Increased Locomotor Activity Research Articles

Kynurenine 3-monooxygenase deficiency induces depression-like behavior via enhanced antagonism of α7 nicotinic acetylcholine receptors by kynurenic acid

Tryptophan (TRP) is metabolized via the kynurenine (KYN) pathway, which is related to the pathogenesis of major depressive disorder (MDD). Kynurenine 3-monooxygenase (KMO) is a pivotal enzyme in the metabolism of KYN to 3-hydroxykynurenine. In rodents, KMO deficiency induces a depression-like behavior and increases the levels of kynurenic acid (KA), a KYN metabolite formed by kynurenine aminotransferases (KATs). KA antagonizes α7 nicotinic acetylcholine receptor (α7nAChR). Here, we investigated the involvement of KA in depression-like behavior in KMO knockout (KO) mice. KYN, KA, and anthranilic acid but not TRP or 3-hydroxyanthranilic acid were elevated in the prefrontal cortex of KMO KO mice. The mRNA levels of KAT1 and α7nAChR but not KAT2−4, α4nAChR, or β2nAChR were elevated in the prefrontal cortex of KMO KO mice. Nicotine blocked increase in locomotor activity, decrease in social interaction time, and prolonged immobility in a forced swimming test, but it did not decrease sucrose preference in the KMO KO mice. Methyllycaconitine (an α7nAChR antagonist) antagonized the effect of nicotine on decreased social interaction time and prolonged immobility in the forced swimming test, but not increased locomotor activity. Galantamine (an α7nAChR allosteric agonist) blocked the increased locomotor activity and prolonged immobility in the forced swimming test, but not the decreased social interaction time in the KMO KO mice. In conclusion, elevation of KA levels contributes to depression-like behaviors in KMO KO mice by α7nAChR antagonism. The ameliorating effects of nicotine and galantamine on depression-like behaviors in KMO KO mice are associated with the activation of α7nAChR.

The acute effects of multiple doses of methamphetamine on locomotor activity and anxiety-like behavior in adolescent and adult mice

Methamphetamine (MA) is a highly addictive psychomotor stimulant drug. Research has shown that the acute effects of MA can be modulated by age, although previous findings from our lab do not find age differences in the effects of MA. Relatively little research has examined the effects of adolescent MA exposure; thus, it is important to understand how MA affects adolescent behavior and brain function compared to adults. In order to better understand the age differences in the effects of acute MA exposure, this research examined the effects of MA exposure on locomotor and anxiety-like behavior and plasma corticosterone levels in adolescent and adult C57BL/6 J mice. Mice were exposed to saline, 2 mg/kg MA, or 4 mg/kg MA and behavior was measured in the open field test. Immediately following behavioral testing, serum was collected, and plasma corticosterone levels were measured. MA-exposed mice showed increased locomotor activity and anxiety-like behavior compared to saline controls, regardless of age and dose of MA. However, adolescent mice showed the greatest locomotor response to the high dose of MA (4 mg/kg), whereas the adult mice showed the greatest locomotor response to the low dose of MA (2 mg/kg). There were no differences in stereotyped behavior between the adolescent and adult mice exposed to the low dose of MA (2 mg/kg) and the high dose of MA (4 mg/kg). There was no effect of MA exposure on plasma corticosterone levels. These data suggest age modulates the locomotor response to MA and further research is warranted to determine the developmental neurobiological mechanism underlying the dose-response age differences in the response to acute MA exposure.

Repeated crack cocaine administration alters panic-related responses and delta FosB immunoreactivity in panic-modulating brain regions.

