T-maze Alternation Research Articles

The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents

The present study investigated the putative pro-cognitive effects of the novel selective PDE9 inhibitor BAY 73-6691. The effects on basal synaptic transmission and long-term potentiation (LTP) were investigated in rat hippocampal slices. Pro-cognitive effects were assessed in a series of learning and memory tasks using rodents as subjects. BAY 73-6691 had no effect on basal synaptic transmission in hippocampal slices prepared from young adult (7- to 8-week-old) Wistar rats. A dose of 10 μM, but not 30 μM, BAY 73-6691 enhanced early LTP after weak tetanic stimulation. The dose effective in young adult Wistar rats did not affect LTP in hippocampal slices prepared from young (7- to 8-week-old) Fischer 344 X Brown Norway (FBNF1) rats, probably reflecting strain differences. However, it increased basal synaptic transmission and enhanced early LTP after weak tetanic stimulation in hippocampal slices prepared from very old (31- to 35-month-old) FBNF1 rats. BAY 73-6691 enhanced acquisition, consolidation, and retention of long-term memory (LTM) in a social recognition task and tended to enhance LTM in an object recognition task. Bay 73-6691 attenuated the scoplamine-induced retention deficit in a passive avoidance task, and the MK-801-induced short-term memory deficits in a T-maze alternation task. The mechanism of action, possibly through modulation of the NO/cGMP-PKG/CREB pathway, is discussed. Our findings support the notion that PDE9 inhibition may be a novel target for treating memory deficits that are associated with aging and neurodegenerative disorders such as Alzheimer's disease.

Basal behavioral characterization of hsf1 deficient mice and its cellular and behavioral abnormalities underlying chronic unpredictable stressors

The heat shock factor 1 (HSF1) is a major transcriptional factor that controls the rapid induction of heat shock proteins in response to various environmental stressors. In this study, we globally investigated the effect of HSF1 deficiency on animal behaviors during postnatal growth, and abnormalities in hippocampal neurons and behavior in response to chronic unpredictable stressors (CUS). Mouse behaviors were measured in several behavioral paradigms, including elevated plus maze, open field, closed field, T-maze continuous alternation task (T-CAT), bridge-walking, and wire suspension tests. The hsf1-null mice exhibited reduction in basal anxiety levels and exploratory behavior, and working memory deficits, but normal motor coordination abilities. Chronic unpredictable stressors significantly increased apoptosis in hippocampal CA3 cells in both the hsf1-null and wild-type (WT) mice in the in situ TUNEL staining and induced more anxiety-like behavior in the hsf1-null mice than WT mice in the plus T-maze paradigm. We conclude that hsf1 gene deficiency results in significant abnormalities in mouse basal behaviors and sensitization to chronic unpredictable stressors.

Place cell firing correlates with memory deficits and amyloid plaque burden in Tg2576 Alzheimer mouse model

Alzheimer's disease (AD) is associated with progressive memory decline. Hippocampal place cells are a well understood candidate for the neural basis of one type of memory in rodents; these cells identify the animal's location in an environment and are crucial for spatial memory and navigation. We have recorded place cells in the Tg2576 mouse model of AD, and we report that aged (16 mo) but not young (3 mo) transgenic mice show degraded neuronal representations of the environment. The level of place cell degradation correlates with the animals' (poorer) spatial memory as tested in a forced-choice spatial alternation T-maze task and with hippocampal, but not neocortical, amyloid plaque burden. Place cell recording provides a sensitive assay for measuring the amount and rate of functional deterioration in animal models of dementia as well as providing a quantifiable physiological indication of the beneficial effects of potential therapies.

Therapeutic window of hyperbaric oxygen therapy for hypoxic–ischemic brain damage in newborn rats

Previous studies showed that hyperbaric oxygen (HBO) promoted cell proliferation in hypoxic–ischemic (HI) neonate rats. Neural stem cells (NSC) existed in the brain lifelong and can be activated. This study was undertaken to assess whether HBO treatment promoted the proliferation of NSC and repaired the brain damage regardless of when it is started, thus to explore the therapeutic window of HBO treatment. Seven-day-old Sprague–Dawley rats underwent left carotid ligation followed by 2 h of hypoxic stress (8% O 2 at 37 °C). Hyperbaric oxygen therapy was administered 3, 6, 12, 24, and 72 h after HI. 5-bromo-2′-deoxyurindine and 5-bromo-2′-deoxyuridine/nestin were detected by immunofluorescence and nestin was examined by western blot analysis 10 days after HI. T-maze forced alternation, the foot-fault test, and the radial arm maze were conducted at P 22 days (14 days after HI), P 30 days, and P 34 days. Thereafter, cerebral morphology was examined by Nissl-staining 28 days after HI. There were remarkable increases in the proliferation of neural stem cells in the HBO-treated group, 3, 6, 12, and 24 h after HI, as compared with the HIBD group. The HBO-treated group, 3, 6, and 12 h after HI, performed better in the behavioral test and had less neural loss in the hippocampal CA1 region as compared with the HIBD group. The therapeutic window for effective HBO treatment could be delayed up to 12 h after HIBD, while the effect decreased 24 h after HI.

