Moderate aerobic training enhances the effectiveness of insulin therapy through hypothalamic IGF1 signaling in rat model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurological condition that is connected with a decline in a person's memory as well as their cognitive ability. One of the key topics of AD research has been the exploration of metabolic causes. We investigated the effects of treadmill exercise and intranasal insulin on learning and memory impairment and the expression of IGF1, BDNF, and GLUT4 in hypothalamus. The animals were put into 9 groups at random. In this study, we examined the impact of insulin on spatial memory in male Wistar rats and analyzed the effects of a 4-week pretreatment of moderate treadmill exercise and insulin on the mechanisms of improved hypothalamic glucose metabolism through changes in gene and protein expression of IGF1, BDNF, and GLUT4. We discovered that rat given Aß25-35 had impaired spatial learning and memory, which was accompanied by higher levels of Aß plaque burden in the hippocampus and lower levels of IGF1, BDNF, and GLUT4 mRNA and protein expression in the hypothalamus. Additionally, the administration of exercise training and intranasal insulin results in the enhancement of spatial learning and memory impairments, the reduction of plaque burden in the hippocampus, and the enhancement of the expression of IGF1, BDNF, and GLUT4 in the hypothalamus of rats that were treated with Aß25-35. Our results show that the improvement of learning and spatial memory due to the improvement of metabolism and upregulation of the IGF1, BDNF, and GLUT4 pathways can be affected by pretreatment exercise and intranasal insulin.

Beta-sitosterol mitigates cognitive deficit and hippocampal neurodegeneration in mice with trimethyltin-induced toxicity.

The present study investigated the neural health benefit of beta-sitosterol (BSS) against trimethyltin (TMT)-induced neurodegeneration in mice. Forty male ICR mice were randomly divided into Sham-veh, TMT-veh, TMT-BSS50, and TMT-BSS100. A one-time intraperitoneal injection of 2.6 mg/kg of TMT was given to mice in TMT groups. Vehicle (veh), BSS 50 mg/kg or BSS 100 mg/kg were orally given for 2 weeks. Spatial learning and memory were evaluated. Brain oxidative status, hippocampal neuropathology, and reactive astrocytes were done. White matter pathology was also evaluated. The results indicated the massy effect of TMT on induced motor ability and spatial memory deficits in accordance with increased neuronal degeneration in CA1, CA3, and DG and internal capsule white matter damage. TMT also induced the reduction of reactive astrocytes in CA1 and DG. Brain's catalase activity was significantly reduced by TMT, but not in mice with BSS treatments. Both doses of BSS treatment exhibited improvement in motor ability and spatial memory deficits in accordance with the activation of reactive astrocytes in CA1, CA3, and DG. However, they successfully prevented the increase of neuronal degeneration in CA1 found only with the BSS dose of 100 mg/kg, and it was indicated as the effective dose for neuroprotection in the vulnerable brain area. This study demonstrated mitigative effects of BSS against motor ability and memory deficits with neural health benefits, including a protective effect against CA1 neurodegeneration and a nurturing effect on hippocampal reactive astrocytes.

Astaxanthin and DHA Supplementation Modulates the Maternal Undernutrition-induced Impairment of Cognitive Behavior and Synaptic Plasticity in Adult Life of Offspring's -Exploring the Molecular Mechanism.

