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It is to investigate the effects of β-asarone on learning and memory, hippocampal morphology, synaptophysin (SYP) and postsynaptic density 95(PSD95) protein expression, N-methyl-D-aspartic acid receptor 2B (NR2B)- Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) - Extracellular signal-regulated kinase (ERK) / Cyclic-AMP response element binding protein (CREB) signal in hippocampus of rats with exhaustive exercise-induced fatigue. Fifty Sprague-Dawley male rats were randomly divided into five groups: normal group, exercise group, exercise and β-asarone (2.5, 10, 40 mg/kg)–treated groups. The learning and memory in rats were tested by Morris water maze experiment. We measured the hippocampal morphology by Nissl staining. The levels of SYP, PSD95, NR2B, CaMKII, ERK1/2, CREB, p-NR2B, p-CaMKII, p-ERK1/2 and p-CREB expression were measured by western blot analysis. The results demonstrated that β-asarone (10, 40 mg/kg) treatment significantly decreased the latency to find the platform, increased the time spent in the target quadrant and the number of crossing the platform of rats with exhaustive exercise-induced fatigue. β-asarone (10, 40 mg/kg) treatment increased the cell density in the hippocampus CA1 region, significantly up-regulated NR2B-CaMKII-ERK/CREB signal and improved the protein expression levels of SYP and PSD95 in hippocampus of rats with exhaustive exercise-induced fatigue. It suggests that β-asarone could improve learning and memory of rats with exhaustive exercise-induced fatigue. The mechanism might be related to β-asarone protecting the morphology of hippocampus, increasing the protein expression levels of SYP and PSD95 and up-regulating NR2B-CaMKII-ERK/CREB signal in hippocampus of rats with exhaustive exercise-induced fatigue. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders have a pathophysiology that heavily involves neuroinflammation. In this study, we used lipopolysaccharide (LPS) to create a model of cognitive impairment by inducing systemic and neuroinflammation in experimental animals. LPS was injected intraperitoneally at a dose of 0.5 mg/kg during the last seven days of the study. Adalimumab (ADA), a TNF-α inhibitor, was injected at a dose of 10 mg/kg a total of 3 times throughout the study. On the last two days of the experiment, 50 mg/kg of curcumin was administered orally as a positive control group. Open field (OF) and elevated plus maze tests (EPM) were used to measure anxiety-like behaviors. The tail suspension test (TST) was used to measure depression-like behaviors, while the novel object recognition test (NOR) was used to measure learning and memory activities. Blood and hippocampal TNF α and nitric oxide (NO) levels, hippocampal BDNF, CREB, and ACh levels, and AChE activity were measured by ELISA. LPS increased anxiety and depression-like behaviors while decreasing the activity of the learning-memory system. LPS exerted this effect by causing systemic and neuroinflammation, cholinergic dysfunction, and impaired BDNF release. ADA controlled LPS-induced behavioral changes and improved biochemical markers. ADA prevented cognitive impairment induced by LPS by inhibiting inflammation and regulating the release of BDNF and the cholinergic pathway. • LPS caused anxiety and depression in mice and impaired learning. • LPS induced neuroinflammation and disrupted BDNF and cholinergic pathways. • ADA ameliorated LPS-induced behavioral changes. • ADA prevented inflammation and regulated BDNF release and the cholinergic pathway. [ABSTRACT FROM AUTHOR]

Polygala tenuifolia Wild is an ancient traditional Chinese medicine. Its main component, tenuifolin (TEN), has been proven to improve cognitive impairment caused by neurodegenerative diseases and ovariectomy. However, there was hardly any pharmacological research about TEN and its potential gender differences. Considering the reduction of TEN on learning and memory dysfunction in ovariectomized animals, therefore, we focused on the impact of TEN in different mice genders in the current study. Spontaneous alternation behavior (SAB), light-dark discrimination, and Morris water maze (MWM) tests were used to evaluate the mice's learning and memory abilities. The field excitatory postsynaptic potential (fEPSP) of the hippocampal CA1 region was recorded using an electrophysiological method, and the morphology of the dendritic structure was examined using Golgi staining. In the behavioral experiments, TEN improved the correct rate in female mice in the SAB test, the correct rate in the light-dark discrimination test, and the number of crossing platforms in the MWM test. Additionally, TEN reduced the latency of female mice rather than male mice in light-dark discrimination and MWM tests. Moreover, TEN could significantly increase the slope of fEPSP in hippocampal Schaffer-CA1 and enhance the total length and the number of intersections of dendrites in the hippocampal CA1 area in female mice but not in male mice. Collectively, the results of the current study showed that TEN improved learning and memory by regulating long-term potentiation (LTP) and dendritic structure of hippocampal CA1 area in female mice but not in males. These findings would help to explore the improvement mechanism of TEN on cognition and expand the knowledge of the potential therapeutic value of TEN in the treatment of cognitive impairment. • Tenuifolin enhanced learning and memory abilities with a more positive effect on female mice than on male mice. • Tenuifolin improved long-term potentiation and dendritic structure in female mice but not in male mice. • Tenuifolin showed noticeable gender differences in pharmacodynamics. [ABSTRACT FROM AUTHOR]

Impairment of learning and memory caused by sleep deprivation is a common symptom that significantly affects quality of life. Repetitive transcranial magnetic stimulation (rTMS) is a promising approach to exert a positive effect on cognitive impairment. However, there is less known about the mechanism of rTMS for learning and memory induced by chronic REM sleep deprivation (CRSD). This study was to detect the effects of rTMS on spatial learning and memory deficits by CRSD and explore possible mechanism. Sixty male Sprague-Dawley rats were randomly divided into four groups: wide platform (Control), sleep deprivation (SD), sleep deprivation + rTMS (TMS), and sleep deprivation + sham rTMS (Sham-TMS). Morris water maze (MWM) and open field test (OFT) assessed spatial learning and memory and anxiety of rats with pre/post-intervention. Golgi staining and transmission electron microscope (TEM) were used to observe structural variations of synapses in the hippocampus. The alteration in gene expression of different groups was analyzed by RNA-sequencing (RNA-Seq), and the key gene was screened and identified by quantitative polymerase chain reaction (qPCR) and subsequently verified with western blotting and immunofluorescence. The behavioral test showed spatial learning and memory decreased and anxiety increased in the SD group compared to the Control and TMS groups. Moreover, rTMS improved spine density, ultrastructural damage, and quantities of synapses. In accordance with RNA-Seq, 56 differentially expressed genes (DEGs) were identified by comparing alternations in four groups and concentrated on kynurenine 3-monooxygenase (KMO). The expression of KMO increased significantly in rats of the SD group compared to the Control and TMS groups identified by qPCR, western blotting, and immunofluorescence. 1 Hz rTMS alleviated spatial learning and memory deficits induced by CRSD probably via down-regulating the expression of KMO and improving the structure and quantity of synapses in the hippocampus of rats. [Display omitted] • Behavioral tests, pathological methods, RNA-sequencing analysis (RNA-Seq), and some molecular biology methods such as quantitative polymerase chain reaction (qPCR), western blotting and immunofluorescence were employed to explore the underlying mechanisms in spatial learning and memory of rats subjected to chronic REM sleep deprivation (CRSD) and treated with repetitive transcranial magnetic stimulation (rTMS). • Based on RNA-Seq, the potential gene involved in the modulation of spatial learning and memory with CRSD intervened by low-frequency rTMS was investigated. • 1 Hz rTMS alleviated spatial learning and memory deficits induced by CRSD probably via down-regulating the expression of kynurenine 3-monooxygenase (KMO). [ABSTRACT FROM AUTHOR]

Highlights • Feeble effect of acute exposure to hypobaric hypoxia on learning and memory. • Increased antioxidative capacity appeared after simulation of hypobaric hypoxia. • Differences in expressions of NMDA receptors were related to altitude and duration. Abstract The present study aimed to observe the effects of acute exposure to hypobaric hypoxia on learning and memory in adult Sprague-Dawley (SD) rats as well as the changes in N-methyl-D-aspartate receptor (NMDAR) subunits. Learning and memory abilities were evaluated with Morris water maze following simulated hypoxia at 5000 m or 7000 m for 2, 4 or 6 days. The number of red blood cells, the level of hemoglobin, oxidative stress markers, the extent of neuronal damage in the hippocampal CA1, and the expression of NMDAR subunits were all measured. In place navigation test, the escape latency significantly increased only in the 5000 M 6Day (P < 0.05) group than the latency in the plain group on the fourth day. In the spatial probe test, the times of platform passing showed no significant difference between the hypoxia and plain groups. Polycythemia, an increased ratio of superoxide dismutase/malondialdehyde and degeneration of neurons appeared in an elevation-dependent and duration-dependent manner in those hypoxia groups. Furthermore, the protein expression of NR1 increased and the protein expression levels of NR2A, NR2B, and NR3A were all decreased in the 5000M 6Day and 7000M 6Day groups. In summary, the feeble effect of acute exposure to simulated hypobaric hypoxia on learning and memory in adult SD rats may be attributed to increased antioxidative capacities and decreased expression of NR3A. And moreover, differences in the expressions of NMDAR subunits were closely related to the altitude and duration. [ABSTRACT FROM AUTHOR]

