Spontaneous Locomotor Research Articles

Metabolic, behavioral, and locomotive effects of feeding in five cyprinids with different habitat preferences.

Fish generally perform routine swimming behaviors during food digestion; thus, changes in swimming performance and adjustments to spontaneous behavior resulting from digestion can have important ecological significance for wild fishes. The effects of feeding on metabolism, spontaneous activity, fast-start escape movement, and critical swimming speed (U crit) were investigated in five cyprinids with different habitat preferences, specifically the Chinese crucian carp (Carassius auratus), common carp (Cyprinus carpio), black carp (Mylopharyngodon piceus), Chinese bream (Parabramis pekinensis), and qingbo (Spinibarbus sinensis). Generally, species in still water exhibited increased feeding metabolism, whereas species in flowing water showed higher spontaneous activity and locomotion performance. Digestion had no significant effects on either spontaneous activity or fast-start escape movement in the five cyprinids. These results could be due to the small meal sizes (approximately 2% body mass) and active foraging modes of cyprinids. The changes in aerobic swimming performance due to feeding were more complex. No effect of digestion on U crit was observed in crucian carp (still water, high feeding metabolism, and low U crit), common carp (widely distributed, high feeding metabolism, and high U crit), and qingbo (flowing water, low feeding metabolism, and high U crit), but digestion resulted in a significant decrease in the U crit of Chinese bream (moderate feeding metabolism but high U crit) and black carp (moderate feeding metabolism and low U crit), suggesting no connection between postprandial U crit changes and feeding metabolism (or between U crit and preferred habitat). The maximum metabolic rate (MMR) of common carp and crucian carp increased after feeding, whereas the corresponding values for the other three cyprinids remained the same. The oxygen uptake capacity appears to meet the oxygen demand of both aerobic swimming and digestion in common carp and crucian carp, whereas qingbo sacrifices digestion for locomotion, and black carp and Chinese bream sacrifice locomotion for digestion under postprandial swimming conditions. The locomotion-priority mode of qingbo is adaptive to its active foraging mode in the demanding swimming habitat of rapidly flowing water, whereas the high respiratory capacities of postprandial crucian carp and common carp and hence the maintenance of their aerobic swimming performances might be a by-product of natural selection for hypoxia tolerance rather than for swimming speed.

Efficacy of anticonvulsant substances in the 6 Hz seizure test: Comparison of two rodent species

Usually performed in the mouse, the 6Hz seizure test is used for screening potential new anticonvulsant substances against complex partial seizures. Nevertheless, advanced models of temporal lobe epilepsy (TLE) are more often performed in rats, so that possible species-related differences may complicate the development of anticonvulsant substances. The aim of the present study was to evaluate the feasibility of adapting the 6Hz test in the rat.We first compared the effects of increasing current intensities for inducing seizures in the mouse and in the rat. This step was followed by the evaluation of the activity of anticonvulsant substances. Animals received an electrical stimulation with a constant current via corneal electrodes. The seizure was characterized by the presence of forelimb clonus immediately after stimulation. Spontaneous locomotion was evaluated following the 6Hz test.In the rat, the forelimb seizure score was intensity-dependently increased and seizures were observed in all animals tested at 44mA. In the mouse, the seizures were of lower magnitude and they were not observed in all mice stimulated at 44mA. In both species, levetiracetam (LEV) clearly decreased the forelimb seizure score over the dose-range 100–300mg/kg without affecting locomotion. Valproate (VPA) displayed anticonvulsant activity at 200mg/kg and fully protected both species at 300mg/kg, a dose producing sedative effects in the mouse. Phenytoin (PHT) showed slight to moderate anticonvulsant activity at 100mg/kg in the mouse and at 60 and 100mg/kg in the rat without modifying locomotor activity. Lamotrigine (LTG) partially antagonized forelimb seizure at 60mg/kg in the mouse and at 30–60mg/kg in the rat, but it induced clear motor impairments at high dose in both species.Our data suggest that in the 6Hz test, the magnitude and the nature of seizures differed between the mouse and the rat for a given current intensity. Nevertheless, the pharmacological profile of anticonvulsant substances was similar in both species for the 4 substances tested. Dose-dependent efficacy of LEV and VPA was observed and LTG and PHT also showed anticonvulsant activity, even though the magnitude of the effects remained moderate for these two last substances.The 6Hz test in the rat therefore appears as a useful model which may be performed prior to follow-up models of partial seizures performed in the same species.

