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Maternal exposure to elevated levels of steroid hormones during pregnancy is associated with the development of chronic conditions in offspring that manifest in adulthood. However, the effects of progesterone (P4) administration during early pregnancy on fetal development and subsequent offspring behavior remain poorly understood. In this study, we aimed to investigate the effects of P4 treatment during early pregnancy on the transcript abundance in the fetal brain and assess the behavioral consequences in the offspring during adolescence and adulthood. Using RNA-seq analysis, we examined the impact of P4 treatment on the fetal brain transcriptome in a dosage-dependent manner. Our results revealed differential regulation of genes involved in neurotransmitter transport, synaptic transmission, and transcriptional regulation. Specifically, we observed bidirectional regulation of transcription factors (TFs) by P4 at different doses, highlighting the critical role of these TFs in neurodevelopment. To assess behavioral outcomes, we conducted open field and elevated plus maze tests. Offspring treated with low-dose P4 (LP4) displayed increased exploratory behavior during both adolescence and adulthood. In contrast, the high-dose P4 (HP4) group exhibited impaired exploration and heightened anxiety-like behaviors compared to the control mice. Moreover, in a novel object recognition test, HP4-treated offspring demonstrated impaired object recognition memory during both developmental stages. Additionally, both LP4 and HP4 groups showed reduced social interaction in the three-chamber test. These results suggest that prenatal exposure to P4 exerts a notable influence on the expression of genes associated with neurodevelopment and may induce alterations in behavioral characteristics in progeny, highlighting the need to monitor progesterone levels during pregnancy for long-term impacts on fetal brain development and behavior., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

Older adult patients with sepsis frequently experience cognitive impairment. The roles of brain neutrophil gelatinase-associated lipocalin (NGAL) and iron in older sepsis patients remain unknown. We investigated the effects of lipopolysaccharide-induced sepsis on novel object recognition test, NGAL levels, an inflammatory mediator tumor necrosis factor-α (TNFα) levels, and iron ion levels in the hippocampus and cortex of young and aged rats. The effect of an iron chelator deferoxamine pretreatment on aged sepsis rats was also examined. Young sepsis-survivor rats did not show impaired novel object recognition, TNFα responses, or a Fe 2+ /Fe 3+ imbalance. They showed hippocampal and cortical NGAL level elevations. Aged sepsis-survivor rats displayed a decreased object discrimination index, elevation of NGAL levels and Fe 2+ /Fe 3+ ratio, and no TNFα responses. Pretreatment with deferoxamine prevented the reduction in the object recognition of aged sepsis-survivor rats. The elevation in hippocampal and cortical NGAL levels caused by lipopolysaccharide was not influenced by deferoxamine pretreatment. The lipopolysaccharide-induced Fe 2+ /Fe 3+ ratio elevation was blocked by deferoxamine pretreatment. In conclusion, our findings suggest that iron homeostasis in the cortex and hippocampus contributes to the maintenance of object recognition ability in older sepsis survivors., (© 2022. The Author(s).)

Perinatal hypoxic ischemic encephalopathy (HIE) remains a major contributor of infant death and long-term disability worldwide. The role played by the complement system in this ischemia-reperfusion injury remains poorly understood. In order to better understand the role of complement activation and other modifiable mechanisms of injury in HIE, we tested the dual-targeting anti-inflammatory peptide, RLS-0071 in an animal model of HIE. Using the well-established HIE rat pup model we measured the effects of RLS-0071 during the acute stages of the brain injury and on long-term neurocognitive outcomes. Rat pups subject to hypoxia-ischemia insult received one of 4 interventions including normothermia, hypothermia and RLS-0071 with and without hypothermia. We measured histopathological effects, brain C1q levels and neuroimaging at day 1 and 21 after the injury. A subset of animals was followed into adolescence and evaluated for neurocognitive function. On histological evaluation, RLS-0071 showed neuronal protection in combination with hypothermia (P = 0.048) in addition to reducing C1q levels in the brain at 1hr (P = 0.01) and at 8 hr in combination with hypothermia (P = 0.005). MRI neuroimaging demonstrated that RLS-0071 in combination with hypothermia reduced lesion volume at 24 hours (P<0.05) as well as decreased T2 signal at day 21 in combination with hypothermia (P<0.01). RLS-0071 alone or in combination with hypothermia improved both short-term and long-term memory. These findings suggest that modulation by RLS-0071 can potentially decrease brain damage resulting from HIE., Competing Interests: Commercial affiliation with ReAlta Life Sciences Inc, does not alter our adherence to PLOS ONE policies on sharing data and materials.

The development of refractory status epilepticus (SE) induced by sarin intoxication presents a therapeutic challenge. In our current research we evaluate the efficacy of a delayed combined triple treatment in ending the abnormal epileptiform seizure activity (ESA) and the ensuing of long-term neuronal insult. SE was induced in male Sprague-Dawley rats by exposure to 1.2LD 50 sarin insufficiently treated by atropine and TMB4 (TA) 1 min later. Triple treatment of ketamine, midazolam and valproic acid was administered 30 min or 1 h post exposure and was compared to a delayed single treatment with midazolam alone. Toxicity and electrocorticogram activity were monitored during the first week and behavioral evaluation performed 3 weeks post exposure followed by brain biochemical and immunohistopathological analyses. The addition of both single and triple treatments reduced mortality and enhanced weight recovery compared to the TA-only treated group. The triple treatment also significantly minimized the duration of the ESA, reduced the sarin-induced increase in the neuroinflammatory marker PGE2, the brain damage marker TSPO, decreased the gliosis, astrocytosis and neuronal damage compared to the TA+ midazolam or only TA treated groups. Finally, the triple treatment eliminated the sarin exposed increased open field activity, as well as impairing recognition memory as seen in the other experimental groups. The delayed triple treatment may serve as an efficient therapy, which prevents brain insult propagation following sarin-induced refractory SE, even if treatment is postponed for up to 1 h., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Ethnopharmacological Relevance: Phyllanthus niruri L. (Phyllanthaceae) is a plant used in traditional medicine, mainly to treat kidney stones. However, the effects of maternal exposure to P. niruri remain poorly explored., Aim of the Study: The objective of this study was to investigate the effects of administration of aqueous extract of P. niruri (AEPN) during pregnancy and lactation, in maternal toxicity, reflex maturation, and offspring memory., Materials and Methods: Pregnant rats were divided into three groups (n = 8/group): Control (vehicle), AEPN 75, and AEPN 150 (each respectively treated with P. niruri at a dose of 75 and 150 mg/kg/day). The animals were treated via intragastric gavage during pregnancy and lactation. Weight gain, feed intake, and reproductive performance were analyzed in the mothers. In the offspring, the following tests were performed: Neonatal Reflex Ontogeny, Open Field Habituation Test and the Object Recognition Test in adulthood., Results: Maternal exposure to AEPN did not influence weight gain, feed intake, or reproductive parameters. In the offspring, anticipation of reflex ontogenesis (time of completion) was observed (p < 0.05). During adulthood, the AEPN groups presented decreases in exploratory activity upon their second exposure to the Open Field Habituation Test (in a dose-dependent manner) (p < 0.05). In the Object Recognition Test, administration of the extract at 75 and 150 mg/kg induced significant dose-dependent improvements in short and long-term memory (p < 0.05)., Conclusion: Administration of the AEPN accelerated the reflex maturation in neonates, and improved offspring memory while inducing no maternal or neonatal toxicity., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A survey of the literature indicates that the developmental disruptions in serotonin (5-HT) levels can influence the brain development and the function. To the best of our knowledge, so far, there are a few studies about the effects of developmental period 5-HT depletion on cognition and behavior of adult male and female rats. Therefore, in the present study, we examined the effects of postnatal days (PND 10-20) administration of para-chlorophenylalanine (PCPA, 100 mg/kg, s.c) a 5-HT synthesis inhibitor, on anxiety-related behaviors, pain sensitivity, short-term recognition memory, and hippocampal and prefrontal cortex (PFC) brain-derived neurotrophic factor (BDNF) mRNA expression in adult male and female rats. Novel object recognition memory (NORM) and behavioral parameters (anxiety-like behaviors and pain sensitivity) were evaluated in early adulthood and after that, the hippocampi and PFC of the rat's brain were removed for the determination of BDNF mRNA expression. Our results indicated that the postnatal period administration of PCPA impaired short-term NORM. The postnatal developmental period treatment with PCPA also increased anxiety-like behaviors in the open field and elevated plus maze (EPM) tests. Postnatal PCPA treatment increased pain sensitivity in the hot plate test in both male and female rats, especially in female animals. In addition, postnatal days serotonin depletion decreased BDNF level in the hippocampus and PFC of both male and female rats. These findings demonstrate that serotonin plays the main role in neurodevelopment, cognitive functions, and behavior. Therefore, serotonergic system dysregulation during the developmental periods may have more adverse influences on the brain development of rats., (© 2021 International Society for Developmental Neuroscience.)

