Maze Behavior Research Articles

Survival, differentiation, and reversal of heroin neurobehavioral teratogenicity in mice by transplanted neural stem cells derived from embryonic stem cells

Cell therapies in animal models of neurobehavioral defects are normally derived from neural stem cells (NSC) of the developing cortex. However, the clinical feasibility of NSC therapies would be greatly improved by deriving transplanted cells and from a tissue culture source that is self-renewing, containing cells that potentially differentiate into the desired neuronal phenotypes. These cultures can be engineered to contain the appropriate factors to support their therapeutic action and likely evoke lesser immune reactions. In the current study, we employed our model of mice neurobehaviorally impaired via prenatal exposure to heroin, to test the therapeutic efficacy of NSC derived from murine embryonic stem cells culture (ESC). The culture contained elongated bipolar cells, 90% of which are positive for nestin, the intermediate filament protein found in neural precursors. After removal of growth factors, the NSC differentiated into neurons (34.0% +/- 3.8% NF-160 positive), including cholinergic cells (ChAT positive), oligodendrocytes (29.9% +/- 4.2% O(4)), and astrocytes (36.1% +/- 4.7% GFAP positive). Reverse transcriptase polymerase chain reaction (RT-PCR) analysis confirmed the immunocytochemical findings. Mice made deficient in Morris maze behavior by prenatal heroin exposure (10 mg/kg heroin s.c. on gestational days 9-18) were transplanted into the hippocampus region on postnatal day 35 with the ES culture-derived NSC (ES-NSC) labeled with dialkylcarbocyanine (Dil) cell tracker. Dil+ and NF160+ cells were detected in the hippocampal region (50% +/- 8% survival). The transplantation completely restored maze performance to normal; e.g., on day 3, transplantation improved the behavior from the deficient level of 11.9-sec latency to the control of 5.6-sec latency (44.5% improvement).

Chronic prenatal caffeine exposure impairs novel object recognition and radial arm maze behaviors in adult rats

In this report, we demonstrate that chronic prenatal exposure to a moderate dose of caffeine disrupts novel object recognition and radial arm maze behaviors in adult male and female rats. Pregnant dams were administered either tap water or 75 mg/L caffeinated tap water throughout gestation. Oral self-administration in the drinking water led to an approximate maternal intake of 10 mg/kg/day, equivalent to 2–3 cups of coffee/day in humans based on a metabolic body weight conversion. In adulthood, the offspring underwent testing on novel object recognition, radial arm maze, and Morris water maze tasks. Prenatal caffeine exposure was found to impair 24-h memory retention in the novel object recognition task and impair both working and reference memory in the radial arm maze. However, prenatal caffeine exposure did not alter Morris water maze performance in either a simple water maze procedure or in an advanced water maze procedure that included reversal and working memory paradigms. These findings demonstrate that chronic oral intake of caffeine throughout gestation can alter adult cognitive behaviors in rats.