Maternal nutrition was recognized as a significant part of brain growth and maturation in most mammalian species. Timely intervention with suitable nutraceuticals would provide long-term health benefits. We aim to unravel the molecular mechanisms of perinatal undernutrition-induced impairments in cognition and synaptic plasticity, employing animal model based on dietary nutraceutical supplementation. We treated undernourished dams at their gestational, lactational, and at both the time point with Astaxanthin (AsX) and Docosahexaenoic acid (DHA), and their pups were used as experimental animals. We evaluated the cognitive function by subjecting the pups to behavioral tests in their adult life. In addition, we assessed the expression of genes in the hippocampus related to cognitive function and synaptic plasticity. Our results showed downregulation of Brain-derived neurotrophic factor (BDNF), Neurotrophin-3 (NT-3), cAMP response-element-binding protein (CREB), and uncoupling protein-2 (UCP2) gene expression in pups born to undernourished dams in their adult life, which AsX and DHA modulated. Maternal AsX and DHA supplementation ameliorated the undernutrition-induced learning impairment in novel object recognition (NOR) tests and partially baited radial arm maze (RAM) tasks in offspring's. The expressions of Synapsin-1 and PSD-95 decreased in perinatally undernourished groups compared to control and AsX-DHA treated groups at CA1, CA2, CA3, and DG. AsX and DHA supplementation upregulated BDNF, NT-3, CREB, and UCP2 gene expressions in perinatally undernourished rats, which are involved in intracellular signaling cascades like Ras, PI3K, and PLC. The results of our study give new insights into neuronal differentiation, survival, and plasticity, indicating that the perinatal period is the critical time for reversing maternal undernutrition-induced cognitive impairment in offspring's.

Introduction of a model for the modification of masticatory activity to investigate induced neural and behavioral alterations in mice.

In the literature, there is consistent evidence related to the influence of chewing on brain functions, either from experimental models or in humans. In the case of humans, most results are restricted to functional tests, lacking cellular or molecular evidence. In the described method, the possibility of using experimental models is presented, as well as the mimicry of deprivation and rehabilitation of masticatory activity and without stress impact. By opting for the use of mash feed, instead of extracting or implanting an intraoral device, alternations between restriction and rehabilitation of mastication were imposed on murine models. The animals completed various temporal windows, with aging also representing a potential factor for translational dementia associations. Additionally, animals were segregated into environments characterized as either standard, simulating a sedentary lifestyle, or enriched, rich in sensorimotor and visuospatial stimulation. Thus, it was possible to study the influence of changes in masticatory activity, associated with aging and environmental enrichment, on cells from subregions of the hippocampus, as well as on performance in tests of learning and spatial memory.•Animal model for masticatory activity alteration;•Masticatory deprivation and rehabilitation, and•Models to study the interaction among masticatory activity, aging and enrichment environment.

Function and mechanism exploring of icariin in schizophrenia through network pharmacology.

This study aims to explore the therapeutic effect and possible mechanisms of icariin in schizophrenia. SD rats were divided into five groups, a control group, a MK801-induced schizophrenia model group, and three icariin treatment groups, with twelve rats in each group. Morris water maze and open field were used to observe the spatial learning and memory ability of rats. Compared with the control group, rats in the MK801-induced model group showed an increase in stereotypic behavior score, distance of spontaneous activities, escape latency, malondialdehyde (MDA) content, and IL-6, IL-1ß, TNF-α expression, but a decrease in platform crossing times and superoxide dismutase (SOD) activity (P < 0.05). Furthermore, all the above changes of the model group were reversed after icariin treatment in a dose-dependent manner (P < 0.05). Network pharmacology found that icariin can exert anti-schizophrenic effects through some signaling pathways, such as relaxin, estrogen, and TNF signaling pathways. MAPK1, MAPK3, FOS, RELA, TNF, and JUN were the key targets of icariin on schizophrenia, and their expression was detected in animal models, which was consistent with the predicted results of network pharmacology. Icariin treatment may improve the spatial learning and memory ability of schizophrenic rats through TNF signaling pathway.

A shift to a standard diet after exposure to a high-fat, high-sucrose diet from gestation to weaning restores brain metabolism and behavioral flexibility in adult rats.