Highlights • EE prevented the HFECD-induced spatial memory and object recognition impairment. • HFECD induced obesity, glucose intolerance and hypercholesterolemia in mice. • EE did not affect HFECD-induced weight gain or hypercholesterolemia, but improved glucose tolerance. • HFECD decreased the expression of BDNF and IL-6 in the hippocampus of mice. • EE was unable to mitigate the effects of HFECD on BDNF and IL-6 levels. Abstract While chronic high-fat feeding has long been associated with the rising incidence of obesity/type 2 diabetes, recent evidence has established that it is also associated with deficits in hippocampus-dependent memory. In this regard, environmental enrichment (EE) is an animal housing technique composed of increased space, physical activity, and social interactions, which in turn increases sensory, cognitive, motor, and social stimulation. EE leads to improved cerebral health as defined by increased neurogenesis, enhanced learning and memory and resistance to external cerebral insults. In the present study, the impacts of environmental enrichment (EE) on Swiss mice fed a high-fat, cholesterol-enriched diet (HFECD; 20% fat and 1.5% cholesterol) were investigated. Here, we demonstrated that EE, when initiated 4 weeks after the beginning of HFECD in mice, prevents HFECD-induced spatial memory and object recognition impairment, which were tested in T-maze and object recognition tests. Although EE did not affect HFECD-induced weight gain or hypercholesterolaemia, it improved glucose tolerance. On the other hand, EE was unable to mitigate a decrease in brain-derived neurotrophic factor (BDNF) and IL-6 hippocampal levels induced by the HFECD. Overall, while our results reinforce the positive and neuroprotective effects of EE on cognition they do not support a role for EE in preventing the neurochemical changes induced by the HFECD. Based on clinical observations that nondiabetic individuals with mild forms of impaired glucose tolerance have a higher risk of cognitive impairments, one can speculate about the connection between the effects of EE on glucose intolerance and its effects on cognition. [ABSTRACT FROM AUTHOR]

Abstract There are many controversies about the safety of extremely low-frequency electromagnetic field (ELF-EMF) on body health and cognitive performance. In the present study, we explored the effects of ELF-EMF on oxidative stress and behaviors of rats. Seventy-two adult male Wistar rats were randomly divided into following groups, control, sham exposure group and the ELF-EMF exposure groups (1 μT, 100 μT, 500 μT, and 2000 μT). After 60 days exposure (2 h/day), elevated plus maze (EPM), Morris water maze (MWM) and Passive avoidance learning (PAL) tasks were used to evaluate the anxiety-like behavior, spatial and passive learning and memory, respectively. Some days after behavioral examination, oxidative stress markers were measured. During spatial reference memory test, animals in ELF-EMF exposure groups (100, and 2000 μT) spent more time in target zone (F (4, 55) = 5.699, P = 0.0007, One-way ANOVA). In PAL retention, the step through latency in the retention test (STLr) in ELF-EMF exposure groups (100,500, and 2000 μT) was significantly greater than control group (F (4, 55) = 29.13, P < 0.0001, One-way ANOVA). In EPM test, ELF-EMF exposure (500 and 2000 μT) decreased the percentage of the entries into the open arms (F (4, 55) = 26.31, P < 0.0001, one-way ANOVA). ELF-EMF exposure (100, and 500 μT) increased Malondialdehyde (MDA) concentration (F (4, 25) = 79.83, P < 0.0001, One-way ANOVA). Our results may allow the conclusion that exposure to ELF-EMFs can improve memory retention (but not acquisition) in the adult male rats. Although exposure to ELF-EMFs could be a factor in the development of anxious state or oxidative stress. [ABSTRACT FROM AUTHOR]

Highlights • Infusion of 5-HT 1B receptor antagonist GR55562 into hippocampal CA1 did not affect spatial memory acquisition. • Infusion of GR55562 into hippocampal CA1 enhanced spatial memory consolidation. • Infusion of GR55562 into hippocampal CA1 increased, but the 5-HT 1B receptor agonist CP93129 reduced, the spine density on the distal apical dendrites of CA1 pyramidal neurons and Kalirin-7 expression. • Infusion of GR55562 into hippocampal CA1 increased, but CP93129 reduced, the expression of GluA2/3 subunits of AMPA receptors. Abstract Serotonin 5-HT1B receptors (5-HT1BRs) are distributed in hippocampal CA1 and play a pivotal role in cognitive function. Activation of 5-HT1BRs regulates synaptic plasticity at the excitatory synapses in the hippocampus. However, the role and its underlying mechanism of 5-HT1BR activation-mediated glutamatergic synaptic plasticity in spatial memory are not fully understood. In this study, spatial memory of Sprague-Dawley (SD) rats was assessed in a Morris water maze after bilateral dorsal hippocampal CA1 infusion of the 5-HT1BR antagonist GR55562 (25 μg/μL) or agonist CP93129 (25 μg/μL). GR55562 did not affect the spatial memory acquisition but significantly increased the target quadrant preference during the memory consolidation probe performed 14 d after the training session, while CP93129 impaired the memory consolidation process. Moreover, GR55562 significantly increased, while CP93129 significantly decreased, the density of dendritic spines on the distal apical dendrites of CA1 pyramidal neurons. Furthermore, western blot experiments indicated that GR55562 significantly increased, but CP93129 significantly reduced, the expression of Kalirin-7 (Kal-7), PSD95, and GluA2/3 subunits of AMPA receptors. Our results suggest that Kal-7 and Kal-7-mediatedalteration of AMPA receptor subtype expression may play crucial roles in the impact of hippocampal CA1 5-HT1BR activation on spatial memory consolidation. [ABSTRACT FROM AUTHOR]

Sleep deprivation (SD) negatively caused cognitive deficit, which was associated with oxidative stress induced damage. Ginsenoside Rh2 had the ability to protect against damage caused by reactive oxygen species in vitro , showing antioxidant property. Therefore, it was hypothesized that Ginsenoside Rh2 could prevent SD-induced cognitive deficit via its antioxidant properties. In this study, the effect of Ginsenoside Rh2 on memory impairment induced by sleep deprivation was investigated. The mice were sleep deprived continuously for 14 days using our self-made Sleep Interruption Apparatus (SIA). Ginsenoside Rh2 was administered intraperitoneally at two doses (20 and 40 μmol/kg) for 20 days. Thereafter, behavioral studies were conducted to test the learning and memory ability using object location recognition (OLR) experiment and passive avoidance (PA) test. Additionally, the oxidative stress parameters in the serum and the brain tissues (cortex and hippocampus) were assessed, including the superoxide dismutase (SOD) enzyme activity, the total antioxidant reactivity (TAR), the malondialdehyde (MDA) level, the glutathione (GSH) level, and the lipid peroxidation (LPO) content. The results revealed that SD impaired both spatial and non-spatial memory (P < 0.05). Treatment with Ginsenoside Rh2 at both doses prevented memory impairment induced by SD. Moreover, Ginsenoside Rh2 normalized the reduction of SOD and TAR activities in the serum (P < 0.01) and the decrease of GSH content in both the cortex and hippocampus (P < 0.05) induced by SD. Furthermore, Ginsenoside Rh2 significantly decreased the MDA level in the serum (P < 0.05) and the LPO content in both the cortex and hippocampus (P < 0.05) compared to SD group. In conclusion, sleep deprivation impaired both spatial and non-spatial memory and Ginsenoside Rh2 reversed this impairment, probably by preventing the oxidative stress damage in the body, including the serum and brain during sleep deprivation. [ABSTRACT FROM AUTHOR]