Background: Extensive data point to the immune system as an important factor underlying the pathogenesis of brain diseases. Epidemiological studies have shown that long-term treatment with non-steroidal anti-inflammatory drugs (NSAIDs) significantly reduces the onset and progression of Alzheimer's disease. The present study aimed to investigate whether ibuprofen (IBU) is able to prevent the long-lasting alterations of brain function induced by systemic inflammation., Methods: Mice received intraperitoneal injections of lipopolysaccharide (LPS; 250 µg/kg/day) for seven consecutive days. Ibuprofen administration (40 mg/kg/day) was started three days before the LPS injections and continued until the last day of LPS injection. Within the next 2 weeks, mice performances on the behavioral tests were evaluated, and then brain tissue samples for biochemical analyses were collected., Results: The findings showed that ibuprofen significantly improved mice's performance in the passive avoidance test and reduced anxiety- and depressive-like behaviors. However, ibuprofen could not significantly improve spatial memory in the Morris water maze test and recognition ability in the novel object recognition test. TNF-α and IL-1β cytokines levels and malondialdehyde (MDA) concentration in the hippocampal tissues of LPS-treated mice were significantly lowered by ibuprofen treatment, whereas no significant effects on IL-10 production and hippocampal BDNF levels were observed. In addition, ibuprofen did not significantly reduce amyloid-β 1-40 levels in the hippocampus of LPS-treated animals., Conclusion: Overall, the findings of the present study suggest that some, but not all, of the adverse effects of systemic inflammation are alleviated by ibuprofen treatment.

Background: Alzheimer's disease (AD) is a multifactorial disease, implying that multi-target treatments may be necessary to effectively cure AD. Tetrahydrobiopterin (BH4) is an enzymatic cofactor required for the synthesis of monoamines and nitric oxide that also exerts antioxidant and anti-inflammatory effects. Despite its crucial role in the CNS, the potential of BH4 as a treatment in AD has never been scrutinized., Objective: Here, we investigated whether BH4 peripheral administration improves cognitive symptoms and AD neuropathology in the triple-transgenic mouse model of AD (3xTg-AD), a model of age-related tau and amyloid-β (Aβ) neuropathologies associated with behavior impairment., Methods: Non-transgenic (NonTg) and 3xTg-AD mice were subjected to a control diet (5% fat - CD) or to a high-fat diet (35% fat - HFD) from 6 to 13 months to exacerbate metabolic disorders. Then, mice received either BH4 (15 mg/kg/day, i.p.) or vehicle for ten consecutive days., Results: This sub-chronic administration of BH4 rescued memory impairment in 13-month-old 3xTg-AD mice, as determined using the novel object recognition test. Moreover, the HFD-induced glucose intolerance was completely reversed by the BH4 treatment in 3xTg-AD mice. However, the HFD or BH4 treatment had no significant impact on Aβ and tau neuropathologies., Conclusion: Overall, our data suggest a potential benefit from BH4 administration against AD cognitive and metabolic deficits accentuated by HFD consumption in 3xTg-AD mice, without altering classical neuropathology. Therefore, BH4 should be considered as a candidate for drug repurposing, at least in subtypes of cognitively impaired patients experiencing metabolic disorders.

In utero Bisphenol A (BPA) exposure has been linked to many deficits during brain development, including sexual differentiation, behavior, and motor coordination. Yet, how BPA induces these disorders and whether its effects are long lasting are largely unknown. In this study, using a mouse model, we demonstrated that in utero exposure to an environmentally relevant dose of BPA induced locomotor deficits, anxiety-like behavior, and declarative memory impairments that persisted into old age (18 months). Compared to the control animals, the BPA-exposed mice had a significant decrease in locomotor activity, exploratory tendencies, and long-term memory, and an increase in anxiety. The global brain gene expression profile was altered permanently by BPA treatment and showed regional and sexual differences. The BPA-treated male mice had more changes in the hippocampus, while female mice experienced more changes in the cortex. Overall, we demonstrate that in utero exposure to BPA induces permanent changes in brain gene expression in a region-specific and sex-specific manner, including a significant decrease in locomotor activity, learning ability, long-term memory, and an increase in anxiety. Fetal/early life exposures permanently affect neurobehavioral functions that deteriorate with age; BPA exposure may compound the effects of aging., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Alcohol consumption during pregnancy is widespread and contributes to pediatric neurological defects, including hippocampal and neocortex dysfunction, causing cognitive deficits termed fetal alcohol spectrum disorders. However, the critical mechanisms underlying these brain abnormalities remain poorly described., Methods: Using a postnatal ethanol exposure (PEE) animal model and pharmacological, epigenetic, synaptic plasticity-related and behavioral approaches, we discovered a novel persistent epigenetic mechanism of neurodegeneration in neonatal hippocampus and neocortex brain regions and of cognitive decline in adult animals., Results: PEE, which activates caspase-3 (CC3, a neurodegeneration marker), enhanced histone deacetylase (HDAC1-HDAC3) levels and reduced histone 3 (H3) and 4 (H4) acetylation (ac) in mature neurons. PEE repressed the expression of several synaptic plasticity genes, such as brain-derived neurotrophic factor, C-Fos, early growth response 1 (Egr1), and activity-regulated cytoskeleton-associated protein (Arc). Detailed studies on Egr1 and Arc expression revealed HDAC enrichment at their promoter regions. HDAC inhibition with trichostatin A (TSA) before PEE rescued H3ac/H4ac levels and prevented CC3 formation. Antagonism/null mutation of cannabinoid receptor type-1 (CB1R) before PEE to inhibit CC3 production prevented Egr1 and Arc loss via epigenetic events. TSA administration before PEE prevented postnatal ethanol-induced loss of Egr1 and Arc expression and neurobehavioral defects in adult mice via epigenetic remodeling. In adult mice, 3-day TSA administration attenuated PEE-induced behavioral defects., Conclusions: These findings demonstrate that CB1R/HDAC-mediated epigenetic remodeling disrupts gene expression and is a critical step in fetal alcohol spectrum disorder-associated cognitive decline but is reversed by restoration of histone acetylation in the brain., (Published by Oxford University Press on behalf of CINP 2020.)

D-Ribose-L-cysteine (DRLC), an analog of cysteine that boosts glutathione (GSH) content, has been reported to mitigate oxidative stress-mediated diseases. This study seeks to evaluate the effects of DRLC on memory deficits and the biochemical and histo-morphological changes induced by lipopolysaccharide (LPS) in mice. Male Swiss mice (n = 10) were pre-treated orally with three doses of DRLC (25 mg/kg, 50 mg/kg, and 100 mg/kg), donepezil (1 mg/kg), or vehicle (saline) for 30 min prior to the intraperitoneal injection of LPS (0.25 mg/kg) daily for 7 days. Memory functions were evaluated using the Y-maze, object recognition, and social recognition tests. The specific brain regions (prefrontal cortex and hippocampus) were evaluated to determine oxidative stress biomarkers (malondialdehyde, GSH, and catalase), acetyl-cholinesterase activity, proinflammatory cytokines (tumor necrosis factor-α and interleukin-6), expression of nuclear factor-kappa B (NF-κB), and neuronal cell morphology. DRLC (25-100 mg/kg) reversed the memory deficits in the LPS-treated mice (p < 0.05). The increased oxidative stress and proinflammatory cytokines in the brain regions of the LPS-treated mice were significantly (p < 0.05) reduced by DRLC. DRLC (50 mg/kg and 100 mg/kg) also reduced acetyl-cholinesterase activity and decreased NF-κB expression in the brains of LPS-treated mice. Finally, it attenuated the cytoarchitectural distortions and loss of neuronal cells of the prefrontal cortex and hippocampus that were induced by LPS in mice. The results of this study suggest that DRLC attenuates memory deficit induced by LPS in mice through mechanisms related to the inhibition of oxidative stress, release of proinflammatory cytokines, and expression of NF-κB in mice.