Prolonged consumption of diets high in saturated fat and sugar has been related to obesity and overweight, which in turn are linked to cognitive impairment in both humans and rodents. This has become a current issue, especially in children and adolescents, because these stages are crucial to neurodevelopmental processes and programming of adult behavior. To evaluate the effects of gestational and early exposure to an obesogenic diet, three groups with different dietary patterns were established: high-fat and high-sucrose diet (HFS), standard diet (SD), and a dietary shift from a high-fat, high-sucrose diet to a standard diet after weaning (R). Spatial learning and behavioral flexibility in adult male and female Wistar rats were evaluated using the Morris water maze (MWM) at PND 60. Furthermore, regional brain oxidative metabolism was assessed in the prefrontal cortex and the hippocampus. Contrary to our hypothesis, the HFS diet groups showed similar performance on the spatial learning task as the other groups, although they showed impaired cognitive flexibility. The HFS group had increased brain metabolic capacity compared to that of animals fed the standard diet. Shifting from the HFS diet to the SD diet after weaning restored the brain metabolic capacity in both sexes to levels similar to those observed in animals fed the SD diet. In addition, animals in the R group performed similarly to those fed the SD diet in the Morris water maze in both tasks. However, dietary shift from HFS diet to standard diet after weaning had only moderate sex-dependent effects on body weight and fat distribution. In conclusion, switching from an HFS diet to a balanced diet after weaning would have beneficial effects on behavioral flexibility and brain metabolism, without significant sex differences.

The effects of choline supplementation in mothers with hypothyroidism on the alteration of cognitive-behavioral, long-term potentiation, morphology, and apoptosis in the hippocampus of pre-pubertal offspring rats.

The mother's thyroid hormone status during gestation and the first few months after delivery can play a crucial role in maturation during the brain development of the child. Transient abnormalities in thyroid function at birth indicate developmental and cognitive disorders in adulthood. Choline supplementation during gestation and the perinatal period in rats causes long-lasting memory improvement in the offspring. However, it remains unclear whether choline is able to restore the deficits in rats with maternal hypothyroidism. The aim of this study was to evaluate the effects of choline supplementation on the alteration of cognitive-behavioral function, long-term potentiation (LTP), and morphological changes as well as apoptosis in pre-pubertal offspring rats. To induce hypothyroidism, 6-propyl-2-thiouracil was added to the drinking water from the 6th day of gestation to the 21st postnatal day (PND). Choline treatment was started twice a day on the first day of the gestation until PND 21 via gavage. LTP recording and Morris water maze (MWM) test were conducted at PND 28. Then, the rats were sacrificed to assess their brains. The results revealed that developmental thyroid hormone deficiency impaired spatial learning and memory and reduced LTP (both: P < 0.001). Choline treatment alleviated LTP (P < 0.001), as well as learning and memory deficits (P < 0.01) in both male and female hypothyroid rats. However, no significant changes were observed in the number of caspase-3 stained cells in choline-receiving hypothyroid groups. The results revealed that developmental thyroid hormone deficiency impaired spatial learning and memory and reduced LTP. Choline treatment alleviated LTP, as well as learning and memory deficits in both male and female hypothyroid rats.

Repeated pre-exposure to morphine inhibited the amnesic effect of ethanol on spatial memory: Involvement of CaMKII and BDNF.

Evidence has suggested that addiction and memory systems are related, but the signaling cascades underlying this interaction have not been completelyealed yet. The importance of calcium-calmodulin-dependent protein kinase II (CaMKII) and brain-derived neurotrophic factor (BDNF) in the memory processes and also in drug addiction has been previously established. In this present investigation, we examined the effects of repeated morphine pretreatment on impairment of spatial learning and memory acquisition induced by systemic ethanol administration in adult male rats. Also, we assessed how these drug exposures influence the expression level of CaMKII and BDNF in the hippocampus and amygdala. Animals were trained by a single training session of 8 trials, and a probe test containing a 60-s free-swim without a platform was administered 24 h later. Before training trials, rats were treated with a once-daily subcutaneous morphine injection for 3 days followed by a 5-day washout period. The results showed that pre-training ethanol (1 g/kg) impaired spatial learning and memory acquisition and down-regulated the mRNA expression of CaMKII and BDNF. The amnesic effect of ethanol was suppressed in morphine- (15 mg/kg/day) pretreated animals. Furthermore, the mRNA expression level of CaMKII and BDNF increased significantly following ethanol administration in morphine-pretreated rats. Conversely, this improvement in spatial memory acquisition was prevented by daily subcutaneous administration of naloxone (2 mg/kg) 15 min prior to morphine administration. Our findings suggest that sub-chronic morphine treatment reverses ethanol-induced spatial memory impairment, which could be explained by modulating CaMKII and BDNF mRNA expressions in the hippocampus and amygdala.