Extracts and constituents of Leontopodium alpinum enhance cholinergic transmission: Brain ACh increasing and memory improving properties

Leontopodium alpinum (‘Edelweiss’) was phytochemically investigated for constituents that might enhance cholinergic neurotransmission. The potency to increase synaptic availability of acetylcholine (ACh) in rat brain served as key property for the bioguided isolation of cholinergically active compounds using different chromatographic techniques. The dichlormethane (DCM) extract of the root, fractions and isolated constituents were injected i.c.v. and the effect on brain ACh was detected via the push–pull technique. The DCM extract enhanced extracellular ACh concentration in rat brain and inhibited acetylcholinesterase (AChE) in vitro. The extracellular level of brain ACh was significantly increased by the isolated sesquiterpenes, isocomene and 14-acetoxyisocomene, while silphiperfolene acetate and silphinene caused a small increasing tendency. Only silphiperfolene acetate showed in vitro AChE inhibitory activity, thus suggesting the other sesquiterpenes to stimulate cholinergic transmission by an alternative mechanism of action. Isocomene was further investigated with behavioural tasks in mice. It restored object recognition in scopolamine-impaired mice and showed nootropic effects in the T-maze alternation task in normal and scopolamine-treated mice. Additionally, this sesquiterpene reduced locomotor activity of untreated mice in the open field task, while the activity induced by scopolamine was abolished. The enhancement of synaptic availability of ACh, the promotion of alternation, and the amelioration of scopolamine-induced deficit are in accordance with a substance that amplifies cholinergic transmission. Whether the mechanism of action is inhibition of AChE or another pro-cholinergic property remains to be elucidated. Taken together, isocomene and related constituents of L. alpinum deserve further interest as potential antidementia agents in brain diseases associated with cholinergic deficits.

Dissociable onset of cognitive and motivational dysfunctions following neonatal lesions of the ventral hippocampus in rats.

This research examined cognitive and motivational processes at different developmental stages in rats with neonatal ventral hippocampus (VH) lesions, an approach used to model schizophrenia. In Experiment 1, performance in a T-maze alternation task was assessed on postnatal days (PNDs) 22 and 23. VH-lesioned rats displayed a severe deficit relative to controls. In Experiment 2, behaviorally naive rats were tested for spontaneous alternation at PND 29. Alternation was intact in VH-lesioned rats only when successive alternations were separated by >5 s. In Experiment 3, motivation was tested in a cost-benefit T-maze task and in a saccharine-water preference test. Between PNDs 22-37, behaviorally naive rats with neonatal VH lesions displayed weaker saccharine preference than controls, but the 2 groups did not differ on the cost-benefit task. At adulthood, between PNDs 56-72, the difference on saccharine preference persisted and an impairment on the cost-benefit task emerged. Overall, these results suggest that working memory deficits observed at the weaning stage were not secondary to spontaneous alternation or motivation dysfunctions.

The effects of hippocampal system lesions on a novel temporal discrimination task for rats

A novel, appetitive, Pavlovian conditioning task was used to assess interval timing. Experiment 1 showed that normal rats could discriminate between tones of 1.5 s and 0.5 s duration, or between tones of 12.0 s and 3.0 s duration. Learning was demonstrated by a greater duration of magazine responding in the period before the delivery of a food reward and after cessation of the CS+ compared to the same time period after cessation of the CS−. Learning was, however, asymmetric as it was much quicker when the CS+ was the longer of the two durations (1.5 s and 12.0 s, respectively). Experiment 2 assessed the impact of fornix lesions on the acquisition of one version of this task (CS+ 1.5 s, CS− 0.5 s). No evidence was found of a change in discrimination learning following surgery. Experiment 3 examined whether rats with either fornix or hippocampal lesions affected discriminations between 12.0 s and 3.0 s stimuli. Again, there was no evidence of a lesion-induced deficit. T-maze alternation training confirmed the effectiveness of these lesions. The results not only reveal that neither the fornix nor the hippocampus is necessary for distinguishing temporal intervals within the ranges tested but also showed how under some circumstances these lesions can leave trace conditioning intact.