Maternal Separation Compromises Hippocampal-Dependent Memory in Aged Rats

Event Abstract Back to Event Maternal Separation Compromises Hippocampal-Dependent Memory in Aged Rats Joana Vital1, Vasco C. Sousa1, Ana M. Sebastiao1, Joaquim Alexandre-Ribeiro1 and Luisa V. Lopes1* 1 Instituto de Medicina Molecular, University of Lisbon, Institute of Pharmacology and Neurosciences, Faculty of Medicine and Unit of Neurosciences, Portugal The neonatal stress in the form of compromised mother-infant interactions results in permanent changes in the central nervous system in adulthood (Ladd et al., 2000, Prog. Brain Res., 122, 81-103) and is accepted as a valid model for studying chronic depression and anxiety (Kalueff and Tuohimaa, 2004, Acta Neurobio.l Exp., 64, 439-48). It is still unclear whether in situations of cognitive decline, such as in ageing, these changes are hastened. We now investigated the effect of an early-life stress, in the form of maternal-separation, on the hippocampal dependent memory of old rats.Male Wistar rats were assigned to control (CTR) or maternal separated (MS) group. The MS were separated from their mothers for 3h/day from 2-14 postnatal days while CTR were left undisturbed. Their behaviour in the open-field arena, elevated-plus maze and Morris water maze was assessed at 6-8 weeks (young) and at 70 weeks of age (old). In spite of the slower speed observed in old (1.8±0.1 cm/s, n=8) compared to young animals (8.6±1.3 cm/s, n=3), the locomotion measured in the open-field arena was not affected by stress in the two age groups tested. However, in the elevated plus-maze, MS animals displayed higher anxiety-related behaviour: Young MS animals spent only 15.5±4.2% (n=13) of total time in open arms, while CTR animals spent 33.7±6.3% (n=7; P<0.05). Surprisingly, these differences were still present in aged animals. Old MS animals spent 6.6±1.6 % (n=12) in open arms, while CTR animals spent 19.8±4.8 % (n=8; P<0.05). On the spatial reference memory protocol of the Morris water maze, young MS animals displayed visible differences during acquisition: young CTR reached the platform faster than MS during the 5 days training period and spent more time in the platform quadrant during probe test: 58.5±8.8 % (n=7) as compared to 48.7±5.7 % (n=8; P<0.05) spent by young MS animals. Old animals displayed a slower latency curve during acquisition compared to young animals, but more importantly, the stress induced early in life exacerbated these changes: time on the platform quadrant by old MS was only of 40.6±14.2 % (n=10) as compared to 52.5±8.8 % (n=6; P<0.05) by old CTR animals.The neonatal stress induces sustained changes in anxiety-related behaviour and lower performance in the Morris water maze in adulthood. Noteworthy, the maternal separation induced early in life has an impact that remains until old life, possibly affecting hippocampal-dependent memory.Supported by FCT Conference: 11th Meeting of the Portuguese Society for Neuroscience, Braga, Portugal, 4 Jun - 6 Jun, 2009. Presentation Type: Poster Presentation Topic: Neuronal Communication Citation: Vital J, Sousa VC, Sebastiao AM, Alexandre-Ribeiro J and Lopes LV (2009). Maternal Separation Compromises Hippocampal-Dependent Memory in Aged Rats. Front. Neurosci. Conference Abstract: 11th Meeting of the Portuguese Society for Neuroscience. doi: 10.3389/conf.neuro.01.2009.11.134 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 11 Aug 2009; Published Online: 11 Aug 2009. * Correspondence: Luisa V Lopes, Instituto de Medicina Molecular, University of Lisbon, Institute of Pharmacology and Neurosciences, Faculty of Medicine and Unit of Neurosciences, Lisbon, Portugal, lvlopes@medicina.ulisboa.pt Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Joana Vital Vasco C Sousa Ana M Sebastiao Joaquim Alexandre-Ribeiro Luisa V Lopes Google Joana Vital Vasco C Sousa Ana M Sebastiao Joaquim Alexandre-Ribeiro Luisa V Lopes Google Scholar Joana Vital Vasco C Sousa Ana M Sebastiao Joaquim Alexandre-Ribeiro Luisa V Lopes PubMed Joana Vital Vasco C Sousa Ana M Sebastiao Joaquim Alexandre-Ribeiro Luisa V Lopes Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Decreased acetylcholine release is correlated to memory impairment in the Tg2576 transgenic mouse model of Alzheimer's disease