Stroke is considered a major cause of global morbidity. Currently, there are no effective treatments for post-stroke cognitive impairment. Enriched environment (EE) has been brought forward as a preconditioning method to induce cerebral tolerance in an ischemic event. However, the subjacent mechanisms involved in this tolerance are not yet clear. Herein we aimed to identify the mechanisms of neuroprotection triggered by EE preconditioning in a murine model of ischemic stroke. In order to do so, C57Bl/6 mice were kept for five weeks either in EE or in standard environment (SC) prior to ischemic injury through bilateral carotid occlusion (BCCAo) or sham surgery. To evaluate cognitive deficits resulting from ischemia, animals were subjected to a set of behavioral test to assess short-term (STM), long-term (LTM) and working memory (WM) performance. Despite no effect of EE having been observed in LTM and WM, EE preconditioning was able to prevent short-term deficits in response to ischemia. This improvement was accompanied by a reduction in the infarct volume in animals following EE pre-exposure. Next, we aimed to analyze the expression of genes involved in cholinergic (M1 and alpha 7 receptors) and glutamatergic (NMDA subunits GluN1, GluN2A, GluN2B and GluN2C) neurotransmission, inflammatory mediators (GFAP and IL-1β) and of the neurotrophin BDNF. Animals tested for STM did not present alterations in the expression of glutamatergic or cholinergic receptors; however, EE was shown to prevent increased expression of IL1-β. On the other hand, in animals submitted to LTM task, EE exposure lead to increased GFAP expression in EE animals that underwent ischemic injury, affecting also the expression of NMDA subunits. In spite of that, no alterations in glutamate content were observed in either group. Altogether, this study suggests that the changes observed in the expression of glutamatergic receptors, the reduction of the inflammatory cytokine IL1-β expression and the increased expression of GFAP in ischemic animals might contribute to the cognitive improvement induced by the EE paradigm. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI)-induced agitation and aggression pose major obstacles to clinicians in the acute hospital and rehabilitation settings. Thus, management of these symptoms is crucial. Antipsychotic drugs (APDs) are a common treatment approach for alleviating these symptoms. However, previous preclinical TBI studies have indicated that daily and chronic administration of these drugs (e.g., haloperidol; HAL) can exacerbate cognitive and motor deficits. Quetiapine (QUE) is an atypical APD that differs from many typical APDs, such as HAL, in its relatively rapid dissociation from the D 2 receptor. The goal of this study was to test the hypotheses that intermittent HAL and QUE would not hinder recovery of cognitive and motor function following TBI and that daily QUE would also not impair functional recovery, which would be in contrast to HAL. Seventy anesthetized male rats received either a controlled cortical impact or sham injury and were then randomly assigned to TBI and sham groups receiving HAL (0.5 mg/kg) or QUE (10 mg/kg) intraperitoneally once per day or once every other day and compared to each other and vehicle (VEH) controls. Motor function was assessed by beam balance/walk tests on post-operative days 1–5 and cognitive function was evaluated with a Morris water maze task on days 14–19. No differences were revealed among the sham groups in any task, and hence the data were pooled. No overall differences were detected among the TBI groups, regardless of treatment or administration paradigm [ p > 0.05], but all were impaired vs. SHAM controls [ p < 0.05]. The SHAM controls also performed significantly better in the cognitive test vs. all TBI groups [ p < 0.05]. Moreover, the TBI + continuous HAL group performed worse than the TBI + continuous VEH, TBI + continuous QUE, and TBI + intermittent QUE groups [ p < 0.05], which did not differ from one another. Overall, the data suggest that QUE does not exacerbate TBI-induced cognitive and motor deficits, which supports the hypothesis. QUE may prove useful as an alternative APD treatment for management of agitation and aggression after clinical TBI. HAL may also be safe, but only if used sparingly. [ABSTRACT FROM AUTHOR]

Agitation and aggression are common sequelae of traumatic brain injury (TBI) and pose a challenge to physicians and other health providers during acute patient care and subsequent neurorehabilitation. Antipsychotic drugs (APDs) are routinely administered to manage TBI patients displaying such maladaptive behaviors despite several clinical and preclinical studies demonstrating that they hinder recovery. A potentially viable alternative to APDs may be the benzodiazepines, which have differing mechanisms of action. Hence, the aim of the study was to test the hypothesis that lorazepam (LOR) would not impede recovery after TBI. Anesthetized adult male rats received a cortical impact or sham injury and then were intraperitoneally administered LOR (0.1 mg/kg, 1.0 mg/kg, or 2.0 mg/kg) or vehicle (VEH; 1 mL/kg) commencing 24-h after surgery and once daily for 19 days. Motor and cognitive outcomes were assessed on post-operative days 1–5 and 14–19, respectively. No differences were revealed among the four sham control groups and thus they were pooled into one inclusive SHAM group. The SHAMs performed better than all TBI groups on all assessments ( p < 0.05). Regarding TBI, the 2.0 mg/kg LOR group performed better than the VEH and 0.1 mg/kg or 1.0 mg/kg LOR groups on every task ( p < 0.05); no differences were observed among the latter three groups on any endpoint ( p > 0.05). Overall, these preclinical behavioral data support the hypothesis and reveal a therapeutic benefit with the higher dose of LOR. The findings suggest that LOR may be an alternative, to APDs, for controlling agitation without compromising spontaneous recovery and perhaps could afford a dual benefit by also promoting therapeutic efficacy. [ABSTRACT FROM AUTHOR]

The sigma-1 receptor (S1R) is a molecular chaperone which activity modulates several intracellular signals including calcium mobilization at mitochondria-associated endoplasmic reticulum membranes. S1R agonists are potent neuroprotectants against neurodegenerative insults and particularly in rodent models of Alzheimer's disease (AD). We here analyzed whether S1R inactivation modifies vulnerability to amyloid toxicity in AD models. Two strategies were used: (1) amyloid β[25-35] (Aβ 25-35 ) peptide (1, 3, 9 nmol) was injected intracerebroventricularly in mice treated repeatedly with the S1R antagonist NE-100 or in S1RKO mice, and (2) WT, APP SweInd , S1RKO, and APP SweInd /S1RKO mice were created and female littermates analyzed at 8 months of age. Learning deficits, oxidative stress, Bax level and BDNF content in the hippocampus were analyzed. Aβ 25-35 induced learning impairment, oxidative stress, Bax induction and BDNF alteration at lower dose in NE-100-treated mice or S1RKO mice as compared to WT animals. The extent of learning deficits and biochemical alterations were also higher in APP SweInd /S1RKO mice as compared to WT, APP SweInd , and S1RKO animals. S1R inactivation or altered S1R expression augmented the pathological status in pharmacologic and genetic AD mouse models. These observations, in relation with the well-known protective effects of S1R agonists, are coherent with a role of signal amplifier in neurodegeneration and neuroprotection proposed for S1R in AD and related neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most prevalent form of dementia with multiple etiology and no effective remedy. Statins are a group of medicines that are basically used to lower cholesterol. However, several studies have recently done to assess the potential relationship between statins use and dementia but presented controversial results. In this study, using ovariectomy and D‐galactose injection, a model of AD was induced in female rats, and then the protective effects of oral administration of simvastatin were investigated. shuttle box and Y-maze tests were done to assess the animals' learning and memory performance. Using GC-MC, ELISA, Immunohistochemistry and tissue staining techniques, changes in the amount of short-chain fatty acids (SCFAs), plasma and hippocampus neuroinflammatory markers and histological changes in the intestine and hippocampus were assessed in sham, disease and treatment groups. Oral administration of simvastatin improved the gut microbiome activity (increased the amount of SCFAs in fecal samples) and strengthened the tight junctions of intestinal cells. Moreover, simvastatin reduced the amount of TNF-α and IL-1β in plasma and hippocampus. Also, cell death and Amyloid plaques notably decreased in the simvastatin-treated hippocampal tissue. All these physiological changes led to better performance in behavioral tasks in the treatment group in comparison to the disease group. These findings provide evidence that simvastatin may improve gut-brain axis followed by improvement in learning and memory via an anti-inflammatory effect. [Display omitted] • Simvastatin improves gut-brain axis by strengthening of intestinal tight junctions and increasing short chain fatty acids. • Simvastatin decreases the amount of inflammatory markers in plasma and hippocampal level. • Simvastatin increases the cell survival rate and decreases the amount of Aβ deposition. • Simvastatin decreases the risk of learning and memory impairment in an ovariectomized/ D -galactose Alzheimer's rat model. [ABSTRACT FROM AUTHOR]

There is an increasing number of studies showing that occlusal dysfunction impairs learning and memory. We previously demonstrated that the brain has a mechanism to calibrate between the activities of spindle afferents and periodontal-mechanoreceptor afferents for controlling the chewing movement, and the accurate calibration can be done only at the proper vertical dimension of occlusion (VDO). Then, the chewing at an inappropriate VDO may induce a severe mental stress due to a mal-calibration. However, it is not clear how the impairment of learning/memory progresses over the period of stress induced by occlusal dysfunction. We investigated by passive avoidance test how the behavior and learning/memory are altered in guinea pigs in which the VDO was raised by 2–3 mm over the period up to 8 weeks. We found that the guinea pigs reared under the raised occlusal-condition (ROC) for 1 week showed a very high sensitivity to electrical stimulation whereas this did not cause the memory consolidation in the 1st-day retention trial, suggesting that such hypersensitivity rather hampered the fear learning. In the guinea pigs reared under the ROC for 2 and 8 weeks, the learning ability was not largely affected and memory consolidation occurred similarly whereas the memory retention deteriorated more severely in the latter guinea pigs than in the former ones. In the guinea pigs reared under the ROC for 3 and 4 weeks, learning was severely impaired, and memory consolidation did not occur. These results suggest that the occlusal dysfunction for varying periods differentially impairs learning and memory. • Occlusal dysfunction for one week caused a hypersensitivity to pain stimulation. • Occlusal dysfunction for 2 weeks moderately impaired memory retention. • Occlusal dysfunction for 3–4 weeks transiently impaired fear learning. • Occlusal dysfunction for 8 weeks impaired memory retention but not its acquisition. • Occlusal dysfunction for varying periods differentially impaired learning and memory. [ABSTRACT FROM AUTHOR]

