (an inhibitor of CDK5) was applied before isoflurane treatment, cleaved Caspase-3, Bcl-2, Bax, MEF2 and phospho-MEF2A-Ser-408 expressions were determined. Dominant-Negative CDK5 was transfected before isoflurane treatment. Neuronal apoptosis was evaluated by Flow cytometry (FCM) and TUNEL-staining. Cognitive functions were assessed by Morris water maze. We found that isoflurane treatment led to an aberrant CDK5 activation due to its activator p25 that was cleaved from p35 by calpain. Inhibition of CDK5 activity with Roscovitine enhanced Bcl-2, and decreased cleaved Caspase-3 and Bax expressions. In addition, isoflurane exposure resulted in a decrease of MEF2 and increase of phospho-MEF2A-Ser-408, which were rescued by Roscovitine or Dominant-Negative CDK5 transfection. Dominant-Negative CDK5 transfection also decreased the percentage of TUNEL-positive cells in isoflurane neurotoxicity. Moreover, Roscovitine remarkably alleviated the learning and memory deficits induced by postnatal isoflurane exposure. These results indicated that aberrant CDK5 activity-dependent MEF2 phosphorylation mediates developmental isoflurane neurotoxicity. Inhibition of CDK5 overactivation contributes to the relief of isoflurane neurotoxicity in the developing brain. [Copyright &y& Elsevier]

Abstract: Sub-acute brain ischemia is a risk factor for the development of vascular dementia (VaD). Sub-acute brain ischemia induced VaD, participates in a negative role in impaired cognition. Imidazoline receptors are widely expressed in the central nervous system. But the role of I1-imidazoline and α2-adrenoceptors in VaD are still unknown. The present study has been designed to investigate the role of selective I1-imidazoline receptor modulator; moxonidine as well as α2-adrenoceptor modulator; clonidine in sub-acute brain ischemia induced VaD in mice (n=8). Permanent bilateral common carotid arteries ligation (2VO) technique was used to induce sub-acute brain ischemia in mice. Assessment of spatial learning and memory was done by using Morris water maze. Brain damage was assessed as percent infarct, using TTC staining of brain coronal sections. Oxidative stress was assessed by estimating brain malondialdehyde (MDA), catalase (CAT), glutathione (GSH) and superoxide dismutase (SOD). Cholinergic status was assessed by brain acetylcholinesterase (AChE) activity. 2VO animals have shown significant reduction in learning and memory as well as brain CAT, GSH and SOD, with significant increase in brain infarct size, MDA and AChE activity. Whereas, administration of moxonidine and clonidine significantly attenuated 2VO induced learning and memory deficits, brain damage, brain oxidative stress and higher AChE activity. It may be concluded that 2VO induced sub-acute brain ischemia has elicited dementia, which was attenuated by moxonidine and clonidine. Thus, modulators of I1-imidazoline receptors may be explored further for their benefits in sub-acute brain ischemia induced vascular dementia. [Copyright &y& Elsevier]

Highlights: [•] Long-term potentiation was measured in hippocampal slices from two mouse strains. [•] The level of long-term potentiation is different in one strain than the other. [•] Social isolation stress reduces long-term potentiation expression in both strains. [•] Corticosterone levels increase after social stress isolation. [•] Long-term potentiation was restored by glucocorticoid receptor antagonist. [ABSTRACT FROM AUTHOR]

Highlights: [•] A novel extract of natural herbal, tripchlorolide has anti-dementia action. [•] Long-term T4 treatment prevents learning and memory loss in aged SAMP8 mice. [•] T4 ameliorates hippocampal LTP in aged SAMP8 mice. [•] T4 alleviates synaptic plasticity dysfunction of the hippocampus. [•] T4 intensified the signal pathway of CaMKII-CREB-BDNF in SAMP8 mice. [Copyright &y& Elsevier]

Background: Opioids have been shown to affect learning and memory processes. Different protocols of morphine withdrawal can substantially vary in their success to prevent opioid induced impairments of cognitive performance. In the present study, we report the effects of single and repetitive ultra-rapid detoxification (URD) on spatial learning and memory in morphine addicted rats. Methods: Morphine (10 mg/kg) was intraperitoneally (IP) injected in male rats once a day over one week and after which they were detoxified with naloxone administration under anesthesia. For the repetitive procedure, a second one week morphine treatment with a second subsequent detoxification was performed. Control groups received an equivalent volume of saline injections. Spatial learning and memory was evaluated using the Morris water maze (MWM) task. Findings: Both protocols of morphine administration resulted in a severe spatial memory impairment that could be significantly prevented by both single and repetitive URD. However, memory abilities in animals treated with repetitive URD were still significantly lower than in animals of the corresponding control group. Alterations in motor activity or sensory-motor coordination between morphine treated and control animals could be ruled out by comparing swimming speed and visible platform performances that were not different between groups. Thus, URD and, specifically single URD, can prevent the spatial memory impairments in addicted rats. Conclusion: As opioid addiction is an extending and serious concern in many societies, these findings may have clinical values and therapeutic implications for patients who experience multiple opioid relapses. [ABSTRACT FROM AUTHOR]