Mercury-induced epigenetic transgenerational inheritance of abnormal neurobehavior is correlated with sperm epimutations in zebrafish.

Methylmercury (MeHg) is a ubiquitous environmental neurotoxicant, with human exposures predominantly resulting from fish consumption. Developmental exposure of zebrafish to MeHg is known to alter their neurobehavior. The current study investigated the direct exposure and transgenerational effects of MeHg, at tissue doses similar to those detected in exposed human populations, on sperm epimutations (i.e., differential DNA methylation regions [DMRs]) and neurobehavior (i.e., visual startle and spontaneous locomotion) in zebrafish, an established human health model. F0 generation embryos were exposed to MeHg (0, 1, 3, 10, 30, and 100 nM) for 24 hours ex vivo. F0 generation control and MeHg-exposed lineages were reared to adults and bred to yield the F1 generation, which was subsequently bred to the F2 generation. Direct exposure (F0 generation) and transgenerational actions (F2 generation) were then evaluated. Hyperactivity and visual deficit were observed in the unexposed descendants (F2 generation) of the MeHg-exposed lineage compared to control. An increase in F2 generation sperm epimutations was observed relative to the F0 generation. Investigation of the DMRs in the F2 generation MeHg-exposed lineage sperm revealed associated genes in the neuroactive ligand-receptor interaction and actin-cytoskeleton pathways being effected, which correlate to the observed neurobehavioral phenotypes. Developmental MeHg-induced epigenetic transgenerational inheritance of abnormal neurobehavior is correlated with sperm epimutations in F2 generation adult zebrafish. Therefore, mercury can promote the epigenetic transgenerational inheritance of disease in zebrafish, which significantly impacts its environmental health considerations in all species including humans.

Involvement of serotonergic, noradrenergic and dopaminergic systems in the antidepressant-like effect of ginsenoside Rb1, a major active ingredient of Panax ginseng C.A. Meyer

Ethnopharmacology relevanceGinsenoside Rb1, a 20 (S)-protopanaxadiol, is a major active ingredient of Panax ginseng C.A. Meyer, which as the King of Chinese herbs, has been wildly used for the treatment of central nervous system diseases. Previous studies have shown that 20 (S)-protopanaxadiol possesses a novel antidepressant-like effect in the treatment of depression, whereas ginsenoside Rb1 in depression has been rarely reported. Aim of the reviewThe present study was to investigate the antidepressant-like effect of ginsenoside Rb1 and its relevant mechanisms. Materials and methodsThe whole experiment was divided into two parts: one part we examined the antidepressant-like effect of ginsenoside Rb1 with open-field test (OFT), tail suspension test (TST), forced swim test (FST), 5-HTP induced head-twitch and reserpine response in mice, another part we used chronic unpredicted mild stress (CUMS) model to further explore the antidepressant-like effect of ginsenoside Rb1 with caffeine, fluoxetine and p-Chlorophenylalanine (PCPA) in rats. Furthermore, the levels of monoamine neurotransmitters of NE, 5-HT, DA and their metabolites 5-HIAA, DOPAC, HVA were all measured by ELISA kits after the CUMS protocol. ResultsOur data indicated that 7 days treatment with ginsenoside Rb1 (4, 8, 10mg/kg, p.o.) significantly decreased immobility time in the FST and TST in mice, and played important roles in mice which were induced by 5-HTP (200mg/kg, i.p.) and reserpine (4mg/kg, i.p.). On the basis of CUMS model, 21 days treatment with ginsenoside Rb1 not only had effective interactions with caffeine (5mg/kg, i.p.), fluoxetine (1mg/kg, i.p.) and PCPA (100mg/kg, i.p.), but also significantly up-regulated the 5-HT, 5-HIAA, NE and DA levels in CUMS rats’ brain, whereas HVA and DOPAC had no significant difference. Moreover, there was no alteration in spontaneous locomotion in any experimental group. ConclusionsThese results suggest that ginsenoside Rb1 exhibits significant antidepressant-like effect in behavioral tests, chronic animal model and drug interactions, its mechanisms mainly mediated by central neurotransmitters of serotonergic, noradrenergic and dopaminergic systems.