In recent years, there has been a growing appreciation that 17β-estradiol (E2) can rapidly modulate learning and memory processes by binding to membrane estrogen receptors and cause the activation of a number of signaling cascades within the central nervous system. In this study, we sought to investigate the effects of post-training administration of E2 (100 ng/g, 1 μg/g, 10 μg/g) and involvement of the estrogen receptors (ERs) using selective ER agonists on the consolidation of object recognition (OR) and object placement memory (OP) in adult male zebrafish. The general activation of ERs with the highest E2 dose improved consolidation of memory in both learning tasks within 1.45 h of administration. Activation of classical ERs (ERα and ERβ) improved consolidation of OR memory, but had no effect on fish performance in OP task. On the other hand, activation of G protein-coupled ER1 impaired and enhanced consolidation of OR and OP memories, respectively. Memory improvement in both tasks was accompanied by a marked up-regulation in the expression of genes encoding ionotropic and metabotropic glutamate receptors in a task-dependent manner. In contrast, the down-regulation in the expression of certain ionotropic glutamate receptors was observed in fish with impaired OR memory. Moreover, our study also revealed an increase in the transcript abundance of genes associated with synaptic protein synthesis (brain-derived neurotrophic factor, synaptophysin, and the mechanistic target of rapamycin). These results suggest that E2 may affect consolidation of memory in zebrafish likely through rapid changes in synaptic morphology and function., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease. The present study investigated the effects of 50 and 100 mg/kg berberine (BRB) on recognition memory, oxidative stress, and purinergic neurotransmission, in a model of sporadic dementia of the Alzheimer's type induced by intracerebroventricular (ICV) injection of streptozotocin (STZ) in rats. Rats were submitted to ICV-STZ 3 mg/kg or saline, and 3 days later, were started on a treatment of BRB or saline for 21 days. The results demonstrated that BRB was effective in protecting against memory impairment, increased reactive oxygen species, and the subsequent increase in protein and lipid oxidation in the cerebral cortex and hippocampus, as well as δ-aminolevulinate dehydratase inhibition in the cerebral cortex. Moreover, the decrease in total thiols, and the reduced glutathione and glutathione S-transferase activity in the cerebral cortex and hippocampus of ICV-STZ rats, was prevented by BRB treatment. Besides an antioxidant effect, BRB treatment was capable of preventing decreases in ecto-nucleoside triphosphate diphosphohydrolase (NTPDase), 5'-nucleotidase (EC-5'-Nt), and adenosine deaminase (ADA) activities in synaptosomes of the cerebral cortex and hippocampus. Thus, our data suggest that BRB exerts a neuroprotective effect on recognition memory, as well as on oxidative stress and oxidative stress-related damage, such as dysfunction of the purinergic system. This suggests that BRB may act as a promising multipotent agent for the treatment of AD.

Research in Alzheimer's disease is going through a big turnaround. New palliative therapies are being reconsidered for the effective management of disease because of setbacks in the development of disease-modifying therapies. Serotonin 6 (5-HT6) receptor has long been pursued as a potential target for the symptomatic treatment of Alzheimer's disease. SUVN-502 is a novel 5-HT6 receptor antagonist (Ki=2.04 nmol/l) with high receptor affinity and high degree of selectivity. SUVN-502 at doses ranging from 1 to 10 mg/kg, per os (p.o.) demonstrated procognitive effects in various behavioral animal models (object recognition task, water maze, and radial arm maze), and it acts on three phases of cognition, viz., acquisition, consolidation, and retention (object recognition task). SUVN-502 (3 and 10 mg/kg, p.o.) modulated glutamate levels when administered alone (microdialysis). At doses ranging from 1 to 10 mg/kg p.o., SUVN-502 potentiated the effects of donepezil (microdialysis). SUVN-502 [1 mg/kg, intravenous (i.v.)] also potentiated pharmacological effects of memantine (1 mg/kg, i.v.) and/or donepezil (0.3 mg/kg, i.v.) (θ modulation). The beneficial effects of SUVN-502 on learning and memory might be mediated through the modulation of cholinergic and/or glutamatergic neurotransmission in relevant brain regions. In summary, behavioral, neurochemical, and electrophysiological outcomes indicate that SUVN-502 may augment the beneficial effects of donepezil and memantine combination.

Background: Menopause is associated with increased oxidative stress and memory impairment. Based on the antioxidant property of ascorbic acid (AA), It's effect on cognitive function, the serum level of the brain-derived neurotrophic factor (BDNF) and the activity of antioxidant enzymes within the brain in ovariectomized (OVX) mice was investigated., Methods: AA (100, 300 and 500 mg/kg), was orally administrated per day in OVX mice for 30 days. Tactile learning and working memory were evaluated by the novel object recognition task and T-maze continuous alternation task, respectively. The levels of serum BDNF were measured and animals' brains were analyzed for the superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity., Results: AA prevented from the deleterious effects of ovariectomy on learning memory (300 and 500 mg/kg) and working memory (100 and 500 mg/kg). The serum BDNF level was also increased in OVX animals treated with AA (100 and 500 mg/kg). Furthermore, AA (500 mg/kg) increased the SOD and GPx activity in the brain of OVX animals., Conclusions: Collectively, the results of the present study suggest that AA might be an appropriate choice in loss or reduction of estradiol for the amelioration of cognitive impairment., (Copyright © 2018 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.)

While memory encoding and consolidation processes have been linked with dopaminergic signaling for a long time, the role of dopamine in episodic memory retrieval remained mostly unexplored. Based on previous observations of striatal activity during memory retrieval, we used pharmacological functional magnetic resonance imaging to investigate the effects of dopamine on retrieval performance and metacognitive memory confidence in healthy humans. Dopaminergic modulation by the D2 antagonist haloperidol administered acutely during the retrieval phase improved recognition accuracy of previously learned pictures significantly and was associated with increased activity in the substantia nigra/ventral tegmental area, locus coeruleus, hippocampus, and amygdala during retrieval. In contrast, confidence for new decisions was impaired by unsystematically increased activity of the striatum across confidence levels and restricted range of responsiveness in frontostriatal networks under haloperidol. These findings offer new insights into the mechanisms underlying memory retrieval and metacognition and provide a broader perspective on the presence of memory problems in dopamine-related diseases and the treatment of memory disorders.

In the pathophysiology of Alzheimer's disease (AD), the deposition of amyloid β protein (Aβ) is associated with oxidative stress, leading to cognitive impairment and neurodegeneration. Betaine (glycine betaine or trimethylglycine), known as an osmolyte and methyl donor in mammalian cells, has been reported to suppress the proinflammatory response and oxidative stress in the kidneys, but the effects of betaine on brain diseases remain to be determined. Here, to investigate the effects of betaine treatment on cognitive impairment and the increase in oxidative stress in the brain of an AD animal model, we performed a novel object recognition test and measured the malondialdehyde (MDA; a marker of oxidative stress) levels in the frontal cortex and hippocampus of mice intracerebroventricularly injected with Aβ 25-35 , an active fragment of Aβ. Betaine prevented cognitive impairment as well as increases of the cortical and hippocampal MDA levels in Aβ 25-35 -injected mice. Of note, NNC 05-2090, a selective inhibitor of betaine/GABA transporter-1 (GAT2/BGT-1), reduced the preventive effects of betaine on Aβ 25-35 -induced cognitive impairment without affecting the increased MDA levels in the brain of Aβ 25-35 -injected mice. As betaine is used as a substrate of GAT2/BGT-1, these results suggest that betaine is transported through GAT2/BGT-1 and prevents cognitive impairment in Aβ 25-35 -injected mice, but GAT2/BGT-1 function is not required for the antioxidant effects of betaine., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Hypertension and mineralocorticoid receptor activation cause cerebral parenchymal arteriole remodeling; this can limit cerebral perfusion and contribute to cognitive dysfunction. We used a mouse model of angiotensin II-induced hypertension to test the hypothesis that mineralocorticoid receptor activation impairs both transient receptor potential vanilloid (TRPV)4-mediated dilation of cerebral parenchymal arterioles and cognitive function. Mice (16-18 wk old, male, C57Bl/6) were treated with angiotensin II (800 ng·kg -1 ·min -1 ) with or without the mineralocorticoid receptor antagonist eplerenone (100 mg·kg -1 ·day -1 ) for 4 wk; sham mice served as controls. Data are presented as means ± SE; n = 5-14 mice/group. Eplerenone prevented the increased parenchymal arteriole myogenic tone and impaired carbachol-induced (10 -9 -10 -5 mol/l) dilation observed during hypertension. The carbachol-induced dilation was endothelium-derived hyperpolarization mediated because it could not be blocked by N-nitro-l-arginine methyl ester (10 -5 mol/l) and indomethacin (10 -4 mol/l). We used GSK2193874 (10 -7 mol/l) to confirm that in all groups this dilation was dependent on TRPV4 activation. Dilation in response to the TRPV4 agonist GSK1016790A (10 -9 -10 -5 mol/l) was also reduced in hypertensive mice, and this defect was corrected by eplerenone. In hypertensive and eplerenone-treated animals, TRPV4 inhibition reduced myogenic tone, an effect that was not observed in arterioles from control animals. Eplerenone treatment also improved cognitive function and reduced microglia density in hypertensive mice. These data suggest that the mineralocorticoid receptor is a potential therapeutic target to improve cerebrovascular function and cognition during hypertension. NEW & NOTEWORTHY Vascular dementia is a growing public health issue that lacks effective treatments. Transient receptor potential vanilloid (TRPV)4 channels are important regulators of parenchymal arteriole dilation, and they modulate myogenic tone. The data presented here suggest that TRPV4 channel expression is regulated by the mineralocorticoid receptor (MR). MR blockade also improves cognitive function during hypertension. MR blockade might be a potential therapeutic approach to improve cerebrovascular function and cognition in patients with hypertension.