Acetylcholine (ACh) release is one of the key factors in memory mechanisms. To clarify whether beta-amyloid (Aβ) induces a disturbance of the cholinergic system leading to memory impairment, we examined memory impairment and measured hippocampal ACh release in Tg2576 (Tg) mice that over-express the Swedish mutant amyloid precursor protein (APPsw). Furthermore, we examined Aβ burden with aging. Tg mice aged 9–11 months, but not aged 4–6 months, showed memory impairment in the 8-arm radial maze behavior test. Spontaneous ACh release was not altered in Tg mice compared with age-matched control mice at 4–6 or 9–11 months of age. On the other hand, high-K +-evoked ACh release was decreased in Tg mice aged 9–11 months, but not in Tg mice aged 4–6 months. Hippocampal Aβ increased in an age-dependent manner, but evident amyloid plaques were not found in the hippocampus of Tg mice aged 11 months. These results suggest that memory impairment in Tg mice could be attributed to cholinergic synapse dysfunction that could not be caused predominantly by amyloid plaques. Measuring ACh release in this model might be a useful index for the screening of new drugs to treat the early-phase of Alzheimer's disease.

Effect of behavior training on learning and memory of young rats with fetal growth restriction

Objective To investigate the effect of behavior training on the learning and memory of young rats with fetal growth restriction (FGR). Methods The model of FGR was established by passive smoking method to pregnant rats. The new-born rats were divided into FGR group and normal group, and then randomly subdivided into trained and untrained group respectively. Morris water maze behavior training was performed on postnatal months 2 and 4, then learning and memory abilities of young rats were measured by dark-avoidance testing and step-down testing. Results In the dark-avoidance and step-down testing, the young rats' performance of FGR group was worse than that of control group, and the trained group was better than the untrained group significantly. Conclusion FGR young rats have descended learning and memory abilities. Behavior training could improve the young rats' learning and memory abilities, especially for the FGR young rats.

Spatial Cognition and Motor Development: A Study of Children with Spina Bifida

The purpose of this study was to examine the relation between motor development and spatial cognition. The sample was 20 children with Spina bifida (M age: 11.4 yr., SD = 1.7) and 20 healthy children as controls (M age: 11.8, SD = 1.8 yr.). An experimental assessment of motor development in spatial cognition in a simulated virtual maze by school-age children is lacking. In this study children with Spina bifida, who were impaired in walking since birth, completed four visuospatial tasks in a small-scale space (Mental Rotation, Water-Level Task, Embedded Figures Test, Visual Short-term Memory Test), and a spatial behaviour and knowledge task in a virtual maze. These children showed poorer performance than children in the control group on most measures. The results are discussed with respect to theoretical implications and further research.

Anxiogenesis in adult rats treated chronically with cocaine during adolescence: Effects of extended abstinence and 8-OH-DPAT treatment

Our laboratory has recently observed the development of an anxiogenic response after a short abstinence period (∼10 days) in young adult rats treated repeatedly with cocaine during adolescence. The present study was conducted to determine if this effect persists into adulthood following extended durations of abstinence and whether it could be modulated with the 5-HT 1A agonist (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT). Accordingly, 30-day-old rats were injected with either 10 mg/kg cocaine or saline for 8 consecutive days. Approximately 8 weeks after the final injection, anxiety levels in subjects were assessed with an elevated zero maze with a second assessment performed 4 weeks thereafter. Shortly prior to each test session, half the subjects in each of the two adolescent drug conditions received injections of 300 μg/kg 8-OH-DPAT while the other half received injections of the vehicle. Based on total time spent in the open areas of the maze, the results obtained at the first abstinent duration indicated that adolescent cocaine treatment did not induce an anxiogenic response. Assessment of maze behavior at the second abstinent duration was aided with a digital tracking and computerized scoring system ( LimeLight, Actimetrics). Similar to the results obtained at the first abstinent duration, the amount of time spent in the open areas of the maze was unrelated to prior cocaine treatment. However, cocaine-treated rats did show evidence of an anxiogenic response at this abstinent duration based on more frequent entries into and out of the open and enclosed areas of the maze, more frequent and longer durations of exploratory bouts beyond the perimeter of the maze, excessive number of cautious protrusions into the open areas, and faster running velocities through the open areas. These results were not artifacts of generalized motor activation in that comparable total distance traveled scores were noted for all subjects. Treatment with 8-OH-DPAT shortly prior to elevated zero maze testing normalized these behaviors induced by adolescent cocaine. It is concluded that the anxiogenic response produced by cocaine exposure during adolescence persists 12 weeks beyond cessation of drug treatment and that this effect is reversible with 8-OH-DPAT. In addition, the results underscore the importance of taking multiple measures when assessing anxiety in experimental animals. Implications for the neurobiology of drug abuse and the role of serotonin are discussed.

