Total Number Of Arm Entries Research Articles

Role of the medial agranular cortex in unilateral spatial neglect.

Unilateral spatial neglect (USN) results from impaired attentional networks and can affect various sensory modalities, such as visual and somatosensory. The rodent medial agranular cortex (AGm), located in the medial part of the forebrain from rostral to caudal direction, is considered a region associated with spatial attention. The AGm selectively receives multisensory input with the rostral AGm receiving somatosensory input and caudal part receiving visual input. Our previous study showed slower recovery from neglect with anterior AGm lesion using the somatosensory neglect assessment. Conversely, the functional differences in spatial attention across the entire AGm locations (anterior, intermediate, and posterior parts) are unknown. Here, we investigated the relationship between the severity of neglect and various locations across the entire AGm in a mouse stroke model using a newly developed program-based analysis method that does not require human intervention. Among various positions of the lesions, the recovery from USN during recovery periods (postoperative day; POD 10-18) tended to be slower in cases with more rostral lesions in the AGm (r = - 0.302; p = 0.028). Moreover, the total number of arm entries and maximum moving speed did not significantly differ between before and after AGm infarction. According to these results, the anterior lesions may slowly recover from USN-like behavior, and there may be a weak association between the AGm infarct site and recovery rate. In addition, all unilateral focal infarctions in the AGm induced USN-like behavior without motor deficits.

Evaluation of Nootropic Potential of the Fruits of Artocarpus altilis by in vivo and in vitro Studies

Abstract: Background: Artocarpus altilis is an evergreen plant having a variety of medicinal values due to the presence of compounds like cyclopropane sterols, quercetin, camphorol, artocarpine, and many more. The fruits typically contain cycloprane sterols. Objectives: The present study was carried out to evaluate the nootropic potential of the ethanolic extract of the fruits of Artocarpus altilis (EFAA). Materials and Methods: The nootropic activity was evaluated using various models. The animals were divided into eight groups (n=6) consisting of normal control, amnesic control (scopolamine: 1mg/kg), standard drug (piracetam, 200mg/kg), extract, piracetam with scopolamine and three test groups (200, 400 and 800mg/kg, orally). Various in vivo models like Elevated Plus maze, Hebb-William's Maze, and Y-maze were used to evaluate the nootropic potential of EFAA. The brain was isolated, homogenized, and used for biochemical analysis like percentage inhibition of brain Acetylcholinesterase enzyme using Ellman's method and microplate array method. Results: The study revealed that EFAA has significant dose-dependent nootropic activity. A significant decrease in Initial transfer latency, retention transfer latency, the total number of arm entries and AChE enzyme activity, and an increase in percentage alteration. Conclusion: The findings from the present study suggest that EFAA demonstrated a nootropic effect. Keywords: Acetyl-cholinesterase, Amnesia, Artocarpus altilis, Cognitive functions, Scopolamine.

Vaccinium bracteatum Improves Spatial Learning and Memory by Regulating N-methyl-D-aspartate Receptors and Tau Phosphorylation in Chronic Restraint Stress-Induced Memory Impaired Mice.

Vaccinium bracteatum Thunb. Leaves (VBL) are a component of traditional herbal medicines. However, molecular mechanisms of VBL in stress-related memory impairment are still unclear. This study aimed to investigate the spatial memory improvement effects of VBL in an animal model of chronic restraint stress (CRS) by using Y maze test and identified possible protective mechanisms against oxidative stress inducers (e.g., corticosterone and hydrogen peroxide [H2O2]) in SH-SY5Y neuronal cells. VBL showed neuroprotective effects via reduced release of lactate dehydrogenase (LDH) in corticosterone or H2O2-induced cell death that was mediated through the regulation of cleaved caspase-3 and Nrf2 pathways. Furthermore, CRS-exposed mice were orally administered VBL (10, 50, 100, and 200 mg/kg) daily for 21 days. CRS-exposed mice treated with VBL showed significantly increased spontaneous alternation in short-term memory (STM) and long-term memory (LTM) trials, and number of total arm entries in LTM trials as measured by the Y maze test. Moreover, VBL (50, 100, and 200 mg/kg) decreased acetylcholinesterase (AChE) activity in the hippocampus (HC, [Formula: see text] ¡ 0.01 and [Formula: see text] ¡ 0.001, respectively) and prefrontal cortex (PFC). CRS-exposed mice treated with VBL had dramatically decreased total Tau and Tau phosphorylation in the synapse of the HC and PFC which might be mediated by the regulation of CaMKII and GSK3[Formula: see text] phosphorylation. Additionally, VBL reduced CRS-induced upregulation of N-methyl-D-aspartate (NMDA) receptor subunits (NMDAR1, 2A, and 2B). Thus, VBL exerts spatial memory improvement by regulating CRS-induced NMDA receptor neurotoxicity and Tau hyperphosphorylation.