Background: The etiology of depression and its effective therapeutic treatment have not been clearly identified. Using behavioral phenotyping and resting-state functional magnetic resonance imaging (r-fMRI), we investigated the behavioral impact and cerebral alterations of chronic unpredictable mild stress (CUMS) in the rat. We also evaluated the efficacy of telmisartan therapy in this rodent model of depression., Methods: Thirty-two rats were divided into 4 groups: a control group(C group), a stress group(S group), a stress + telmisartan(0.5 mg/kg)group (T-0.5 mg/kg group) and a stress + telmisartan(1 mg/kg) group (T-1 mg/kg group). A behavioral battery, including an open field test (OFT), a sucrose preference test (SPT), and an object recognition test (ORT), as well as r-fMRI were conducted after 4 weeks of CUMS and telmisartan therapy. The r-fMRI data were analyzed using the amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) approach. The group differences in the behavior and r-fMRI test results as well as the correlations between these 2 approaches were examined., Results: CUMS reduced the number of rearings and the total moved distance in OFT, the sucrose preference in SPT, and novel object recognition ability in ORT. The telmisartan treatment (1 mg/kg) significantly improved B-A/B + A in the ORT and improved latency scores in the OFT and SPT. The S group exhibited a decreased ReHo in the motor cortex and pons, but increased ReHo in the thalamus, visual cortex, midbrain, cerebellum, hippocampus, hypothalamus, and olfactory cortex compared to the C group. Telmisartan (1 mg/kg)reversed or attenuated the stress-induced changes in the motor cortex, midbrain, thalamus, hippocampus, hypothalamus, visual cortex, and olfactory cortex. A negative correlation was found between OFT rearing and ReHo values in the thalamus. Two positive correlations were found between ORT B-A and the ReHo values in the olfactory cortexand pons., Conclusions: Telmisartan may be an effective complementary drug for individuals with depression who also exhibit memory impairments. Stress induced widespread regional alterations in the cerebrum in ReHo measures while telmissartan can reverse part of theses alterations. These data lend support for future research on the pathology of depression and provide a new insight into the effects of telmisartan on brain function in depression.

Elucidating how cannabinoids affect brain function is instrumental for the development of therapeutic tools aiming to mitigate 'on target' side effects of cannabinoid-based therapies. A single treatment with the cannabinoid receptor agonist, WIN 55,212-2, disrupts recognition memory in mice. Here, we evaluate how prolonged, intermittent (30 days) exposure to WIN 55,212-2 (1 mg/kg) alters recognition memory and impacts on brain metabolism and functional connectivity. We show that chronic, intermittent treatment with WIN 55,212-2 disrupts recognition memory (Novel Object Recognition Test) without affecting locomotion and anxiety-like behaviour (Open Field and Elevated Plus Maze). Through 14 C-2-deoxyglucose functional brain imaging we show that chronic, intermittent WIN 55,212-2 exposure induces hypometabolism in the hippocampal dorsal subiculum and in the mediodorsal nucleus of the thalamus, two brain regions directly involved in recognition memory. In addition, WIN 55,212-2 exposure induces hypometabolism in the habenula with a contrasting hypermetabolism in the globus pallidus. Through the application of the Partial Least Squares Regression (PLSR) algorithm to the brain imaging data, we observed that prolonged WIN 55,212-2 administration alters functional connectivity in brain networks that underlie recognition memory, including that between the hippocampus and prefrontal cortex, the thalamus and prefrontal cortex, and between the hippocampus and the perirhinal cortex. In addition, our results support disturbed lateral habenula and serotonin system functional connectivity following WIN 55,212-2 exposure. Overall, this study provides new insight into the functional mechanisms underlying the impact of chronic cannabinoid exposure on memory and highlights the serotonin system as a particularly vulnerable target., (© 2018 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Glyphosate-based herbicides (Gly-BHs) lead the world pesticide market. Although are frequently promoted as safe and of low toxicity, several investigations question its innocuousness. Previously, we described that oral exposure of rats to a Gly-BH during pregnancy and lactation decreased locomotor activity and anxiety in the offspring. The aim of the present study was to evaluate the mechanisms of neurotoxicity of this herbicide. Pregnant Wistar rats were supplied orally with 0.2 and 0.4% of Gly-BH (corresponding to 0.65 and 1.30 g/l of pure Gly, respectively) from gestational day (GD) 0, until weaning (postnatal day, PND, 21). Oxidative stress markers were determined in whole brain homogenates of PND90 offspring. The activity of acetylcholinesterase (AChE), transaminases, and alkaline phosphatase (AP) were assessed in prefrontal cortex (PFC), striatum, and hippocampus. Recognition memory was evaluated by the novel object recognition test. Brain antioxidant status was altered in Gly-BH-exposed rats. Moreover, AChE and transaminases activities were decreased and AP activity was increased in PFC, striatum and hippocampus by Gly-BH treatment. In addition, the recognition memory after 24 h was impaired in adult offspring perinatally exposed to Gly-BH. The present study reveals that exposure to a Gly-BH during early stages of rat development affects brain oxidative stress markers as well as the activity of enzymes involved in the glutamatergic and cholinergic systems. These alterations could contribute to the neurobehavioral variations reported previously by us, and to the impairment in recognition memory described in the present work.

Toluene, a commonly used organic solvent, produces a variety of behavioral disturbances in both humans and animals comparable to noncompetitive N-methyl-D-aspartate receptor (NMDARs) antagonists, such as phencyclidine (PCP). N-acetylcysteine (NAC) is capable of reversing the psychotomimetic effects of PCP via activation of cystine-glutamate antiporters (xCT). The present study examined whether NAC is capable of attenuating the toluene-induced brain stimulation reward enhancement and behavioral manifestations. Male mice received various doses of NAC prior to toluene exposure for assessment of intracranial self-stimulation (ICSS) thresholds, rotarod test, novel object recognition task and social interaction test. NAC ameliorated the lowering of ICSS thresholds, motor incoordination, object recognition memory impairments and social withdrawal induced by toluene. Furthermore, the capacity of NAC to ameliorate acute toluene-induced deficits in object recognition and social interaction was blocked by the xCT inhibitor (S)-4-carboxyphenylglycine and the mGluR2/3 antagonist LY341495. These results indicate that NAC could prevent toluene-induced reward facilitation and behavioral disturbances and its beneficial effects, at least for cognitive function and social interaction, are associated with activation of the xCT and mGluR2/3. These findings show the potential promise for NAC to treat toluene dependence and to prevent toluene intoxication caused by unintentional or deliberate inhalation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Methotrexate is a dihydrofolate reductase inhibitor widely employed in curative treatment for children with acute lymphoblastic leukemia (ALL). However, methotrexate administration is also associated with persistent cognitive deficits among long-term childhood cancer survivors. Animal models of methotrexate-induced cognitive deficits have primarily utilized adult animals. The purpose of present study is to investigate the neurotoxicity of methotrexate in juvenile rats and its relevant mechanisms. The doses and schedule of systemic and intrathecal methotrexate, given from post-natal age 3-7 weeks, were chosen to model the effects of repeated methotrexate dosing on the developing brains of young children with ALL. This methotrexate regimen had no visible acute toxicity and no effect on growth. At 15 weeks of age (8 weeks after the last methotrexate dose) both spatial pattern memory and visual recognition memory were impaired. In addition, methotrexate-treated animals demonstrated impaired performance in the set-shifting assay, indicating decreased cognitive flexibility. Histopathological analysis demonstrated decreased cell proliferation in methotrexate-treated animals compared to controls, as well as changes in length and thickness of the corpus callosum. Moreover, methotrexate suppressed microglia activation and RANTES production. In conclusion, our study demonstrated that a clinically relevant regimen of systemic and intrathecal methotrexate induces persistent deficits in spatial pattern memory, visual recognition memory and executive function, lasting at least 8 weeks after the last injection. The mechanisms behind methotrexate-induced deficits are likely multifactorial and may relate to suppression of neurogenesis, alterations in neuroinflammation and microglial activation, and structural changes in the corpus callosum., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Traumatic brain injury (TBI), resulting from external force on the head, usually leads to long-term deficits in motor and cognitive functions. Inducible nitric oxide synthase (iNOS)-mediated excessive inflammation could exacerbate brain damage after TBI. The present study therefore investigated the potential neuroprotective effects of iNOS inhibition after TBI. Male C57BL/6J mice were subjected to controlled cortical impact injury and then treated with high selective iNOS inhibitor 1400W. Expression of iNOS mRNA was determined by quantitative RT-PCR. Western blotting was carried out to determine iNOS protein levels. Motor and cognitive functions, and long-term potentiation (LTP) in the medial prefrontal cortex (mPFC) and hippocampus were examined. Expression of iNOS was induced after TBI in a temporal manner. Treatment with 1400W after TBI improved motor and cognitive functions. TBI mice showed deficits in LTP in both the mPFC and hippocampus, and treatment with 1400W could rescue this impairment. Inhibition of iNOS attenuated deficits in synaptic plasticity and brain functions after TBI. The neuroprotective effect of iNOS inhibition on cognitive function might be via rescuing the TBI-induced LTP impairment.

