Locomotor Hypoactivity Research Articles

5-hydroxytryptamine 2C/1A receptors modulate the biphasic dose response of the head twitch response and locomotor activity induced by DOM in mice.

The phenylalkylamine hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine (DOM) exhibits an inverted U-shaped dose-response curve for both head twitch response (HTR) and locomotor activity in mice. Accumulated studies suggest that HTR and locomotor hyperactivity induced by DOM are mainly caused by the activation of serotonin 5-hydroxytryptamine 2A receptor (5-HT2A receptor). However, the mechanisms underlying the biphasic dose response of HTR and locomotor activity induced by DOM, particularly at high doses, remain unclear. The primary objective of this study is to investigate the modulation of 5-HT2A/2C/1A receptors in HTR and locomotor activity, while also exploring the potential receptor mechanisms underlying the biphasic dose response of DOM. In this study, we employed pharmacological methods to identify the specific 5-HT receptor subtypes responsible for mediating the biphasic dose-response effects of DOM on HTR and locomotor activity in C57BL/6J mice. The 5-HT2A receptor selective antagonist (R)-[2,3-di(methoxy)phenyl]-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol (M100907) (500µg/kg, i.p.) fully blocked the HTR at every dose of DOM (0.615-10mg/kg, i.p.) in C57BL/6J mice. M100907 (50µg/kg, i.p.) decreased the locomotor hyperactivity induced by a low dose of DOM (0.625, 1.25mg/kg, i.p.), but had no effect on the locomotor hypoactivity induced by a high dose of DOM (10mg/kg) in C57BL/6J mice. The 5-HT2C antagonist 6-chloro-5-methyl-1-[(2-[2-methylpyrid-3yloxy]pyrid-5yl)carbamoyl]indoline (SB242084) (0.3, 1mg/kg, i.p.) reduced the HTR induced by a dose of 2.5mg/kg DOM, but did not affect the response to other doses. SB242084 (1mg/kg, i.p.) significantly increased the locomotor activity induced by DOM (0.615-10mg/kg, i.p.) in mice. The 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]N-(2-pyridinyl) cyclohexane carboxamide maleate (WAY100635) (1mg/kg, i.p.) increased both HTR and locomotor activity induced by DOM in mice. The 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1mg/kg, i.p.) significantly reduced both the HTR and locomotor activity induced by DOM in mice. Additionally, pretreatment with the Gαi/o inhibitor PTX (0.25µg/mouse, i.c.v.) enhanced the HTR induced by DOM and attenuated the effect of DOM on locomotor activity in mice. Receptor subtypes 5-HT2C and 5-HT1A are implicated in the inverted U-shaped dose-response curves of HTR and locomotor activity induced by DOM in mice. The biphasic dose-response function of HTR and locomotor activity induced by DOM has different mechanisms in mice.

Bambusa vulgaris attenuates Haloperidol-induced motor deficit and non-Motor co-morbidity in rats through up-regulation of Dopamine transmission and mitigation of pro-inflammatory cytokines activities

BackgroundBamboo is a plant widely distributed in many parts of the world and grows in about 18 provinces in China. One of the species of the plant is Bambusa vulgaris. An ethnobotanical survey of the plant revealed its values in managing neurodegenerative diseases, including Parkinson's disease. ObjectiveThis study examined the effect of hydroethanolic leaf extract of Bambusa vulgaris (BVE) on motor functions and non-motor co-morbidity, dopamine content, pro-inflammatory cytokines and oxidative species in haloperidol-treated rats. MethodsRats were pretreated with distilled water (10 mL/kg), B. vulgaris extract (100, 200 and 400 mg/kg) and levodopa-carbidopa (LD-CD; 25/100 mg/kg, orally). Precisely one hour post every treatment, haloperidol (2 mg/kg, i.p) was administered to the rats across all groups every 48 h for 21 days. Motor and non-motor functions were assessed on day 22. After that, brains were removed and processed for dopamine content evaluation, pro-inflammatory cytokines determination, oxidative damage assessment and histopathological examinations of the striatum and substantia nigra. ResultsB. vulgaris increased (P < 0.01; 400 mg/kg) the distance covered and decreased the frequency foot slips (P < 0.01, 0.001; 200–400 mg/kg) in the beam work test; decreased (P < 0.05–0.0001; 100–400 mg/kg) the catalepsy behavior in the catalepsy bar test; reversed hypo-locomotor activity (P < 0.0001; 400 mg/kg) in open field test; and decreased (P < 0.05–0.001; 100–400 mg/kg) the non-motor behavioural deficit in tail suspension test. BVE increased (P < 0.01; 200 mg/kg) dopamine concentration in the brain and decreased TNF-α (P < 0.05; 200 mg/kg) and IL-6 (P < 0.01, 0.001; 100–400 mg/kg) concentrations in the brain. BVE significantly increased the GSH (P < 0.05, 0.001; 100–200 mg/kg) and Catalase (P < 0.05, 0.01; 100–400 mg/kg) levels and decreased the MDA level (P < 0.05, 0.01; 200–400 mg/kg) in the brain tissue. ConclusionOur findings suggest that the hydroethanol leaf extract of Bambusa vulgaris reverses the haloperidol-induced motor deficits and non-motor co-morbidity by mitigating the pathophysiological abnormalities associated with the progression of the disease. Based on these outcomes, the peak effect was observed at 200 mg/kg.