Selective breeding for deficient sensorimotor gating is accompanied by increased perseveration in rats

Prepulse inhibition (PPI) of the acoustic startle response is a measure of sensorimotor gating that is deficient in some neuropsychiatric disorders, such as schizophrenia and Tourette’s syndrome. Experimentally induced PPI deficits in rats are regarded as endophenotype to study the biological mechanisms and therapeutic strategies of these disorders. We have recently shown that selectively breeding rats for high and low PPI levels, respectively, leads to groups with different PPI performance that remains stable from the second generation on. We here tested whether the low PPI is accompanied by other behavioral deficits. Different spatial and operant learning paradigms were used to assess rats’ learning and memory abilities as well as their behavioral flexibility. In the delayed alternation T-maze task the two groups did not differ in task acquisition and working memory. Rats with low PPI showed enhanced perseveration during switching between an egocentric and allocentric radial maze task. Enhanced perseveration was also found in an operant behavioral task, where different demands, i.e. a different number of lever presses for a pellet-reward, were assigned to and switched between two levers of a Skinner box. Rats with low PPI stayed longer at the ineffective lever before switching, thus being less able to adjust their behavior to changing reward values. Additionally, PPI low rats had a higher breakpoint value during a progressive ratio-schedule of reinforcement. Rats selectively bred for low PPI showed some cognitive deficits that are apparent in a number of psychiatric disorders with deficient information processing. Specifically in both, spatial and operant behavioral paradigms, PPI low rats are deteriorated in their ability to modulate behavior based upon new changing information. They may thus provide a non-pharmacological model that can be used to evaluate new therapeutic strategies ranging from pharmacological treatment to functional neurosurgery.

Dorsal hippocampal N-methyl-d-aspartate receptors underlie spatial working memory performance during non-matching to place testing on the T-maze

Previous lesion studies have suggested a functional dissociation along the septotemporal axis of the hippocampus. Whereas the dorsal hippocampus has been implicated in spatial memory processes, the ventral hippocampus may play a role in anxiety. However, these lesion studies are potentially confounded by demyelination of fibres passing through the lesion site, and the possibility of secondary, downstream changes in associated brain structures as a consequence of their chronic denervation following the lesion. In the present study, we have used the microinfusion of muscimol to temporarily inactivate either the dorsal or ventral hippocampus in order to re-examine the contribution of the hippocampal sub-regions to spatial memory. Microinfusion studies spare fibres of passage and offer fewer opportunities for compensatory changes because the effects are transient and short-lasting. Rats were infused prior to spatial working memory testing on a non-matching to place T-maze alternation task. Spatial working memory was impaired by dorsal but not ventral hippocampal inactivation. In a second experiment, infusion of the NMDAR antagonist, D-AP5, into dorsal hippocampus also impaired spatial working memory performance, suggesting that NMDAR function within the dorsal hippocampus makes an essential contribution to this aspect of hippocampal information processing.

Delayed alternation performance following subchronic phencyclidine administration in rats depends on task parameters

The cognitive effects of subchronic phencyclidine administration in rats are still unsettled in the literature. Possible causes of discrepancies are different drug treatment regimens and task parameters. The current experiment tested whether variations in procedures of the delayed T-maze alternation task result in performance differences following identical PCP treatments. Sixteen rats were trained on a continuous version of the T-maze task where they alternated between successive free-choice runs. Another sixteen were trained on a discrete trials version where each trial started with a forced run followed by a free choice test. After training, half of the rats submitted to each task version were treated daily for 14 days with i.p. injections of PCP (10 mg/kg) and the remaining half received a saline solution. At 48 h after the last injection, the subjects were tested for 10 days in their respective task version. Results showed that rats treated with PCP were impaired relative to controls in the continuous alternation task whereas performance of PCP and Saline groups did not differ in the discrete trials version. Cognitive control from prefrontal cortex and/or striatal response-related processes could have been damaged by PCP exposure. The systematic study of differences in tasks parameters may help reconcile discordant findings on PCP's functional outcomes.