The lipid sphingosine 1-phosphate (S1P) is a potent neuroprotective signalling molecule that signals through its own family of five G-protein coupled receptors. S1P signalling enhances presynaptic glutamate release and is essential for neural development. S1P is synthesized by the enzymes sphingosine kinases 1 and 2 (SPHK1 and SPHK2), of which SPHK2 mRNA and activity is more abundant in the brain. In this study we investigated the consequences of global SphK2 knockout ( SphK2 −/− ) on basic motor capabilities, anxiety, learning, and memory in mice, using a range of tests including the elevated plus maze, the cheeseboard, contextual and cued fear conditioning, and fear extinction. Loss of SphK2 resulted in an 85–90% reduction in brain S1P levels, and was associated with a notably higher freezing response in a novel context. SphK2 knockout mice also exhibited increased contextual fear conditioning but the extinction of contextual fear memory was similar to control mice. SphK2 −/− mice, contrary to their control littermates, did not respond to cue presentation with increased freezing . Anxiety measures in the elevated plus maze were not different between SphK2 −/− mice and control littermates. Also, knockout mice showed no deficits in neurological reflexes or motor functions, and performed as well as their control littermates in the spatial memory test. Our findings demonstrate that SphK2 is responsible for the vast majority of S1P synthesis in the mouse brain, and plays a role in freezing responses as evaluated in the fear conditioning paradigm. [ABSTRACT FROM AUTHOR]

Prenatal ethanol exposure (PAE) in humans results in a spectrum of disorders including deficits in learning and memory. Animal models to date have typically used high ethanol doses but have not identified the biochemical changes underlying the cognitive deficit. This study used treatment of mouse breeding harems with 5% ethanol via drinking water throughout pregnancy and lactation and explored the behavioural consequences in the progeny at 3–6 months of age using the open field test, novel object recognition test and elevated plus maze to measure anxiety and memory consolidation. The effects of angiotensin IV on behaviour of the progeny were also determined. The results indicated that PAE increased anxiety-like behaviour as determined in the open field test in male but not female progeny. In control animals, angiotensin IV enhanced memory consolidation in males, but this effect was abolished by PAE. The abolition of the pro-cognitive effect of angiotensin IV was not a consequence of increased anxiety, and there was some evidence of a long-lasting anxiolytic effect of angiotensin IV in the male PAE progeny. These results suggest that PAE may act via alteration of the actions of the brain renin-angiotensin system to impair memory consolidation, but these effects may be partially sex-dependent. [ABSTRACT FROM AUTHOR]

In contact sports, repetitive concussive brain injury (rCBI) is the prevalent form of head injury seen in athletes. The need for effective treatment is urgent as rCBI has been associated with a host of cognitive, behavioral and neurological complaints. There has been a growing trend in the use of female animals in pre-clinical research, but few studies have investigated possible sex differences following rCBI. The goal of the current study was to determine any differences between male and female C57BL/6J mice on assessments of learning and memory after repetitive concussive injury. Following rCBI by impact to the scalp, male mice exhibited longer righting reflexes during acute recovery. In both sexes, there were no evident histopathological changes observed in the underlying cerebral cortex or hippocampus. Reactive astrogliosis was elevated in the corpus callosum and optic tract, and astrogliosis was slightly less in the optic tract of female mice. rCBI mice exhibited impairment during the learning phase of the Morris water maze (MWM), but female mice, in comparison to male mice, were observed to have superior spatial memory during standard MWM probe trials. Female mice were overall more active, evidenced by greater distances traveled in the y-maze and greater swim speeds in the MWM. The results of this study demonstrate sex differences in cognitive performance following rCBI and support previous research suggesting the neuroprotective role of sex in brain injury. [ABSTRACT FROM AUTHOR]

Zinc is an important element in all cells of the body, having structural, enzymatic, and regulatory functions. In some neurons, zinc is loaded into synaptic vesicles by zinc transporter 3 (ZnT3) and released into the synaptic cleft, where it can modulate neuronal function. ZnT3 knockout (KO) mice lack ZnT3 and thus lack synaptic zinc. Previous studies have examined the behavioral phenotype of ZnT3 KO mice, mostly using mixed-sex or male-only groups. In the present study we focused specifically on the behavior of female ZnT3 KO mice (2–3 months old). An extensive battery of tests was administered to assess sensorimotor and cognitive behaviours, as well as to examine for a possible schizophrenia-like phenotype. ZnT3 KO mice performed similarly to wild type controls in the majority of tests. However, they were less accurate in the skilled reach task, suggesting impaired skilled motor learning, and faster to descend a vertical pole. ZnT3 KO mice were also slower in the open field and made fewer chamber entries in the social preference test, suggesting decreased exploratory locomotion. No differences were observed in the Morris water task or fear conditioning test. This is the first study to show a behavioural phenotype specifically for female ZnT3 KO mice. Comparing our results to previous studies, it appears that there may be sex-specific effects of eliminating ZnT3. Female ZnT3 KO mice exhibit abnormalities in locomotion and at skilled motor learning, but we were unable to detect spatial or fear learning deficits previously described in male ZnT3 KO mice. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that targeting bradykinin receptors is a promising strategy to counteract the cognitive impairment related with aging and Alzheimer’s disease (AD). The hippocampus is critical for cognition, and abnormalities in this brain region are linked to the decline in mental ability. Nevertheless, the impact of bradykinin signaling on hippocampal function is unknown. Therefore, we sought to determine the role of hippocampal bradykinin receptors B 1 R and B 2 R on the cognitive decline of middle-aged rats. Twelve-month-old rats exhibited impaired ability to acquire and retrieve spatial information in the Morris water maze task. A single intra-hippocampal injection of the selective B 1 R antagonist des-Arg 9 -[Leu 8 ]-bradykinin (DALBK, 3 nmol), but not the selective B 2 R antagonist D-Arg-[Hyp 3 ,Thi 5 ,D-Tic 7 ,Oic 8 ]-BK (Hoe 140, 3 nmol), reversed the spatial learning and memory deficits on these animals. However, both drugs did not affect the cognitive function in 3-month-old rats, suggesting absence of nootropic properties. Molecular biology analysis revealed an up-regulation of B1R expression in the hippocampal CA1 sub-region and in the pre-frontal cortex of 12-month-old rats, whereas no changes in the B 2 R expression were observed in middle-aged rats. These findings provide new evidence that inappropriate hippocampal B 1 R expression and activation exert a critical role on the spatial learning and memory deficits in middle-aged rats. Therefore, selective B 1 R antagonists, especially orally active non-peptide antagonists, may represent drugs of potential interest to counteract the age-related cognitive decline. [ABSTRACT FROM AUTHOR]

Disruption of the cyclic feature of the day-night environment can cause negative effects on daily activity and advanced brain functions such as learning, memory and decision-making behaviour. These functions in songbirds, including corvids, involve the hippocampus, pallium and midbrain, as revealed by ZENK (a neuronal activation marker) and tyrosine hydroxylase (TH) expressions. TH is rate-limiting marker enzyme of the biosynthesis of dopamine, widely implicated in learning and memory. Here, we measured ZENK and TH immunoreactivity in the hippocampal, pallial and midbrain regions in response to cognitive performance (learning-memory retrieval) tests in Indian house crows ( Corvus splendens ) exposed to constant light environment (LL) with controls on 12 h light:12 h darkness. Along with the decay of circadian rhythm in activity behaviour, LL caused a significant decline in the cognitive performance. There was also a decrease under LL in the activity of neurons in the hippocampus, medial and central caudal nidopallium, and hyperpallium apicale, which are widely distributed with TH-immunoreactive fibres. Further, under LL, TH- immunoreactive neurons were reduced in number in midbrain dopamine synthesis sites, the venteral tegmental area (VTA) and substantia nigra (SN), with a negative correlation of co-localized ZENK/TH- immunoreactive cells on errors during the association tasks. These results show decreased activity of learning and memory neural systems, and underscore the role of dopamine in reduced cognitive performance of diurnal corvids with disrupted circadian rhythms under an abrupt light environment. [ABSTRACT FROM AUTHOR]

Prenatal alcohol exposure (PAE) can result in fetal alcohol spectrum disorder (FASD), characterized by developmental disability. As children with FASD are often raised in suboptimal conditions, we have investigated the combination of PAE via maternal preference consumption of 10% ethanol in water with early life stress (ELS) via daily 3 h maternal separation and isolation. Our results focus on development and behavioral features, including activity, anxiety-like behavior, as well as learning and memory. PAE influenced the number of pups surviving to postnatal day 2 and 70, with fewer surviving pups associated with the severity of ethanol exposure. PAE and ELS both had effects on pup weight at postnatal day 21, with amount of ethanol exposure positively correlating with pup weight. We found females were more active than males in a novel open field environment, but not following PAE. In addition, PAE resulted in overall increased exploratory behavior in the open field. Further, PAE and ELS both resulted in overnight hypoactivity in a home cage environment, as well as learning deficits that were influenced by sex in the Barnes Maze for learning and memory. These results are attributed to environmental interactions involving PAE and ELS. [ABSTRACT FROM AUTHOR]