Transient inhibition and long-term facilitation of locomotion by phasic optogenetic activation of serotonin neurons.

Serotonin (5-HT) is associated with mood and motivation but the function of endogenous 5-HT remains controversial. Here, we studied the impact of phasic optogenetic activation of 5-HT neurons in mice over time scales from seconds to weeks. We found that activating dorsal raphe nucleus (DRN) 5-HT neurons induced a strong suppression of spontaneous locomotor behavior in the open field with rapid kinetics (onset ≤1 s). Inhibition of locomotion was independent of measures of anxiety or motor impairment and could be overcome by strong motivational drive. Repetitive place-contingent pairing of activation caused neither place preference nor aversion. However, repeated 15 min daily stimulation caused a persistent increase in spontaneous locomotion to emerge over three weeks. These results show that 5-HT transients have strong and opposing short and long-term effects on motor behavior that appear to arise from effects on the underlying factors that motivate actions.

Involvement of BDNF/TrkB signaling in the effect of diphenyl diselenide on motor function in a Parkinson's disease rat model

Parkinson's disease is a progressive neurodegenerative disorder characterized by degeneration of nigrostriatal dopaminergic neurons. Diphenyl diselenide [(PhSe)2] is a compound with pharmacological proprieties, such as antidepressant and neuroprotective. Therefore, this study investigated whether (PhSe)2 reverses motor impairment and neurochemical alterations in a model of Parkinson's disease induced by 6-hydroxydopamine (6-OHDA) in rats. For this, male Wistar rats received 20μg/3μl of 6-OHDA or vehicle into the right striatum. Three weeks later, animals were subjected to rotational behavioral test induced by D-amphetamine and randomly divided into four groups: Sham; (PhSe)2; 6-OHDA and 6-OHDA+(PhSe)2. The rats received (PhSe)2 (1mg/kg/day; i.g.) or vehicle (canola oil) during 30 days. After treatment, behavioral tests were performed in order to evaluate the motor function and the ipsilateral striatal tissue was collected for immunoblotting assay. (PhSe)2 treatment restored the normal motor behavior of 6-OHDA-infused rats in the cylinder, stepping and bridge tests, but not in the rotarod test. The 6-OHDA infusion and/or (PhSe)2 treatment did not alter the muscle strength and spontaneous locomotion in the forelimb support and open-field tests, respectively. Additionally, striatal brain-derived neurotrophic factor (BDNF), proBDNF and tyrosine hydroxylase (TH) levels of 6-OHDA-lesioned rats were decreased, while the tropomyosin-related kinase B (TrkB) levels were increased. (PhSe)2 treatment restored striatal proBDNF, TrkB and TH levels. Thus, (PhSe)2 treatment reversed some motor impairment and TH levels in a 6-OHDA model of Parkinson's disease in rats, demonstrating a potential neurorestorative role. Additionally, the BDNF/TrkB signaling recovery can be involved in its neurorestorative effect.

Combined repeated-dose and reproductive/developmental toxicity screening test of 1-tert-butoxy-4-chlorobenzene in rats

We have carried out animal toxicity tests of chemicals for a chemical safety program implemented by the Ministry of Economy, Trade, and Industry of Japan. Here, we tested 1-tert-butoxy-4-chlorobenzene in a combined repeat-dose and developmental and reproductive toxicity test. The test chemical was administered daily by gavage to 9-week-old Crl:CD (SD) rats at doses of 0, 20, 100, and 500 mg/kg/d. Males were treated for 42 d beginning 14 d before mating. Females were treated from 14 d before mating to day 4 of lactation. Decreased spontaneous locomotion, decreased respiratory rate, and incomplete eyelid opening were observed at 500 mg/kg/d (both sexes), but resolved within 30 min of administration, suggesting central nervous system depression. No notable changes were observed in body weight, food consumption, functional battery tests, or blood test. Increased liver weight with centrilobular or diffuse hepatocyte hypertrophy was observed at 100 and 500 mg/kg/d (both sexes). There were no biochemical or histopathological changes related to hepatotoxicity. Increased kidney weight with basophilic tubules, tubule dilatation, and increased hyaline droplets were observed in males dosed at 100 and 500 mg/kg/d. Immunohistochemical staining indicated α2u-globulin nephropathy, a male rat-specific toxicity. Although kidney weight was also increased in females dosed at 500 mg/kg/d, it was not considered to be an adverse effect because there were no histopathological changes. Pup weights on postnatal day 0 were decreased at 500 mg/kg/d and still decreased on postnatal day 4. Our data indicated the no-observed-adverse-effect-level for repeated-dose and reproductive/developmental toxicity for 1-tert-butoxy-4-chlorobenzene was 100 mg/kg/d.