Crack cocaine is the crystal form of cocaine, produced by adding sodium bicarbonate to cocaine base paste. Brazil is the largest consumer of crack cocaine in the world. Users of crack cocaine show important physiological and behavioral alterations, including neuropsychiatric symptoms, such as anxiety-related symptoms. Nevertheless, few pre-clinical studies have been previously performed to understand the neurobiological effects of crack cocaine. The purpose of the present study was to investigate effects of the subchronic treatment (5days, IP) of rats with crack cocaine in an animal model of anxiety/panic, the elevated T-maze (ETM). The ETM model allows the measurement of two behavioral defensive responses, avoidance and escape, in clinical terms, respectively, associated to generalized anxiety and panic disorder, the two main psychiatric conditions that accompany substance use disorders. Immediately after the ETM model, animals were tested in an open field for locomotor activity assessment. Analysis of delta FosB protein immunoreactivity was used to map areas activated by crack cocaine exposure. Results showed that crack treatment selectively altered escape displayed by rats in the ETM test, inducing either a panicolytic (18mg/kg IP) or a panicogenic-like effect (25 and 36mg/kg IP). These effects were followed by the altered functioning of panic-modulating brain regions, i.e., the periaqueductal gray and the dorsal region and lateral wings of the dorsal raphe nucleus. Treatment with 36mg/kg of crack cocaine also increased locomotor activity. These are the first observations performed with crack cocaine in a rodent model of anxiety/panic and contribute to a better understanding of the behavioral and neurobiological effects of crack cocaine.

Depression-/Anxiety-Like Behavior Alterations in Adult Slit2 Transgenic Mice.

Background: Slit2 is a member of the Slit family of secreted glycoproteins that plays highly conserved roles in neuronal axon guidance and cellular migration. Our previous experimental results showed Alzheimer's disease-like alterations and increased permeability of the blood–brain barrier in Slit2-overexpressing transgenic (Slit2-Tg) mice aged 8–9 months. Nevertheless, relatively little is known about behavioral alterations in adult Slit2-Tg mice (2–6 months of age). To observe the age-related behavioral effects of Slit2 overexpression in adult mice, we performed a battery of behavioral tests with adult Slit2-Tg mice at 2–6 months of age.Results: The body weight of Slit2-Tg mice was lower than that of the wild-type mice from 15 weeks of age. Compared with the control mice, depression-like behaviors were found in Slit2-Tg mice from 15 to 21 weeks of age in the sucrose preference test, although Slit2-Tg mice were hyperactive in the tail suspension test. The anxiety-like behaviors were found in Slit2-Tg mice in the open field test, as well as increased locomotor activity. The anxiety-like behaviors were also found in adult Slit2-Tg mice in the elevated plus maze. Compared to wild-type mice at 23 weeks old, impairment of the hippocampal neurons were found in Slit2-Tg mice at the same age in hematoxylin–eosin staining (H&E), including some eccentric dispersion and expansion of neuronal bodies. In addition, the messenger RNA (mRNA) expression of TNF-α was elevated in the hippocampus of adult Slit2-Tg mice.Conclusions: Slit2 overexpression causes depression-/anxiety-like behaviors in adult mice that may be related to an increase in inflammatory factors and damage to hippocampal neurons.

Prophylactic effect of the aqueous extract of Pimpinella anisum on the behavior of Wistar rats exposed to mercury

The purpose of this study was to evaluate the prophylactic effect of Pimpinella anisum (green anis) on neurobehavioral status following mercury chloride intoxication during the developmental period. For this purpose, rats exposed to 100 mg/L of HgCl2 during the gestation and lactation period. A group of rats was treated with the anis extract for 15 days before becoming intoxicated with mercury. In contrast, one group was orally administered aqueous anis extract for 15 days after intoxication. The forced swimming test, the open field test and the Morris pool respectively recorded an increase in immobility time, a decrease in the number of cross-cells (p <0.001), (p <0.05) and an increase in latency (p <0.01), (p <0.001), (p <0.001) and decreased time spent in the target frame during the probe test (p <0.01) and increased latency in the visible test (p <0.01) in HgCl2 - exposed rats compared to control rats. However, preventive and curative aniseed-based treatment reduced the rate of depression, increased locomotor activity and improved learning performance. In conclusion, the aqueous extract of Pimpinella anisum could have a corrective effect on some neurological disorders caused by mercury.