Psychosocial stress and chronic ethanol ingestion in male rats: Effects on elevated plus maze behavior and ultrasonic vocalizations

Psychosocial stress is known to enhance anxiety levels in rodents. The present study evaluated the effect of long-term ingestion of ethanol (EtOH) on anxiety levels of male Long Evans rats housed either singly or in triads (three/cage). Based on measures of offensive and defensive behaviors, triad-housed rats were designated as being dominant, subdominant or subordinate. The effect of chronic ingestion of a 6% EtOH solution was assessed on behaviors in the elevated plus maze (EPM) test, and on air-puffs elicited 22 kHz ultrasonic vocalizations (USV). EtOH naïve dominant rats showed less anxiogenic-like (open arms time) and displacement behavior (grooming), but more risk assessment behavior (stretch-attend postures) than their cage-mates or the single-housed rats. Intake of EtOH prior to the EPM test was lower in dominant and single-housed rats compared to subdominant and subordinate rats. Triad-housed rats, but not the single-housed rats, decreased their intake of EtOH after the EPM test. Overall, EtOH intake had an anxiolytic effect in all rats, but the effect was most prominent in single-housed rats. Furthermore, EtOH intake decreased air-puff induced USVs of triad-housed rats, but increased USVs of single-housed rats. These data indicate that housing condition and rank status influence the emotional state of male rats. Furthermore, the anxiolytic effect of voluntarily ingested EtOH was depended on these variables.

Morphine withdrawal affects both delayed-escape behaviour in Morris water maze and hippocampal NR2A/2B expression ratio

Repeated low-dose morphine treatment facilitates delayed-escape behaviour of hippocampus-dependent Morris water maze and morphine withdrawal influences hippocampal NMDA receptor-dependent synaptic plasticity. Here, we examined whether and how morphine withdrawal influenced delayed-escape behaviour and NR2A/2B expression ratio of hippocampal synaptosomes. We found that both delayed-escape behaviour and NR2A/2B expression ratio showed an inverted-U curve and peaked on 4-day withdrawal during a 20-day withdrawal period. Furthermore, treatment of the glucocorticoid receptor antagonist RU38486 for 3 days reduced delayed-escape behaviour and NR2A/2B ratio on 4-day withdrawal to a level similar to those of 18-h withdrawal. In contrast, elevated-platform stress enabled delayed-escape behaviour of 18-h withdrawal to a higher level similar to that of 4-day withdrawal, but had no significant effect on the NR2A/2B ratio. Similar behavioural effects were also found after intrahippocampal infusions of the NMDAR antagonist AP-5 or NR2B-containing NMDAR antagonist Ro25-6981 for 3 days. These findings suggest that delayed-escape behaviour enabled by repeated low-dose morphine treatment may be a useful and simple rat model for studying addictive memories to be retrieved by stress exposure.

Use of a conditioning technique to reduce stress associated with repeated intra-peritoneal injections in laboratory rats