Paeoniflorin (PF) is a natural monoterpene glycoside in Paeonia lactiflora pall with anti-diabetic, antioxidant, anti-inflammatory, and neuro-protective properties. This study was designed to investigate the neuroprotective effects of PF against cognitive deficits induced by intracerebroventricular (ICV) injection of streptozotocin (STZ) in mice. STZ was injected twice intracerebroventrically (3 mg/kg ICV) on alternate days (day 1 and day 3) in mice. Daily treatment with PF (10 mg/kg per day, intraperitoneally) starting from the first dose of STZ for 21 days showed an improvement in ICV-STZ induced cognitive deficits as assessed by novel object recognition and Morris water maze (MWM) test. PF significantly attenuated STZ induced mitochondrial dysfunction manifested by dramatically elevated cytochrome c oxidase activity and ATP synthesis, and restoration of the mitochondrial membrane potential (MMP), and oxidative stress in hippocampus and in the cortex compared to control. Moreover, PF treatment also markedly increased synaptic density in the CA1 region of the hippocampus compared to control. Furthermore, PF ameliorated defective insulin signaling by up-regulating p-PI3K and p-Akt protein expression while downregulating p-IRS-1 protein expression. Taken together, the outcomes of the current study suggest the therapeutic potential of PF in the cognitive deficits induced by ICV-STZ., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The amount, composition, and sources of nutrition support provided to preterm infants is critical for normal growth and development, and particularly for structural and functional neurodevelopment. Although omega-3 long chain polyunsaturated fatty acids (LC-PUFA), and particularly docosahexanoic acid (DHA), are considered of particular importance, results from clinical trials with preterm infants have been inconclusive because of ethical limitations and confounding variables. A translational large animal model is needed to understand the structural and functional responses to DHA. Neurodevelopment of preterm pigs was evaluated in response to feeding formulas to term-equivalent age supplemented with DHA attached to phosphatidylserine (PS-DHA) or sunflower oil as the placebo. Newborn term pigs were used as a control for normal in utero neurodevelopment. Supplementing formula with PS-DHA increased weight of the brain, and particularly the cerebellum, at term-equivalent age compared with placebo preterm pigs ( P 's < 0.10 and 0.05 respectively), with a higher degree of myelination in all regions of the brain examined (all p < 0.06). Brains of pigs provided PS-DHA were similar in weight to newborn term pigs. Event-related brain potentials and performance in a novel object recognition test indicated the PS-DHA supplement accelerated development of sensory pathways and recognition memory compared with placebo preterm pigs. The PS-DHA did not increase weight gain, but was associated with higher survival. The benefits of PS-DHA include improving neurodevelopment and possibly improvement of survival, and justify further studies to define dose-response relations, compare benefits associated with other sources of DHA, and understand the mechanisms underlying the benefits and influences on the development of other tissues and organ systems.

People preferably take zero or low-calorie beverages and foods with artificial sweeteners even though it has been recently suggested that long-term artificial sweetener use affects physiological functions. In addition, a lower body weight was considered to be more healthful, but an abnormally low body weight caused by an excessive diet has been reported to cause health problems. Acesulfame potassium (AceK) is one of the most commonly used for foods and beverages because of its resistance to thermal degradation and marked sweetness. However, the combined effect of AceK and a low body weight on the physiological functions remains unknown. Here, we investigated the effect of long-term AceK fluid intake on the cognitive function under dietary restriction. We administered AceK to mice fed a low carbohydrate (LC) diet for 4 weeks, and behavioral assays were then performed for a week. The mice fed the LC diet with AceK treatment for 4 weeks showed an increase in water intake and a decrease in short-term and object cognitive memories in the Y-maze and novel object recognition tests, respectively. Mice were sacrificed after behavioral tests to measure glucose levels. The glucose levels in the frontal cortex were significantly decreased in mice fed the LC diet with AceK treatment in comparison with mice fed the LC diet alone, although there was no significant difference in the plasma glucose levels. These results suggest that the combination of long-term AceK intake and the LC diet affects the cognitive function through the reduction of cortical glucose levels., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Sleep deprivation (SD) is associated with oxidative stress that causes learning and memory impairment. 20(S)-Protopanaxadiol (PPD), one of the protopanaxadiol-type saponins, has antioxidant and neuroprotective effect. This study was designed to research the protective effect of PPD against cognitive deficits induced by chronic sleep deprivation (CSD) in mice. The CSD model was induced by subjecting the mice to our self-made Sleep Interruption Apparatus (SIA) continuously for 14 days. The memory enhancing effects of PPD were evaluated by behavioral tests and the related mechanism was further explored by observing the oxidative stress changes in the cortex and hippocampus of mice. The results revealed that PPD (20 and 40 μmol/kg, i.p.) administration significantly improved the cognitive performance of CSD model mice in object location recognition experiment, novel object recognition task and Morris water maze test. Furthermore, PPD effectively restored the levels/activities of antioxidant defense biomarkers in the cortex and hippocampus, including the superoxide dismutase (SOD) enzyme activity, catalase (CAT) enzyme activity, glutathione (GSH), and lipid peroxidation (LPO). In conclusion, PPD could attenuate cognitive deficits induced by CSD, and the neuroprotective effect of PPD might be mediated by alleviation of oxidative stress. It was assumed that PPD has the potential to be a neuroprotective substance for cognition dysfunction., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Adjuvant chemotherapy has been used for decades to treat cancer, and it is well known that disruptions in cognitive function and memory are common chemotherapeutic adverse effects. However, studies using neuropsychological metrics have also reported group differences in cognitive function and memory before or without chemotherapy, suggesting that complex factors obscure the true etiology of chemotherapy-induced cognitive dysfunction (CICD) in humans. Therefore, to better understand possible mechanisms of CICD, we explored the effects of CICD in rats through cognition testing using novel object recognition (NOR) and contextual fear conditioning (CFC), and through metabolic neuroimaging via [ 18 F]fluorodeoxyglucose (FDG) positron emission tomography (PET). Cancer-naïve, female Sprague-Dawley rats were administered either saline (1 mL/kg) or doxorubicin (DOX) (1 mg/kg in a volume of 1 mL/kg) weekly for five weeks (total dose = 5 mg/kg), and underwent cognition testing and PET imaging immediately following the treatment regime and 30 days post treatment. We did not observe significant differences with CFC testing post-treatment for either group. However, the chemotherapy group exhibited significantly decreased performance in the NOR test and decreased 18 F-FDG uptake only in the prefrontal cortex 30 days post-treatment. These results suggest that long-term impairment within the prefrontal cortex is a plausible mechanism of CICD in this study, suggesting DOX-induced toxicity in the prefrontal cortex at the dose used.

We have recently shown that the tocotrienol-rich fraction (TRF) of palm oil, a mixture of vitamin E analogs, improves amyloid pathology in vitro and in vivo. However, precise mechanisms remain unknown. In this study, we examined the effects of long-term (10 months) TRF treatment on behavioral impairments and brain metabolites in (15 months old) AβPP/PS1 double transgenic (Tg) Alzheimer's disease (AD) mice. The open field test, Morris water maze, and novel object recognition tasks revealed improved exploratory activity, spatial learning, and recognition memory, respectively, in TRF-treated Tg mice. Brain metabolite profiling of wild-type and Tg mice treated with and without TRF was performed using ultrahigh performance liquid chromatography (UHPLC) coupled to high-resolution accurate mass (HRAM)-orbitrap tandem mass spectrometry (MS/MS). Metabolic pathway analysis found perturbed metabolic pathways that linked to AD. TRF treatment partly ameliorated metabolic perturbations in Tg mouse hippocampus. The mechanism of this pre-emptive activity may occur via modulation of metabolic pathways dependent on Aβ interaction or independent of Aβ interaction.

Drug-induced changes in electroencephalographic (EEG) characteristics in animals may be used to predict central activity of drugs in humans. Previous studies have established that drugs affect EEG characteristics in humans and rodents in a similar manner. However, there has been little work to establish correlations between drug effects on behavioral and EEG characteristics in rats. In the current study, we have simultaneously monitored EEG characteristics during a novel object recognition task (NORT) or open field (OF) test in rats. EEG was monitored using telemetric device from epidural and hippocampal regions during the choice trial in the NORT after treatment with scopolamine (0.1 mg/kg, intraperitoneal) alone or in combination with donepezil (0.3 mg/kg, subcutaneous). Power changes across spectral frequency bands during exploration of novel and familiar object were assessed separately. Amphetamine (2 mg/kg, intraperitoneal) was used to monitor effects on locomotor activity and EEG changes in the OF test. In the NORT, scopolamine impaired object recognition, but no differences were observed in the power densities across spectral bands during exploration of novel and familiar objects. Treatment with donepezil reversed scopolamine-induced cognitive impairment, and the power density in the theta frequency band was increased during exploration of the novel object. In OF, amphetamine increased locomotion and produced an overall decrease in the power densities of all frequency bands. Overall, the results indicate that EEG characteristics are closely related to behavioral changes in the NORT and OF in rodents.