Optogenetic Globus Pallidus Stimulation Improves Motor Deficits in 6-Hydroxydopamine-Lesioned Mouse Model of Parkinson's Disease.

Excessive inhibition of the external globus pallidus (GPe) by striatal GABAergic neurons is considered a central mechanism contributing to motor symptoms of Parkinson's disease (PD). While electrophysiological findings support this view, behavioral studies assessing the beneficial effects of global GPe activations are scarce and the reported results are controversial. We used an optogenetic approach and the standard unilateral 6-hydroxydopamine nigrostriatal dopamine (DA) lesion model of PD to explore the effects of GPe photostimulation on motor deficits in mice. Global optogenetic GPe inhibition was used in normal mice to verify whether it reproduced the typical motor impairment induced by DA lesions. GPe activation improved ipsilateral circling, contralateral forelimb akinesia, locomotor hypoactivity, and bradykinesia in 6-OHDA-lesioned mice at ineffective photostimulation parameters (532 nm, 5 Hz, 3 mW) in normal mice. GPe photoinhibition (450 nm, 12 mW) had no effect on locomotor activity and forelimb use in normal mice. Bilateral photoinhibition (450 nm, 6 mW/side) reduced directed exploration and improved working memory performances indicating that recruitment of GPe in physiological conditions may depend on the behavioral task involved. Collectively, these findings shed new light on the functional role of GPe and suggest that it is a promising target for neuromodulatory restoration of motor deficits in PD.

Butyrate ameliorates chronic alcoholic central nervous damage by suppressing microglia-mediated neuroinflammation and modulating the microbiome-gut-brain axis

BackgroundAlcohol abuse triggers neuroinflammation, leading to neuronal damage and further memory and cognitive impairment. Few satisfactory advances have been made in the management of alcoholic central nervous impairment. Therefore, novel and more practical treatment options are urgently needed. Butyrate, a crucial metabolite of short-chain fatty acids (SCFAs), has been increasingly demonstrated to protect against numerous metabolic diseases. However, the impact of butyrate on chronic alcohol consumption-induced central nervous system (CNS) lesions remains unknown. MethodsIn this study, we assessed the possible effects and underlying mechanisms of butyrate on the attenuation of alcohol-induced CNS injury in mice. Firstly, sixty female C57BL/6 J mice were randomly divided into 4 groups: pair-fed (PF) group (PF/CON), alcohol-fed (AF) group (AF/CON), PF with sodium butyrate (NaB) group (PF/NaB) and AF with NaB group (AF/NaB). Each group was fed a modified Lieber-DeCarli liquid diet with or without alcohol. After six weeks of feeding, the mice were euthanized and the associated indicators were investigated. ResultsAs indicated by the behavioral tests and brain morphology, dietary NaB administration significantly ameliorated aberrant behaviors, including locomotor hypoactivity, anxiety disorder, depressive behavior, impaired learning, spatial recognition memory, and effectively reduced chronic alcoholic central nervous system damage. To further understand the underlying mechanisms, microglia-mediated inflammation and the associated M1/M2 polarization were measured separately. Firstly, pro-inflammatory TNF-α, IL-1β, and IL-6 in brain and peripheral blood circulation were decreased, but IL-10 were increased in the AF/NaB group compared with the AF/CON group. Consistently, the abnormal proportions of activated and resting microglial cells in the hippocampus and cortex regions after excessive alcohol consumption were significantly reduced with NaB treatment. Moreover, the rectification of microglia polarization (M1/M2) imbalance was found after NaB administration via binding GPR109A, up-regulating the expression of PPAR-γ and down-regulating TLR4/NF-κB activation. In addition to the direct suppression of neuroinflammation, intriguingly, dietary NaB intervention remarkably increased the levels of intestinal tight junction protein occludin and gut morphological barrier, attenuated the levels of serum lipopolysaccharide (LPS) and dysbiosis of gut microbiota, suggesting that NaB supplementation effectively improved the integrity and permeability of gut microecology. Finally, the neurotransmitters including differential Tryptophan (Trp) and Kynurenine (Kyn) were found with dietary NaB administration, which showed significantly altered and closely correlated with the gut microbiota composition, demonstrating the complex interactions in the microbiome-gut-brain axis involved in the efficacy of dietary NaB therapy for alcoholic CNS lesions. ConclusionDietary microbial metabolite butyrate supplementation ameliorates chronic alcoholic central nervous damage and improves related memory and cognitive functions through suppressing microglia-mediated neuroinflammation by GPR109A/PPAR-γ/TLR4-NF-κB signaling pathway and modulating microbiota−gut−brain axis.