Schisandrin A Alleviates Spatial Learning and Memory Impairment in Diabetic Rats by Inhibiting Inflammatory Response and Through Modulation of the PI3K/AKT Pathway.

Clinical and epidemiological research shows that people with diabetes mellitus frequently experience diabetic cognitive impairment. Schisandrin A (SchA), one of the lignans found in the dried fruit of Schisandra chinensis, has a variety of pharmacological effects on immune system control, apoptosis suppression, anti-oxidation and anti-inflammation. The goal of the current investigation was to clarify the probable neuro-protective effects of SchA against streptozotocin-induced diabetes deficiencies of the spatial learning and memory in rats. The outcomes show that SchA therapy effectively improved impaired glucose tolerance, fasting blood glucose level and serum insulin level in diabetic rats. Additionally, in the Morris water maze test, diabetic rats showed deficits in spatial learning and memory that were ameliorated by SchA treatment. Moreover, giving diabetic rats SchA reduced damage to the hippocampus structure and increased the production of synaptic proteins. Further research revealed that SchA therapy reduced diabetic-induced hippocampus neuron damage and the generation of Aß, as demonstrated by the upregulated phosphorylation levels of insulin signaling pathway connected proteins and by the decreased expression levels of inflammatory-related factors. Collectively, these results suggested that SchA could improve diabetes-related impairments in spatial learning and memory, presumably by reducing inflammatory responses and regulating the insulin signaling system.

Gallic acid ameliorates behavioral dysfunction, oxidative damage, and neuronal loss in the prefrontal cortex and hippocampus in stressed rats.

Gallic acid (GA) is known to be a natural phenolic compound with antioxidant and neuroprotective effects. This study aims to investigate the impact of GA against restraint stress-induced oxidative damage, anxiety-like behavior, neuronal loss, and spatial learning and memory impairment in male Wistar rats. The animals were divided into four groups (n = 8) and subjected to restraint stress for 4 h per day for 14 consecutive days or left undisturbed (control without inducing stress). In the treatment group, the animals were treated with 2 mL normal saline plus 100 mg/kg GA per day for 14 consecutive days (STR + GA group). The animals received the drug or normal saline by gavage 2 h before inducing restraint stress. ELISA assay measured oxidative stress factors. Elevated-plus maze and Morris water maze tests assessed anxiety-like behavior and spatial learning and memory, respectively. Also, neuronal density was determined using Nissl staining. Restraint stress significantly increased MDA and reduced the activities of GPX and SOD in the stressed rats, which were reserved by treatment with 100 mg/kg GA. Restraint stress markedly enhanced the anxiety-like behavior and spatial learning and memory impairment that were reserved by GA. In addition, treatment with GA reduced the neuronal loss in the stressed rats in the hippocampus and prefrontal cortex (PFC) regions. Taken together, our findings suggest that GA has the potential to be used as a good candidate to attenuate neurobehavioral disorders as well as neuronal loss in the hippocampus and PFC induced by restraint stress via reducing oxidative damage.

Tirzepatide ameliorates spatial learning and memory impairment through modulation of aberrant insulin resistance and inflammation response in diabetic rats.