Audiovisual overstimulation in childhood and adolescence promotes hyperactive behaviour in adult mice

There is a discussion about the impact of technological development on behavioural aspects, a nuance that the present study aimed to assess. p21, p26 and p36 mice were subjected to audio (70 db) and visual stimulation (flashing lights) for 2 or 6 h per day until p64. Naive animals were included. From p74 onwards, the animals were subjected to tests to assess their locomotion, depression, anxiety, aggressiveness, and nociception behaviours. Weight assessment was also performed. The animals that received stimulation for 2 h a day since p21 showed a decrease in rearing and grooming behaviour in the open field test, as well as in the mechanical orofacial sensitivity. Animals that received stimulation for 6 h daily since p21 showed increased locomotor activity in the open field test. Animals that received stimulation for 2 h a day since p26 showed an increase in locomotor activity and a decrease in grooming behaviour in the open field test, in addition to a reduction in the number of entries in the closed arm of the elevated plus maze. Animals stimulated from p26 for 6 h daily increased the reaction time to the thermal stimulus. Animals that received stimulation for 2 h daily since p36 showed an increase in locomotor activity and a decrease in grooming behaviour in the open field test. Taken together, these findings suggest that audiovisual overstimulation during critical periods of brain development may have adverse effects compatible with hyperactivity in adulthood.

Exercise associated with γ-oryzanol supplementation suppresses oxidative stress and prevents changes in locomotion in Drosophila melanogaster

Association to early mortality and sedentarism was already demonstrated in the literature; nevertheless, some possible biochemical mechanisms around physical inactivity still need answers. The use of an invertebrate model, such as Drosophila melanogaster, can reproduce reliable responses in inducing an exercise protocol with exogenous antioxidant supplementation. This study main evaluates the effect of exercise (EXE) associated with γ-oryzanol (ORY) supplementation to improve locomotor behavior, antioxidant defenses, and survival in Drosophila melanogaster. Two-day old flies were submitted to a protocol for seven days, divided into five groups: Control, Movement-Limited Flies (MLF), EXE, ORY [25 µM], and EXE + ORY [25 µM]. The survival rate was evaluated, followed by open field and negative geotaxis. Flies were euthanized and subjected to analysis for acetylcholinesterase (AChE) and antioxidant enzymes activity, glycidic and lipid parameters, body weight, reactive species (RS), and lipid peroxidation. EXE and EXE + ORY flies showed increased survival and locomotor activity, improved glycidic and lipid parameters, with a lower RS production, and increased antioxidant defenses compared to Control, and EXE + ORY when compared to the EXE group, obtained an increase in the ratio of protein levels/body weight, decreased ratio of triglyceride levels/body weight and decreased lipid peroxidation. However, MLF showed less survival and decreased locomotor activity, possibly due to increased AChE activity and reduced antioxidant defenses. The EXE and EXE + ORY demonstrate effective results in maintaining endogenous defenses, with increased locomotor activity, supporting evidence on EXE benefits, and supplementation with antioxidant compounds face of health paradigms. Highlights New protocol system of exercise on Drosophila melanogaster model. ORY demonstrates synergistic effect with EXE. Exercise with ORY supplementation increases locomotor behavior. Exercise with ORY supplementation decrease oxidative damages on flies.

Evaluation of Nootropic Activity of Limonia acidissima Against Scopolamine-induced Amnesia in Rats.

The present study aimed to evaluate the nootropic activity of Limonia acidissima in rats. Methanolic extract of Limonia acidissima was used to evaluate nootropic activity, piracetam (200 mg/kg, i.p.) was used as a standard, and scopolamine (1 mg/kg, i.p.) was used to induce amnesia. The effect of drugs on learning and memory in rats was evaluated by using the Y-maze task and elevated plus maze on scopolamine-induced amnesia models. Locomotor activity was performed using an actophotometer. Also, levels of acetylcholinestrease, including histopathological examination of rat brains, were assessed. Methanolic extract of Limonia acidissima showed increased alteration of the behavior response and percentage spontaneous alteration with the Y-maze task. In the elevated plus maze scopolamine-induced amnesia model, methanolic extract of Limonia acidissima showed a decrease in transfer latency, which is indicative of cognition improvement. Methanolic extract increased locomotor activity in rats and decreased the levels of acetylcholinestrease enzyme significantly. A histopathological study with both low and high doses of extract showed effective regenerative scores as compared to normal control, negative control and standard treatment. The results suggested that the administration of methanolic extract of Limonia acidissima enhances learning and memory in different experimental models. The histopathological study revealed the neuroprotective property of the extract. The study indicates that the extract may be used in the treatment of Alzheimer's disease.