Neuroprotective effect of Foeniculum vulgare essential oil in developing Wistar rats exposed to manganese chloride

The present study was carried out in order to evaluate, on the one hand, the modifications induced by manganese chloride according to a neurobehavioral, biochemical and histological approach in developing Wistar rats and, on the other hand, to test the effectiveness of Foeniculum vulgare (fennel) essential oil (FEO) in restoring or not the harmful effects of manganese chloride (MnCl2). The characterization of this essential oil by gas chromatography showed that the major component is E-anethole (34.7907%). The administration of FEO corrected the depressive state, anxiety and locomotor hypoactivity respectively observed in rats exposed to MnCl2, thus, the FEO restored the activity of the various antioxidant enzymes with a clear improvement of the cerebral tissue architecture in intoxicated rats treated with FEO. In conclusion, the FEO has a beneficial effect on the nervous system of rats intoxicated with MnCl2 which justifies the importance of this oil in traditional medicine.

Neurobenifical Effect of Anised In Rats Exposed to Mercury

Purpose: Mercury is one of the metallic trace elements. This metal is harmful to health. However, Green anis is a plant widely used in the medical field for its various therapeutic virtues. The aim of this study is to evaluate the effect of subchonic exposure to mercury chloride (HgCl2) on the neurobehavioral status of young wistar rats as well as the neurocorrective effect of essential oil of green anis. Methods: Extraction of essential oil by hydrodisillation. Exposure of developing rats to a dose of (100mg/L). Then, a group of the intoxicated animals underwent therapy with one dose (0.25 ml/kg) for 21 days intraperitoneally. In addition, the realization of a behavior test battery namely; the forced swimming test to assess the state of despair of the pups, the open field to assess the locomotor activity as well as the exploratory capacities followed by a histopathological study of the brain. Data were analyzed by two-way analysis of variance (ANOVA). Results: The results of this study demonstrate that exposure to mercury induced significant decreases in body weight (p &lt; 0.001) and brain weight (p &lt; 0.05), respectively, increases the level of depression (p &lt; 0.001), locomotor hypoactivity (p &lt; 0.01) compared to control rats. Histological study revealed Purkinje cell degeneration, vascular congestion and lesions. Administration of Pimpinella anisum oil reduced levels of depression (p &lt; 0.01), corrected locomotor hypoactivity (p &lt; 0.05), and reduced mercury damage. Conclusion: According to this study, exposure to mercury disrupted the neurobehavioral state of young rats by affecting certain brain structures. These disturbances can be regulated by the essential oil of anis

Acute toxicity of methomyl commercial formulation induces morphological and behavioral changes in larval zebrafish (Danio rerio)

The use of pesticides has continue grown over recent years, leading to several environmental and health concerns, such as the contamination of surface and groundwater resources and associated biota, potentially affecting populations that are not primary targets of these complex chemical mixtures. In this work, we investigate lethal and sublethal effects of acute exposure of methomyl commercial formulation in zebrafish embryo and larvae. Methomyl is a broad-spectrum carbamate insecticide and acaricide that acts primarily in acetylcholinesterase inhibition (AChE). Methomyl formulation 96 h-LC50 was determined through the Fish Embryo Acute Toxicity Test (FET) and resulted in 1.2 g/L ± 0.04. Sublethal 6-day exposure was performed in six methomyl formulation concentrations (0.5; 1.0; 2.2; 4.8; 10.6; 23.3 mg/L) to evaluate developmental, physiological, morphological, behavioral, biochemical, and molecular endpoints of zebrafish early-development. Methomyl affected embryo hatching and larva morphology and behavior, especially in higher concentrations; resulting in smaller body and eyes size, failure in swimming bladder inflation, hypolocomotor activity, and concentration-dependent reduction of AChE activity; demonstrating methomyl strong acute toxicity and neurotoxic effect.