Senescence-accelerated mouse (SAM) is inbred lines of mice originally developed from AKR/J mice. Among the six SAM prone (SAMP) substrains, 8- to 12-month-old SAMP8 have long been used as a model of age-related cognitive impairments. However, little is still known for younger SAMP8 mice. Here, we examined the phenotypical characteristics of 4-month-old SAMP8 using a battery of behavioral tests. Four-month-old SAMP8 mice failed to recognize spatially displaced object in an object recognition task and performed poorly in the probe test of the Morris water maze task compared to SAMR1, suggesting that SAMP8 have impaired spatial memory. In addition, young SAMP8 exhibited enhanced anxiety-like behavior in an open field test and showed depression-like behavior in the forced-swim test. Their circadian rhythm was also disrupted. These abnormal behaviors of young SAMP8 are similar to behavioral alterations also observed in aged mice. In summary, age-related behavioral alterations occur in SAMP8 as young as 4 months old. [ABSTRACT FROM AUTHOR]

Cognitive deficits have an extensive influence on the quality of life of the Parkinson’s disease (PD) patients. Previous studies have shown that lack of steroid hormones have an important role in the development of PD. Therefore, in this study the effects of neurosteroid allopregnanolone (Allo) on the PD-induced cognitive disorders were assessed. To simulate PD, 6-hydroxydopamine (6-OHDA) was injected into the rat’s substantia nigra. Allo (5 and 20 mg/kg, orally) were administered on the day after the 6-OHDA injection and continued during the entire treatment period (two months). Cognitive behaviors were assessed by Moris water maze (MWM), novel object recognition (NOR) and object location tasks . The data indicated that Allo significantly improved the 6-OHDA-induced cognitive impairment which revealed by the reduction of time spent to find out platform (escape latency) and the increase of retention time in MWM test and also with increase in the exploration index in NOR and object location tasks . Present study strongly supports the pro-cognitive property of allopregnanolone in PD. [ABSTRACT FROM AUTHOR]

Good sleep is necessary for optimal health, especially for mental health. Insomnia, sleep deprivation will make your ability to learn and memory impaired. Nevertheless, the underlying pathophysiological mechanism of sleep disorders-induced cognitive decline is still largely unknown. In this study, the sleep deprivation of animal model was induced by chronical sleep interruption (CSI), the behavioral tests, biochemical index determinations, and a liquid chromatography-mass spectrometry (LC–MS) based serum metabolic profiling analysis were performed to explore the effects of CSI on cognitive function and the underlying mechanisms. After 14-days CSI, the cognitive function of the mice was evaluated by new objects preference (NOP) task and temporal order judgment (TOJ) task. Serum corticosterone (CORT), and brain Malondialdehyde (MDA), Superoxide Dismutase (SOD), and Catalase (CAT) levels were determined by ELISA kits. Data were analyzed by Principal Component Analysis (PCA), Partial Least Squares project to latent structures-Discriminant Analysis (PLS-DA), and Student’s t -test. We found that the cognitive function of the mice was significantly affected by CSI. Besides, levels of CORT and MDA were higher, and SOD and CAT were lower in CSI mice than those of control. Obvious body weight loss of CSI mice was also observed. Thirteen potential serum biomarkers including choline, valine, uric acid, allantoic acid, carnitines, and retinoids were identified. Affected metabolic pathways involve metabolism of purine, retinoid, lipids, and amino acid. These results showed that CSI can damage the cognitive performance notably. The cognitive decline may ascribe to excessive oxidative stress and a series of disturbed metabolic pathways. [ABSTRACT FROM AUTHOR]

Mild traumatic brain injury (mTBI) accounts for the majority of all brain injuries and affected individuals typically experience some extent of cognitive and/or neuropsychiatric deficits. Given that repeated mTBIs often result in worsened prognosis, the cumulative effect of repeated mTBIs is an area of clinical concern and on-going pre-clinical research. Animal models are critical in elucidating the underlying mechanisms of single and repeated mTBI-associated deficits, but the neurobehavioral sequelae produced by these models have not been well characterized. Thus, we sought to evaluate the behavioral changes incurred after single and repeated mTBIs in mice utilizing a modified impact-acceleration model. Mice in the mTBI group received 1 impact while the repeated mTBI group received 3 impacts with an inter-injury interval of 24 h. Classic behavior evaluations included the Morris water maze (MWM) to assess learning and memory, elevated plus maze (EPM) for anxiety, and forced swim test (FST) for depression/helplessness. Additionally, species-typical behaviors were evaluated with the marble-burying and nestlet shredding tests to determine motivation and apathy. Non-invasive vibration platforms were used to examine sleep patterns post-mTBI. We found that the repeated mTBI mice demonstrated deficits in MWM testing and poorer performance on species-typical behaviors. While neither single nor repeated mTBI affected behavior in the EPM or FST, sleep disturbances were observed after both single and repeated mTBI. Here, we conclude that behavioral alterations shown after repeated mTBI resemble several of the deficits or disturbances reported by patients, thus demonstrating the relevance of this murine model to study repeated mTBIs. [ABSTRACT FROM AUTHOR]

Butyrylcholinesterase (BChE) is an important enzyme for detoxication and metabolism of ester compounds. It also hydrolyzes the neurotransmitter acetylcholine (ACh) in pathological conditions and may play a role in Alzheimer’s disease (AD). We here compared the learning ability and vulnerability to Aβ toxicity in male and female BChE knockout (KO) mice and their 129 Sv wild-type (Wt) controls. Animals tested for place learning in the water-maze showed increased acquisition slopes and presence in the training quadrant during the probe test. An increased passive avoidance response was also observed for males. BChE KO mice therefore showed enhanced learning ability in spatial and non-spatial memory tests. Intracerebroventricular (ICV) injection of increasing doses of amyloid-β[25–35] (Aβ 25–35 ) peptide oligomers resulted, in Wt mice, in learning and memory deficits, oxidative stress and decrease in ACh hippocampal content. In BChE KO mice, the Aβ 25–35 -induced deficit in place learning was attenuated in males and blocked in females. No change in lipid peroxidation or ACh levels was observed after Aβ 25–35 treatment in male or female BChE KO mice. These data showed that the genetic invalidation of BChE in mice augmented learning capacities and lowered the vulnerability to Aβ toxicity. [ABSTRACT FROM AUTHOR]

Housing animals in enriched environments (EEs) results in improved learning and memory (L&M) performance. While increased intrinsic cellular excitability in the hippocampal neurons might underlie the environmental enrichment-dependent L&M enhancement, literature in respect to this remains scarce and controversial. In this study, we explore whether intrinsic cellular excitability in hippocampal CA1 pyramidal cells is modulated differently, depending on housing duration and anatomical location of cells. Using in vitro patch clamp recordings in mice, we first demonstrate that cellular excitability of hippocampal CA1 pyramidal cells is significantly increased only in animals housed in an EE for a relatively short (<40 days) duration. Second, anatomical analysis shows that increased excitability is mainly restricted to the dorsal and proximal sections of the CA1 region. Further analysis reveals that the input resistance and the spike threshold, which are differently modulated by anatomical location and housing duration, respectively, may underlie the increased excitability. These results indicate that housing duration and anatomical location are crucial factors for environmental enrichment-dependent modulations of intrinsic excitability. While the dorsally restricted increase in excitability is in agreement with the specific up-regulation of L&M supported by the dorsal hippocampus, the selective modulation of the proximal area is in line with enhanced spatial abilities often observed after environmental enrichment. The housing duration specificity we observed here, together with previous findings, suggests that the modulation of some physiological properties by an environmental enrichment is transient. Finally, these results could coherently account for earlier controversial reports. [ABSTRACT FROM AUTHOR]

Which behavioral test is the most sensitive for detecting cognitive deficits in the 3xTg-AD at 6.5 months of age? The 3xTg-AD mouse model of Alzheimer's disease (AD) has three transgenes (APPswe, PS1M146V, and Tau P301L) which cause the development of amyloid beta plaques, neurofibrillary tangles, and cognitive deficits with age. In order to determine which task is the most sensitive in the early detection of cognitive deficits, we compared male and female 3xTg-AD and B6129SF2 wildtype mice at 6.5 months of age on a test battery including spontaneous alternation in the Y-Maze, novel object recognition, spatial memory in the Barnes maze, and cued and contextual fear conditioning. The 3xTg-AD mice had impaired learning and memory in the Barnes maze but performed better than B6129SF2 wildtype mice in the Y-Maze and in contextual fear conditioning. Neither genotype demonstrated a preference in the novel object recognition task nor was there a genotype difference in cued fear conditioning but females performed better than males. From our results we conclude that the 3xTg-AD mice have mild cognitive deficits in spatial learning and memory and that the Barnes maze was the most sensitive test for detecting these cognitive deficits in 6.5-month-old mice. [ABSTRACT FROM AUTHOR]