Therapeutic Effects of Human Amniotic Epithelial Stem Cells in a Transgenic Mouse Model of Alzheimer's Disease.

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is characterized clinically by cognitive decline and pathologically by the development of amyloid plaques. AD is the most common cause of dementia among older people. However, there is currently no cure for AD. In this study, we aimed to elucidate the therapeutic effects of human amniotic epithelial stem cells (hAESCs) in a transgenic mouse model of AD. Tg2576 transgenic (Tg) mice underwent behavioral tests, namely the Morris water maze and Y-maze tests, to assess their cognitive function. In the Morris water maze test, hAESC-treated Tg mice exhibited significantly shorter escape latencies than vehicle-treated Tg mice. In the Y-maze test, hAESC-treated Tg mice exhibited significantly higher rate of spontaneous alteration than vehicle-treated Tg mice, while the total number of arm entries did not differ between the groups. Furthermore, Congo red staining revealed that hAESCs injection reduced the number of amyloid plaques present in the brains of Tg mice. Finally, beta-secretase (BACE) activity was significantly decreased in Tg mice at 60 min after hAESCs injection. In this study, we found that intracerebral injection of hAESCs alleviated cognitive impairment in a Tg2576 mouse model of AD. Our results indicate that hAESCs injection reduced amyloid plaques caused by reduced BACE activity. These results indicate that hAESCs may be a useful therapeutic agent for the treatment of AD-related memory impairment.

The effect of housing conditions on working memory and anxiety in male C57BL/6 mice

Event Abstract Back to Event The effect of housing conditions on working memory and anxiety in male C57BL/6 mice An Buckinx1*, Andries Van Schuerbeek1*, Yana Van Den Herrewegen1, Ilse Smolders1 and Dimitri De Bundel1* 1 Experimental Pharmacology (EFAR/FASC), Vrije Universiteit Brussel, Belgium Laboratory mice are often single housed during experiments due to protocol requirements or in case of aggression towards cage mates. Several conflicting studies exist regarding behavioral consequences of individual housing of mice. However, the overall suggestion is that individual housing of mice is associated with increased anxiety and memory impairments (1, 2), and may affect scientific endpoints of experiments. In an attempt to reduce negative effects associated with single housing, we wanted to explore the potential use of a new type of cage that could improve animal welfare. This cage includes a cage divider that separates mice, as such avoiding physical contact while maintaining olfactory contact. The aim of this study is therefore to investigate anxiety and memory processing in mice housed in this new cage set-up compared to mice that are paired housed and single housed. 8-week-old male C57BL/6 mice were paired housed, single housed, or housed in a cage with a cage divider for a duration of four weeks, after which we performed behavioral tests, fear conditioning and the dexamethasone suppression test to assess plasma corticosterone levels. First, we performed the Y maze spontaneous alternation test, a test that is used to assess working memory, locomotor activity and exploratory drive in mice (2). The total number of arm entries and the spontaneous alternation percentage did not differ between the three groups. The open field test revealed no difference between the three experimental groups regarding locomotor activity nor anxiety-like behavior. An elevated plus maze test was performed to evaluate anxiety-like behavior. The total time spent in the open arms and the total distance travelled did not differ between groups, confirming the results obtained in the previous test. We performed a discriminative fear conditioning protocol (3), in which no significant differences were observed between experimental groups. The dexamethasone suppression test was performed at the end of the experiment to evaluate the responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis (4, 5). Dexamethasone-treated mice had significantly lower corticosterone plasma levels compared to vehicle-treated mice, while basal corticosterone levels did not differ between groups. We dissected the adrenal glands and pituitary gland for further analysis, as the weight of the adrenal glands is associated with anxiety and stress (6). The weight of the pituitary gland and adrenal gland normalized against body weight did not significantly differ between experimental groups. Our results suggest that four weeks of single housing did not affect anxiety nor working memory in single housed mice, a much-debated topic in view of animal welfare. Behavioral observations were consistent with serum corticosterone levels, as the dexamethasone suppression test suggested no HPA axis dysregulation in neither of the experimental conditions. These results are possibly due to the short duration of housing conditions as previous studies were able to demonstrate differences in anxiety-like behavior, memory impairments and an increase in locomotor activity after eight weeks of single housing (1, 2). Therefore, future perspectives are to evaluate anxiety-like behavior and working memory after a housing duration of ten weeks. This will enable us to more effectively study the potential use of the cage with a cage divider that could improve animal welfare. * These authors contributed equally to this work.