Background: One of the typical symptoms of diabetes mellitus patients was memory impairment, which was followed by gradual cognitive deterioration and for which there is no efficient treatment. The anti-diabetic incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were demonstrated to have highly neuroprotective benefits in animal models of AD. We wanted to find out how the GLP-1/GIP dual agonist tirzepatide affected diabetes's impairment of spatial learning memory. Methods: High fat diet and streptozotocin injection-induced diabetic rats were injected intraperitoneally with Tirzepatide (1.35 mg/kg) once a week. The protective effects were assessed using the Morris water maze test, immunofluorescence, and Western blot analysis. Golgi staining was adopted for quantified dendritic spines. Results: Tirzepatide significantly improved impaired glucose tolerance, fasting blood glucose level, and insulin level in diabetic rats. Then, tirzepatide dramatically alleviated spatial learning and memory impairment, inhibited Aß accumulation, prevented structural damage, boosted the synthesis of synaptic proteins and increased dendritic spines formation in diabetic hippocampus. Furthermore, some aberrant changes in signal molecules concerning inflammation signaling pathways were normalized after tirzepatide treatment in diabetic rats. Finally, PI3K/Akt/GSK3ß signaling pathway was restored by tirzepatide. Conclusion: Tirzepatide obviously exerts a protective effect against spatial learning and memory impairment, potentially through regulating abnormal insulin resistance and inflammatory responses.

Multilevel meta-analysis and dose-response analysis for bisphenol A (BPA) exposure on metabolic and neurobehavioral effects.

Evidence suggests that oral exposure to bisphenol A (BPA) may result in adverse metabolic and neurobehavioral effects. The aim of the present meta-analysis is to examine this association based on systematically selected laboratory rodent studies published from 2012 to 2021 and sourced from Scopus, Web of Science, EmBase, and PubMed. Articles satisfying eligibility and inclusion criteria were included for the calculation of the summary standardised mean difference (SMD). Subgroup analysis and subsequent dose-response analysis were conducted if applicable. In total, 32 studies were analysed for 6 metabolic endpoints (cholesterol, triglycerides, insulin, glucose, leptin, and adiponectin) and 6 neurobehavioral endpoints (locomotor activity, exploratory, anxiety, depression, spatial learning and memory, non-spatial learning and memory). Summary SMDs implied that no significant effects were observed in endpoints considered. The dose was not determined as a significant moderator with regards to medium or high heterogeneity; however, there was significant impairment of spatial learning and memory at health-based guidance value ('HBGV') (0.05-9 mg (kg bw)-1 day-1) and 'High' (>9 mg (kg bw)-1 day-1) dose group. As a result, an indicative toxicological reference dose value of 0.034 mg (kg bw)-1 day-1 was proposed due to large variability. Potential harm to spatial learning and memory from BPA exposure requires further investigation. This study has provided some additional information on potential adverse metabolic and neurobehavioral effects of BPA from the perspective of meta-analysis which can inform the public, regulatory authorities, and policymakers.

Inhibition of Anaplastic Lymphoma Kinase (Alk) as Therapeutic Target to Improve Brain Function in Neurofibromatosis Type 1 (Nf1).

Neurofibromatosis type 1 (Nf1) is a neurodevelopmental disorder and tumor syndrome caused by loss of function mutations in the neurofibromin gene (Nf1) and is estimated to affect 100,000 people in the US. Behavioral alterations and cognitive deficits have been found in 50-70% of children with Nf1 and include specific problems with attention, visual perception, language, learning, attention, and executive function. These behavioral alterations and cognitive deficits are observed in the absence of tumors or macroscopic structural abnormalities in the central nervous system. No effective treatments for the behavioral and cognitive disabilities of Nf1 exist. Inhibition of the anaplastic lymphoma kinase (Alk), a kinase which is negatively regulated by neurofibromin, allows for testing the hypothesis that this inhibition may be therapeutically beneficial in Nf1. In this review, we discuss this area of research and directions for the development of alternative therapeutic strategies to inhibit Alk. Even if the incidence of adverse reactions of currently available Alk inhibitors was reduced to half the dose, we anticipate that a long-term treatment would pose challenges for efficacy, safety, and tolerability. Therefore, future efforts are warranted to investigate alternative, potentially less toxic and more specific strategies to inhibit Alk function.