Context-dependent efficacy of a counter-conditioning strategy with atypical neuroleptic drugs in mice previously sensitized to cocaine

RationaleWe have previously demonstrated that treatment with ziprasidone and aripiprazole selectively inhibit the development of behavioral sensitization to cocaine in mice. We now investigate their effects on a counter-conditioning strategy in mice and the importance of the treatment environment for this phenomenon. ObjectiveEvaluate the context-specificity of ziprasidone and aripiprazole on conditioned locomotion to cocaine and cocaine-induced hyperlocomotion and behavioral sensitization in a counter-conditioning strategy in mice. MethodsAnimals were sensitized with saline or cocaine injections in the open-field apparatus in a 15-day intermittent treatment and subsequently treated with vehicle, 5mg/kg ziprasidone or 0.1mg/kg aripiprazole paired to the open-field or the home-cage for 4 alternate days. Mice were then challenged with saline and cocaine in the open-field apparatus on subsequent days. ResultsWhile treatment with ziprasidone decreased spontaneous locomotion and conditioned locomotion alike, treatment with aripiprazole specifically attenuated the expression of conditioned hyperlocomotion to cocaine. Ziprasidone and aripiprazole had no effects on cocaine-induced conditioned hyperlocomotion observed during saline challenge after drug withdrawal. Treatment with either ziprasidone or aripiprazole when previously given in the cocaine-paired environment attenuated the subsequent expression of behavioral sensitization to cocaine. Animals treated with aripiprazole in the open-field, but not in the home-cage, showed a blunted response to cocaine when receiving a cocaine challenge for the first time. ConclusionsBoth neuroleptic drugs showed a context-dependent effectiveness in attenuating long-term expression of cocaine-induced behavioral sensitization when administered in the cocaine-associated environment, with aripiprazole also showing effectiveness in blocking the expression of acute cocaine effects.

Clozapine N-Oxide Administration Produces Behavioral Effects in Long-Evans Rats: Implications for Designing DREADD Experiments.

Clozapine N-oxide (CNO) is a ligand for a powerful chemogenetic system that can selectively inhibit or activate neurons; the so-called Designer Receptors Exclusively Activated by Designer Drugs (DREADD) system. This system consists of synthetic G-protein-coupled receptors, which are not believed to be activated by any endogenous ligand, but are activated by the otherwise inert CNO. However, it has previously been shown that the administration of CNO in humans and rats leads to detectable levels of the bioactive compounds clozapine and N-desmethylclozapine (N-Des). As a follow-up, experiments were conducted to investigate the effects of CNO in male Long–Evans rats. It was found that 1 mg/kg CNO reduced the acoustic startle reflex but had no effect on prepulse inhibition (PPI; a measure of sensorimotor gating). CNO (2 and 5 mg/kg) had no effect on the disruption to PPI induced by the NMDA antagonist phencyclidine or the muscarinic antagonist scopolamine. In locomotor studies, CNO alone (at 1, 2, and 5 mg/kg) had no effect on spontaneous locomotion, but 5 mg/kg CNO pretreatment significantly attenuated d-amphetamine-induced hyperlocomotion. In line with the behavioral results, fast-scan cyclic voltammetry found that 5 mg/kg CNO significantly attenuated the d-amphetamine-induced increase in evoked dopamine. However, the effects seen after CNO administration cannot be definitively ascribed to CNO because biologically relevant levels of clozapine and N-Des were found in plasma after CNO injection. Our results show that CNO has multiple dose-dependent effects in vivo and is converted to clozapine and N-Des emphasizing the need for a CNO-only DREADD-free control group when designing DREADD-based experiments.

Altered Electroencephalographic Activity Associated with Changes in the Sleep-Wakefulness Cycle of C57BL/6J Mice in Response to a Photoperiod Shortening.