Involvement of catecholaminergic and GABAAergic mediations in the anxiety-related behavior in long-term powdered diet-fed mice

Dietary habits are important factors which affect metabolic homeostasis and the development of emotion. We have previously shown that long-term powdered diet feeding in mice increases spontaneous locomotor activity and social interaction (SI) time. Moreover, that diet causes changes in the dopaminergic system, especially increased dopamine turnover and decreased dopamine D4 receptor signals in the frontal cortex. Although the increased SI time indicates low anxiety, the elevated plus maze (EPM) test shows anxiety-related behavior and impulsive behavior. In this study, we investigated whether the powdered diet feeding causes changes in anxiety-related behavior. Mice fed a powdered diet for 17 weeks from weaning were compared with mice fed a standard diet (control). The percentage (%) of open arm time and total number of arm entries were increased in powdered diet-fed mice in the EPM test. We also examined the effects of diazepam, benzodiazepine anti-anxiety drug, bicuculline, GABA-A receptor antagonist, methylphenidate, dopamine transporter (DAT) and noradrenaline transporter (NAT) inhibitor, atomoxetine, selective NAT inhibitor, GBR12909, selective DAT inhibitor, and PD168077, selective dopamine D4 receptor agonist, on the changes of the EPM in powdered diet-fed mice. Methylphenidate and atomoxetine are clinically used to treat attention deficit/hyperactivity disorder (ADHD) symptoms. The % of open arm time in powdered diet-fed mice was decreased by treatments of atomoxetine, methylphenidate and PD168077. Diazepam increased the % of open arm time in control diet-fed mice, but not in powdered diet-fed mice. The powdered diet feeding induced a decrease in GABA transaminase, GABA metabolic enzymes, in the frontal cortex. Moreover, the powdered diet feeding induced an increase in NAT expression, but not DAT expression, in the frontal cortex. These results suggest that the long-term powdered diet feeding may cause low anxiety or impulsivity, possibly via noradrenergic and/or dopaminergic, and GABAAergic mediations and increase the risk for onset of ADHD-like behaviors.

Abstract LB-326: Unresolved microgliosis and impaired neurogenesis are associated with cognitive deficiency in a clinically relevant mouse model of fractionated whole brain radiation

Abstract The objective of this study is to evaluate the cellular and molecular changes associated with the cognitive function as a late- effect of clinically relevant fractionated whole brain irradiation (fWBI) treatment using immunocompetent mouse model. Microglia are not only the immune mediators of the brain but also involved in synaptic pruning and neurogenesis. However, the microglial response to fractionated radiation and how this contributes to radiation-induced cognitive impairment is poorly understood. Here, C57BL/6J mice were randomized into two groups. One group received X-radiation (XRT) and another was sham treated (CTL). The whole brain of each XRT mouse received a total of 30 Gy (3 Gy/fraction) of radiation over two weeks. XRT and CTL mice were then evaluated for cognitive and behavioral functions after one, four, and six months of radiation treatment using the rotarod test, novel object recognition test, the free running Y-Maze and Barnes Maze. Whole brains were harvested and stored after completion of behavioral studies for immunohistochemical analysis. Microglia were enriched by Percoll gradient separation and extracted mRNA was characterized by qPCR analysis. A significant (P<0.05) decline in latency to fall from rotarod, total number of arm entries from Y maze, were observed in mice four and six months after X-radiation. A significant (P<0.05) decrease in novel object recognition was observed four months after radiation. However, no significant effects of radiation treatment were observed on errors or latency at all the time points measured by the Barnes maze. At the molecular level, microglial MHC II and IFN-γ expression was significantly upregulated (P<0.05) in XRT brains at all the time points tested. Immunohistochemical analysis revealed a significant increase (P< 0.05) in the number of de-ramified Iba1 positive microglia throughout the hippocampal sub-regions of radiated brains till six months. Neurogenesis was impaired in XRT brains as measured by significant decrease in the number of Dcx+, BrdU+, and BrdU+/Dcx+ cells at all time points. These results indicate that sustained microgliosis along with chronic impairment of neurogenesis are associated with delayed long-term cognitive impairment induced by fWBI in an immunocompetent mouse model. Unlike previous studies, here, we have employed a clinically relevant fractionated dosage regimen to address the cellular and molecular deregulations in association with cognitive impairment. This fractionated radiation induced late delayed cognitive deficit mouse model will further allow us to elucidate the cross talk between microgliosis and neurogenesis in radiation induced cognitive impairment. Citation Format: Suman Kanji, Benjamin Johnson, Kristina Witcher, Pooja Gulati, John Gregory Bodnar, Julie Fitzgerald, Courtney DeVries, Randy Nelson, Jonathan Godbout, Saikh Jaharul Haque, Saikh Jaharul Haque, Arnab Chakravarti. Unresolved microgliosis and impaired neurogenesis are associated with cognitive deficiency in a clinically relevant mouse model of fractionated whole brain radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-326.