Amelioration of the abnormal phenotype of a new L1 syndrome mouse mutation with L1 mimetics.

L1 syndrome is a rare developmental disorder characterized by hydrocephalus of varying severity, intellectual deficits, spasticity of the legs, and adducted thumbs. Therapy is limited to symptomatic relief. Numerous gene mutations in the L1 cell adhesion molecule (L1CAM, hereafter abbreviated L1) were identified in L1 syndrome patients, and those affecting the extracellular domain of this transmembrane type 1 glycoprotein show the most severe phenotypes. Previously analyzed rodent models of the L1 syndrome focused on L1-deficient animals or mouse mutants with abrogated cell surface expression of L1, making it difficult to test L1 function-triggering mimetic compounds with potential therapeutic value. To overcome this impasse, we generated a novel L1 syndrome mouse with a mutation of aspartic acid at position 201 in the extracellular part of L1 (p.D201N, hereafter termed L1-201) that displays a cell surface-exposed L1 accessible to the L1 mimetics. Behavioral assessment revealed an increased neurological deficit score and increased locomotor activity in male L1-201 mice carrying the mutation on the X-chromosome. Histological analyses of L1-201 mice showed features of the L1 syndrome, including enlarged ventricles and reduced size of the corpus callosum. Expression levels of L1-201 protein as well as extent of cell surface biotinylation and immunofluorescence labelling of cultured cerebellar neurons were normal. Importantly, treatment of these cultures with the L1 mimetic compounds duloxetine, crotamiton, and trimebutine rescued impaired cell migration and survival as well as neuritogenesis. Altogether, the novel L1 syndrome mouse model provides a first experimental proof-of-principle for the potential therapeutic value of L1 mimetic compounds.

Limonene has anti-anxiety activity via adenosine A2A receptor-mediated regulation of dopaminergic and GABAergic neuronal function in the striatum

BackgroundLimonene, a common terpene found in citrus fruits, is assumed to reduce stress and mood disorders. Dopamine and γ-aminobutyric acid (GABA) have been reported to play an important role in modulating anxiety in different parts of the brain. Hypothesis/PurposeHerein, we report the anxiolytic activity of limonene. In addition, we identified a possible mechanism underlying the effect of limonene on DAergic and GABAergic neurotransmission. Study DesignIn this study, mice were injected with saline in the control group and limonene in the test group before behavioral analysis. We performed immunoblotting and high-performance liquid chromatography (HPLC) analysis after the behavioral study. ResultsThe limonene treated group showed increased locomotor activity and open-arm preference in the elevated plus maze experiment. Limonene treatment increased the expression of both tyrosine hydroxylase and GAD-67 proteins and significantly upregulated dopamine levels in the striatum. Furthermore, tissue dopamine levels were increased in the striatum of mice following limonene treatment, and depolarization-induced GABA release was enhanced by limonene pre-treatment in PC-12 cells. Interestingly, limonene-induced anxiolytic activity and GABA release augmentation were blocked by an adenosine A2A receptor (A2AR) antagonist. ConclusionOur results suggest that limonene inhibits anxiety-related behavior through A2A receptor-mediated regulation of DAergic and GABAergic neuronal activity.

Integrated Metabolomics and Lipidomics Analysis Reveal Remodeling of Lipid Metabolism and Amino Acid Metabolism in Glucagon Receptor-Deficient Zebrafish.