Alzheimer disease is the most common neurodegenerative disorder and cause of senile dementia. It is characterized by an accelerated memory loss, and alterations of mood, reason, judgment and language. The main neuropathological hallmarks of the disorder are β-amyloid (βA) plaques and neurofibrillary Tau tangles. The triple transgenic 3xTgAD mouse model develops βA and Tau pathologies in a progressive manner which mimicks the pattern that takes place in the human brain with AD, and showing cognitive alterations characteristic of the disease. The present study intended to examine whether 3xTgAD mice of both sexes present cognitive, emotional and other behavioral alterations at the early age of 4 months, an age in which only some intraneuronal amyloid accumulation is found. Neonatal handling (H) is an early-life treatment known to produce profound and long-lasting behavioral and neurobiological effects in rodents, as well as improvements in cognitive functions. Therefore, we also aimed at evaluating the effects of H on the behavioral/cognitive profile of 4-month-old male and female 3xTgAD mice. The results indicate that, (1) 3xTgAD mice present spatial learning/memory deficits and emotional alterations already at the early age of 4 months, (2) there exists sexual dimorphism effects on several behavioral variables at this age, (3) neonatal handling exerts a preventive effect on some cognitive (spatial learning) and emotional alterations appearing in 3xTgAD mice already at early ages, and 4) H treatment appears to produce stronger positive effects in females than in males in several spatial learning measures and in the open field test. [ABSTRACT FROM AUTHOR]

Age-related memory decline in mammals has been well documented. By contrast, very little is known about memory decline in birds as they age. In the current study we trained younger and older homing pigeons on a reference memory task in which a goal location could be encoded by spatial and feature cues. Consistent with a previous working memory study, the results revealed impaired acquisition of combined spatial–feature reference memory in older compared to younger pigeons. Following memory acquisition, we used cue-conflict probe trials to provide an initial assessment of possible age-related differences in cue preference. Both younger and older pigeons displayed a similarly modest preference for feature over spatial cues. [ABSTRACT FROM AUTHOR]

Numerous clinical and animal studies have found that antenatal chronic stress can lead to pathological changes the hippocampal development from embryos to adult, but the mechanisms are not well understood. Proteomic analyses provide a new insight to explore the potential mechanisms of this impairment. In this study, gestating rats were subjected to chronic unpredictable mild stress (CUMS) during pregnant days using nine different stimulations, and the changes of the learning and memory performance and the expression of proteins in the hippocampus of offspring were measured. It was found that prenatal chronic stress led to growth retardation, impaired spatial learning and memory ability in the offspring. Furthermore, prenatal stress caused various degrees of damage to neurons, Nissl body, mitochondria and synaptic structures in hippocampal CA3 region of offspring. In addition, 26 significantly different expressed proteins (DEPs) were found between the two groups by using isoquantitative tag-based relative and absolute quantification (iTRAQ) proteomics analysis. Further analyses of these DEPs showed that involved with different molecular functions and several biological processes, such as biological regulation and metabolic processes. Among these, the KEGG pathway enrichment showed that learning and memory impairment was mainly associated with the cyclic guanosine monophosphate protein kinase G (cGMP-PKG) pathway. At the same time, compared with OPC group, the NO, nNOS and cGMP level were significantly decreased, and the expression of PKG protein was also dropped. All of these results suggested that pregnant rats exposed to chronic psychological stress might impair spatial learning and memory ability of offspring, by disturbing the NO/cGMP/PKG signaling pathway. • The maternal chronic prenatal psychological stress impaired spatial learning and memory ability in the offspring. • An iTRAQ proteomics analysis showed that 26 DEPs and 8 signaling pathways were found in the hippocampus of offspring, and the impairment may mediate through inhibition of the NO/cGMP/PKG signaling pathway. [ABSTRACT FROM AUTHOR]

SV2B is a synaptic protein widely distributed throughout the brain, which is part of the complex vesicle protein machinery involved in the regulation of synaptic vesicle endocytosis and exocytosis, and therefore in neurotransmitters release. The aims of the present work were twofold: (1) phenotype SV2B knockout mice (SV2B KO) in a battery of cognitive tests; and (2) examine their vulnerability to amyloid-β25-35 (Aβ25-35) peptide-induced toxicity. SV2B KO mice showed normal learning and memory abilities in absence of Aβ25-35 injection. SV2B KO mice were protected against the learning deficits induced after icv injection of an oligomeric preparation of amyloid-β25-35 peptide, as compared to wild-type littermates (SV2B WT). These mice failed to show Aβ25-35-induced impairments in a number of cognitive domains: working memory measured by a spontaneous alternation procedure, recognition memory measured by a novel object recognition task, spatial reference memory assessed in a Morris water-maze, and long-term contextual memory assessed in a inhibitory avoidance task. In addition, SV2B KO mice were protected against Aβ25-35-induced oxidative stress and decrease in ChAT activity in the hippocampus. These data suggest that SV2B could be a key modulator of amyloid toxicity at the synaptic site. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that cognitive processes, such as learning and memory, are affected in depression and antidepressant treatment may ameliorate cognitive impairments. Recent studies have shown that curcumin exhibits antidepressant-like effects. The aim of the present study was to determine whether curcumin administration influences chronic unpredictable stress (CUS)-induced cognitive deficits and explores underlying mechanisms. Male Wistar rats were subjected to CUS protocol for a period of 5 weeks to induce depression. The depressive-like behavior was tested using sucrose preference test, open field test and Morris water maze test. Effects of curcumin on brain-derived neurotrophic factor (BDNF) and extracellular signal-regulated kinase (ERK) levels in the hippocampus were also examined. Chronic treatment with curcumin significantly reversed the CUS-induced behavioral and cognitive parameters (reduced sucrose preference and impaired learning and memory function) in stressed rats. Additionally, CUS reduced hippocampal BDNF and ERK levels, while curcumin effectively reversed these alterations. Taken together, our results indicate that the antidepressant-like effects of curcumin in CUS rats are related to its aptitude to promote BDNF and ERK in the hippocampus. [ABSTRACT FROM AUTHOR]

Highlights: [•] Aged 3×TgAD mice show deficits in spatial learning, short-term and working memory. [•] 3×TgAD mice show signs of increased anxiety and normal sensorimotor functions. [•] Sexual dimorphism is reflected by increased behavioral inhibition in males. [•] Sexual dimorphism is reflected by increased cognitive deficits in females. [•] Environmental enrichment in adulthood induces beneficial effects on working memory. [ABSTRACT FROM AUTHOR]

Highlights: [•] Exposure of rats to homocysteine (Hcy) leads to learning and memory dysfunctions. [•] Hcy decreases the generation of endogenous H2S in the hippocampus of rats. [•] Hcy up-regulates the endoplasmic reticulum (ER) stress in the hippocampus of rats. [•] Disturbed H2S formation and ER stress involve in Hcy-caused memory disorder. [ABSTRACT FROM AUTHOR]

Abstract: The role of VEGF in the nervous system is extensive; apart from its angiogenic effect, VEGF has been described as a neuroprotective, neurotrophic and neurogenic molecule. Similar effects have been described for enriched environment (EE). Moreover, both VEGF and EE have been related to improved spatial memory. Our aim was to investigate the neurovascular and cognitive effects of intracerebrally-administered VEGF and enriched environment during the critical period of the rat visual cortex development. Results showed that VEGF infusion as well as enriched environment induced neurovascular and cognitive effects in developing rats. VEGF administration produced an enhancement during the learning process of enriched animals and acted as an angiogenic factor both in primary visual cortex (V1) and dentate gyrus (DG) in order to counteract minipump implantation-induced damage. This fact revealed that DG vascularization is critical for normal learning. In contrast to this enriched environment acted on the neuronal density of the DG and V1 cortex, and results showed learning enhancement only in non-operated rats. In conclusion, VEGF administration only has effects if damage is observed due to injury. Once control values were reached, no further effects appeared, showing a ceiling effect. Our results strongly support that in addition to neurogenesis, vascularization plays a pivotal role for learning and memory. [Copyright &y& Elsevier]