Early-stage hippocampal hyperexcitability and impaired synaptic plasticity in the TgF344-AD rat model of Alzheimer's disease.

The transgenic TgF344-AD (TG) rat is emerging as a useful model for investigating age-dependent AD features that include behavioural, electrophysiological and pathological phenotypes of relevance to disease. In this study we investigated changes related to early stages of AD in 9 month old animals. Male and female TG rats and wild-type (WT) littermates undertook longitudinal behavioural testing at 3, 6 & 9 months (n=6-13/sex-genotype combination) and were tested for: (i) hippocampus-dependent rapid place learning in a delayed-matching-to place watermaze (DMP) test, (ii) novel object recognition (NOR) memory, (iii) expression of startle/pre-pulse inhibition; and (iv) open-field locomotor activity. In another cohort of rats at 9 months (n=8 males per genotype), spontaneous and evoked activities were record and measured in hippocampal CA3->CA1 circuit to study synaptic plasticity using in vivo electrophysiology under urethane anaesthesia. Following behavioural or electrophysiology testing brains were collected for post-mortem analyses (n=10 males per genotype). GABAergic and synaptic markers including parvalbumin, GAD67 , GABAA α5, SNAP-25 and PSD95 were measured by Simple Western analysis in the frontal cortex, prefrontal cortex, dorsal and ventral hippocampus. Behaviour: WT rats showed poor DMP performance with no clear genotype effect. Object exploration was low with no significant NOR. We found startle and locomotor sex differences, replicating previous reports. Interestingly, at 9 months, TG rats showed locomotor hypoactivity at the beginning and hyperactivity at the end of the 30-min open-field test, indicating impaired habituation, which may reflect impaired hippocampal contextual memory. Electrophysiology: 9-month-old TG rats showed reduced long-term potentiation with an increased baseline connectivity. A general decrease in power across frequency bands was found in the TG, especially for theta band. Western analysis: TG rats showed reduced levels of parvalbumin with a clear effect of genotype at 9-months. There was no detectable changes in synaptic markers. Impaired locomotor habituation of TG rats suggests abnormal hippocampal function emerges around 9 months, reflected by impaired hippocampal CA1 plasticity. A reduction of parvalbumin was also seen in the TG animals at this age. However, poor memory performance may limit the suitability of the TG model for testing clinically relevant memory deficits.

Behavioral effects of early-life exposure to perfluorooctanoic acid might synthetically link to multiple aspects of dopaminergic neuron development and dopamine functions in zebrafish larvae.

Perfluorooctanoic acid (PFOA) is known as an environmental endocrine disruptor and has developmental neurotoxicity that could be associated with behavior changes in human and animal studies. Previous studies have shown that PFOA might affect the dopaminergic nervous system. However, the mode of action underlying the effects of PFOA remains poorly understood. Our study used zebrafish as an animal model to investigate the effects of early-life PFOA exposure on dopaminergic neuron development and dopamine functions in zebrafish larvae. Zebrafish fertilized eggs were exposed to different concentrations of PFOA (0, 10, 100, 1000μg/L). After exposure to PFOA for 7 days, the locomotor activity of zebrafish was decreased; the mRNA levels of nuclear receptor subfamily 4 group a member 2b (nr4a2b), paired box 2 and 5 (pax2, pax5), tyrosine hydroxylase 1/2 (th1/th2) and dopamine transporter (dat) were increased; mRNA and protein level of mesencephalic astrocyte-derived neurotrophic factor (manf) were decreased. Neural cell proliferation in the preoptic area of hypothalamus was increased. In conclusion, dopaminergic neuron development might be one of the targets of early-life PFOA exposure. The neurobehavior changes induced by PFOA exposure might link to multiple aspects of dopaminergic neuron development and dopamine functions in zebrafish larvae.