β2-microglobulin induces depressive- and anxiety-like behaviors in rat.

β2-microglobulin (B2M), the light chain of major histocompatibility complex class I (MHC I) molecules, has been found to impair hippocampal neurogenesis. Based on the crucial role of hippocampal neurogenesis disturbance in the process of depression and anxiety, the aim of the present study is to investigate whether B2M leads to depressive- and anxiety-like behaviors. We found that 6 days after intracerebroventricular injection with B2M (0.3 μg), the immobility times of rats in the tail suspension test and the forced swimming test were increased, the swimming and climbing time in the forced swimming test was decreased, and the latency to feed in the novelty-suppressed feeding test was increased, indicating that B2M induces depressive-like behaviors. In addition, in the elevated plus maze test, B2M-treated rats displayed obvious decline in the number of entries into and the proportion of time spent in the open arm, while the number of total arm entries was no change, which indicated that B2M induces anxiety-like behaviors. Our present findings suggest that target B2M might represent a novel approach for treatment of depression and anxiety.

Protective effect of naringin on pentylenetetrazole (PTZ)-induced kindling; possible mechanisms of antikindling, memory improvement, and neuroprotection

The present study investigated the effects of Naringin on seizure severity, progress of kindling, memory impairment, oxidative stress, neurochemicals, and neural damage in Pentylenetetrazole (PTZ)-induced kindling. Alternate intra-peritoneal injections of PTZ induced kindling at 22 injections of PTZ. In comparison with the PTZ group, pretreatment with Naringin 30 min prior to PTZ administration and on a PTZ-free day was found to lead to a decreased seizure score, a mitigated progress of kindling, decreased transfer latency, and increased total number of arm entries, % alternation behavior in Y maze, and % conditioned avoidance response in a pole climbing apparatus. Biochemical analysis of the frontal and temporal cortexes and the hippocampus of the brain showed that Naringin attenuated the level of lipid peroxidation (MDA) and augmented the reduced glutathione, superoxide dismutase, catalase, and total thiol results in decreased oxidative stress compared with the PTZ group and control group. Investigation of neurochemicals revealed a minute change in gamma amino butyric acid (GABA), glutamate and dopamine, and decreased AChE in the three regions. Increased CA1 neuronal density in the hippocampus and increased cell density in the frontal and temporal regions indicate the potential of naringin to act against PTZ-induced kindling, memory impairment, oxidative stress, neurochemical changes, and histological aberrations.

Functional perturbation of forebrain principal neurons reveals differential effects in novel and well-learned tasks

Neural circuits in mammalian brains consist of large numbers of different cell types having different functional properties. To better understand the separate roles of individual neuron types in specific aspects of spatial learning and memory, we perturbed the function of principal neurons in vivo during maze performance or in hippocampal slices during recording of evoked excitatory synaptic potentials. Transgenic mice expressing the Drosophila allatostatin receptor (AlstR) in cortical and hippocampal pyramidal cells were tested on an elevated plus maze, in a Y-maze, and in the Morris water maze. Relative to a control cohort, AlstR-positive mice treated with allatostatin exhibited no difference in open arm dwell time on the elevated plus maze or total number of arm entries in a Y-maze, but displayed reduced spontaneous alternation. When animals received massed or spaced training trials in the Morris water maze, and the peptide was delivered prior to an immediate probe, no effects on performance were observed. When the peptide was delivered during a probe trial performed 24h after seven days of spaced training, allatostatin delivery to AlstR positive mice enhanced direct navigation to the escape platform. Combined, these results suggest that cortical and hippocampal pyramidal neurons are required during spatial decision-making in a novel environment and compete with other neural systems after extended training in a long-term reference memory task. In hippocampal slices collected from AlstR positive animals, allatostatin delivery produced frequency dependent alterations in the Schaffer collateral fiber volley (attenuated accommodation at 100Hz) and excitatory postsynaptic potential (attenuated facilitation at 5Hz). Combined, the neural and behavioral discoveries support the involvement of short-term plasticity of Schaffer collateral axons and synapses during exploration of a novel environment and during initial orientation to a goal in a well-learned setting.

