T-maze Continuous Alternation Task Research Articles

Stereotypy and spontaneous alternation in deer mice and its response to anti-adenosinergic intervention.

Repetitive behavioral phenotypes are a trait of several neuropsychiatric disorders, including obsessive-compulsive disorder (OCD). Such behaviors are typified by complex interactions between cognitive and neurobiological processes which most likely contribute to the suboptimal treatment responses often observed. To this end, exploration of the adenosinergic system may be useful, since adenosine-receptor modulation has previously shown promise to restore control over voluntary behavior and improve cognition in patients presenting with motor repetition. Here, we employed the deer mouse (Peromyscus maniculatus bairdii) model of compulsive-like behavioral persistence, seeking to investigate possible associations between stereotypic motor behavior and cognitive flexibility as measured in the T-maze continuous alternation task (T-CAT). The effect of istradefylline, a selective adenosine A2A receptor antagonist at two doses (10 and 20mgkg-1 day-1 ) on the expression of stereotypy and T-CAT performance in high (H) and non-(N) stereotypical animals, was investigated in comparison to a control intervention (six groups; n=8 or 9 per group). No correlation between H behavior and T-CAT performance was found. However, H but not N animals presented with istradefylline-sensitive spontaneous alternation and stereotypy, in that istradefylline at both doses significantly improved the spontaneous alternation scores and attenuated the stereotypical expression of H animals. Thus, evidence is presented that anti-adenosinergic drug action improves repetitive behavior and spontaneous alternation in stereotypical deer mice, putatively pointing to a shared psychobiological construct underlying naturalistic stereotypy and alterations in cognitive flexibility in deer mice.

Ascorbic acid attenuates cognitive impairment and brain oxidative stress in ovariectomized mice.

Menopause is associated with increased oxidative stress and memory impairment. Based on the antioxidant property of ascorbic acid (AA), It's effect on cognitive function, the serum level of the brain-derived neurotrophic factor (BDNF) and the activity of antioxidant enzymes within the brain in ovariectomized (OVX) mice was investigated. AA (100, 300 and 500 mg/kg), was orally administrated per day in OVX mice for 30 days. Tactile learning and working memory were evaluated by the novel object recognition task and T-maze continuous alternation task, respectively. The levels of serum BDNF were measured and animals' brains were analyzed for the superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity. AA prevented from the deleterious effects of ovariectomy on learning memory (300 and 500 mg/kg) and working memory (100 and 500 mg/kg). The serum BDNF level was also increased in OVX animals treated with AA (100 and 500 mg/kg). Furthermore, AA (500 mg/kg) increased the SOD and GPx activity in the brain of OVX animals. Collectively, the results of the present study suggest that AA might be an appropriate choice in loss or reduction of estradiol for the amelioration of cognitive impairment.

Role of orexin-A in experimental autoimmune encephalomyelitis

The aim of this study was to evaluate the effects of orexin-A (OX-A) on behavioral and pathological parameters and on gene expression of some multiple sclerosis-related peptides in a model of experimental autoimmune encephalomyelitis (EAE). EAE was induced by subcutaneous administration of MOG 35–55. Following immunization, the treatment was initiated by using SB.334867 (orexin-1 receptor antagonist) and/or OX-A. Locomotor activity and exploratory behaviors were monitored using open field and T-maze continuous alternation task (T-CAT) respectively. Pain sensitivity was assessed by hot-plate test. Histopathological assessments were performed by H&E staining. The expression of TGF-β, MBP, MMP-9, IL-12, iNOS and MCP-1 were measured using real-time PCR method in lumbar spinal cord. OX-A administration in EAE mice remarkably attenuated the clinical symptoms, increased latency response in hot plate test, inhibited infiltration of inflammatory cells, up-regulated mRNA expression of TGF-β as well as MBP and down-regulated mRNA expression of iNOS, MMP-9 and IL-12. In contrast SB.334867 administration in EAE mice deteriorated the clinical symptoms, decreased the alternation in T-CAT, increased infiltration of inflammatory cells, down-regulated mRNA expression of TGF-β and MBP and up-regulated mRNA expression of iNOS. Results of this study suggest that the orexinergic system might be involved in pathological development of EAE. These findings suggest orexinergic system as a potential target for treatment of multiple sclerosis.