The use of tocofersolan as a rescue agent in larval zebrafish exposed to benzo[a]pyrene in early development

Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants created by incomplete combustion. Benzo(a)pyrene (BaP), the prototypic PAH, is known to exert toxicity through oxidative stress which is thought to occur through inhibition of antioxidant scavenging systems. The use of agents that reduce oxidative stress may be a valuable route for ameliorating the adverse effects of PAHs on neural development and behavior. This study was conducted to determine if tocofersolan (a synthetic water-soluble analog of vitamin E) supplementation can prevent or reduce neurobehavioral deficits in zebrafish embryos exposed to BaP during early development. Newly hatched zebrafish were assessed on locomotor activity and light responsivity. Zebrafish embryos were exposed to vehicle (DMSO), tocofersolan (0.3 μM–3 μM), and/or BaP (5 μM) from 5−120 hours post-fertilization. This concentration range was below the threshold for producing overt dysmorphogenesis or decreased survival. One day after the end of exposure the larval fish were tested for locomotor activity under alternating light and dark 10 min periods, BaP (5 μM) was found to cause locomotor hypoactivity in larval fish. Co-exposure of tocofersolan (1 μM) restored control-like locomotor function. Based on the findings of this study, this model can be expanded to assess the outcome of vitamin E supplementation on other potential environmental neurotoxicants, and lead to determination if this rescue persists into adulthood.

Multiple Screening of Pesticides Toxicity in Zebrafish and Daphnia Based on Locomotor Activity Alterations.

Pesticides are widely used to eradicate insects, weed species, and fungi in agriculture. The half-lives of some pesticides are relatively long and may have the dire potential to induce adverse effects when released into the soil, terrestrial and aquatic systems. To assess the potential adverse effects of pesticide pollution in the aquatic environment, zebrafish (Danio rerio) and Daphnia magna are two excellent animal models because of their transparent bodies, relatively short development processes, and well-established genetic information. Moreover, they are also suitable for performing high-throughput toxicity assays. In this study, we used both zebrafish larvae and water flea daphnia neonates as a model system to explore and compare the potential toxicity by monitoring locomotor activity. Tested animals were exposed to 12 various types of pesticides (three fungicides and 9 insecticides) for 24 h and their corresponding locomotor activities, in terms of distance traveled, burst movement, and rotation were quantified. By adapting principal component analysis (PCA) and hierarchical clustering analysis, we were able to minimize data complexity and compare pesticide toxicity based on locomotor activity for zebrafish and daphnia. Results showed distinct locomotor activity alteration patterns between zebrafish and daphnia towards pesticide exposure. The majority of pesticides tested in this study induced locomotor hypo-activity in daphnia neonates but triggered locomotor hyper-activity in zebrafish larvae. According to our PCA and clustering results, the toxicity for 12 pesticides was grouped into two major groups based on all locomotor activity endpoints collected from both zebrafish and daphnia. In conclusion, all pesticides resulted in swimming alterations in both animal models by either producing hypo-activity, hyperactivity, or other changes in swimming patterns. In addition, zebrafish and daphnia displayed distinct sensitivity and response against different pesticides, and the combinational analysis approach by using a phenomic approach to combine data collected from zebrafish and daphnia provided better resolution for toxicological assessment.

Gγ7-specific prothymosin alpha deletion causes stress- and age-dependent motor dysfunction and anxiety

We previously showed that prothymosin alpha (ProTα) improves cerebral ischemia-induced motor dysfunction. Our recent study also demonstrated that heterozygous ProTα deletion exhibited an enhanced anxiety-like behavior in mice. However, it remains elusive which brain regions or cells are related to these phenotypes. Here we generated conditional Gγ7-specific ProTα knockout mice using G protein γ7 subunit gene (Gng7)-cre promoter to see the brain robustness roles of ProTα in the striatum and hippocampus. The younger conditional ProTα (Gng7) knockout mice at the age of 10 weeks showed no significant phenotypes in motor dysfunction in the Rotarod test and locomotor activity in the open-field test, whereas significant motor dysfunction was obtained by 15 min transient middle cerebral artery occlusion (tMCAO)-induced cerebral ischemia. The aged conditional ProTα (Gng7) knockout mice at the age of 20 weeks showed hypolocomotor activity with less center time in the open-field test and impaired motor coordination in the Rotarod test without ischemia. Thus, this study suggests that ProTα has important roles in the maintenance of motor coordination and anxiety-like behavior.