Molecular processes in GABAergic local circuit neurons critically contribute to information processing in the hippocampus and to stress-induced activation of the amygdala. In the current study, we determined expression changes in GABA-related factors induced in subregions of the dorsal hippocampus as well as in the BLA of rats 5 h after spatial learning in a Morris water maze (MWM), using laser microdissection and quantitative real-time PCR. Spatial learning resulted in highly selective pattern of changes in hippocampal subregions: gene expression levels of neuropeptide Y (NPY) were reduced in the hilus of the dentate gyrus (DG), whereas somatostatin (SST) was increased in the stratum oriens (SO) of CA3. The GABA-synthesizing enzymes GAD65 and GAD67 as well as the neuropeptide cholecystokinin (CCK) were reduced in SO of CA1. In the BLA, expression of GAD65 and GAD67 were reduced compared to a handled Control group. These expression patterns were further compared to alterations in a group of rats that have been exposed to the water maze but were not provided with an invisible escape platform. In this Water Exposure group, no expression changes were observed in any of the hippocampal subregions, but a differential regulation of all selected target genes was evident in the BLA. These findings suggest that expression changes of GABAergic factors in the hippocampus are associated with spatial learning, while additional stress effects modulate expression alterations in the BLA. Indeed, while in both experimental groups plasma corticosterone (CORT) levels were enhanced, only Water Exposure stress activated the basolateral amygdala (BLA), as indicated by increased levels of phosphorylated ERK 1/2. Altered GABAergic function in the BLA may thus contribute to memory consolidation in the hippocampus, in relation to levels of stress and emotionality associated with the experience. [ABSTRACT FROM AUTHOR]

Highlights: [•] Amyloid precursor protein transgenic mice show substantial memory dysfunction. [•] Neurons with cholinergic neuron phenotype were generated from hiPS cells. [•] After grafting, human cholinergic/GABAergic neurons were found in mouse hippocampus. [•] Spatial memory in PDAPP mice improved significantly after grafting. [ABSTRACT FROM AUTHOR]

Abstract: Alzheimer's disease (AD) is the most common form of dementia and remains a growing worldwide health problem. As life expectancy continues to increase, the number of AD patients presenting for surgery and anesthesia will steadily rise. The etiology of sporadic AD is thought to be multifactorial, with environmental, biological and genetic factors interacting together to influence AD pathogenesis. Recent reports suggest that general anesthetics may be such a factor and may contribute to the development and exacerbation of this neurodegenerative disorder. Intra-neuronal neurofibrillary tangles (NFT), composed of hyperphosphorylated and aggregated tau protein are one of the main neuropathological hallmarks of AD. Tau pathology is important in AD as it correlates very well with cognitive dysfunction. Lately, several studies have begun to elucidate the mechanisms by which anesthetic exposure might affect the phosphorylation, aggregation and function of this microtubule-associated protein. Here, we specifically review the literature detailing the impact of anesthetic administration on aberrant tau hyperphosphorylation as well as the subsequent development of neurofibrillary pathology and degeneration. [Copyright &y& Elsevier]

Abstract: Sevoflurane is a general anesthetic commonly used in the pediatric setting because it is sweet-smelling, nonflammable, fast acting and has a very short recovery time. Although recent clinical data suggest that early anesthesia exposure is associated with subsequent learning and memory problems, it is difficult to determine the exact scope of developmental neurotoxicity associated with exposure to specific anesthetics such as sevoflurane. This is largely due to inconsistencies in the literature. Thus, in the present studies we evaluated the effect of early life exposure to sevoflurane (1%, 2%, 3% or 4%) on adulthood memory impairment in Sprague-Dawley rats. Animals were exposed to different regimens of sevoflurane anesthesia on postnatal days (PNDs) 3, 7, or 14 or at 7 weeks (P7W) of age and spatial memory performance was assessed in adulthood using the Morris Water Maze (MWM). Rats exposed to sevoflurane exhibited significant memory impairment which was concentration and exposure duration dependent. Disruption of MWM performance was more severe in animals exposed on both PNDs 3 and 7 than in animals exposed on both PNDs 3 and 14. The younger the animal's age at the time of exposure, the more significant the effect on later MWM performance. Compared to the neonates, animals exposed at P7W were relatively insensitive to sevoflurane: memory was impaired in this group only after repeated exposures to low doses or single exposures to high doses. Early life exposure to sevoflurane can result in spatial memory impairments in adulthood and the shorter the interval between exposures, the greater the deficit. [Copyright &y& Elsevier]