Maternal fluoride exposure during gestation and lactation decreased learning and memory ability, and glutamate receptor mRNA expressions of mouse pups.

Previous investigations demonstrated that high fluoride (F) exposure may adversely affect the neurodevelopment and learning and memory ability. However, whether maternal F exposure during gestation and lactation can influence the learning, memory ability, and glutamate receptor expressions of offspring has not yet been elucidated. Hence, in the present study, maternal mice were exposed to F (25, 50, or 100 mg/L sodium fluoride (NaF) in drinking water) during gestation and lactation. Results showed that exposure to 100 mg/L NaF significantly enhanced the number of total arm entries and working memory errors of offspring in the radial arm maze test compared to the control group. However, no difference was observed in open-field behaviors. For the subtypes of glutamate receptors in hippocampus, expression of GluR2 mRNA was significantly reduced by 25, 50, and 100 mg/L NaF. Besides, F exposure also suppressed the expression of NR2A, NR2B, and mGluR2 mRNA levels in a dose-dependent manner, where NR2A was significantly suppressed by 50 mg/L NaF and NR2B and mGluR2 by 100 mg/L NaF. However, no significant changes were observed in GluR1 and mGluR5 mRNA expression levels. Collectively, these findings suggested that F can pass through the cord blood and breast milk and may have deleterious impact on learning and memory of the mouse pups, which was mediated by reduced mRNA expression of glutamate receptor subunits.

Intracerebroventricular Oxytocin Self-Administration in Female Rats.

Oxytocin (OT) is a neuromodulator that facilitates pair-bonding, maternal care and social approach. OT is considered to promote these social behaviours by enhancing the salience and reinforcing effects of relevant social stimuli. There is the additional possibility that OT per se may be rewarding. To test this, we investigated whether female rats would voluntarily self-administer OT. Female Long-Evans rats were ovariectomised and then received an oestrogen implant and an i.c.v. cannula. Rats were tested in an operant chamber with active and inactive levers. They were initially tested for 4h/day on a fixed-ratio 5 schedule for self-administration of artificial cerebral spinal fluid (aCSF) for 5days, followed by aCSF, or OT, at 1 or 10ng/μl for another 5days. Rats self-administering aCSF made 36.2±6.2 active lever responses/4h versus 14.9±3.4 inactive responses. Responses for 1ng/μl OT were similar. However, rats self-administering 10ng/μl OT made significantly more active lever responses (67.8±12.0 per 4h), and received 121.4±21.0ng OT/4h. To determine whether reduced anxiety contributes to the reinforcing effects of OT, rats received an infusion of aCSF or OT at 0.3 or 3.0μg immediately before testing on the elevated plus maze. There was no effect of OT on anxiety as reflected by percentage time spent on the open arms, as well as no effect of OT on locomotion as measured either by the number of closed arm entries or the number of total arm entries. These results suggest that OT may be rewarding, and that this is not a result of the anxiolytic effects of OT.

EFFECTS OF EARLY PROTEIN MALNUTRITION AND REPEATED TESTING UPON LOCOMOTOR AND EXPLORATORY BEHAVIORS IN THE ELEVATED PLUS-MAZE

An elevated plus-maze was used to investigate the effects of repeated testing on the locomotor and exploratory behaviors of malnourished rats. Pup malnutrition was induced during the lactation period (0 to 21 days of age) by feeding the dams a protein-deficient diet (6% protein) and the animals were allowed to recover from weaning to 70 days of age by eating a commercial lab chow diet. Control animals were suckled by dams receiving normal protein diet (16% protein) during the lactation period and were fed a commercial lab chow diet after weaning. At 70 days, malnourished and control animals were placed on the central platform of the elevated plus-maze facing an enclosed arm and allowed to explore for 5 min. This procedure was repeated at 24-h intervals of 6 days. The repeated testing in the elevated plus-maze did not change the total number of arm entries and attempts to enter open arms, but decreased the percentage of open arm entries, time spent in open arms, and total time spent on the central platform. These data suggest an increase in anxiety with repeated testing in the elevated plus-maze. In addition, the malnourished animals showed a large number of these animals as compared to control. The elevated plus-maze proved to be useful animal model to evaluate exploratory behaviors in early protein malnourished animals. Keywords: Early protein malnutrition Elevated plus-maze Impulsiveness Exploration Anxiety Repeated testing

Involvement of l-arginine-nitric oxide pathway in anxiolytic-like effects of zinc chloride in rats.