Investigations on learning and memory function in extended one-generation reproductive toxicity studies - when considered needed and based on what?

To justify investigations on learning and memory (L&M) function in extended one-generation reproductive toxicity studies (EOGRTS; Organization for Economic Co-operation and Development (OECD) test guideline (TG) 443) for registration under Registration, Evaluation, Authorization, and Restriction of Chemical (REACH), the European Chemicals Agency has referred to three publications based on which the Agency concluded that "perturbation of thyroid hormone signaling in offspring affects spatial cognitive abilities (learning and memory)" and "Therefore, it is necessary to conduct spatial learning and memory tests for F1 animals". In this paper, the inclusion of the requested L&M tests in an EOGRTS is challenged. In addition, next to the question on the validity of rodent models in general for testing thyroid hormone-dependent perturbations in brain development, the reliability of the publications specifically relied upon by the agency is questioned as these contain numerous fundamental errors in study methodology, design, and data reporting, provide contradicting results, lack crucial information to validate the results and exclude confounding factors, and finally show no causal relationship. Therefore, in our opinion, these publications cannot be used to substantiate, support, or conclude that decreases in blood thyroid (T4) hormone level on their own would result in impaired L&M in rats and are thus not adequate to use as fundament to ask for L&M testing as part of an EOGRTS.

Long-Term Effect of Moderate Hypoxia and Chronic Administration of Fluoxetine during the Neonatal Period on Cognitive and Stress-Hormonal Functions in Adult Male Rats.

We studied the effect of moderate neonatal normobaric hypoxia on the indicators of spatial learning, memory, and reactivity of the hypothalamic-pituitary-adrenocortical system in adult male Wistar rats. The pharmacological effect of chronic injections of the serotonin reuptake inhibitor fluoxetine during the neonatal period on the studied behavioral and the physiological indices was evaluated. Hypoxia impaired spatial training, increased the short-term memory performance, but did not change long-term memory and stress indicator in response to its testing. The use of fluoxetine normalized learning, but did not change memory indicators and the stress-induced level of corticosterone in blood plasma in the hypoxic rats and control animals. New results indicate a protective effect of fluoxetine in the neonatal period under conditions of moderate normobaric hypoxia.

The RNA cargo in small extracellular vesicles from chicken eggs is bioactive in C57BL/6 J mice and human peripheral blood mononuclear cells ex vivo.

Small extracellular vesicles (sEVs) and their RNA cargo in milk are bioavailable in humans, pigs, and mice, and their dietary depletion and supplementation elicits phenotypes. Little is known about the content and biological activity of sEVs in foods of animal origin other than milk. Here we tested the hypothesis that sEVs in chicken eggs (Gallus gallus) facilitate the transfer of RNA cargo from an avian species to humans and mice, and their dietary depletion elicits phenotypes. sEVs were purified from raw egg yolk by ultracentrifugation and authenticated by transmission electron microscopy, nano-tracking device, and immunoblots. The miRNA profile was assessed by RNA-sequencing. Bioavailability of these miRNAs in humans was assessed by egg feeding study in adults, and by culturing human peripheral blood mononuclear cells (PBMCs) with fluorophore-labeled egg sEVs ex vivo. To further assess bioavailability, fluorophore-labeled miRNAs, encapsulated in egg sEVs, were administered to C57BL/6 J mice by oral gavage. Phenotypes of sEV RNA cargo depletion were assessed by feeding egg sEV and RNA-defined diets to mice and using spatial learning and memory in the Barnes and water mazes as experimental readouts. Egg yolk contained 6.30 × 1010 ± 6.06 × 109 sEVs/mL, which harbored eighty-three distinct miRNAs. Human PBMCs internalized sEVs and their RNA cargo. Egg sEVs, loaded with fluorophore-labeled RNA and administered orally to mice, accumulated primarily in brain, intestine and lungs. Spatial learning and memory (SLM) was compromised in mice fed on egg sEV- and RNA-depleted diet compared to controls. Egg consumption elicited an increase of miRNAs in human plasma. We conclude that egg sEVs and their RNA cargo probably are bioavailable. The human study is registered as a clinical trial and accessible at https://www.isrctn.com/ISRCTN77867213.