We hypothesized that using classical conditioning to pair a stressful procedure such as injection with a rewarding experience decreases the stress associated with repeated exposure to this procedure. We investigated the effectiveness of pairing repeated intra-peritoneal injections with a positive stimulus to reduce physiological and behavioural stress responses of laboratory rats by comparing injection with 1 ml/kg of saline followed by one of three different reward types (food treat (F), stroking (S) and tickling (T)), delivered in a treatment box, with two control conditions (handling without injection (CH) and injected (CI)) followed by an equivalent period in the treatment box. Treatments were applied to rats ( N = 40; 8 rats/treatment) daily for 10 days. Audible and 50 kHz (laughing) vocalizations were assessed during handling and while in the treatment box. Chromodacryorrhea (an indicator of stress) was assessed daily in the home cage. Body weight, and behaviour in the Human Approach (HA) test, were assessed before (baseline) and after the 10-day treatment period. Behaviour in the Elevated Plus Maze (EPM) test was assessed after the 10-day treatment period. Rats on all treatments produced more chromodacryorrhea during the treatment period compared to baseline, suggesting that all treatments induced stress. Principal component analyses on behaviour in the HA and EPM tests revealed two and three factors that explained 86.8% and 98.7% of total variance, respectively. Multivariate analysis of variance on these factors, along with the other variables, revealed a significant contrast between CH and the other treatments. CH rats performed fewer audible vocalizations when handled compared to rats given injections. We found no clear benefit of providing a food treat, stroking, or tickling to alleviate stress associated with injection under the conditions of this study, possibly due to differences between rats in their perception of the aversiveness of handling restraint and injection, their stress response style (active or passive), and their perception of the pleasantness of the different rewards. Rats on all treatments emitted 50 kHz chirps in the treatment box, suggesting that being placed in the box after handling was rewarding regardless of treatment.

Functional dissection of the neural substrates for gravitaxic maze behavior in Drosophila melanogaster

In animals, sensing gravity is supported by mechanosensory neurons that send information to the central brain for integration along with other modalities. In Drosophila, candidate sensory organs for detecting the gravity vector were predicted from the results of a recent forward genetic screen. This analysis also suggested possible roles for the central complex and antennal system in Drosophila. Using the same vertical maze assay employed in the original screen, we investigated the roles of these candidate neural structures by spatial and temporal inactivation of synaptic transmission with the GAL4/UAS-shibire[ts1] system. We correlate changes in the maze behavior of flies with specific inhibition of synaptic transmission for key brain neuropil that includes the central complex and antenno-glomerular tract. Further, our results point toward a minimal, or nonexistent, role for the mushroom bodies.

Contextual control of rats’ foraging behaviour in a radial maze

This study demonstrated that with experience rats were able to discriminate the background contextual cues in order to foraging correctly in an eight-arm radial maze if the background contexts signaled to the rats which of two bait patterns was in effect in that context. Four of the eight arms were context-dependent: two arms were baited in the "night" context, while the other two were baited in the "daytime" context. The remaining four arms were context-independent: three of them were never baited, while the remaining one was baited in both contexts. The rats gradually began to avoid the arms that were uniquely baited in the other context, suggesting a contextual or conditional control of arm selection. Interestingly, these rats also showed better performance in avoiding the never-baited arms, compared with control rats. Namely, disambiguating the incentive values of the four arms by contextual cues collaterally facilitated the context-independent arm performance. Another interesting finding of the present study is that the rats did not visit the always-baited arm earlier than the arms uniquely baited in that context.

High-dose MDMA does not result in long-term changes in impulsivity in the rat

Evidence suggests that recreational users of (+/-)3,4-methylenedioxymethamphetamine HCl (MDMA, "ecstasy") have cognitive and behavioral deficits and show increased impulsivity consistent with 5-hydroxytryptamine (5-HT) neurotoxicity. MDMA effects on impulsivity in users are difficult to establish being confounded by polydrug use and individual predisposition to impulsivity or behavioral inhibition. We previously observed a long-term anxiolytic effect of a neurotoxic dose of MDMA on elevated plus maze behavior in Dark Agouti (DA) rats while other strains were reported to show anxiogenesis. We have now examined whether MDMA influences impulsivity producing disinhibited behavior interpretable as anxiolysis. Impulsivity was measured using an operant visuospatial discrimination procedure. Male DA rats (n = 24) were trained to lever press for food reward in response to a light-stimulus and subsequently required to withhold responding. Correct responses, premature responses, and response latencies were used as measures of accuracy and impulsivity. Trained rats were administered MDMA (5 mg/kg, i.p. at 3-h intervals to a total of three injections). Performance was measured at 3 h and 7, 27, 49, and 80 days posttreatment. There was a short-term effect of MDMA on the percentage of correct responses at 3 h and day 1 with recovery to control levels by days 7-8 and no significant long-term changes up to day 80. There was no effect of MDMA on premature responses on any of the days measured. MDMA reduced cortical 5-HT content (MDMA 363 +/- 14 ng/g and control 440 +/- 10 ng/g tissue). These results suggest that impulsivity may not be directly altered by MDMA despite serotonergic neurotoxicity.