Spatial Representations of Hippocampal CA1 Neurons Are Modulated by Behavioral Context in a Hippocampus-Dependent Memory Task

Although it is well known that hippocampal neurons code spatial information, it is less clear how these spatial representations are influenced by memory demands, especially in hippocampus-dependent tasks. Recently, our laboratory has demonstrated that hippocampal spatial representations are influenced by mnemonic factors in a T-maze continuous alternation task. Another unique experimental approach that might reveal the ways in which task-related factors impact hippocampal spatial representations is to compare firing patterns between events that require distinct episodic memory processes. Therefore, we recorded from CA1 single neurons during a discrete trial delayed-nonmatch-to-place task that allowed within-trial comparison between an encoding (sample) phase and a retrieval (choice) phase. A large subset of neurons that fired on the central stem of the maze showed dramatic selectivity for either the sample or choice phase of the trial. However, surprisingly, there were fewer neurons that showed differential firing rates between left- and right-bound trajectories. Our results suggest that trial-phase-selective coding is common in tasks that require rapid alternation between encoding and retrieval processes.

Induction of autoimmune depression in mice by anti–ribosomal P antibodies via the limbic system

Autoantibodies against ribosomal P proteins are linked to the neuropsychiatric manifestations of systemic lupus erythematosus (SLE). The present study was undertaken to assess how the specific brain-binding autoantibody anti-ribosomal P can induce a depression-type psychiatric disorder in mice. Mice were injected intracerebroventricularly with affinity-purified human anti-ribosomal P antibodies or IgG as control. Pharmacologic and immunologic treatments included the antidepressant drug fluoxetine, the antipsychotic drug haloperidol, and antiidiotypic antibodies. Behavior was assessed by the forced swimming test, motor deficits by rotarod, grip strength, and staircase tests, and cognitive deficits by T-maze alternation and passive avoidance tests. Anti-ribosomal P antibodies induced depression-like behavior in the mice (mean +/- SEM 147.3 +/- 19.2 seconds of immobility versus 75.2 +/- 12.1 seconds of immobility in IgG-injected control mice; P < 0.005). The anti-ribosomal P antibody-induced depression-like behavior was partially blocked by a specific antiidiotypic antibody and significantly blocked by long-term treatment with fluoxetine, but not by short- or long-term treatment with haloperidol. The depressive behavior was not associated with any motor or cognitive deficits. Anti-ribosomal P antibodies specifically stained neurons in the hippocampus, cingulate cortex, and the primary olfactory piriform cortex, compatible with the previously described binding to the membrane-bound P0 ribosomal protein. This is the first report of an experimental depression induced by a specific autoantibody. The results implicate olfactory and limbic areas in the pathogenesis of depression in general, and in central nervous system dysfunction in SLE in particular.

A longitudinal study of rats chronically exposed to aluminum at human dietary levels

According to the World Health Organization, oral ingestion of aluminum additives is the main form of aluminum exposure for the general public. Aluminum salts are added to a range of commercially-prepared foods and beverages: to clarify drinking water, make salt free-pouring, color snack/dessert foods, and make baked goods rise. In the present study, six Wistar rats chronically consumed aluminum from 16 months of age to the conclusion of their lifespan (averaging 29.8 months) in an amount (1.5 mg/kg bodyweight) equivalent to the high end of the total aluminum range ingested daily by humans living in contemporary urban society. The rats were memory-trained in a continuous rewarded alternation T-maze task and tested weekly from 5 months of age onwards. This longitudinal study compared their mean memory performances over 15 consecutive weeks during middle age (12–23 months) and old age (≥24 months). Four out of six rats continued to perform the memory task in old age without significant deficit. The remaining two obtained significantly lower mean memory scores in old age than in middle age and exhibited soft signs associated with dementia. Their hippocampal neurons stained for aluminum, showing some but not all features of aluminum accumulation that occur in human hippocampal neurons. In view of evidenced linkages of aluminum with β-amyloid plaque and neurofibrillary tangle formation in humans with Alzheimer's disease, the findings suggest this protocol is worth testing in larger groups of animals.