Clinical studies show higher levels of cannabinoid CB1 receptors (CB1R) in the brain of schizophrenic patients while preclinical studies report a significant functional interaction between dopamine D2 receptors and CB1Rs as well as an upregulation of CB1Rs after antipsychotic treatment. These findings prompted us to study the effects of chronic oral intake of a first and a second generation antipsychotic, haloperidol and olanzapine, on the levels and distribution of CB1Rs in the rat brain. Rats consumed either regular chow or high-fat food and drank water, haloperidol drinking solution (1.5mg/kg), or olanzapine drinking solution (10mg/kg) for four weeks. Motor and cognitive functions were tested at the end of treatment week 3 and upon drug discontinuation. Two days after drug discontinuation, rats were euthanized and brains were processed for in vitro receptor autoradiography. In chow-fed animals, haloperidol and olanzapine increased CB1R levels in the basal ganglia and the hippocampus, in a similar, but not identical pattern. In addition, olanzapine had unique effects in CB1R upregulation in higher order cognitive areas, in the secondary somatosensory cortex, in the visual and auditory cortices and the geniculate nuclei, as well as in the hypothalamus. High fat food consumption prevented antipsychotic-induced increase in CB1R levels in all regions examined, with one exception, the globus pallidus, in which they were higher in haloperidol-treated rats. The results point towards the hypothesis that increased CB1R levels could be a confounding effect of antipsychotic medication in schizophrenia that is circumveneted by high fat feeding., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Essential fatty acids, being indispensable during the stages of pregnancy, lactation and infancy influence the transmission of nerve impulses and brain function, and cashew nuts are a good source of these fatty acids. The objective of this study was to evaluate the effects of cashew nut consumption on reflex development, memory and profile of fatty acids of rat offspring treated during pregnancy and lactation. The animals were divided into three groups: Control (CONT), treated with 7% lipid derived from soybean oil; Normolipidic (NL) treated with 7% lipids derived from cashew nuts; and Hyperlipidic (HL) treated with 20% lipids derived from cashew nuts. Reflex ontogeny, Open-field habituation test and the Object Recognition Test (ORT) were assessed. The profile of fatty acids in the brain was carried out when the animals were zero, 21 and 60days old. Accelerated reflex maturation was observed in animals treated with cashew nuts (p<0.05). NL presented better memory in the Open-field habituation test; the NL and HL showed improvement of short-term memory in the ORT, but long term damage in HL (p<0.05). The results of the lipid profile of the brain at the end of the experiment showed an increase in levels of saturated fatty acids and less Docosahexaenoic acid (DHA) in animals of the HL. The data showed that maternal consumption of cashew nuts can accelerate reflex maturation and facilitate memory in offspring when offered in adequate quantities., (Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.)

Atorvastatin (Ator), competitive inhibitors of 3-hydroxymethyl-3-glutaryl-coenzyme-A reductase, is a cholesterol lowering drug. Ator has been shown to have neuroprotective, antioxidant and anti-inflammatory properties making that a potential candidate for the treatment of central nervous system (CNS) disorders. Here we assessed the effect of Ator on the d-galactose (d-gal)-induced aging in mice. For this purpose, Ator (0.1 and 1mg/kg/p.o.), was administrated daily in d-gal-received (500mg/kg/p.o.) mice model of aging for six weeks. Anxiety-like behaviors and cognitive functions were evaluated by the elevated plus-maze and novel object recognition tasks, respectively. Physical power was assessed by forced swimming capacity test. Animals brains were analyzed for the superoxide dismutase (SOD) and brain-derived neurotrophic factor (BDNF). We found that Ator decreases the anxiety-like behaviors in d-gal-treated mice. Also, our behavioral tests showed that Ator reverses the d-gal induced learning and memory impairment. Furthermore, we found that Ator increases the physical power of d-gal-treated mice. Our results indicated that the neuroprotective effect of Ator on d-gal induced neurotoxicity is mediated, at least in part, by an increase in the SOD and BDNF levels. The results of present study suggest that Ator could be used as a novel therapeutic strategy for the treatment of age-related conditions., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Although MDMA (3,4-methylendioxymethamphetamine, ecstasy) neurotoxicity in serotonin neurons is largely recognized in a wide variety of species including man, neurotoxicity in dopamine (DA) neurons is thought to be species-specific. MDMA is mainly consumed by adolescents, often in conjunction with caffeine (Energy Drinks) and this association has been reported to exacerbate MDMA toxic effects. In order to model these aspects of MDMA use, vis-à-vis their impact on DA neurons, we investigated the effects of adolescent exposure to low doses of MDMA (5 mg/kg for 10 days), alone or in combination with caffeine (10 mg/kg) on neuronal and functional DA indices and on recognition memory in adult rats. MDMA reduced density of tyrosine hydroxylase (TH) positive neurons in the ventral tegmental area and in the substantia nigra pars compacta, and immunoreactivity of TH and DA transporter in the nucleus accumbens (NAc) shell and core, and caudate-putamen. This same treatment caused a reduction of basal dialysate DA in the NAc core. MDMA-pretreated rats also showed behavioral sensitization to a MDMA challenge at adulthood and potentiation of MDMA-induced increase of dialysate DA in the NAc core, but not in the NAc shell. In addition, MDMA-treated rats displayed a deficit in recognition memory. Caffeine co-administration did not affect the above outcomes. Our results show that adolescent exposure of rats to low doses of MDMA induces long-lasting and widespread reduction of DA neurons indicative of a neurotoxic effect on DA neurons and suggestive of a degeneration of the same neurons., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Parkinson's disease (PD) is characterized by motor dysfunction, which is preceded by a number of non-motor symptoms including olfactory deficits. Aggregation of α-synuclein (α-syn) gives rise to Lewy bodies in dopaminergic neurons and is thought to play a central role in PD pathology. However, whether amyloid fibrils or soluble oligomers of α-syn are the main neurotoxic species in PD remains controversial. Here, we performed a single intracerebroventricular (i.c.v.) infusion of α-syn oligomers (α-SYOs) in mice and evaluated motor and non-motor symptoms. Familiar bedding and vanillin essence discrimination tasks showed that α-SYOs impaired olfactory performance of mice, and decreased TH and dopamine levels in the olfactory bulb early after infusion. The olfactory deficit persisted until 45days post-infusion (dpi). α- SYO-infused mice behaved normally in the object recognition and forced swim tests, but showed increased anxiety-like behavior in the open field and elevated plus maze tests 20 dpi. Finally, administration of α-SYOs induced late motor impairment in the pole test and rotarod paradigms, along with reduced TH and dopamine content in the caudate putamen, 45 dpi. Reduced number of TH-positive cells was also seen in the substantia nigra of α-SYO-injected mice compared to control. In conclusion, i.c.v. infusion of α-SYOs recapitulated some of PD-associated non-motor symptoms, such as increased anxiety and olfactory dysfunction, but failed to recapitulate memory impairment and depressive-like behavior typical of the disease. Moreover, α-SYOs i.c.v. administration induced motor deficits and loss of TH and dopamine levels, key features of PD. Results point to α-syn oligomers as the proximal neurotoxins responsible for early non-motor and motor deficits in PD and suggest that the i.c.v. infusion model characterized here may comprise a useful tool for identification of PD novel therapeutic targets and drug screening., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Mushrooms are valued for their nutritional as well as medicinal properties. Ganoderma species are used traditionally to treat neurological disorders but scientific evidence for this is insufficient. The present study was designed to systematically evaluate the anti-amnesic effect of selected Ganoderma species i.e. G. mediosinense and G. ramosissimum. Extracts of selected mushroom species were evaluated for their antioxidant activity and acetylcholinesterase (AChE) inhibition using in-vitro assays (DPPH and Ellman tests respectively). The anti-amnesic potential of the most active extract (i.e. 70% methanol extract of G. mediosinense) was confirmed using mouse model of scopolamine-induced amnesia. Mice were treated with bioactive extract and donepezil once orally before the induction of amnesia. Cognitive functions were evaluated using passive shock avoidance (PSA) and novel object recognition (NOR) tests. The effect on brain AChE activity, brain oxidative stress (TBARS level) and neuronal damage (H & E staining) were also assessed. In-vitro results showed strong antioxidant and AChE inhibitory activities by G. mediosinense extract (GME). Therefore, it was selected for in-vivo studies. GME pre-treatment (800mg/kg, p.o.) reversed the effect of scopolamine in mice, evident by significant decrease (p <0.05) in the transfer latency time and increase in object recognition index in PSA and NOR, respectively. GME significantly reduced the brain AChE activity and oxidative stress. Histopathological examination of brain tissues showed decrease in vacuolated cytoplasm and increase in pyramidal cells in brain hippocampal and cortical regions. GME exerts anti-amnesic effect through AChE inhibition and antioxidant mechanisms., (Copyright © 2017. Published by Elsevier Masson SAS.)