Prevention of neurotoxicity and cognitive impairment induced by zinc nanoparticles by oral administration of saffron extract.

The accumulation of relatively higher dose of zinc oxide nanoparticles in brain was reported to produce neurotoxicity. Indeed, nanoparticles have a high ability to penetrate biological membranes and be uptaken by cells, which may cause cell disorders and physiological dysfunctions. The aim of the current study was to evaluate, whether oral administration of saffron extract, in rats, can protect from neurotoxicity and behavioural disturbances induced by chronic administration of ZnO-NPs. Daily oral administration of ZnO-NPs was performed for 21 consecutive days to induce oxidative stress-like situation. Then after the saffron extract was concomitantly administrated in several rat groups to overcome the nanotoxicological effect induced by ZnO-NPs. In the frontal cortex, the hippocampus and the cerebellum, ZnO-NPs induced a H2 O2 -oxydative stress-like effect reflected in reduced enzymatic activities of catalase, superoxide dismutase and glutathione S-transferase, and decreased acetylcholinesterase activity. In addition, increased levels of proinflammatory interleukins IL-6 and IL-1-⍺ occurred in the hippocampus, reveal the existence of brain inflammation. The concomitant administration of saffron extract to animals exposed to ZnO-NPs prevented the enhanced anxiety-related to the behaviour in the elevated plus-maze test, the open field test and preserved spatial learning abilities in the Morris water maze. Moreover, animals exposed to ZnO-NPs and saffron showed abnormal activity of several antioxidant enzymes as well as acetylcholinesterase activity, an effect that may underly the preserved anxiety-like behaviour and spatial learning abilities observed in these animals. Saffron extract has a potential beneficial therapeutic effect: antioxidant, anti-inflammatory and neuroprotective agent.

Prenatal PM2.5 exposure impairs spatial learning and memory in male mice offspring: from transcriptional regulation to neuronal morphogenesis.

BACKGROUND: As one of the environmental risk factors for human health, atmospheric fine particulate matter (PM2.5) contributes to cognitive deterioration in addition to respiratory and cardiovascular injuries. Recently, increasing evidence implicates that PM2.5 inhalation can affect neurological functions in offspring, but the sex-specific outcomes and the underlying biological processes are largely unknown. OBJECTIVES: To observe the influence of prenatal PM2.5 exposure on cognitive performance in offspring, to elucidate the neuronal morphological alterations and possible transcriptional regulation based on mRNA-sequencing (mRNA-Seq) data after birth, and to determine the key components of PM2.5 contributing to the adverse effects. METHODS: Pregnant C57BL/6J mice were exposed to sterile saline or PM2.5 suspension. Morris water maze test was used to assess the cognitive function in weanling offspring. Microscopic observation was applied to detect neuronal morphogenesis in vivo and in vitro. The cortex tissues from male offspring were collected on postnatal days (PNDs) 1, 7, and 21 for mRNA-Seq analysis. The organic and inorganic components of PM2.5 were separated to assess their contributions using primary cultured neurons. RESULTS: Prenatal PM2.5 exposure impaired spatial learning and memory in weanling male mice, but not female mice. The sex-specific outcomes were associated with mRNA expression profiles of the cortex during postnatal critical windows, and the annotations in Gene Ontology (GO) of differentially expressed genes (DEGs) revealed that the exposure persistently disrupted the expression of genes involved in neuronal features in male offspring. Consistently, axonal growth impairment and dendritic complexity reduction were observed. Importantly, Homeobox A5 (Hoxa5), a critical transcription factor regulating all of the neuronal morphogenesis-associated hub genes on PNDs 1, 7, and 21, significantly decreased in the cortex of male offspring following PM2.5 exposure. In addition, both inorganic and organic components were harmful to axonal and dendritic growth, with organic components exhibiting stronger inhibition than inorganic ones. CONCLUSION: Prenatal PM2.5 exposure affected spatial learning and memory in male mice by disrupting Hoxa5-mediated neuronal morphogenesis, and the organic components, including polycyclic aromatic hydrocarbons (PAHs), posed more adverse effects than the inorganic components.