Zinc is crucial for normal development of the brain, and Zinc deficiency has been shown to associate with neurological disorders (e.g. anxiety) through interactions with several neurotransmitter systems such as nitric oxide (NO). In this regard, our study aimed to evaluate the possible involvement of l-arginine NO pathway on anxiolytic effects of zinc in adult male rats. Zinc chloride at doses of 2.5 and 10mg/kg (intraperitoneal or ip) or saline (1ml/kg, ip) were injected 30min before the anxiety test. Zinc administrated rats (10mg/kg) were pre-treated with intra-CA1 microinjection of l-arginine in sub-effective dose of 1μg/rat (dorsal hippocampus, vehicle: saline1μl/rat). In addition, zinc chloride and NG-nitro-l-arginine methyl ester (l-NAME) were intraperitoneally co-administrated in sub-effective doses of 2.5mg/kg and 80mg/kg, respectively. The percentage of open arm time (OAT%), percentage of open arm entry (OAE%), as measures of anxiety, and total number of arm entries, as measures of locomotor activity, were recorded. Treatment with zinc (10mg/kg) markedly produced an increase in OAT% and OAE% in the Elevated plus maze test (EPM). A decrease of OAT% and OAE% was shown in groups which received zinc (10mg/kg) and l-arginine (1μg/rat) concomitantly as compared to the control group. Moreover, an increase of OAE% was revealed in the group exposed to Zinc (2.5mg/kg) and l-NAME (80mg/kg) co-administration. Although, Two-way ANOVA showed no significant differences of anxiety indices in rats received drug+zinc chloride in compare to the zinc pretreated with saline group. Anxiolytic- like effect of zinc reversed by nitric oxide precursor l-arginine. Additionally, the synergistic effects of l-NAME and ZnCl2 were shown in the EPM. Thus our findings suggest that at least in part the anxiolytic effects of zinc can be mediated through the nitric oxide system.

Acute injury to ce.rebral function produced by isoflurane anesthesia given at different time interval in neonatal rats

To investigate effects of isoflurane anesthesia of different time interval on acute injury of brain function in neonatal rats with consistent total time of isoflurane anesthesia. Seven-day neonatal Sprague-Dawley (SD) rats were randomly divided into normal control group (breathe the air), continuous anesthesia group (a single 6-hour exposure to 1.5% isoflurane), and intermittent anesthesia 1 day and 3 days groups (three times of 2-hour exposure to anesthesia with an interval of 1 day or 3 days), 12 rats in each group. The ratio of male to female was 5:7. They underwent the test of learning and memory in the radial arm maze (RAM) 21 days after birth, twice a day for 4 days. The number of entry into wrong arms, number of repeated errors, number of total arm entries, and time for completing the task were recorded for evaluation of effect of neonatal isoflurane on cognitive behavior in rats. ① Compared with normal control group, the percentage of number of errors > 3 in anesthesia of 3-day interval group was significantly decreased (33.3% vs. 46.9%, P < 0.05), the percentages of repeated errors > 0 and total arm entries > 8 were significantly increased (33.3% vs. 18.8%, 27.1% vs. 13.5%, both P < 0.05), but there were no statistically significant difference in the percentage of mistake number > 3 between continuous anesthesia group, interval anesthesia 1-day group and the normal control group (44.8%, 44.8% vs. 46.9%), the percentages of number of repeated mistake > 0 and total arm entries > 8 in above three groups were slightly increased as compared with those of normal control group (27.1%, 22.9% vs. 18.8%, 20.8%, 21.9% vs. 13.5%, all P > 0.05). No statistical differences in completing the task among normal control group, continuous anesthesia group, interval anesthesia 1 day and 3 days groups were found (minutes: 1.32±0.91, 1.54±1.05, 1.46±0.86, 1.38±0.79, all P > 0.05). ② It was found by gender analysis that the percentages number of repeated errors > 0 and total arm entries > 8 were significantly lower in female rats than those in the male rats only in normal control group (5.0% vs. 28.6%, P < 0.01; 5.0% vs. 19.6%, P < 0.05). There was no obvious gender difference in exposed groups. ③ Compared between groups of female rats, the percentages of repeated mistake > 0 in continuous anesthesia group, interval anesthesia 1 day and 3 days groups (25.0%, 25.0%, 30.0% vs. 5.0%, P < 0.05 or P < 0.01) and the percentage of total arm entries > 8 in interval anesthesia 1 day and 3 days groups were significantly higher than that of normal control group (22.5%, 25.0% vs. 5.0%, both P < 0.05). No significant difference about the RAM task in male rats of all the four groups was found. Different time interval of neonatal isoflurane exposure may develop certain degree of acute brain injury in rats, characterized by cognitive function. Prolongation of the interval time significantly enhanced long-term memory in rats. Multiple neonatal exposures to isoflurane were associated with greater cognitive impairment than a single exposure. In addition, isoflurane can significantly increase cognitional functional disorder in the female, not in the male rats.