Enhancing effects of chronic lithium on memory in the rat

Background In spite of recent enrichment of neurochemical and behavioural data establishing a neuroprotective role for lithium, its primary effects on cognitive functioning remain ambiguous. This study examines chronic lithium effects on spatial working memory and long-term retention. Methods In three discrete experiments, rats subjected to 30 daily intraperitoneal injections (2 mmol/kg) of lithium (lithium groups: serum lithium = 0.5 ± 0.4 mEq/l, 12 h post-injection) or saline (controls) were trained in 0-s delay T-maze alternation and then tested in 30-, 45- and 60-s delay alternation (Experiments 1, 2, 3, respectively). Animals from Experiment 1 were further tested in one-trial step-through passive avoidance under mild shock parameters (0.5 mA, 1 s). Retention was assessed 6 h later. Daily lithium or saline injections continued throughout behavioural testing. Results Lithium animals were indistinguishable from controls during 0-delay alternation baseline (Experiments 1–3, accuracy > 88%) but showed significantly higher accuracy than controls at 30- and 45-s delays (93% versus 85% and 92% versus 82%, Experiments 1 and 2, respectively). At 60-s delay (Experiment 3) this beneficial effect of lithium was no longer apparent (lithium and control accuracy = 78%). In Experiment 4, the shock used did not support 6-h passive avoidance retention in controls, whereas lithium animals showed significant step-through latency increases. Conclusions Chronic lithium enhanced spatial working memory and promoted long-term retention of a weak aversive contingency. The results suggest that lithium may have potential as a cognitive enhancer.

Behavioral alterations in mice lacking the translation repressor 4E-BP2

The requirement for de novo protein synthesis during multiple forms of learning, memory and behavior is well-established; however, we are only beginning to uncover the regulatory mechanisms that govern this process. In order to determine how translation initiation is regulated during neuroplasticity we engineered mutant C57Bl/6J mice that lack the translation repressor eukaryotic initiation factor 4E-binding protein 2 (4E-BP2) and have previously demonstrated that 4E-BP2 plays a critical role in hippocampus-dependent synaptic plasticity and memory. Herein, we examined the 4E-BP2 knockout mice in a battery of paradigms to address motor activity and motor skill learning, anxiety and social dominance behaviors, working memory and conditioned taste aversion. We found that the 4E-BP2 knockout mice demonstrated altered activity in the rotating rod test, light/dark exploration test, spontaneous alternation T-maze and conditioned taste aversion test. The information gained from these studies builds a solid foundation for future studies on the specific role of 4E-BP2 in various types of behavior, and for a broader, more detailed examination of the mechanisms of translational control in the brain.

D-4F decreases brain arteriole inflammation and improves cognitive performance in LDL receptor-null mice on a Western diet

LDL receptor-null mice on a Western diet (WD) have inflammation in large arteries and endothelial dysfunction in small arteries, which are improved with the apolipoprotein A-I mimetic D-4F. The role of hyperlipidemia in causing inflammation of very small vessels such as brain arterioles has not previously been studied. A WD caused a marked increase in the percent of brain arterioles with associated macrophages (microglia) (P < 0.01), which was reduced by oral D-4F but not by scrambled D-4F (ScD-4F; P < 0.01). D-4F (but not ScD-4F) reduced the percent of brain arterioles associated with CCL3/macrophage inflammatory protein-1alpha (P < 0.01) and CCL2/monocyte chemoattractant protein-1 (P < 0.001). A WD increased (P < 0.001) brain arteriole wall thickness and smooth muscle alpha-actin, which was reduced by D-4F but not by ScD-4F (P < 0.0001). There was no difference in plasma lipid levels, blood pressure, or arteriole lumen diameter with D-4F treatment. Cognitive performance in the T-maze continuous alternation task and in the Morris Water Maze was impaired by a WD and was significantly improved with D-4F but not ScD-4F (P < 0.05). We conclude that a WD induces brain arteriole inflammation and cognitive impairment that is ameliorated by oral D-4F without altering plasma lipids, blood pressure, or arteriole lumen size.

Gradual Translocation of Spatial Correlates of Neuronal Firing in the Hippocampus toward Prospective Reward Locations

In a continuous T-maze alternation task, CA1 complex-spike neurons in the hippocampus differentially fire as the rat traverses overlapping segments of the maze (i.e., the stem) repeatedly via alternate routes. The temporal dynamics of this phenomenon were further investigated in the current study. Rats learned the alternation task from the first day of acquisition and the differential firing pattern in the stem was observed accordingly. More importantly, we report a phenomenon in which spatial correlates of CA1 neuronal ensembles gradually changed from their original firing locations, shifting toward prospective goal locations in the continuous T-maze alternation task. The relative locations of simultaneously recorded firing fields, however, were preserved within the ensemble spatial representation during this shifting. The within-session shifts in preferred firing locations in the absence of any changes in the environment suggest that certain cognitive factors can significantly alter the location-bound coding scheme of hippocampal neurons.