Mechanism‐Based Approaches for the Reversal of Drug Neurobehavioral Teratogenicity

Understanding the mechanism of neurobehavioral teratogenicity is the primary prerequisite for reversal of the defect. Progress in such studies can be best achieved if the investigation focuses on behaviors related to a specific brain region and innervation. Our model focused on teratogen-induced deficits in hippocampus-related eight-arm and Morris maze behaviors. Different "cholinergic" teratogens, mainly heroin, induced both pre- and postsynaptic hyperactivity in the hippocampal cholinergic innervation that terminated in desensitization of Protein Kinase C (PKC) isoforms to cholinergic receptor stimulation. Understanding this mechanism enabled its reversal with a pharmacological therapy-nicotine infusion. Studies by others provided similar findings by targeting the deficits respective to the model investigated. Consistently, destruction of the A10-septal dopaminergic pathways that downregulate the septohippocampal cholinergic innervation ameliorated maze performance. Grafting of embryonic differentiated cholinergic cells or neural progenitors similarly reversed the biochemical/molecular alterations and the resulting deficits. Reversal therapies offer a model for the understanding of neurobehavioral teratogenicity and, clinically, offer a model for potential treatment of these deficits. Whereas neural progenitor grafting appears to be the most effective treatment, pharmacological reversal with nicotine infusion seems to possess the most feasible and immediate therapy for neurobehavioral birth defects produced by various teratogens, including drugs. This is true even though the effect of pharmacological therapies is diffuse, affecting multiple areas of the brain. "Everybody is talking about the weather but nobody does anything about it." (Mark Twain).

NMDA receptor activity in learning spatial procedural strategies: II. The influence of cerebellar lesions

Experimental data support the involvement of cerebellar circuits in the acquisition of spatial procedural competences. Since the ability to acquire new procedural competences is lost when cerebellar regions are lesioned or when NMDA receptor activity is blocked, we analyzed whether the learning of explorative strategies is affected by blocking NMDA receptor activity in the presence of cerebellar lesions. To this aim, the NMDA receptor antagonist (CGS 19755, 7 mg/kg) was administered i.p. to un-lesioned rats, or rats subjected to total ablation of the cerebellum or to hemi-cerebellectomy. CGS 19755 and cerebellectomy both produced water maze behavior characterized by circling. Administration of CGS 19755 did not modify the Morris Water Maze (MWM) peripheral circling behavior of cerebellectomized animals. Circling was the dominant strategy of hemicerebellectomized animals in the absence of drugs. However, increasingly compulsive circling was observed under the action of CGS 19755. Circling was not observed if the drug-treated animals (un-lesioned or lesioned) had been previously trained. In conclusion, the NMDA antagonist caused severe impairment in the acquisition of spatial procedures, thus mimicking the consequences of cerebellar ablation on spatial procedural learning. Based on the present findings, we hypothesize that cerebellar NMDA receptor activity is involved in the acquisition of procedural spatial competence.