The dysfunctionality of hippocampal synapses may be directly related to PM-induced impairments in spatial learning and memory in juvenile rats.

Epidemiological studies have demonstrated that exposure to air particulate matter (PM) increases the incidence of cardiovascular and respiratory diseases and exerts a significant neurotoxic effect on the nervous system, especially on the immature nervous system. Here, we selected PND28 rats to simulate the immature nervous system of young children and used neurobehavioral methods to examine how exposure to PM affected spatial learning and memory, as well as electrophysiology, molecular biology, and bioinformatics to study the morphology of hippocampus and the function of hippocampal synapses. We discovered that spatial learning and memory were impaired in rats exposed to PM. The morphology and structure of the hippocampus were altered in the PM group. In addition, after exposure to PM, the relative expression of synaptophysin (SYP) and postsynaptic density 95 (PSD95) proteins decreased dramatically in rats. Furthermore, PM exposure impaired long-term potentiation (LTP) in the hippocampal Schaffer-CA1 pathway. Interestingly, RNA sequencing and bioinformatics analysis revealed that the differentially expressed genes (DEGs) were rich in terms associated with synaptic function. Five hub genes (Agt, Camk2a, Grin2a, Snca, and Syngap1) that may play a significant role in the dysfunctionality of hippocampal synapses were identified. Our findings implied that exposure to PM impaired spatial learning and memory via exerting impacts on the dysfunctionality of hippocampal synapses in juvenile rats and that Agt, Camk2a, Grin2a, Snca, and Syngap1 may drive PM-caused synaptic dysfunction.

Prenatal Exposure to Δ9-Tetrahydrocannabinol Affects Hippocampus-Related Cognitive Functions in the Adolescent Rat Offspring: Focus on Specific Markers of Neuroplasticity.

Previous evidence suggests that prenatal exposure to THC (pTHC) derails the neurodevelopmental trajectories towards a vulnerable phenotype for impaired emotional regulation and limbic memory. Here we aimed to investigate pTHC effect on hippocampus-related cognitive functions and markers of neuroplasticity in adolescent male offspring. Wistar rats were exposed to THC (2 mg/kg) from gestational day 5 to 20 and tested for spatial memory, object recognition memory and reversal learning in the reinforce-motivated Can test and in the aversion-driven Barnes maze test; locomotor activity and exploration, anxiety-like behaviour, and response to natural reward were assessed in the open field, elevated plus maze, and sucrose preference tests, respectively. The gene expression levels of NMDA NR1-2A subunits, mGluR5, and their respective scaffold proteins PSD95 and Homer1, as well as CB1R and the neuromodulatory protein HINT1, were measured in the hippocampus. pTHC offspring exhibited deficits in spatial and object recognition memory and reversal learning, increased locomotor activity, increased NR1-, decreased NR2A- and PSD95-, increased mGluR5- and Homer1-, and augmented CB1R- and HINT1-hippocampal mRNA levels. Our data shows that pTHC is associated with specific impairment in spatial cognitive processing and effectors of hippocampal neuroplasticity and suggests novel targets for future pharmacological challenges.