The glucagon receptor (GCGR) is activated by glucagon and is essential for glucose, amino acid, and lipid metabolism of animals. GCGR blockade has been demonstrated to induce hypoglycemia, hyperaminoacidemia, hyperglucagonemia, decreased adiposity, hepatosteatosis, and pancreatic α cells hyperplasia in organisms. However, the mechanism of how GCGR regulates these physiological functions is not yet very clear. In our previous study, we revealed that GCGR regulated metabolic network at transcriptional level by RNA-seq using GCGR mutant zebrafish (gcgr−/−). Here, we further performed whole-organism metabolomics and lipidomics profiling on wild-type and gcgr−/− zebrafish to study the changes of metabolites. We found 107 significantly different metabolites from metabolomics analysis and 87 significantly different lipids from lipidomics analysis. Chemical substance classification and pathway analysis integrated with transcriptomics data both revealed that amino acid metabolism and lipid metabolism were remodeled in gcgr-deficient zebrafish. Similar to other studies, our study showed that gcgr−/− zebrafish exhibited decreased ureagenesis and impaired cholesterol metabolism. More interestingly, we found that the glycerophospholipid metabolism was disrupted, the arachidonic acid metabolism was up-regulated, and the tryptophan metabolism pathway was down-regulated in gcgr−/− zebrafish. Based on the omics data, we further validated our findings by revealing that gcgr−/− zebrafish exhibited dampened melatonin diel rhythmicity and increased locomotor activity. These global omics data provide us a better understanding about the role of GCGR in regulating metabolic network and new insight into GCGR physiological functions.

Identification of the antidepressive properties of C1, a specific inhibitor of Skp2, in mice.

We have reported that SMIP004, an inhibitor of S-phase kinase-associated protein 2 (Skp2), displays antidepressant-like activities in stress-naïve and chronically stressed mice. Here, we investigated the antidepressant-like effect of C1, another inhibitor of Skp2, in mouse models following acute or chronic drug administration at different doses and treatment times by using the tail suspension test (TST), forced swimming test (FST), and social interaction test (SIT). The time- and dose-dependent results showed that the antidepressant-like effect of C1 occurred 8 days after the drug treatment, and C1 produced antidepressant-like activities at the dose of 5 and 10 but not 1 mg/kg in male or female mice. C1 administration (5 mg/kg) also induced antidepressant-like effects in stress-naïve mice in a three-times administration mode within 24 h (24, 5, and 1 h before the test) but not in an acute administration mode (1 h before the test). The C1 and fluoxetine co-administration produced additive effect on depression-like behaviors in stress-naïve mice. The antidepressant-like effect of C1 was not associated with the change in locomotor activity, as no increased locomotor activity was observed in different treatment modes. Furthermore, the long-term C1 treatment (5 mg/kg) was found to ameliorate the depression-like behaviors in chronic social defeat stress-exposed mice, suggesting that C1 can produce antidepressant-like actions in stress conditions. Since C1 is a specific inhibitor of Skp2, our results demonstrate that inhibition of Skp2 might be a potential strategy for the treatment of depression, and Skp2 may be potential target for the development of novel antidepressants.

Reducing l-lactate release from hippocampal astrocytes by intracellular oxidation increases novelty induced activity in mice.

Astrocytes are in control of metabolic homeostasis in the brain and support and modulate neuronal function in various ways. Astrocyte‐derived l‐lactate (lactate) is thought to play a dual role as a metabolic and a signaling molecule in inter‐cellular communication. The biological significance of lactate release from astrocytes is poorly understood, largely because the tools to manipulate lactate levels in vivo are limited. We therefore developed new viral vectors for astrocyte‐specific expression of a mammalianized version of lactate oxidase (LOx) from Aerococcus viridans. LOx expression in astrocytes in vitro reduced their intracellular lactate levels as well as the release of lactate to the extracellular space. Selective expression of LOx in astrocytes of the dorsal hippocampus in mice resulted in increased locomotor activity in response to novel stimuli. Our findings suggest that a localized decreased intracellular lactate pool in hippocampal astrocytes could contribute to greater responsiveness to environmental novelty. We expect that use of this molecular tool to chronically limit astrocytic lactate release will significantly facilitate future studies into the roles and mechanisms of intercellular lactate communication in the brain.

Behavioural and Metabolical Changes Associated with the Pathophysiology of Alzheimer’s Disease in Zebrafish