Aim: Under natural conditions diurnal rhythms of biological processes of the organism are synchronized with each other and to the environmental changes by means of the circadian system. Disturbances of the latter affect hormonal levels, sleep-wakefulness cycle and cognitive performance. To study mechanisms of such perturbations animal models subjected to artificial photoperiods are often used. The goal of current study was to understand the effects of circadian rhythm disruption, caused by a short light-dark cycle regime, on activity of the cerebral cortex in rodents.Methods: We used electroencephalogram to assess the distribution of vigilance states, perform spectral analysis, and estimate the homeostatic sleep drive. In addition, we analyzed spontaneous locomotion of C57BL/6J mice under symmetric, 22-, 21-, and 20-h-long light–dark cycles using video recording and tracking methods.Results and Conclusions: We found that shortening of photoperiod caused a significant increase of slow wave activity during non-rapid eye movement sleep suggesting an elevation of sleep pressure under such conditions. While the rhythm of spontaneous locomotion was completely entrained by all light–dark cycles tested, periodic changes in the power of the θ- and γ-frequency ranges during wakefulness gradually disappeared under 22- and 21-h-long light–dark cycles. This was associated with a significant increase in the θ–γ phase-amplitude coupling during wakefulness. Our results thus provide deeper understanding of the mechanisms underlying the impairment of learning and memory retention, which is associated with disturbed circadian regulation.

Effect of light colour temperature and intensity on τhε behaviour of male C57CL/6J mice

Light is an important environmental factor affecting laboratory animals' well-being but still there is a range of light parameters in animal research facilities that need further study. Behavioural testing was conducted to study the impact of different conditions of light colour temperature and intensity (4000K, 60lx; 4000K, 30lx; 2500K, 60lx; 2500K, 30lx) on rodents' behaviour. 24 C57BL/6J mice were subjected to marble burying, open field and elevated plus-maze test to detect effects of lighting on spontaneous behaviour, locomotor activity and anxiety-like behaviour, respectively. Data, as normally distributed, were analysed using analysis of variance (ANOVA). Mice exposed to cool light (4000K) of high intensity (60lx) exhibited the highest level of anxiety-like behaviour in the elevated plus-maze test in comparison to the groups of mice exposed to the other lighting conditions, while those exposed to warm light (2500K) of low intensity (30lx) were the less anxious, since a main effect of colour temperature (P<0.05) as well as a main effect of intensity (P<0.05) were detected. However, spontaneous repetitive behaviour and locomotion seemed to be unaffected by both light parameters. In conclusion, light colour temperature of either 4000 or 2500K combined with intensity of either 60 or 30lx did not affect spontaneous behaviours and locomotor activity levels, but mice exposed to light colour temperature of 4000K and intensity of 60lx were more stressed, which is indicative of an undesirable, more anxiogenic environment for the mice.

Antidepressant-like effects of ascorbic acid and ketamine involve modulation of GABAA and GABAB receptors.

It has been suggested that dysregulation of γ-aminobutyric acid (GABA)-mediated neurotransmission is involved in the etiology of major depressive disorder and in the action of the fast-acting antidepressant ketamine. Considering that recent evidence has suggested that ascorbic acid may exert an antidepressant-like effect through mechanisms similar to ketamine, this study evaluated the involvement of GABAA and GABAB receptors in the antidepressant-like effect of ascorbic acid, comparing the results with those obtained with ketamine. To investigate the involvement of GABAA in the antidepressant-like effect of ascorbic acid and ketamine in the tail suspension test (TST), mice were treated with a sub-effective dose of ascorbic acid (0.1mg/kg, po), ketamine (0.1mg/kg, ip) or vehicle and 30minutes later, a sub-effective dose of muscimol (0.1mg/kg, ip, GABAA receptor agonist) or vehicle was administered. In another set of experiments, mice were treated with ascorbic acid (1mg/kg, po, active dose in the TST) or vehicle and 30minutes later, baclofen (1mg/kg, ip, GABAB receptor agonist) was administered. A similar experimental protocol was performed with ketamine (1mg/kg, ip). The administration of muscimol combined with ascorbic acid or ketamine produced a synergistic antidepressant-like effect in the TST. Moreover, the antidepressant-like effects of ascorbic acid and ketamine were abolished by baclofen. There was no alteration in spontaneous locomotion in any experimental group. Results indicate that the anti-immobility effect of ascorbic acid and ketamine in TST may involve an activation of GABAA receptors and a possible inhibition of GABAB receptors.