Alleviation of diazepam-induced conditioned place preference and its withdrawal-associated neurobehavioral deficits following pre-exposure to enriched environment in rats

Diazepam is one of the widely prescribed sedative drugs for the treatment of anxiety and sleep disorders. However, its continuous use can induce addiction, tolerance, and withdrawal symptoms and, therefore, the pharmacological use of diazepam is restricted. Exposure to enriched environment can reduce the addiction to stimulants including amphetamine, cocaine, and nicotine. However, the protective effect of enriched environment against preference of sedative drugs is not yet investigated. This study, therefore, determined the effects of enriched environment to prevent diazepam-preference using conditioned place preference (CPP) paradigm. Adult rats were reared in social (n = 12) or physically (n = 12) enriched environment for four weeks. Each group was then sub-divided into two groups and were administered either saline (Control; n = 6) or diazepam (1 mg/kg; n = 6) on alternate days for thirteen days. During the administration of diazepam, the CPP was conducted to monitor drug preference on 5th, 9th and 13th day of experiment. It was observed that the diazepam administration significantly (p < .01) induced preference in rats. Neurobehavioral deficits including hypolocomotor activity, depression-like behavior, impaired learning and memory functions were also observed after 24 h of drug abstinence. Exposure to enriched environment significantly reduced diazepam-preference and other neurobehavioral deficits. This study provides preliminary evidence to highlight the importance of enriched environment in the attenuation of diazepam-preference.

Oleoylethanolamide restores alcohol-induced inhibition of neuronal proliferation and microglial activity in striatum

Previous findings demonstrate a homeostatic role for oleoylethanolamide (OEA) signaling in the ethanol-related neuroinflammation and behavior. However, extensive research is still required in order to unveil the effects of OEA on a number of neurobiological functions such as adult neurogenesis, cell survival and resident neuroimmunity that become notably altered by alcohol. Daily consumption of ethanol (10%) for 2 weeks (6.3 ± 1.1 g/kg/day during last 5 days) caused hypolocomotor activity in rats. This effect appears to rely on central signaling mechanisms given that alcohol increased the OEA levels, the gene expression of OEA-synthesizing enzyme Nape-pld and the number of PPARα-immunoreactive neurons in the striatum. Ethanol-related neurobiological alterations such as a reduction in the number of microglial cells expressing iNOS (a cytokine-inducible immune defense) and in adult neural stem/progenitor cell (NSPC) proliferation (phospho-H3 and BrdU) and maturation (BrdU/β3-tubulin), as well as an increase in damage cell activity (FosB) and apoptosis (cleaved caspase 3) were also observed in the rat striatum. Pharmacological administration of OEA (10 mg/kg) for 5 days during ethanol exposure exacerbated ethanol-induced hypolocomotion and cell apoptosis in the striatum. Interestingly, OEA abrogated the impaired effects of ethanol on PPARα-positive cell population and NSPC proliferation and maturation. OEA also decreased astrocyte-related vimentin immunoreactivity and increased microglial cell population (Iba-1, iNOS) in the striatum. These results suggest that OEA-PPARα signaling modulates glial activation, cell apoptosis and NSPC proliferation and maturation in response to striatal-specific neurobiological alterations induced by prolonged ethanol intake in rats.

Exposure to aflatoxin B1 interferes with locomotion and neural development in zebrafish embryos and larvae

Aflatoxin B1 (AFB1) is the major mycotoxin that contaminates aquafeeds and regarded as a causative agent in illnesses and the mortality of aquacultural species. However, the effects of AFB1 on developing fish and associated toxic mechanism are still unknown. This study examines the behavioral changes, neuronal morphology and gene expression in zebrafish embryos and larvae upon exposure to aflatoxin solutions. Treatment of 6 h post fertilization (hpf) embryos with AFB1 at 15–75 ng/mL significantly changed the swimming patterns of seven days post-fertilization (dpf) zebrafish larvae. Larvae in the 15 ng/mL group demonstrated a hypolocomotor activity in free swimming, but hyperlocomotion was observed in the larvae exposed to 30–75 ng/mL AFB1. AFB1 at 75 ng/mL also significantly reduced the startle response of 7 dpf larvae after tapping stimulus. Exposure to AFB1 resulted in an aberrant morphology of trigeminal ganglion and hindbrain neurons in transgenic embryos (HuC:eGFP); this finding was supported by acetylated alpha-tubulin staining in wild-type fish. Additionally, AFB1 altered the levels of neurotoxic markers, including gfap and huC. The transcriptomic profile of AFB1-treated embryos revealed several differentially expressed genes that are related to neuroactivity and neurogenesis. PCR analysis verified that AFB1 significantly down-regulated the expression of ngfa and atp1b1b genes and increased that of prtga gene. The results herein indicate the toxicological impacts of AFB1 on the behaviors and neurodevelopment of fish in the early embryonic stage. Disruption of neural formation and synapse dysfunction may be responsible for the behavioral alteration.