Affecting 60% of the people diagnosed with dementia, Alzheimer’s disease is a neurodegenerative pathology that negatively impacts the cognitive function. It is characterised by symptoms as memory loss, locomotor difficulties, behavioural changes, and even rationalization issues. This disease has been studied on both rodents and fishes. Rodents helped science people establish the basic neurobiology of dementia, while fishes (Danio rerio – the zebra fish, especially) were more appropriate as transgenic models. Recent studies proved that transgenically induced Alzheimer’s disease at zebra fishes is not defined only by cognitive decline but also by motor function disorders. Objectives. This study aims to analyse how iron chloride and sucrose impact zebra fishes’ locomotion and memory by using the T maze. Methods. 50 zebra fishes were purchased from a local pisciculturist and randomly divided in 4 experimental groups. They were accommodated in the Ecotoxicology laboratory at “Alexandru Ioan Cuza” University for 3 weeks according to the European Union Commission and European Union Council recommendations regarding experimental purposes animals' protection and accommodation. Fishes’ possible behavioural changes were analysed after they were given sucrose and iron chloride separately and in their combination. Results. We observed that sucrose administration negatively impacted the locomotory activity while iron chloride surprisingly increased it. The possible explanation is the fact that iron chloride generated anxiety - an early-stage Alzheimer's disease symptom, and therefore improved fishes' swimming performance. Successive sucrose and iron chloride administration also led to increased locomotor activity.

POSSIBLE ANTI-DEPRESSANT EFFECT OF THE SELECTIVE COX-2 INHIBITOR MELOXICAM, ITS RELATIONSHIP WITH THE DOPAMINERGIC BRAIN SYSTEM

Inflammation is now believed to play an important role in the development of depression, and it is suggested that inflammation may be a promising target for the treatment and prevention of mood disorders. It is not surprising that various non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase-2 (COX-2), are being tested for their antidepressant properties. At the same time, it is known that inhibition of COX-2 has a certain effect on the dopaminergic (DA) system. However, in the literature, there are also opposite opinions on this matter, for example, that the neuroprotective effect of NSAIDs is associated not with COX-2, but with the PI3K/Akt signaling pathway, and inhibition of COX-2 does not have a neuroprotective effect, and even negatively affects the central nervous system up to until the pathophysiology of depression aggravates. Therefore, the question of the antidepressant properties of COX-2 inhibitors remains open for further research. In addition, because of the dynamic nature of depression, it is important to ascertain whether NSAIDs may be prophylactic in the early stages of depression. Accordingly, the aim of this study was to determine the presence or absence of antidepressant potential in the selective COX-2 inhibitor meloxicam (21 days, 1 mg/kg), its possible relationship with the DA system, by tracing these effects over time. The combined use of meloxicam and haloperidol (24 days, 2.5 mg kg) in the first 7 days of the experiment did not significantly affect the level of immobility of rats in the «Forced swim test», but on days 8, 12–19, and 21 of the experiment, the level of immobility in this the group was significantly higher than in the haloperidol group. The administration of meloxicam also failed to reverse the negative effects of stress: on days 1–5, 7–12 and 15–19, there were no differences between the groups in the level of immobility, and on days 6, 13–14 and 20-21, meloxicam even increased immobility by compared with the stress group. Another evidence in favor of the depressant effect of meloxicam is the fact that it increases the level of immobility in intact rats, while the MAO inhibitor selegiline (24 days, 3 mg/kg), on the contrary, does not affect the level of immobility – the data are indistinguishable from control. Meloxicam also failed to increase locomotor activity in rats in the «Actimeter», suppressed by the combined use of haloperidol and stress. The positive effect of meloxicam was manifested only in the improvement of the task performance on the Rotarod against the background of D2-receptor blockade. Inhibition of COX-2 by meloxicam did not have the expected antidepressant effect in the «Forced swim test» and «Actimeter», but, on the contrary, led to a worsens emotional state of the animals. At the behavioral level, we were unable to obtain convincing evidence of a direct connection between the effects of meloxicam and the functioning of the DA system, although its activating effect on animal locomotion in the Rotarod test after blockade of D2-receptors with haloperidol was established.

Preliminary study on effect of access to pasture of finished broilers on their abdominal fat and carcass contents Key

Access to pasture improves poultry welfare, as it provides fresh grass, insects and worms which lead to enhanced product quality. The increased locomotor activity in the pasture system can improve leg health and lower the proportion of body fat. The objective of this study therefore,was to determine the effect of access to pasture on abdominal fat content and carcass characteristics of finished broilers. Eighteen (18) mature Hubbard-classic broilers at eight (8) weeks of age were used for the study. The birds were separated into two treatments with nine birds per treatment. Treatment 1 was the birds placed on pasture, while treatment 2 was the birds kept indoors on deep litter. Data from both treatments were analyzed as from a completely randomized design and compared using t-test. The result shows that there was no significant difference (t ) between the two treatments in all the parameters considered.Hence, itwas concluded that pasture access for finished broilers has no effect on abdominal fat content and carcass traits comparedwith finished broilers on deep litter.