Abstract: Daily patterns of light exposure have become increasingly variable since the widespread adoption of electrical lighting during the 20th century. Seasonal fluctuations in light exposure, shift-work, and transmeridian travel are all associated with alterations in mood. These studies implicate fluctuations in environmental lighting in the development of depressive disorders. Here we argue that exposure to light at night (LAN) may be causally linked to depression. Male C3H/HeNHsd mice, which produce nocturnal melatonin, were housed in either a standard light/dark (LD) cycle or exposed to nightly dim (5lux) LAN (dLAN). After four weeks in lighting conditions mice underwent behavioral testing and hippocampal tissue was collected at the termination of the study for qPCR. Here were report that mice exposed to dLAN increase depressive-like responses in both a sucrose anhedonia and forced swim test. In contrast to findings in diurnal grass rats, dLAN mice perform comparably to mice housed under dark nights in a hippocampus-dependent learning and memory task. TNFα and IL1β gene expression do not differ between groups, demonstrating that changes in these pro-inflammatory cytokines do not mediate dLAN induced depressive-like responses in mice. BDNF expression is reduced in the hippocampus of mice exposed to dLAN. These results indicate that low levels of LAN can alter mood in mice. This study along with previous work implicates LAN as a potential factor contributing to depression. Further understanding of the mechanisms through which LAN contributes to changes in mood is important for characterizing and treating depressive disorders. [Copyright &y& Elsevier]

Abstract: The autocrine motility factor receptor (AMFR) is a multifunctional protein involved in cellular adhesion, proliferation, motility and apoptosis. Our study showed that increased AMFR protein expression in the hippocampus of KM mice correlated with enhanced capacity for learning and memory following the shuttle-box test and was significantly elevated in the highest score group. Also, AMF and AMFR mRNA expression positively correlates with the mRNA expression of the synapse marker synaptophysin (Syp). Aging studies in the senescence-accelerated mouse strain (SAM) prone/8 (SAMP8), an animal model of Alzheimer''s disease (AD), revealed significantly decreased mRNA and protein expression of AMF and AMFR in the hippocampus. This is especially true for AMFR and AMF protein expression compared with age-matched SAM resistant/1 (SAMR1) mouse strain as the control. Additionally, the low mRNA expression of AMFR could be up-regulated by the four nootropic traditional Chinese medicinal prescriptions (TCMPs): Ba-Wei-Di-Huang decoction (BW), Huang-Lian-Jie-Du decoction (HL), Dang-Gui-Shao-Yao-San (DSS) and Tiao-Xin-Fang decoction (TXF). AMFR protein expression could be up-regulated by two TCMPs, Liu-Wei-Di-Huang decoction (LW) and BW. This indicated that AMFR is involved in the process of learning and memory in the central nervous system. These results may provide useful clues for understanding the etiology of AD. [Copyright &y& Elsevier]

Abstract: Although habituation is ubiquitous in the animal kingdom, its underlying mechanisms remain poorly understood. In this study, we began to explore the molecular cascades underlying short-term habituation in the leech Hirudo medicinalis. In H. medicinalis, a training paradigm, consisting of low-frequency repetitive electrical stimulation of the skin, produces a gradual increase in the latency to swim that spontaneously recovers within 20–30min. As first step in determining the molecular pathways in short-term habituation, we examined the role of Ca2+. Both Ca2+ influx through voltage-gated channels and Ca2+ release from intracellular stores were found to contribute to short-term habituation. The analysis of the downstream targets of elevated cytosolic Ca2+ revealed that the activation of the phosholipase A2 was required for the induction of short-term habituation. Finally, we reported that the recruitment of arachidonic acid metabolites, generated by the 5-lipoxygenase pathway, was also necessary for the induction of swim induction habituation. These results provide the framework for a comprehensive characterization of the molecular underpinnings of habituation. This outcome will allow us to compare the mechanisms of habituation with those underlying other forms of nonassociative learning in the leech, such as sensitization and dishabituation, and, more in general, with those governing habituation in different vertebrate and invertebrate model systems. [Copyright &y& Elsevier]

Abstract: Sub-concussive brain injuries may result in neurophysiological changes, cumulative effects, and neurodegeneration. The current study investigated the effects of a mild lateral fluid percussion injury (0.50–0.99atm) on rat behavior and neuropathology to address the need to better understand sub-concussive brain injury. Male Long-Evans rats received either a single mild lateral fluid percussion injury or a sham-injury, followed by either a short (24h) or long (4 weeks) recovery period. After recovery, rats underwent extensive behavioral testing consisting of tasks for rodent cognition, anxiety- and depression-like behaviors, social behavior, and sensorimotor function. At the completion of behavioral testing rats were sacrificed and brains were examined immunohistochemically with markers for neuroinflammation and axonal injury. No significant group differences were found on behavioral and axonal injury measures. However, rats given one mild fluid percussion injury displayed an acute neuroinflammatory response, consisting of increased microglia/macrophages and reactive astrogliosis, at 4 days post-injury. Neuroinflammation is a mechanism with the potential to contribute to the cumulative and neurodegenerative effects of repeated sub-concussive injuries. The current findings are consistent with findings in humans experiencing a sub-concussive blow, and provide support for the use of mild lateral fluid percussion injury in the rat as a model of sub-concussive brain injury. [Copyright &y& Elsevier]

Abstract: The mechanism underlying the decline of age-related learning and memory remains unclear. Brain-region-specific changes of synaptic proteins and decreased thyroid hormones (THs) have been implied involving this decline. During normal aging, however, the relationships among synaptic proteins, THs and abilities of learning and memory remain to be elucidated. In this study, the age-related spatial learning and memory ability of 41 Kunming mice (KM) (14 mice aged 6 months, 13 mice aged 11 months, 14 mice aged 22 months) was measured with radial six-arm water maze. The levels of SNAP-25 and Munc18-1 in brain regions were semi-quantified by Western blotting and the serum THs were detected by radioimmunoassay. Our results showed the old Kunming mice had marked impairment of spatial learning and memory, with decreased serum free triiodothyronine (FT3) and increased SNAP-25 and Munc18-1 in dorsal hippocampus (DH), ventral hippocampus (VH) and frontal lobe (F). The Pearson''s correlation test showed the impairment of spatial learning ability positively correlated with SNAP-25 in DH and Munc18-1 in DH and VH. While, the levels of SNAP-25 (DH, VH and F) and Munc18-1 (DH) negatively correlated with the serum FT3 level, and the spatial memory decline marginal negatively correlate with serum THs. These results suggested that increased hippocampal SNAP-25 and Munc18-1 which seemingly result from decreased serum THs might involve the age-related impairment of spatial learning and memory. [Copyright &y& Elsevier]

Abstract: Transgenic mice that express familial Alzheimer''s disease mutant forms of the human amyloid precursor protein (hAPP) have proved to be invaluable in determining the impact that the neurotoxic amyloid-β peptide has in vivo. In addition to the propensity to accumulate cerebral amyloid plaques, a crucial characteristic of hAPP mouse models is their cognitive impairments. To date the most widely used test for analyzing cognitive impairment in hAPP mice is the Morris water maze (MWM) which, due to the fact that mice are not “natural” swimmers, may not always be the ideal paradigm to investigate cognitive behaviours. Furthermore, not all cognitive impairments have been replicated across research laboratories. In the current study, we characterised the cognitive abilities of the J20 transgenic mouse line (expressing the Swedish 670/671KM->NL and Indiana (717V->F hAPP mutations) and non-transgenic mice. Mice were assessed in the cheeseboard task (i.e., a ‘dry version’ of the MWM) and a variety of other cognitive paradigms to test fear conditioning, object recognition and short-term memory to broaden the understanding of the cognitive deficits in J20 mice. hAPP transgenic mice perform normally in tasks for fear conditioning, short-term object recognition and short-term memory of context familiarity. However, they were profoundly impaired in their spatial reference memory capabilities in the cheeseboard task. The cheeseboard task has potential to replace the MWM task in situations where the MWM is not suitable for particular mouse models. [Copyright &y& Elsevier]

Abstract: Neuregulin 1 (Nrg1) has been implicated in the development of schizophrenia and influences key neurodevelopmental processes such as myelination and neuronal migration. The heterozygous transmembrane domain Nrg1 mutant mouse (Nrg1 TM HET) exhibits a sex-specific phenotype relevant for schizophrenia research, which is characterized by the development of locomotor hyperactivity, social withdrawal, and changes to the serotonergic system. Cognitive impairments are characteristic of schizophrenia patients and male Nrg1 TM HET mice exhibit cognitive deficits in novel object recognition and contextual fear conditioning. Thus, we investigated the cognitive performance of female Nrg1 mutants, using a cognitive test battery for a variety of paradigms, including fear conditioning, cheeseboard, Y maze, object exploration and passive avoidance. Female Nrg1 mutant mice displayed impairments in the fear conditioning tasks, including significantly reduced fear conditioning to a context and a strong trend towards a decreased ability for cue fear conditioning. These cognitive deficits were task-specific, as no differences were seen between mutant and control mice in spatial learning of the cheeseboard for reference memory measures, in the Y-maze for working memory measures, or in novel object recognition and passive avoidance paradigms. These findings indicate that neuregulin 1 plays only a minor role in cognition in female test mice. The current study provides a further behavioural validation of this genetic mouse model for the schizophrenia candidate gene neuregulin 1 and confirms the importance of considering female test animals in animal models for schizophrenia. [Copyright &y& Elsevier]