Current drug treatments for schizophrenia (SCZ) can alleviate positive symptoms, but have little effect on the negative symptoms and cognitive deficits that are difficult to translate into preclinical models for drug development. Therefore, we aimed to determine the dose-response effects of acute phencyclidine (PCP, 1.0-5.0 mg/kg) on rat brain connectivity and detect markers for different SCZ-like symptoms. Pharmacological functional magnetic resonance imaging (phMRI) and microdialysis were used to investigate PCP-induced effects on functional connectivity (FC) and dopamine levels, respectively. Next, we evaluated the association between PCP-induced changes in imaging parameters and behavior. PCP at doses of 3.0-5.0 mg/kg induced fMRI signal changes in several brain regions associated with SCZ. Additionally, the FC was globally disturbed, dopamine levels increased, and locomotor activity increased, reflecting the manifestation of SCZ-like positive symptoms. A distinct pattern in the measures was observed at lower PCP doses (1.0-2.0 mg/kg); PCP induced fMRI signal changes in the fronto-cortical regions, and increased dopamine levels in the medial prefrontal cortex. In addition to the dysconnectivity of these regions, the hippocampal FC was disrupted. These observations are consistent with the induction of SCZ-like cognitive deficits and negative symptoms, which were observed as impaired novel object recognition and decreased social interaction. No indicators for positive symptoms were observed at lower PCP doses. We conclude that acute PCP induces SCZ-like symptom classes in a dose-dependent manner; PCP doses of 1.0-2.0 mg/kg are more suitable for modeling SCZ-like negative symptoms and cognitive deficits, while SCZ-like positive symptoms dominate at doses of 3.0-5.0 mg/kg., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Prenatal exposure to maternal infection increases the risk of neurodevelopmental disorders, including schizophrenia and autism. The molecular processes underlying this pathological association, however, are only partially understood. Here, we combined unbiased genome-wide transcriptional profiling with follow-up epigenetic analyses and structural magnetic resonance imaging to explore convergent molecular and neuromorphological alterations in corticostriatal areas of adult offspring exposed to prenatal immune activation. Genome-wide transcriptional profiling revealed that prenatal immune activation caused a differential expression of 116 and 251 genes in the medial prefrontal cortex and nucleus accumbens, respectively. A large part of genes that were commonly affected in both brain areas were related to myelin functionality and stability. Subsequent epigenetic analyses indicated that altered DNA methylation of promoter regions might contribute to the differential expression of myelin-related genes. Quantitative relaxometry comparing T1, T2, and myelin water fraction revealed sparse increases in T1 relaxation times and consistent reductions in T2 relaxation times. Together, our multi-system approach demonstrates that prenatal viral-like immune activation causes myelin-related transcriptional and epigenetic changes in corticostriatal areas. Even though these abnormalities do not seem to be associated with overt white matter reduction, they may provide a molecular mechanism whereby prenatal infection can impair myelin functionality and stability., (© The Author 2017. Published by Oxford University Press.)

Aluminum is associated with etiology of many neurodegenerative diseases specially Alzheimer's disease. Chronic exposure to aluminum via drinking water results in aluminum deposition in the brain that leads to cognitive deficits. The study aimed to determine the effects of aluminum on cholinergic biomarkers, i.e., acetylcholine level, free choline level, and choline acetyltransferase gene expression, and how cholinergic deficit affects novel object recognition and sociability in mice. Mice were treated with AlCl 3 (250 mg/kg). Acetylcholine level, free choline level, and choline acetyltransferase gene expression were determined in cortex, hippocampus, and amygdala. The mice were subjected to behavior tests (novel object recognition and social novelty preference) to assess memory deficits. The acetylcholine level in cortex and hippocampus was significantly reduced in aluminum-treated animals, as compared to cortex and hippocampus of control animals. Acetylcholine level in amygdala of aluminum-treated animals remained unchanged. Free choline level in all the three brain parts was found unaltered in aluminum-treated mice. The novel object recognition memory was severely impaired in aluminum-treated mice, as compared to the control group. Similarly, animals treated with aluminum showed reduced sociability compared to the control mice group. Our study demonstrates that aluminum exposure via drinking water causes reduced acetylcholine synthesis in spite of normal free choline availability. This deficit is caused by reduced recycling of acetylcholine due to lower choline acetyltransferase level. This cholinergic hypofunction leads to cognitive and memory deficits. Moreover, hippocampus is the most affected brain part after aluminum intoxication.

Salvia miltiorrhiza (Lamiaceae), one of the most important and popular plants of traditional medicine of Asia, is used for the prevention and treatment of cardiovascular diseases and in central nervous system disturbances. The main aim of this study was to assess the influence of subchronic (28-fold) administration of Salvia miltiorrhiza root extract (SE, 200mg/kg, p.o.) on behavioural activity and memory of rats and to evaluate the activities of cholinesterases (AChE and BuChE) and gene expression levels of AChE and BuChE as well as of beta-secretase (BACE1) in the hippocampus and frontal cortex in vivo. Huperzine A (HU, 0.5mg/kg b.w., p.o.) served as a positive control substance, whereas scopolamine (0.5mg/kg, i.p.) injection was used as a well-known model of memory impairment. The results showed that subchronic administration of SE led to an improvement of long-term memory of rats. Strong inhibition of AChE and BuChE mRNA transcription in the frontal cortex of rats treated with SE or HU was observed. The BACE1 transcript level was significantly decreased. AChE activity was statistically significantly inhibited in the frontal cortex and the hippocampus by SE (47% and 55%, respectively). Similar effects were observed in the case of HU. In summary, activity of SE provides evidence that the plant can be a source of drugs used in the treatment of Alzheimer disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Tobacco withdrawal is associated with deficits in cognitive function, including attention, working memory, and episodic memory. Understanding the neurobiological mechanisms involved in these effects is crucial because cognitive deficits during nicotine withdrawal may predict relapse in humans., Methods: We investigated in mice the role of CB 1 cannabinoid receptors (CB 1 Rs) in memory impairment and spine density changes induced by nicotine withdrawal precipitated by the nicotinic antagonist mecamylamine. Drugs acting on the endocannabinoid system and genetically modified mice were used., Results: Memory impairment during nicotine withdrawal was blocked by the CB 1 R antagonist rimonabant or the genetic deletion of CB 1 R in forebrain gamma-aminobutyric acidergic (GABAergic) neurons (GABA-CB 1 R). An increase of 2-arachidonoylglycerol (2-AG), but not anandamide, was observed during nicotine withdrawal. The selective inhibitor of 2-AG biosynthesis O7460 abolished cognitive deficits of nicotine abstinence, whereas the inhibitor of 2-AG enzymatic degradation JZL184 did not produce any effect in cognitive impairment. Moreover, memory impairment was prevented by the selective mammalian target of rapamycin inhibitor temsirolimus and the protein synthesis inhibitor anisomycin. Mature dendritic spines on CA1 pyramidal hippocampal neurons decreased 4 days after the precipitation of nicotine withdrawal, when the cognitive deficits were still present. Indeed, a correlation between memory performance and mature spine density was found. Interestingly, these structural plasticity alterations were normalized in GABA-CB 1 R conditional knockout mice and after subchronic treatment with rimonabant., Conclusions: These findings underline the interest of CB 1 R as a target to improve cognitive performance during early nicotine withdrawal. Cognitive deficits in early abstinence are associated with increased relapse risk., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Methamphetamine (MA) studies in animals usually involve acute, binge, or short-term exposure to the drug. However, addicts take substantial amounts of MA for extended periods of time. Here we wished to study the effects of MA exposure on brain and behavior, using an animal model analogous to this pattern of MA intake. MA doses, 4 and 8mg/kg/day, were based on previously reported average daily freely available MA self-administration levels. We examined the effects of 16 week MA treatment on psychomotor and cognitive function in the rat using open field and novel object recognition tests and we studied the adaptations of the dopaminergic system, using in vitro and in vivo receptor imaging. We show that chronic MA treatment, at doses that correspond to the average daily freely available self-administration levels in the rat, disorganizes open field activity, impairs alert exploratory behavior and anxiety-like state, and downregulates dopamine transporter in the striatum. Under these treatment conditions, dopamine terminal functional integrity in the nucleus accumbens is also affected. In addition, lower dopamine D1 receptor binding density, and, to a smaller degree, lower dopamine D2 receptor binding density were observed. Potential mechanisms related to these alterations are discussed., (Copyright © 2016. Published by Elsevier B.V.)

The effects of residual cannabis use on emotional expression recognition and the P3 event-related potential in participants who scored highly for subclinical depression were investigated. Comparisons were made between participants who were classified as depressed or nondepressed cannabis users, depressed non-cannabis users and controls who neither used cannabis nor were characterized as being depressed. In an emotional expression recognition task, participants were asked to respond to faces depicting happy, angry, fearful, and neutral faces either implicitly, explicitly, or empathically. Residual cannabis use and mood was shown to modulate the P3 event related potential during the task. There was a significant reduction in the P3 amplitude between depressed and nondepressed participants. Residual cannabis use further reduced the P3 amplitude with the greatest deficits being associated with cannabis users who scored highly for subclinical depression. These effects were greatest for explicit and empathic processing of faces depicting negative emotions. We conclude from our study that cannabis and mood state interact to reduce the amplitude of the P3 which has been associated with attention to emotion.