Hippocampal network hyperexcitability in young transgenic mice expressing human mutant alpha-synuclein

Abnormal excitability in cortical networks has been reported in patients and animal models of Alzheimer's disease (AD), and other neurodegenerative conditions. Whether hyperexcitability is a core feature of alpha(α)-synucleinopathies, including dementia with Lewy bodies (DLB) is unclear. To assess this, we used two murine models of DLB that express either human mutant α-synuclein (α-syn) the hA30P, or human wild-type α-syn (hWT-α-syn) mice. We observed network hyperexcitability in vitro in young (2–5 months), pre-symptomatic transgenic α-syn mice. Interictal discharges (IIDs) were seen in the extracellular local field potential (LFP) in the hippocampus in hA30P and hWT-α-syn mice following kainate application, while only gamma frequency oscillations occurred in control mice. In addition, the concentration of the GABAA receptor antagonist (gabazine) needed to evoke IIDs was lower in slices from hA30P mice compared to control mice. hA30P mice also showed increased locomotor activity in the open field test compared to control mice. Intracellular recordings from CA3 pyramidal cells showed a more depolarised resting membrane potential in hA30P mice. Quadruple immunohistochemistry for human α-syn, and the mitochondrial markers, porin and the complex IV enzyme cytochrome c oxidase subunit 1 (COX1) in parvalbumin (PV+)-expressing interneurons showed that 25% of PV+ cells contained human α-syn in hA30P mice. While there was no change in PV expression, COX1 expression was significantly increased in PV+ cells in hA30P mice, perhaps reflecting a compensatory change to support PV+ interneuron activity. Our findings suggest that hippocampal network hyperexcitability may be an important early consequence of α-syn-mediated impairment of neuronal/synaptic function, which occurs without any overt loss of PV interneurons. The therapeutic benefit of targeting network excitability early in the disease stage should be explored with respect to α-synucleinopathies such as DLB.

The methionine aminopeptidase 2 inhibitor, TNP-470, enhances the antidiabetic properties of sitagliptin in mice by upregulating xenin

The therapeutic mechanism of action of methionine aminopeptidase 2 (MetAP2) inhibitors for obesity-diabetes has not yet been fully defined. Xenin, a K-cell derived peptide hormone, possesses an N-terminal Met amino acid residue. Thus, elevated xenin levels could represent a potential pharmacological mechanism of MetAP2 inhibitors, since long-acting xenin analogues have been shown to improve obesity-diabetes. The present study has assessed the ability of the MetAP2 inhibitor, TNP-470, to augment the antidiabetic utility of the incretin-enhancer drug, sitagliptin, in high fat fed (HFF) mice. TNP-470 (1 mg/kg) and sitagliptin (25 mg/kg) were administered once-daily alone, or in combination, to diabetic HFF mice (n = 10) for 18 days. Individual therapy with TNP-470 or sitagliptin resulted in numerous metabolic benefits including reduced blood glucose, increased circulating and pancreatic insulin and improved glucose tolerance, insulin sensitivity, pyruvate tolerance and overall pancreatic islet architecture. Further assessment of metabolic rate revealed that all treatments reduced respiratory exchange ratio and increased locomotor activity. All sitagliptin treated mice also exhibited increased energy expenditure. In addition, treatment with TNP-470 alone, or in combination with sitagliptin, reduced food intake and body weight, as well as elevating plasma and intestinal xenin. Importantly, combined sitagliptin and TNP-470 therapy was associated with further significant benefits beyond that observed by either treatment alone. This included more rapid restoration of normoglycaemia, superior glucose tolerance, increased circulating GIP concentrations and an enhanced pancreatic beta:alpha cell ratio. In conclusion, these data demonstrate that TNP-470 increases plasma and intestinal xenin levels, and augments the antidiabetic advantages of sitagliptin.