Effect of hypothyroxinemia on the emotion in developing rats

Objective To investigate the effect of hypothyroxinemia on emotion and hippocampus neurons in developing rats.Methods Sixty-nine healthy postnatal day (PD) 1 rats were randomly divided into control group (n =36) and experimental group (n =33).On PD1,experimental group was bilaterally thyroidectomized to establish hypothyroxinemia model,the control group was only given thyroid exposure operation without thyroid resection.On PD10,21,40,serum triiodothyronine (T3),thyroxine (T4),thyrotropicstimulating hormone (TSH) were detected by radioimmunoassay.Tail suspension test,forced swimming test,the elevated-plus maze and open field were respectively employed to detect the anxiety/depression like behavior on PD30,31,32,33.Nisslg staining was used to determine the survival of neurons at PD10,21,40 in hippocampus CA1,CA3,DG regions.Results Serum T4 levels on PD10,21,40 in experimental group decreased significantly as compared with control group (P ＜0.01),while there was no significant difference in serum T3 or TSH level (P ＞ 0.05).In the tail suspension test,immobility time of experimental group [(197.00 ± 19.50) s] was longer than control group [(158.33 ± 32.90) s,P ＜0.05].In the forced swimming test,immobility time of experimental group[(92.11 ± 35.24) s] was longer than control group [(62.00 ± 23.73) s,P ＜ 0.05].In the elevated plus-maze test,total number of arm entries and closed arm entries in experimental group were increased as compared with control group(P ＜ 0.05),percentage of closed arm/total time of experimental group was decreased as compared with control group(P ＜ 0.05).In the open field,there was no obvious difference between the two groups(P ＞ 0.05).On PD10,21,40,the amount of neurons in DG region of experimental group were less than control group(P ＜0.05),while there was no significant difference in CA1 or CA3 on PD10,21,40(P ＞0.05).Contusions Hypothyroxinemia can cause depression,hyperactivity and hippocampus neuron damage of developing rats. Key words: Hypothyroxinemia; Rat; Depression; Anxiety; Emotion; Hippocampus

Androgen insensitive male rats display increased anxiety-like behavior on the elevated plus maze

Male rats carrying the testicular feminization mutation (Tfm-affected males) are insensitive to androgens, resulting in a female-typical peripheral phenotype despite possession of inguinal testes that are androgen secretory. Androgen-dependent neural and behavioral processes may likewise show atypical sexual differentiation. Interestingly, these mutant rats display elevated serum corticosterone, suggesting a chronic anxiety phenotype and dysregulated hypothalamic–pituitary–adrenal axis. In order to understand if elevated anxiety-like behavior is a possible mediating variable affecting the display of certain androgen-dependent behaviors, we compared the performance of Tfm-affected males to wild type males and females in the elevated plus maze (EPM). Two well-established indicators of anxiety-like behavior in the EPM were analyzed: total percentage of time spent on the open arms, and the percentage of open arm entries. We also analyzed the total number of open arm entries. Interestingly, Tfm-affected males spent less percentage of time on the open arms than both males and females, suggesting increased anxiety-like behavior. Percentage of open arm entries and the total number of arm entries was comparable between the groups, indicating that the observed decrease in the percentage of time spent on the open arms was not due to a global reduction in exploratory behavior. These data, in contrast to earlier reports, thus implicate androgen receptor-mediated functions in the expression of anxiety behaviors in male rats. Given that anxiety is widely reported as a precipitating factor in depression, studying the role of the androgen receptor in anxiety may give insights into the pathogenesis of major depressive disorder.

Protracted withdrawal from ethanol and enhanced responsiveness stress: Regulation via the dynorphin/kappa opioid receptor system