Preceding functional tooth loss delays recovery from acute cerebral hypoxia and locomotor hypoactivity after murine subarachnoid haemorrhage.

Tooth loss and related changes in the functionality may lead to worse outcome of stroke patients, but the effect on hemorrhagic stroke remains unclear. This study aimed to determine the impact of impaired masticatory function on acute cerebral oxygenation and locomotor activity after experimental subarachnoid haemorrhage (SAH). Twenty C57BL/6 mice with (MC-treated group) or without (control group) prior treatment of cutting off the upper molars were subjected to SAH by endovascular perforation. Grading of SAH and acute cerebral infarction were assessed by MR images. Brain tissue oxygen saturation (SbtO2 ) by photoacoustic imaging and parameters related to locomotor activity by open-field test were analyzed serially after SAH. In all mice, global SbtO2 depression was notable immediately after SAH induction (P<.001), which recovered close to the baseline levels until day 3. However, MC-treated mice demonstrated a prolonged relative cerebral hypoxia (<40% of the baseline SbtO2) as compared to the control (3±1 vs 1±1days; P<.05). The average distance travelled on day 7 and the ratio of central-area distance/total travelled distance by open-field test between days 7 and 14 were significantly lower in MC-treated mice than in the control mice (P<.05), although the occurrences of new infarction were not statistically different (P>.05). These data suggest a possible link between preceding masticatory impairment and early brain injury to deteriorate neurobehavioural function in patients after SAH.

Repeated daily administration of increasing doses of lipopolysaccharide provides a model of sustained inflammation-induced depressive-like behaviour in mice that is independent of the NLRP3 inflammasome

Mounting preclinical evidence has implicated the NLRP3 inflammasome in depression-related behaviours elicited by chronic stress or acute lipopolysaccharide (LPS) challenge. However, the relevance of acute LPS as a model of depression has been questioned and behavioural time-courses of its effects can be inconsistent. The aims of this study were (1) to develop a novel protocol for repeated daily LPS administration and (2) to use this model to assess the involvement of NLRP3 inflammasome signalling in sustained inflammation-induced depressive-like behaviour in adult C57BL/6J mice deficient in NLRP3.Acute LPS (0.83mg/kg; i.p.) induced sickness behaviour evident as hypolocomotor activity. However, there was no significant increase in depressive-like behaviour in the forced swim test 24h post-administration. Interestingly, depressive-like behaviours were observed in the female urine sniffing test and in the sucrose preference test at 24h, but not 48h, post-administration of acute LPS. To mimic a period of sustained inflammation, 3-day repeated increasing LPS doses (0.1, 0.42 and 0.83mg/kg; i.p.) was compared to constant LPS doses (0.83mg/kg; i.p.). Sickness behaviour was seen in response to increasing doses, but tolerance developed to repeated constant doses of LPS. Furthermore, 3-day increasing doses of LPS resulted in a significant increase in immobility time in the forced swim test, consistent with depressive-like behaviour. When NLRP3−/− mice received this 3-day increasing dose regimen of LPS, sickness behaviours were attenuated compared to wild-type mice. The behaviour in the forced swim test was not significantly altered in NLRP3−/− mice.We propose that this increasing repeated dosing LPS model of inflammation-induced depressive-like behaviour may better model the sustained inflammation observed in depression and may provide a more translationally relevant paradigm to study the inflammatory mechanisms that contribute to depression.

Antioxidant and antiapoptotic actions of selegiline protect against 3-NP-induced neurotoxicity in rats.