Dementia caused by Alzheimer's disease (AD) is mainly characterized by accumulation in the brain of extra- and intraneuronal amyloid-β (Aβ) and tau proteins, respectively, which selectively affect specific regions, particularly the neocortex and the hippocampus. Sporadic AD is mainly caused by an increase in apolipoprotein E, a component of chylomicrons, which are cholesterol transporters in the brain. Recent studies have shown that high lipid levels, especially cholesterol, are linked to AD. Adenosine is an atypical neurotransmitter that regulates a wide range of physiological functions by activating four P1 receptors (A1, A2A, A2B, and A3) and P2 purinergic receptors that are G protein-coupled. A1 receptors are involved in the inhibition of neurotransmitter release, which could be related to AD. The aim of the present work was to study the effects of a lard-enriched diet (LED) on cognitive and memory processes in adult rats (6 months of age) as well as the effect of theobromine on these processes. The results indicated that the fat-enriched diet resulted in a long-term deterioration in cognitive and memory functions. Increased levels of Aβ protein and IL-1β were also observed in the rats fed with a high-cholesterol diet, which were used to validate the AD animal model. In addition, the results of qPCR and immunohistochemistry indicated a decrease in gene expression and distribution of A1 purinegic receptor, respectively, in the hippocampus of LED-fed rats. Interestingly, theobromine, at both concentrations tested, restored A1 receptor levels and improved cognitive functions and Aβ levels for a dose of 30 mg/L drinking water.

Alzheimer's disease (AD) is the most common cause of progressive cognitive impairment in the aged. The aggregation of the amyloid β-protein (Aβ) is a hallmark of AD and is linked to synapse loss and cognitive impairment. Capsaicin, a specific agonist of the transient receptor potential vanilloid 1 (TRPV1), has been proven to ameliorate stress-induced AD-like pathological and cognitive impairments, but it is unclear whether TRPV1 activation can affect cognitive and synaptic functions in Aβ-induced mouse model of AD. In this study, we investigated the effects of TRPV1 activation on spatial memory and synaptic plasticity in mice treated with Aβ. To induce AD-like pathological and cognitive impairments, adult C57Bl/6 mice were microinjected with Aβ42 (100 μM, 2.5 μl/mouse, i.c.v.). Two weeks after Aβ42 microinjection, spatial learning and memory as well as hippocampal long-term potentiation (LTP) were examined. The results showed that Aβ42 microinjection significantly impaired spatial learning and memory in the Morris water maze and novel object recognition tests compared with controls. These behavioral changes were accompanied by synapse loss and impaired LTP in the CA1 area of hippocampus. More importantly, daily capsaicin (1 mg/kg, i.p.) treatment throughout the experiment dramatically improved spatial learning and memory and synaptic function, as reflected by enhanced hippocampal LTP and reduced synapse loss, whereas the TRPV1 antagonist capsazepine (1 mg/kg, i.p.) treatment had no effects on cognitive and synaptic function in Aβ42-treated mice. These results indicate that TRPV1 activation by capsaicin rescues cognitive deficit in the Aβ42-induced mouse model of AD both structurely and functionally.

Hyperlipidemia is a risk factor for the development of cognitive dysfunction and atherosclerosis. Natural compounds have recently received special attention in relation to the treatment of disease due to their low cost and wide margin of safety. Thus, the aim of this study was to determine the possible preventive effect of guarana powder (Paullinia cupana) on memory impairment and acetylcholinesterase (AChE) activity in the brain structures of rats with Poloxamer-407-induced hyperlipidemia. Adult male Wistar rats were pretreated with guarana (12.5, 25 and 50mg/kg/day) and caffeine (0.2mg/kg/day) by gavage for a period of 30days. Simvastatin (0.04mg/kg) was administered as a comparative standard. Acute hyperlipidemia was induced with intraperitoneal injections of 500mg/kg of Poloxamer-407. Memory tests and evaluations of anxiety were performed. The cortex, cerebellum, hippocampus, hypothalamus and striatum were separated to assess acetylcholinesterase activity. Our results revealed that guarana powder was able to reduce the levels of TC and LDL-C in a manner similar to simvastatin. Guarana powder also partially reduced the liver damage caused by hyperlipidemia. Guarana was able to prevent changes in the activity of AChE and improve memory impairment due to hyperlipidemia. Guarana powder may therefore be a source of promising phytochemicals that can be used as adjuvant therapy in the management of hyperlipidemia and cognitive disorders., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Type 2 diabetes and hypertension are associated with cognitive dysfunction that includes pathological changes in brain tissue. It was speculated that the beneficial hypotensive effect of telmisartan, an angiotensin receptor 1 blocker, and its unique hypoglycemic effect due to its PPARγ-activation, could ameliorate the ​ pathological changes in the brain​ that accompany​ these diseases. We examined the effect of telmisartan on brain changes in magnetic resonance imaging (MRI) T2-weighted scans, and behavioral and histological findings in the Cohen-Rosenthal Diabetic Hypertensive (CRDH) rat. Baseline and post-treatment values with telmisartan/vehicle (3 months) of blood pressure, blood glucose levels, behavioral tests, brain MRI scanning and immunohistological staining were obtained. Telmisartan significantly lowered blood pressure and blood glucose levels; induced consistent T2 reduction in specific gray and white regions including hippocampus, corpus callosum, amygdala and cortical regions; and significantly improved performance on behavioral tasks. Immunohistological analysis of the brain revealed significant amelioration of diabetes/hypertension-induced changes in white matter regions and microglia, evidenced by preserved myelin (LBF marker), and improved microglial neuronal markers GFAP, GAP43 and Iba1 expression. In conclusion, the behavioral performance, longitudinal MRI study and histology staining revealed the protective effects of telmisartan on brain microstructure and cognitive function., (Copyright © 2016. Published by Elsevier B.V.)

Diabetes is associated with loss of cognitive function and increased risk for Alzheimer's disease (AD). Advanced glycation end products (AGEs) are elevated in diabetes and AD and have been suggested to act as mediators of the cognitive decline observed in these pathologies. Methylglyoxal (MG) is an extremely reactive carbonyl compound that propagates glycation reactions and is, therefore, able to generate AGEs. Herein, we evaluated persistent behavioral and biochemical parameters to explore the hypothesis that elevated exogenous MG concentrations, induced by intracerebroventricular (ICV) infusion, lead to cognitive decline in Wistar rats. A high and sustained administration of MG (3μmol/μL; subdivided into 6days) was found to decrease the recognition index of rats, as evaluated by the object-recognition test. However, MG was unable to impair learning-memory processes, as shown by the habituation in the open field (OF) and Y-maze tasks. Moreover, a single high dose of MG induced persistent alterations in anxiety-related behavior, diminishing the anxiety-like parameters evaluated in the OF test. Importantly, MG did not alter locomotion behavior in the different tasks performed. Our biochemical findings support the hypothesis that MG induces persistent alterations in the hippocampus, but not in the cortex, related to glyoxalase 1 activity, AGEs content and glutamate uptake. Glial fibrillary acidic protein and S100B content, as well as S100B secretion (astroglial-related parameters of brain injury), were not altered by ICV MG administration. Taken together, our data suggest that MG interferes directly in brain function and that the time and the levels of exogenous MG determine the different features that can be seen in diabetic patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Magnesium (Mg) is the fourth most abundant biological mineral essential for good health. Neuroprotective, anxiolytic and antidepressant effects of magnesium following stress and brain injuries are well established. In present study, we analyzed the protective effects of magnesium in rats exposed to sub-chronic noise stress. Magnesium Chloride (MgCl2, 100 mg/kg) was administered intraperitoneally once daily for 15 days prior exposure to noise stress. Rats were exposed to noise stress for 4 h after administration of magnesium for 15 days. At the end of treatment behavioral alterations were assessed. Animals were decapitated following behavioral testing and the brains were dissected out for neurochemical estimations by HPLC-EC. Improvement in noise-induced memory deficits as assessed by novel object recognition (NOR) test and elevated plus maze (EPM) test was found in magnesium treated rats. This improvement in noise-induced behavioral deficits following treatment with magnesium may be attributed to a significant decrease (p < 0.01) in dopamine (DA) and serotonin (5-hydroxytryptamine; 5-HT) turnover as compared to control rats observed in present work. These results suggest that treatment with magnesium can attenuate the noise-induced deficits and may be used as a therapy against noise-induced neurodegeneration. Moreover an adequate amount of magnesium in daily diet may help to develop the ability to resist against or cope up with stressful conditions encountered in daily life.