Although recent work suggests that the dynorphin/kappa opioid receptor (DYN/KOR) system may be a key mediator in the stress-related effects of alcohol, the regulation of long-term changes associated with protracted withdrawal from ethanol via the DYN/KOR system has yet to be explored. The objective of the present study was to determine the role of the DYN/KOR system in the regulation of anxiety-related behaviors during an extended period of abstinence from ethanol in animals with a history of ethanol dependence. Male Wistar rats (n = 94) were fed an ethanol or control liquid diet for 25–30 days. Six weeks after its removal, rats were exposed to 20 min of immobilization, and the ability of the KOR antagonist nor-binaltorphimine (nor-BNI) (0–20 mg/kg, intraperitoneal [i.p.]) to attenuate the enhanced responsiveness to stress observed in rats chronically exposed to ethanol was investigated using the elevated plus maze. In addition, the ability of U50,488 (0–10 mg/kg, i.p.) to prime anxiety-like behavior during protracted withdrawal was also examined. Rats with a history of ethanol dependence showed a significant decrease in open-arm exploration after exposure to restraint, indicating an anxiety-like state, compared to similarly treated controls, an effect that was blocked by nor-BNI. nor-BNI also selectively decreased center time and open-arm approaches in ethanol-exposed rats. The highest dose of U50,488 decreased open-arm exploration and the total number of arm entries in ethanol-exposed and control rats. Although lower doses of U50,488 did not affect open-arm exploration in either group, the 0.1 mg/kg dose selectively decreased motor activity in the ethanol-exposed rats when compared to similarly pretreated controls. These findings further support the hypothesis that behaviors associated with withdrawal from ethanol are in part regulated by the DYN/KOR system, and suggest that these effects may be long lasting in nature.

Curcumin Suppresses Soluble Tau Dimers and Corrects Molecular Chaperone, Synaptic, and Behavioral Deficits in Aged Human Tau Transgenic Mice

The mechanisms underlying Tau-related synaptic and cognitive deficits and the interrelationships between Tau species, their clearance pathways, and synaptic impairments remain poorly understood. To gain insight into these mechanisms, we examined these interrelationships in aged non-mutant genomic human Tau mice, with established Tau pathology and neuron loss. We also examined how these interrelationships changed with an intervention by feeding mice either a control diet or one containing the brain permeable beta-amyloid and Tau aggregate binding molecule curcumin. Transgene-dependent elevations in soluble and insoluble phospho-Tau monomer and soluble Tau dimers accompanied deficits in behavior, hippocampal excitatory synaptic markers, and molecular chaperones (heat shock proteins (HSPs)) involved in Tau degradation and microtubule stability. In human Tau mice but not control mice, HSP70, HSP70/HSP72, and HSP90 were reduced in membrane-enriched fractions but not in cytosolic fractions. The synaptic proteins PSD95 and NR2B were reduced in dendritic fields and redistributed into perikarya, corresponding to changes observed by immunoblot. Curcumin selectively suppressed levels of soluble Tau dimers, but not of insoluble and monomeric phospho-Tau, while correcting behavioral, synaptic, and HSP deficits. Treatment increased PSD95 co-immunoprecipitating with NR2B and, independent of transgene, increased HSPs implicated in Tau clearance. It elevated HSP90 and HSC70 without increasing HSP mRNAs; that is, without induction of the heat shock response. Instead curcumin differentially impacted HSP90 client kinases, reducing Fyn without reducing Akt. In summary, curcumin reduced soluble Tau and elevated HSPs involved in Tau clearance, showing that even after tangles have formed, Tau-dependent behavioral and synaptic deficits can be corrected.

Oral Artesunate-Amodiaquine Combination Causes Anxiolysis and Impaired Cognition in Healthy Swiss Mice.

The present study examined the effects of artesunate –amodiaquine combination therapy on spatial memory and anxietyrelated behaviors in healthy Swiss mice. Neurobehavioural models used were the Y maze and elevated plus maze. Selected for the experiments were eighty adult mice weighing 20-25 g. Forty animals were used in each behavioral model; they were randomly assigned into five groups A, B, C, D and E. Group A served as control and received normal saline, groups B, C and D received artesunate (4 mg/kg), amodiaquine (10 mg/kg) and artesunateamodiaquine combination(4 mg/kg and10 mg/kg) respectively while group E animals were given diazepam (5mg/kg). Drugs and vehicle were given orally for three days. The animals were exposed to the elevated plus maze (EPM) and the Y-maze on day 1 immediately after administering the first dose and day 3 immediately after the last dose, the number of entries and percentage time spent in the open and closed arms after five minutes’ exposure to the plus maze and Y–maze spontaneous alternations over a five minute period was scored for each animal. Statistical analysis was carried out using a one way ANOVA followed by a post-hoc test. Results of elevated plus maze tests revealed a significant increase in number of open arm entries and percentage time spent in the open arm and a significant reduction in the total number of arm entries compared to control; Y-maze task performance showed a significant reduction in percentage correct alternations compared to control .In conclusion artesunateamodiaquine administered over a three day period had anxiolytic and memory retarding effects in healthy mice thereby giving an insight into the possible behavioral effects in humans.