Exercise intervention increases spontaneous locomotion but fails to attenuate dopaminergic system loss in a progressive MPTP model in aged mice

While exercise is commonly recommended for PD patients to improve motor function, little is known about the disease-altering potential of exercise. Although others have demonstrated neuroprotective or neurorestorative effects of exercise in animal models of PD, the majority of these studies utilize young animals. In order to assess the effects of exercise intervention in a more clinically relevant model, we have subjected aged mice to progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioning and daily treadmill exercise, initiated early in the course of the disease. The MPTP model elicited a 55% reduction in striatal TH as measured by immunohistochemistry compared to sedentary controls, and exercise did not attenuate this loss in exercised MPTP animals. Furthermore, striatal TH and DAT loss, as assessed by western blotting, were not significantly impacted by treadmill exercise in MPTP-lesioned mice. We did find an increase in spontaneous locomotion in exercised mice that was not decreased by MPTP lesioning. This finding may be due, in part, to an increase in TH expression in the motor cortex in exercised MPTP mice.

Characterization of Rett Syndrome-like phenotypes in Mecp2-knockout rats.

BackgroundRett Syndrome (RTT) is a neurodevelopmental disease caused by the disruption of the MECP2 gene. Several mouse models of RTT have been developed with Mecp2 disruptions. Although the mouse models are widely used in RTT research, results obtained need to be validated in other species. Therefore, we performed these studies to characterize phenotypes of a novel Mecp2−/Y rat model and compared them with the Mecp2tm1.1Bird mouse model of RTT.MethodsRTT-like phenotypes were systematically studied and compared between Mecp2−/Y rats and Mecp2−/Y mice. In-cage conditions of the rats were monitored. Grip strength and spontaneous locomotion were used to evaluate the motor function. Three-chamber test was performed to show autism-type behaviors. Breathing activity was recorded with the plethysmograph. Individual neurons in the locus coeruleus (LC) were studied in the whole-cell current clamp. The lifespan of the rats was determined with their survival time.ResultsMecp2−/Y rats displayed growth retardation, malocclusion, and lack of movements, while hindlimb clasping was not seen. They had weaker forelimb grip strength and a lower rate of locomotion than the WT littermates. Defects in social interaction with other rats were obvious. Breathing frequency variation and apnea in the null rats were significantly higher than in the WT. LC neurons in the null rats showed excessive firing activity. A half of the null rats died in 2 months. Most of the RTT-like symptoms were comparable to those seen in Mecp2−/Y mice, while some appeared more or less severe. The findings that most RTT-like symptoms exist in the rat model with moderate variations and differences from the mouse models support the usefulness of both Mecp2−/Y rodent models.ConclusionsThe novel Mecp2−/Y rat model recapitulated numerous RTT-like symptoms as Mecp2−/Y mouse models did, which makes it a valuable alternative model in the RTT studies when the body size matters.

Role of astrocyte activation in fine particulate matter-enhancement of existing ischemic stroke in Sprague-Dawley male rats

ABSTRACTExposure to particulate matter (PM) with an aerodynamic diameter of less than 2.5 μm (PM2.5) is associated with increased risk of ischemic stroke, but potential neurotoxic mechanisms remain to be determined. In this study, adult male Sprague- Dawley (SD) rats were divided into four groups as follows: control (CON), PM2.5 exposure (PM alone), ischemic stroke (IS), and ischemic stroke and PM2.5 (IS-PM). Ischemic stroke groups were prepared by middle cerebral artery occlusion (MCAO), and neurobehavior was assessed daily for 7 consecutive days. The control group was administered intranasally 20 μl PBS, while PM2.5 alone was given as 20 μl of PM2.5 (10 mg/ml) intranasal daily for 7 consecutive days. The spontaneous locomotion and exploratory behavior of rats were assessed by the open field test. Cells positive for glial fibrillary acidic protein (GFAP) and inducible nitric oxide synthase (iNOS) were determined for astrocyte activation and inflammatory reactions. Neuronal edema and pyknosis in the cerebral cortex, hippocampus, and midbrain were observed in IS groups with or without PM2.5 treatment. Astrocyte activity was enhanced, whereas spontaneous locomotion and exploratory movements decreased in the IS-PM group. Data demonstrated that astrocytes activation and inflammatory reactions may play a role in IS and that exposure to PM2.5 may aggravate the neurobehavioral alterations observed in rats suffering from IS.