Inhibition of cGMP-metabolizing PDEs as target for cognitive enhancement

Background Inhibition of specific phosphodiesterases (PDEs) in the brain has gained attention as a potential new approach for memory enhancement. Among those PDEs are PDE2A and PDE9A which are either, in case of PDE2A, dualspecific for cyclic guanosine and cyclic adenosine monophosphate (cGMP and cAMP, respectively) or selective for cGMP, in case of PDE9A. Both PDEs are expressed in cognition relevant regions of the brain, and in these regions, especially cGMP plays an important role as second messenger in neurons related to NMDA receptor signalling facilitating synaptic plasticity and memory formation. Thus, PDE2A and PDE9A inhibitors are hypothesized to improve cognitive function via improving glutamatergic neurotransmission and/or signalling pathways leading to strengthening of synaptic plasticity. In order to characterize mechanistically the effects of PDE2A and PDE9A, selective inhibitors of both PDEs were tested on long-term potentiation (LTP) in rat hippocampal slices, a widely accepted cellular experimental model of synaptic plasticity and memory formation as well as on hippocampal pairedpulse facilitation (PPF), a model to assess presynaptic function. Furthermore, both inhibitors were evaluated regarding enhancement of cyclic nucleotide levels in brain and memory performance in rodent cognition tasks. Results Both, the PDE2A inhibitor PF-999 [1] and the PDE9A inhibitor Bay 73-6691 [2] increased hippocampal LTP, but in contrast to PDE2A inhibition, PDE9A inhibition not only enhances early and late LTP, but even transforms early LTP into late LTP. Regarding effects on hippocampal PPF, only the PDE2A inhibitor but not the PDE9A inhibitor was able to modulate presynaptic function, indicating that PDE2A is localized at the presynaptic side whereas PDE9A might be located at the postsynaptic side. Both inhibitors showed a dose-dependent increase of cGMP levels in mouse hippocampus after oral application, but exhibited no effect on cAMP levels. Memory performance could be improved by both inhibitors in the T-maze continuous alternation task using pharmacologically impaired mice or in the object location task using APP-transgenic Tg2576 mice. Conclusion PDE2A and PDE9A inhibition led to an increase of LTP in rat hippocampal slices. Corroborating previous reports on functional effects of other PDE2A and PDE9A inhibitors, these data demonstrate that inhibition of these PDEs may be an effective way of increasing glutamatergic neurotransmission/ signalling and of strengthening synaptic plasticity. Systemic administration of both compounds led to an increase in cGMP levels in the mouse hippocampus demonstrating functional target engagement, i.e. PDE2A or PDE9A inhibition in the brain. In accordance with recent data on memory enhancing efficacy of other PDE2A or PDE9A inhibitors in rodents, our data further demonstrates that PDE2A and PDE9A inhibition may be a potential approach to pharmacologically improve cognition in CNS disorders. Published: 2 September 2015

Nicotine effects on time perception in rats

a7PAMspreserve spatio-temporal patternsofnAChRactivationand unlike AChE inhibitors, activate only the a7 nAChR subtype, which should provide a better side effect profile. We have performed detailed characterization of BNC375, a Type I positive allosteric modulatorofa7nAChR.ActionofBNC375ona7nAChRs invitrowas examined in GH4C1 cells stably, expressing rat a7 nAChR. Manual patch-clamp recordings were made with a fast-application add-on (Dynaflow Resolve, Cellectricon, Sweden). A concentration– response curve of a7 nAChR potentiation by BNC375 yielded an EC50 1.9mM, nH 1.62, Emax 1572% for peak current and 1.3mM, 1.60, 2616% for areaunder curve (AUC), respectively. In the presence of 2mM ( EC50) BNC375 the concentration–response of acetylcholine exhibited 10 fold leftward shift (EC50 14.5mM vs. 127.7mM, nH 1.66 vs. 1.76) as well as 246% potentiation of a saturating ACh concentration. BNC375 had a minimal effect on the kinetics of potentiated currents and in contrast to a classical Type II a7 PAM PNU-120596, was not able to re-activate a7 nAChRs after desensitization with 0.5–1 mM ACh. The cognition-enhancing properties of BNC375 were evaluated using reversal of scopolamine-induced memory deficits in the mouse T-maze Continuous Alternation Task (T-CAT) and the rat novel object recognitionmodel (NOR). In the T-CAT, BNC375 at doses from 0.003 to 3 mg/kg p.o. dose-dependently reversed the memory-impairing effect of scopolamine from0.03 mg/kg. In the NOR all three doses (0.1, 0.3, 1 mg/kg p.o.) showed a significant reversal of scopolamine-induced deficits. In summary, we show that BNC375 potently enhances a7 nAChRmediated currents in vitro and has a favourable PAM Type I-like kinetic profile. The compound is efficacious in a broad range of agonist concentrations – from subthreshold to saturating. BNC375 demonstrates cognition-enhancing properties in two different in vivo animal models of episodic and working memory with a broad therapeutic window (100 fold).