Decreased nesting behavior, selective increases in locomotor activity in a novel environment, and paradoxically increased open arm exploration in Neurogranin knockout mice.

AimsNeurogranin (NRGN) is a postsynaptic protein kinase substrate that binds calmodulin in the absence of calcium. Recent studies suggest that NRGN is involved in neuropsychiatric disorders, including schizophrenia, ADHD, and Alzheimer's disease. Previous behavioral studies of Nrgn knockout (Nrgn KO) mice identified hyperactivity, deficits in spatial learning, impaired sociability, and decreased prepulse inhibition, which suggest that these mice recapitulate some symptoms of neuropsychiatric disorders. To further validate Nrgn KO mice as a model of neuropsychiatric disorders, we assessed multiple domains of behavioral phenotypes in Nrgn KO mice using a comprehensive behavioral test battery including tests of homecage locomotor activity and nesting behavior.MethodsAdult Nrgn KO mice (28‐54 weeks old) were subjected to a battery of comprehensive behavioral tests, which examined general health, nesting behavior, neurological characteristics, motor function, pain sensitivity, locomotor activity, anxiety‐like behavior, social behavior, sensorimotor gating, depression‐like behavior, and working memory.ResultsThe Nrgn KO mice displayed a pronounced decrease in nesting behavior, impaired motor function, and elevated pain sensitivity. While the Nrgn KO mice showed increased locomotor activity in the open field test, these mice did not show hyperactivity in a familiar environment as measured in the homecage locomotor activity test. The Nrgn KO mice exhibited a decreased number of transitions in the light‐dark transition test and decreased stay time in the center of the open field test, which is consistent with previous reports of increased anxiety‐like behavior. Interestingly, however, these mice stayed on open arms significantly longer than wild‐type mice in the elevated plus maze. Consistent with previous studies, the mutant mice exhibited decreased prepulse inhibition, impaired working memory, and decreased sociability.ConclusionsIn the current study, we identified behavioral phenotypes of Nrgn KO mice that mimic some of the typical symptoms of neuropsychiatric diseases, including impaired executive function, motor dysfunction, and altered anxiety. Most behavioral phenotypes that had been previously identified, such as hyperlocomotor activity, impaired sociability, tendency for working memory deficiency, and altered sensorimotor gating, were reproduced in the present study. Collectively, the behavioral phenotypes of Nrgn KO mice detected in the present study indicate that Nrgn KO mice are a valuable animal model that recapitulates a variety of symptoms of neuropsychiatric disorders, such as schizophrenia, ADHD, and Alzheimer's disease.

Acreditation Certificate Acreditation No. 21/E/KPT/2018 Article Tools Print this article Indexing metadata How to cite item Email this article Email the author About The Authors Rodhiyan Rakhmatiar Faculty of Medicine, University of Brawijaya Indonesia Neurology Department Mulyohadi Ali Faculty of Medicine, University of Brawijaya Pharmacology Department M. Dalhar Faculty of Medicine, University of Brawijaya Neurology Department About RJLS Aim and

Parkinson's disease characterized by a decrease in motor activity is a progressive neurodegenerative disorder caused by the degeneration of dopaminergic neurons. Centella asiatica is suspected of having a neuroprotectant effect and is not yet known how Centella asiatica role in the prevention of Parkinson's disease. The study was conducted to prove the effect of Centella asiatica extract on the expression of Hsp60 and locomotor activity zebrafish models of Parkinson's with rotenone exposure. The study was conducted using 25 zebrafish divided into various groups. Centella asiatica extract and rotenone exposure have given for 28 days, observed locomotor activity on days 0, 7, 14, 21 and 28. The expression of Hsp60 measured using immunohistochemical techniques. There is a significant difference between locomotor activity at various doses of Centella asiatica (p<0.05) with a very strong correlation (r=0.929; p<0.01) where the higher doses of Centella asiatica, the higher locomotor activity. Found a significant difference between the reduced expression of Hsp60 to various Centella asiatica dose group (p<0.05) but no correlation between the expression of Hsp60 with Centella asiatica dose groups and locomotor activity. Centella asiatica extract is able to increase locomotor activity and decrease the expression of Hsp60 in zebrafish models of Parkinson's.