Behavioral and hippocampal changes after prenatal invasive interventions with possible relevance to schizophrenia

In an attempt to model neurodevelopmental defects that may contribute to the outbreak of schizophrenia after adolescence, the present study examined the effects of prenatal interventions in rats, including injections of kainic acid, on motor, cognitive and social behaviour, which was assessed repeatedly between PDs 56–62 (week 8) and 168–174 (week 24), as well as on hippocampal morphology. As compared to untreated controls ( n = 5–9), the offspring ( n = 12 or 16) of treated mothers exhibited shorter latencies to leave a dark box and enter an illuminated field on weeks 12, 16 and 20, a higher number of perseverations in a T-maze alternation task on weeks 16 and 20, longer nose contacts with strange and familiar partners in a social interaction test on weeks 12 and 16 and lower weight gains over the course of testing. They also had shorter pyramidal cells in hippocampal area CA3. Thus, the prenatally treated offspring showed certain alterations in their brains and behaviour that resembled the human condition of schizophrenia (e.g., changes at cell level in the hippocampus, perseverative behaviour, lower weight gains), although others (e.g., increased social contacts) did not.

Transient spatial deficit associated with bilateral lesions of the lateral mammillary nuclei

The mammillary bodies have long been implicated in spatial memory, and lesions of this structure in rats can impair some spatial memory tasks. The mammillary bodies, however, comprise two main nuclei that have different electrophysiological and anatomical properties. It is therefore possible that they have different functions. The present study determined whether selective lesions of one of these components, the lateral mammillary nucleus, are sufficient to induce spatial memory deficits. While selective lateral mammillary nuclei lesions induced deficits on a working memory task in the water maze, this impairment was milder and not as persistent as that seen with complete mammillary body lesions. Furthermore, lateral mammillary nuclei lesions did not impair T-maze alternation, which is sensitive to complete mammillary body lesions. From these results it appears that lesions confined to the lateral mammillary nuclei are sufficient to produce mild impairments when rapid, new spatial learning is at a premium. At the same time, the remaining mammillary nuclei also contribute to spatial learning, though this may be in a qualitatively different manner.

Analysis of behavioral asymmetries in the elevated plus-maze and in the T-maze

When studying functional asymmetries in normal laboratory rats, several behavioral tests have been applied and proven their utility, including turning in rotometers or open-fields, handedness in paw usage, T-maze alternation, and others. Here, we analyzed male Wistar rats in two tests, namely the elevated plus-maze and the T-maze. In these tests, behavioral asymmetries are rather likely to occur, since the animals have to show several types of turns towards the left or right when ambulating through these environments. In a first study using the plus-maze, we provide detailed data on (A) the types of turns which the animals showed when changing their direction within arms (i.e., 180 ° turns), and (B) the types of turns when proceeding from one arm to an adjacent one (i.e., 90 ° turns). With respect to asymmetry, we found moderate biases in favor of the right. On the 1st day of plus-maze testing, there was a trend for more rightward turns within arms. On the 2nd day of testing, there was a trend for turns towards the right when alternating between arms of the plus-maze. In a 2nd study, we asked for asymmetries in the plus-maze in animals, which had been treated acutely with the psychostimulatory amphetamine analogue 3,4-methylene-dioxymethamphetamine (MDMA). Psychostimulants drugs, especially amphetamine, have repeatedly been used before in work on functional asymmetry, since they can enhance or reveal asymmetries in normal rats. MDMA had dose-dependent effects on activity, which affected turns within arms, and turns between arms; however, there was only sparse evidence with respect to asymmetry. Interestingly, and if at all, asymmetry was in favor of the right. Finally, we present data for behavior in the T-maze, where we used a spontaneous test version, that is, the animals could explore the maze but had no task to solve. Asymmetries were measured as turns within the start arm (180 °), and as left- or rightward turns between arms (90 °) at the T-point of the maze. In both measures, we again obtained evidence for asymmetries in favor of the right. This work supports previous studies showing that the T-maze is suitable to analyze behavioral asymmetries in rats. In addition, it provides new evidence with respect to the elevated plus-maze, indicating that this standard tool of anxiety research may also be useful in research on behavioral asymmetries and their underlying brain mechanisms. Behavioral biases in favor of the right, as shown here, have often been reported before, especially with Wistar rats. Such biases should be taken into account, since they can serve as an approach to study brain/behavior relationships, and since they may affect the outcome of physiological manipulations or behavioral trainings.