SOLUBLE OLIGOMER TRIGGERS MEMORY LOSS

It's probable that you won't be acquainted with every detail of this article once you have read it, but you will at least remember that it was about the causes of Alzheimer's disease. Unfortunately, a person suffering with Alzheimer's will most likely have forgotten that he has even read the article soon after finishing. Indeed, losing memory is one prominent symptom of Alzheimer's disease. The brains of afflicted individuals exhibit characteristic and invariant alterations, which are believed to account ultimately for the loss of neurons and synapses. These include the formation of intracellular neurofibrillary tau tangles and extracellular plaques of neurotoxic amyloid-β peptide, where aberrant cleavage products of the amyloid-β precursor protein assemble to form insoluble plaques. Although the molecular details of the pathology of Alzheimer's are not completely understood, transgenic mouse models have enabled neurobiologists to dissect some of the underlying pathogenic processes.One such transgenic mouse model that has successfully reproduced amyloid plaque pathology in an age-dependent manner is called Tg2576. These mice express a human variant of the amyloid-β precursor protein (APPswe),which is associated with the early-onset of Alzheimer's disease. As a result of APPswe expression in the brain, Tg2576 mice develop amyloid plaques as well as damaged neurons and there is good evidence that the occurrence of amyloid-β peptide is responsible for the observed age-related memory loss. However, it was not clear which form of the amyloid-β peptides triggers memory loss; no forms of the peptide had been found that corresponded with the onset of memory decline. Previous studies had proposed that soluble assemblies of the amyloid-β peptide might affect memory, but the existence of such a soluble amyloid-β oligomer was uncertain until a US team of neurobiologists led by Karen Ashe provided evidence in a recently published Nature article that the memory-loss trigger may be a soluble dodecamer of the amyloid-β peptide.The key to their discovery was a new extraction method to quantify and compare amyloid-β species from different subcellular compartments in the brains of Tg2576 mice. The scientists identified a 56-kDa dodecameric form of the amyloid-β protein (Aβ*56) in the extracellular soluble fraction of forebrain extracts that appeared at the same time as six-month old TG2576 mice began exhibiting memory loss. As there was no evidence of a correlation between memory loss and intracellular or membrane-associated amyloid-βspecies, the finding suggested that Aβ*56 may be responsible for memory loss. However, if Aβ*56 really disrupts memory, it should also cause memory loss when applied externally to the animals' brains. To test this, the team purified Aβ*56 from the brains of impaired Tg2576 mice and injected it into the lateral ventricles of young rats. Subsequent tests on the rat's behaviour in a water maze revealed that Aβ*56 transiently disrupts memory but does not impair the animals ability to learn.Analysing the pathogenesis of Alzheimer's disease is like solving a complex puzzle. It is clear that altered proteolytic processing of amyloid-βprecursor protein resulting in an insoluble molecule is an important piece in this puzzle. Karen Ashe and coworkers' have added another piece to this complex puzzle by clearly showing the transient effects of the soluble Aβ*56 oligomer on memory loss. Although it is not clear precisely how Aβ*56 disrupts memory, the identification of a specific oligomer involved in memory loss may facilitate the development of new diagnostics and therapeutics to combat Alzheimer's disease.

Central effects of the anabolic steroid 17α methyltestosterone in female anxiety

The androgen 17α-methyltestosterone (17α-meT) is one of the most commonly abused anabolic androgenic steroids (AAS). We assessed the impact of 17α-meT after bilateral infusion into the dorsomedial hypothalamus (DMH) in female anxiety. A paradoxical effect in Vogel conflict test (VCT) behavior was noted: while AAS infusion induced an increase in the latency to display the appetitive reaction of the task, it also increased the number of punished responses. No changes in elevated plus maze (EPM) behavior were noted. However, AAS infusion induced an increase in social interactions. Changes in social interactions were mimicked by muscimol infusion and counteracted by co-infusion of AAS plus the GABA A receptor (GABA A-R) antagonist GABAzine. A reduction of systolic blood pressure was registered after AAS infusion in the DMH. No changes in fluid intake or locomotor behaviors were noted. We conclude that the AAS 17α-meT modulates distinct anxiety domains in females through a fast-acting mechanism.