Abstract: Previous research has demonstrated that diabetes induced learning and memory deficits. However, the mechanism of memory impairment induced by diabetes is poorly understood. Sprague–Dawley rats were used in the present study to investigate the effect of streptozotocin (STZ)-induced diabetes on spatial learning and memory with the Morris water maze. The excitability of CA1 pyramidal neurons in hippocampus was also examined. Diabetes impaired spatial learning and memory of rats. Diabetes decreased the membrane excitability of CA1 pyramidal neurons, effects which may contribute to the behavioral deficits. To investigate the further ionic mechanisms, the sodium currents and the potassium currents were detected. Diabetes decreased both transient and persistent sodium currents, and increased both transient and sustained potassium currents, which leads to the reduction of neuron excitability and to the increase of firing accommodation. The results of the present study suggested that sodium and potassium currents contributed to the inhibitory effect of diabetes on neuron excitability, further influencing learning and memory processing. Modulating the ion channels and increasing the membrane excitability are possible candidates for preventing the impairments of diabetes on hippocampal function. [Copyright &y& Elsevier]

Abstract: Due to anti-diabetic and antioxidant activity of green tea epigallocatechin gallate (EGCG) and the existence of evidence for its beneficial effect on cognition and memory, this research study was conducted to evaluate, for the first time, the efficacy of chronic EGCG on alleviation of learning and memory deficits in streptozotocin (STZ)-diabetic rats. Male Wistar rats were divided into control, diabetic, EGCG-treated-control and -diabetic groups. EGCG was administered at a dose of 20 and 40mg/kg/day for 7 weeks. Learning and memory was evaluated using Y maze, passive avoidance, and radial 8-arm maze (RAM) tests. Oxidative stress markers and involvement of nitric oxide system were also evaluated. Alternation score of the diabetic rats in Y maze was lower than that of control and a significant impairment was observed in retention and recall in passive avoidance test (p <0.01) and EGCG treatment (40mg/kg) of diabetic rats significantly improved these parameters (p <0.05). Also, diabetic animals exhibited fewer correct choices (p <0.01) and more errors (p <0.005) in the RAM task and EGCG (40mg/kg) significantly ameliorated these changes (p <0.05). Further, pretreatment with l-arginine as a substrate for nitric oxide synthase (NOS) and/or 7-nitroindazole as a neuronal NOS inhibitor attenuated and potentiated the beneficial effect of EGCG regarding learning and memory respectively. Meanwhile, increased levels of malondialdehyde (MDA) and nitrite in diabetic rats significantly reduced due to EGCG treatment (p <0.05). In summary, chronic green tea EGCG dose-dependently could ameliorate learning and memory deficits in STZ-diabetic rats through attenuation of oxidative stress and modulation of NO. [Copyright &y& Elsevier]

Abstract: Brain concussion is a serious public health concern and is associated with short-term cognitive impairments and behavioral disturbances that typically occur in the absence of significant brain damage. The current study addresses the need to better understand the effects of a mild lateral fluid percussion injury on rat behavior and neuropathology in an animal model of concussion. Male Long–Evans rats received either a single mild fluid percussion injury or a sham-injury, and either a short (24h) or long (4 weeks) post-injury recovery period. After recovery, rats underwent a detailed behavioral analysis consisting of tests for rodent anxiety, cognition, social behavior, sensorimotor function, and depression-like behavior. After testing all rats were sacrificed and brains were examined immunohistochemically with markers for microglia/macrophage activation, reactive astrocytosis, and axonal injury. Injured rats (mean injury force: 1.20±.03atm) displayed significant short-term cognitive impairments in the water maze and significantly more anxiolytic-like behavior in the elevated-plus maze compared to sham controls. Neuropathological analysis of the brains of injured rats showed an acute increase in reactive astrogliosis and activated microglia in cortex and evidence of axonal injury in the corpus callosum. There were no significant long-term effects on any behavioral or neuropathological measure 4 weeks after injury. These short-term behavioral and neuropathological changes are consistent with findings in human patients suffering a brain concussion, and provide further evidence for the use of a single mild lateral fluid percussion injury to study concussion in the rat. [Copyright &y& Elsevier]

Abstract: Current smoking cessation aids are relatively ineffective at maintaining abstinence during withdrawal. Nicotine withdrawal is associated with a variety of symptoms including cognitive deficits and targeting these deficits may be a useful strategy for maintaining abstinence. Galantamine is an acetylcholinesterase inhibitor and allosteric modulator of nicotinic acetylcholine receptors (nAChRs) with cognitive enhancing effects that may alleviate cognitive deficits associated with nicotine withdrawal. The effects of galantamine on nicotine withdrawal-induced deficits in contextual fear conditioning in C57BL/6 mice were examined. An initial acute dose–response experiment revealed that 0.5 and 1mg/kg galantamine had no effect on fear conditioning. To determine if galantamine would reverse nicotine withdrawal-related deficits in contextual fear conditioning, mice were implanted with osmotic mini-pumps that delivered chronic saline or 6.3mg/kg/d nicotine for 12 days and then pumps were removed. Training and testing of fear conditioning occurred 24 and 48h later, respectively. Nicotine withdrawal disrupted contextual fear conditioning, which was reversed with 1 but not 0.5mg/kg galantamine. Across all conditions in both studies 2mg/kg galantamine led to high levels of freezing that were likely due to nonspecific effects. The ability of galantamine to reverse nicotine withdrawal-deficits in contextual conditioning is likely mediated through enhanced levels of acetylcholine via inhibition of acetylcholinesterase, potentiation of hippocampal α4β2* nAChRs, or both. The present study suggests that acetylcholinesterase inhibitors and/or drugs that act as allosteric modulators of nAChRs might be targets for smoking cessation aids because they may alleviate withdrawal symptoms such as cognitive deficits that can lead to relapse. [Copyright &y& Elsevier]

Abstract: The reuniens nucleus (RE) is the largest nucleus of the midline thalamic nuclei (MLN). RE has strongly connections with the amygdala and hippocampus, the structures that are involved in the learning and memory processes. In our previous report we have shown the role of RE in the spatial learning and memory using Morris water maze (MWM) task. Since RE is connected to multiple limbic structures, its involvement in the emotional learning and memory is a possibility. The present study was designed to elucidate the role of RE in acquisition, consolidation, and retrieval on the passive avoidance (PA) task which depends on a distributed network including the thalamus, amygdala, medial prefrontal cortex (mPFC) and hippocampus. For this purpose, rats were chronically implanted with a cannula aimed at the RE through which 0.5μl tetracaine (2%) or saline were injected. Rats were trained in a PA task and their retention test was performed 24h later. The injection of saline or tetracaine was applied 5min before or 5, 90, and 360min after the acquisition trial and 5min before the retention tests. Our findings showed that inactivation of RE before training did not affect acquisition, but affected memory retention 24h later in PA task. Moreover, inactivation of RE only 5min after training impaired consolidation but not after 90 or 360min. Also, inactivation of the RE, 5min before the retrieval test impaired memory retrieval in PA task. In conclusion, it seems that RE is involved in memory processes in rats. [Copyright &y& Elsevier]

Abstract: We have previously reported that lurasidone, a novel atypical antipsychotic with potent serotonin 5-HT7 antagonist and 5-HT1A partial agonist activities, is superior to other antipsychotics in improving the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801-induced learning and memory impairment in the passive avoidance (PA) and Morris water maze (MWM) tests in rats. In this study, we investigated the effects of selective antagonists of 5-HT7 and 5-HT1A receptors (SB-656104-A and WAY-100635, respectively) on MK-801-induced learning and memory impairment in the same tests. In the PA test, either pre-training (3 and 10mg/kg, p.o.) or post-training (0.3mg/kg, i.v.) administration of lurasidone significantly reversed the test response impaired by MK-801, consistent with our previous reports. Pre-training administration of either SB-656104-A (10 and 30mg/kg, i.p.) or WAY-100635 (1mg/kg, s.c.) also significantly reversed MK-801-induced memory impairment. Furthermore, post-training administration of either SB-656104-A (0.3mg/kg, i.v.) or WAY-100635 (0.01mg/kg, i.v.) counteracted the effect of MK-801, which suggested that both 5-HT receptor subtype-selective antagonists could restore the memory consolidation process. In the MWM test, SB-656104-A (3mg/kg, i.p.) reversed learning impairment induced by MK-801. On the other hand, WAY-100635 (0.3 and 1mg/kg, i.p.) did not have any effect on the MK-801-induced learning impairment. Taken together, our results showed that 5-HT7 and 5-HT1A receptor antagonists mimic the effect of lurasidone in whole or in part, respectively, to reverse MK-801-induced learning and memory impairment, which warrants further investigation of the interaction of lurasidone with these serotonin receptors as a possible mechanism underlying its procognitive effects in these animal models. [Copyright &y& Elsevier]