Abstract: Elderly patients may experience impairments in cognition or mood following surgery. To study the development and underlying mechanisms of these postoperative behavioral changes, young (3months) and aged (18–20months) male rats were subjected to abdominal surgery followed by behavioral testing during a period of 6weeks. Microglia activation (IBA-1) and neurogenesis (DCX) were immunohistochemically determined. In separate experiments, the effects of anesthesia and the cytokine response (IL-6) following surgery were evaluated. Increased age was associated with changes in affective behavior, decreased cognitive flexibility and increased microglia activation as well as increased weight loss and plasma IL-6 following surgery. No effects of surgery on cognition were observed at either age. However, aged rats displayed long-term changes in affective behavior and had increased microgliosis in the CA1 hippocampal region following surgery. Microglia activation following surgery was positively correlated to parameters of behavior and spatial learning. These findings support the hypothesis that elderly patients have an increased behavioral and (neuro)inflammatory response to surgery and these factors may be related. [Copyright &y& Elsevier]

Highlight: [•] Study focuses on sex-specific effects of prenatal ethanol exposure. [•] MWM test and electrophysiological recording were performed. [•] A new index to measure the impairment of synaptic plasticity balance was developed. [•] Ethanol has sexually dimorphism on spatial cognition and synaptic plasticity balance. [•] Imbalance synaptic plasticity could be an underlying mechanism of cognitive deficits. [ABSTRACT FROM AUTHOR]

Abstract: The maternal diet provides critical nutrients that can influence fetal and infant brain development and function. This review highlights the potential benefits of maternal dietary ganglioside supplementation on fetal and infant brain development. English-language systematic reviews, preclinical studies, and clinical studies were obtained through searches on PubMed. Reports were selected if they included benefits and harms of maternal ganglioside supplementation during pregnancy or ganglioside-supplemented formula after pregnancy. The potential benefits of ganglioside supplementation were explored by investigating the following: (1) their role in neural development, (2) their therapeutic use in neural injury and disease, (3) their presence in human breast milk, and (4) their use as a dietary supplement during or after pregnancy. Preclinical studies indicate that ganglioside supplementation at high doses (1% of total dietary intake) can significantly increase cognitive development and body weight when given prenatally. However, lower ganglioside supplementation doses have no beneficial cognitive effects, even when given throughout pregnancy and lactation. In human clinical trials, infants given formula supplemented with gangliosides showed increased cognitive development and an increase in ganglioside content. Ganglioside supplementation may promote brain development and function in offspring when administered at the optimum dosage. We propose that prenatal maternal dietary supplementation with gangliosides throughout pregnancy may promote greater long-term effects on brain development and function. Before this concept can be encouraged in preconception clinics, future research and clinical trials are needed to confirm the ability of dietary gangliosides to improve cognitive development, but available results already encourage this area of research. [Copyright &y& Elsevier]

Abstract: Scope: To evaluate curcumin loaded solid lipid nanoparticles (C-SLNs) in the experimental paradigm of cerebral ischemia (BCCAO model) in rats. Methods and results: Oral administration of free curcumin and C-SLNs (25 and 50mg/kg) was started 5days prior and continued for 3days after BCCAO. Alleviation in behavioral, oxidative and nitrosative stress, acetylcholinesterase, mitochondrial enzyme complexes, and physiological parameters were assessed. Confirmation of effective brain delivery of C-SLNs (p.o) was done using biodistribution studies in mice and confocal microscopy of rat brain section. There was an improvement of 90% in cognition and 52% inhibition of acetylcholinesterase versus cerebral ischemic group (I/R). Neurological scoring improved by 79%. Levels of superoxide dismutase, catalase, glutathione, and mitochondrial complex enzyme activities were significantly increased, while lipid peroxidation, nitrite, and acetylcholinesterase levels decreased (p <0.05) after C-SLNs administration. It is noteworthy to report the restoration of SOD, GSH, catalase, and mitochondrial complex enzyme levels equivalent to sham control values. Gamma-scintigraphic studies show 16.4 and 30 times improvement in brain bioavailability (AUC) upon oral and i.v administration of C-SLNs versus solubilized curcumin (C-S). Conclusions: Study indicates protective role of curcumin against cerebral ischemic insult; provided it is packaged suitably for improved brain delivery. [Copyright &y& Elsevier]

Abstract: Hippocampus functions, including spatial cognition and stress responses, mature during adolescence. In addition, hippocampus neuronal structures are modified by circulating sex steroids, which dramatically increase during adolescence. Therefore, the effects of castration and the circulating levels of the main sex steroid testosterone on spatial learning and memory were examined across postnatal ages to test whether pre-pubertal castration affected rats' spatial ability in the Morris Water maze (MWM). Male rats were either castrated or sham-castrated at 22d (days of age), or left gonadally intact. They were then trained and tested in the MWM beginning at 28d, 35d, 45d or 60d. We found that all of the intact rats learned the spatial task; however, the males at 22d and 28d required more trials to acquire the task than the males at older ages. The males castrated at 22d and tested at 35d had significantly lower escape latency and traveled distance during training than the sham-castrated males trained at the same age. No differences were observed in mean values of escape latency and traveled distance at 45d even though they had comparable levels of testosterone. We conclude that adult-typical performance for male spatial memory emerges during mid-adolescence and that pre-pubertal castration appears to improve spatial learning during this time. [Copyright &y& Elsevier]