Glia as a Therapeutic Target: Selective Suppression of Human Amyloid-β-Induced Upregulation of Brain Proinflammatory Cytokine Production Attenuates Neurodegeneration

A corollary of the neuroinflammation hypothesis is that selective suppression of neurotoxic products produced by excessive glial activation will result in neuroprotection. We report here that daily oral administration to mice of the brain-penetrant compound 4,6-diphenyl-3-(4-(pyrimidin-2-yl)piperazin-1-yl)pyridazine (MW01-5-188WH), a selective inhibitor of proinflammatory cytokine production by activated glia, suppressed the human amyloid-beta (Abeta) 1-42-induced upregulation of interleukin-1beta, tumor necrosis factor-alpha, and S100B in the hippocampus. Suppression of neuroinflammation was accompanied by restoration of hippocampal synaptic dysfunction markers synaptophysin and postsynaptic density-95 back toward control levels. Consistent with the neuropathophysiological improvements, MW01-5-188WH therapy attenuated deficits in Y maze behavior, a hippocampal-linked task. Oral MW01-5-188WH therapy begun 3 weeks after initiation of intracerebroventricular infusion of human Abeta decreased the numbers of activated astrocytes and microglia and the cytokine levels in the hippocampus without modifying amyloid plaque burden or altering peripheral tissue cytokine upregulation in response to an in vivo inflammatory challenge. The results provide a novel integrative chemical biology proof in support of the neuroinflammation hypothesis of disease progression, demonstrate that neurodegeneration can be attenuated independently of plaque modulation by targeting innate brain proinflammatory cytokine responses, and indicate the feasibility of developing efficacious, safe, and selective therapies for neurodegenerative disorders by targeting key glial activation pathways.

Effect of Lipids Extracted from a Salted Herring Roe Food Product on Maze-Behavior in Mice

Male mice (11 mo old) were fed 5% lard, fish oil, or Kazunoko (salted fish roe product) lipids for 4 mo to investigate their effects on maze behavior. The time required and distance traveled to reach the maze exit, and number of times that a mouse strayed into blind alleys in the maze, and the fatty acid compositions of brain lipids after the maze-behavior experiment were measured. The Kazunoko lipid group showed a significant improvement in all three parameters compared with the lard diet group, but the fish oil group showed only a significant decrease in the number of times that a mouse strayed into blind alleys compared with the lard diet group. The mice in the fish oil and Kazunoko lipid groups had significantly lower levels of arachidonic acid and higher percentages of docosahexaenoic acid in brain lipids compared with animals in the lard group. The mice in the Kazunoko lipid group had significantly lower levels of arachidonic acid in brain lipids than those in the fish oil group but the percentages of docosahexaenoic acid were not significantly different between these two diet groups. Our results suggest that an intake of Kazunoko lipids may suppress the percentage of n-6 fatty acids in brain lipids and this diet can be even more effective than fish oil as a supplement to improve learning capacity in mice.

Impairment of water maze behaviour with ageing is counteracted by maze learning earlier in life but not by physical exercise, food restriction or housing conditions

Spatial learning and memory decline with ageing in humans as well as rats. We examined the influence of different interventions on male Sprague Dawley rats with respect to learning ability and memory at the age of 5, 10 and 18 months. The intervention and control groups were: (RW) voluntary exercise in running wheels, (PW) sedentary, food restricted (by about 25%) to keep them at pair weight with RW, (S1) sedentary, fed ad libitum, (TM) forced training in a treadmill, and, (S4) sedentary, fed ad libitum. The animals in all groups were housed individually except those in group S4, which were housed four in each cage. The ability of learning and memory was determined in the Morris water maze. The results showed a significantly better learning ability when young in comparison with their ability when having grown older. At the age of 18 months, the performance was significantly better in the subgroups which had received training also at the age of 10 months compared to the subgroups receiving their first training. None of the various interventions had any significant effect on these functions. Repeated training seems to be the best intervention with respect to retaining learning ability and memory.