The present study was designed to investigate the neuroprotective effect of selegiline on 3-nitropropionic acid (3-NP)-induced neurotoxicity. Selegiline was intraperitoneally injected at doses 2.5, 5, and 10mg/kg, 3days prior to and continued daily, 30min before 3-NP administration. 3-NP (20mg/kg, i.p.) was administered for four consecutive days. 3-NP-treated rats exhibited PPI deficits, locomotor hypoactivity, increased striatal and cortical lipid peroxidation, and reduced respective glutathione (GSH) levels as well as catalase and superoxide dismutase (SOD) activities. Changes in the level of the apoptotic regulatory gene expressions were demonstrated as increased striatal and cortical caspase-3 and Bax and decreased respective Bcl2. The two higher dose levels of selegiline (5 and 10mg/kg) significantly increased locomotor activity, improved prepulse inhibition (PPI), reduced striatal and cortical lipid peroxidation, caspase-3, and Bax, and increased GSH level, catalase, and superoxide dismutase activities and Bcl2 expression. Selegiline at dose 2.5mg/kg could only reverse some of the manifestations of 3-NP-induced neurotoxicity. Histological examination further affirmed the neuroprotective effect of the higher dose levels of selegiline against 3-NP-induced toxicity. Taken together, these results suggest that selegiline could attenuate 3-NP-induced neurotoxicity. This can be attributed to, at least partly, its antioxidant and antiapoptotic effects.

Behavioural effects of the neonicotinoid insecticide thiamethoxam on the predatory insect Platynus assimilis.

Little information is available regarding sublethal effects of neonicotinoids on insect predators, many of which perform important roles in ecosystem functioning and biocontrol. In this study, dose-dependent sublethal effects of a dietary administered neonicotinoid insecticide thiamethoxam on two basic behaviours, locomotion and feeding, were quantified in the carabid Platynus assimilis (Coleoptera, Carabidae) using automated video-tracking and weighing of consumed food, respectively. Acute toxicity tests showed that, when orally administered, the LD50 of thiamethoxam for P. assimilis beetles was 114.5 ng/g. Thiamethoxam at 108.1 ng/g caused a short-term locomotor hyperactivity within several hours of treatment. Next day after exposure to the insecticide, all the beetles were in a state of locomotor hypoactivity independent of the administered dose ranging from 1.1 to 108.1 ng/g. Reduction in clean food consumption rate (CFCR) is another altered behavioural endpoint of poisoned insect predators as first demonstrated in this study. On the first day of thiamethoxam administration, a remarkable reduction in feeding only occurred in beetles treated at 108.1 ng/g but on the next day, this negative effect appeared even at doses ten to a hundred-fold lower. Recovery from locomotion abnormalities and reduced feeding took several days. Both locomotor activity and CFCR are sensitive and valuable ecotoxicological biomarkers of carabids which should be taken into account in Integrated Pest Management programs where optimal combination of reduced insecticide use and biological control by predatory insects is crucial to achieve best results.

Prothymosin alpha-deficiency enhances anxiety-like behaviors and impairs learning/memory functions and neurogenesis.

Prothymosin alpha (ProTα) is expressed in various mammalian organs including the neuronal nuclei in the brain, and is involved in multiple functions, such as chromatin remodeling, transcriptional regulation, cell proliferation, and survival. ProTα has beneficial actions against ischemia-induced necrosis and apoptosis in the brain and retina. However, characterizing the physiological roles of endogenous ProTα in the brain without stress remains elusive. Here, we generated ProTα-deficiency mice to explore whether endogenous ProTα is involved in normal brain functions. We successfully generated heterozygous ProTα knockout (ProTα+/- ) mice, while all homozygous ProTα knockout (ProTα-/- ) offspring died at early embryonic stage, suggesting that ProTα has crucial roles in embryonic development. In the evaluation of different behavioral tests, ProTα+/- mice exhibited hypolocomotor activity in the open-field test and enhanced anxiety-like behaviors in the light/dark transition test and the novelty induced hypophagia test. ProTα+/- mice also showed impaired learning and memory in the step-through passive avoidance test and the KUROBOX test. Depression-like behaviors in ProTα+/- mice in the forced swim and tail suspension tests were comparable with that of wild-type mice. Furthermore, adult hippocampal neurogenesis was significantly decreased in ProTα+/- mice. ProTα+/- mice showed an impaired long-term potentiation induction in the evaluation of electrophysiological recordings from acute hippocampal slices. Microarray analysis revealed that the candidate genes related to anxiety, learning/memory-functions, and neurogenesis were down-regulated in ProTα+/- mice. Thus, this study suggests that ProTα has crucial physiological roles in the robustness of brain.