Fatty Acid Binding Protein 5 Modulates Docosahexaenoic Acid-Induced Recovery in Rats Undergoing Spinal Cord Injury.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) promote functional recovery in rats undergoing spinal cord injury (SCI). However, the precise molecular mechanism coupling n-3 PUFAs to neurorestorative responses is not well understood. The aim of the present study was to determine the spatiotemporal expression of fatty acid binding protein 5 (FABP5) after contusive SCI and to investigate whether this protein plays a role in n-3 PUFA-mediated functional recovery post-SCI. We found that SCI resulted in a robust spinal cord up-regulation in FABP5 mRNA levels (556 ± 187%) and protein expression (518 ± 195%), when compared to sham-operated rats, at 7 days post-injury (dpi). This upregulation coincided with significant alterations in the metabolism of fatty acids in the injured spinal cord, as revealed by metabolomics-based lipid analyses. In particular, we found increased levels of the n-3 series PUFAs, particularly docosahexaenoic acid (DHA; 22:6 n-3) and eicosapentaenoic acid (EPA; 20:5 n-3) at 7 dpi. Animals consuming a diet rich in DHA and EPA exhibited a significant upregulation in FABP5 mRNA levels at 7 dpi. Immunofluorescence showed low basal FABP5 immunoreactivity in spinal cord ventral gray matter NeuN(+) neurons of sham-operated rats. SCI resulted in a robust induction of FABP5 in glial (GFAP(+), APC(+), and NG2(+)) and precursor cells (DCX(+), nestin(+)). We found that continuous intrathecal administration of FABP5 silencing with small interfering RNA (2 μg) impaired spontaneous open-field locomotion post-SCI. Further, FABP5 siRNA administration hindered the beneficial effects of DHA to ameliorate functional recovery at 7 dpi. Altogether, our findings suggest that FABP5 may be an important player in the promotion of cellular uptake, transport, and/or metabolism of DHA post-SCI. Given the beneficial roles of n-3 PUFAs in ameliorating functional recovery, we propose that FABP5 is an important contributor to basic repair mechanisms in the injured spinal cord.

A lasting effect of postnatal sevoflurane anesthesia on the composition of NMDA receptor subunits in rat prefrontal cortex

Sevoflurane is widely used in pediatric anesthesia and studies have shown that it is capable of inducing neurodegeneration and subsequent cognitive disorders in the developing brain. However, the evidence that anesthetics are toxic to the human brain is insufficient. N-Methyl-d-aspartate (NMDA) receptors, critical for learning and memory, display expression changes with age and can be modulated by inhalation anesthetics. Generally, NMDA receptor (NR) type 1 is expressed at birth, peaks around the third postnatal week, and then declines slightly to adult levels. NR2Bs slowly decrease and NR2As gradually increase during postnatal development. These developmental switches of NMDA receptor subunits composition mark the transition from immature to adult neural processing and allow for the final maturation of associative learning abilities. In this study, we aimed to evaluate the effect of repeated sevoflurane anesthesia on NMDA receptor subunits composition in the developing rat brain and related behavioral disorders. Six-day-old male Sprague Dawley rats were randomly allocated into either a control group (group con) or a sevoflurane group (group sevo). Group sevo inhaled 2.1% sevoflurane carried by 70% oxygen for 2h each day from postnatal day (PND) 6 to PND 8. The same procedure, without applying the sevoflurane, was executed in group con. The membrane protein expression of NR1, NR2A and NR2B in the prefrontal cortex (PFC) and hippocampus was assessed at the end of the three days of anesthesia and at PND 21. An open field test was carried out to assess spontaneous locomotion on PNDs 21, 28 and 35. Y maze performance was used to assess attention and working memory on PND 28. Sevoflurane induced upregulation of NR1 and NR2B in the PFC at the end of anesthesia. On PND 21, NR1 and NR2B receptors were significantly increased whereas NR2A receptors were significantly decreased in the PFC in group sevo. Sevoflurane-treated rats showed hyper-locomotion and impairment of working memory in the behavior tests. These results indicate that repeated sevoflurane anesthesia at early stage of life can induce a long lasting effect of interfering with NMDA receptor subunits composition in rat PFC. These changes may contribute to the effects of sevoflurane on neuronal development and subsequent neurobehavioral disorders.

Ancient Anxiety Pathways Influence Drosophila Defense Behaviors

SummaryAnxiety helps us anticipate and assess potential danger in ambiguous situations [1, 2, 3]; however, the anxiety disorders are the most prevalent class of psychiatric illness [4, 5, 6]. Emotional states are shared between humans and other animals [7], as observed by behavioral manifestations [8], physiological responses [9], and gene conservation [10]. Anxiety research makes wide use of three rodent behavioral assays—elevated plus maze, open field, and light/dark box—that present a choice between sheltered and exposed regions [11]. Exposure avoidance in anxiety-related defense behaviors was confirmed to be a correlate of rodent anxiety by treatment with known anxiety-altering agents [12, 13, 14] and is now used to characterize anxiety systems. Modeling anxiety with a small neurogenetic animal would further aid the elucidation of its neuronal and molecular bases. Drosophila neurogenetics research has elucidated the mechanisms of fundamental behaviors and implicated genes that are often orthologous across species. In an enclosed arena, flies stay close to the walls during spontaneous locomotion [15, 16], a behavior proposed to be related to anxiety [17]. We tested this hypothesis with manipulations of the GABA receptor, serotonin signaling, and stress. The effects of these interventions were strikingly concordant with rodent anxiety, verifying that these behaviors report on an anxiety-like state. Application of this method was able to identify several new fly anxiety genes. The presence of conserved neurogenetic pathways in the insect brain identifies Drosophila as an attractive genetic model for the study of anxiety and anxiety-related disorders, complementing existing rodent systems.

Cell Therapy for Parkinson's Disease: A Translational Approach to Assess the Role of Local and Systemic Immunosuppression.

Neural transplantation is a promising therapeutic approach for neurodegenerative diseases; however, many patients receiving intracerebral fetal allografts exhibit signs of immunization to donor antigens that could compromise the graft. In this context, we intracerebrally transplanted mesencephalic pig xenografts into primates to identify a suitable strategy to enable long-term cell survival, maturation, and differentiation. Parkinsonian primates received WT or CTLA4-Ig transgenic porcine xenografts and different durations of peripheral immunosuppression to test whether systemic plus graft-mediated local immunosuppression might avoid rejection. A striking recovery of spontaneous locomotion was observed in primates receiving systemic plus local immunosuppression for 6 mo. Recovery was associated with restoration of dopaminergic activity detected both by positron emission tomography imaging and histological examination. Local infiltration by T cells and CD80/86+ microglial cells expressing indoleamine 2,3-dioxigenase were observed only in CTLA4-Ig recipients. Results suggest that in this primate neurotransplantation model, peripheral immunosuppression is indispensable to achieve the long-term survival of porcine neuronal xenografts that is required to study the beneficial immunomodulatory effect of local blockade of T cell costimulation.

Effects of Voluntary Locomotion and Calcitonin Gene-Related Peptide on the Dynamics of Single Dural Vessels in Awake Mice.

The dura mater is a vascularized membrane surrounding the brain and is heavily innervated by sensory nerves. Our knowledge of the dural vasculature has been limited to pathological conditions, such as headaches, but little is known about the dural blood flow regulation during behavior. To better understand the dynamics of dural vessels during behavior, we used two-photon laser scanning microscopy (2PLSM) to measure the diameter changes of single dural and pial vessels in the awake mouse during voluntary locomotion. Surprisingly, we found that voluntary locomotion drove the constriction of dural vessels, and the dynamics of these constrictions could be captured with a linear convolution model. Dural vessel constrictions did not mirror the large increases in intracranial pressure (ICP) during locomotion, indicating that dural vessel constriction was not caused passively by compression. To study how behaviorally driven dynamics of dural vessels might be altered in pathological states, we injected the vasodilator calcitonin gene-related peptide (CGRP), which induces headache in humans. CGRP dilated dural, but not pial, vessels and significantly reduced spontaneous locomotion but did not block locomotion-induced constrictions in dural vessels. Sumatriptan, a drug commonly used to treat headaches, blocked the vascular and behavioral the effects of CGRP. These findings suggest that, in the awake animal, the diameters of dural vessels are regulated dynamically during behavior and during drug-induced pathological states.