Cognitive and neural correlates of depression-like behaviour in socially defeated mice: an animal model of depression with cognitive dysfunction

Human depression is associated with cognitive deficits. It is critical to have valid animal models in order to investigate mechanisms and treatment strategies for these associated conditions. The goal of this study was to determine the association of cognitive dysfunction with depression-like behaviour in an animal model of depression and investigate the neural circuits underlying the behaviour. Mice that were exposed to social defeat for 14 d developed depression-like behaviour, i.e. anhedonia and social avoidance as indicated by reduced sucrose preference and decreased social interaction. The assessment of cognitive performance of defeated mice demonstrated impaired working memory in the T-maze continuous alternation task and enhanced fear memory in the contextual and cued fear-conditioning tests. In contrast, reference learning and memory in the Morris water maze test were intact in defeated mice. Neuronal activation following chronic social defeat was investigated by c-fosin-situ hybridization. Defeated mice exhibited preferential neural activity in the prefrontal cortex, cingulate cortex, hippocampal formation, septum, amygdala, and hypothalamic nuclei. Taken together, our results suggest that the chronic social defeat mouse model could serve as a valid animal model to study depression with cognitive impairments. The patterns of neuronal activation provide a neural basis for social defeat-induced changes in behaviour.

SLV330, a cannabinoid CB 1 receptor antagonist, ameliorates deficits in the T-maze, object recognition and Social Recognition Tasks in rodents

Cannabinoid CB 1 receptor (CB 1R) signaling has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the CB 1R antagonist SLV330 (doses ranging from 0.3 to 10 mg/kg, given orally, p.o.) could ameliorate impairments in distinct aspects of cognition using different disruption models in both mice and rats. Effects of SLV330 were tested on working memory deficits in the T-maze Continuous Alternation Task (T-CAT) in mice; episodic memory deficits in the Object Recognition Task (ORT) and Social Recognition Task (SRT) in rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept®, approved for symptomatic treatment of Alzheimer’s disease) and nicotine were used as reference compounds. SLV330 markedly improved aging and scopolamine-induced memory deficits in the T-CAT in mice with a lowest effective dose (LED) of 1 mg/kg p.o., while reversing the cognitive dysfunction induced by the N-methyl- d-aspartate (NMDA) antagonist dizocilpine (MK-801) only at the middle dose of 3 mg/kg. In the ORT, we have found that combined administration of subthreshold doses of SLV330 (1 mg/kg, p.o.) and the AChEI donepezil (0.1 mg/kg, p.o.), that had no discernable effects on performance when given alone, enhanced memory performance in Wistar rats with deficits induced by the muscarinic antagonist scopolamine, suggestive of additive synergistic effects of SLV330 and donepezil on cognitive impairment. Finally, SLV330 was found to have cognition enhancing properties in a time delay paradigm in the SRT at a LED dose of 3 mg/kg (p.o.). In conclusion, the CB 1R antagonist SLV330 was found to clearly improve memory in several preclinical models for cognitive impairment.

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.

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.

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.

The T-maze continuous alternation task for assessing the effects of putative cognition enhancers in the mouse

The T-maze continuous alternation task (T-CAT) assesses the spatial exploratory performance in mice. We performed a series of four experiments in order to establish the T-CAT in mice in our laboratory, to replicate published findings, and to investigate the effects of scopolamine and donepezil. In the first experiment, the task was found to be sensitive to differences between mouse strains, corroborating findings reported by Gerlai. HsdWin:CFW1 mice alternated below chance level, C57BL/6JIco and B6D2F 1/JIco mice performed above chance level, and C57BL/6NTac and 129S6/SvEvTac mice performed at chance level. In the second experiment, donepezil (Aricept, E2020) at the dose of 3 mg/kg p.o. increased the rate of alternations above the level of the vehicle-treated control group in C57BL/6JIco mice, suggesting that this drug can act as cognition enhancer in normal animals. 1 mg/kg scopolamine, administered intraperiteoneally (i.p.), impaired the spontaneous alternation behaviour of the mice. The slightly lower dose of 0.75 mg/kg did not affect alternation performance. The high dose of donepezil (3 mg/kg) was able to antagonise the scopolamine-induced performance deficit. With respect to time to complete a session, the results were inconclusive. In the third experiment, we found that scopolamine, administered i.p. at the dose of 1 mg/kg, or subcutaneously (s.c.) at the dose of 0.1 mg/kg, decreased the rate of spontaneous alternations in C57BL mice in the T-CAT and increased the time to complete a session. Most likely due to adverse side effects induced by the dose of 1 mg/kg scopolamine, 4 out of 10 animals did not complete at least eight free-choice trials during the maximum session duration of 30 min. No such adverse effects were seen after 0.1 mg/kg scopolamine, administered s.c. Finally, we evaluated whether the T-CAT yields replicable results. We conclude that the T-CAT provides a reliable tool for assessing the effects of cognition-modulating treatments in mice.

A new continuous alternation task in T-maze detects hippocampal dysfunction in mice: A strain comparison and lesion study

The mammalian hippocampus has been the focus of several neurobiology studies because of its important behavioral function and because long-term potentiation (LTP) is a prominent feature of this brain region. Converging evidence suggests that hippocampal function is associated with learning multiple relationships of environmental cues. In this paper a novel behavioral test procedure is introduced, a modified T-maze continuous alternation task (T-CAT), that may serve as a simple, automatable, and quick test of hippocampal function in addition to the frequently applied water maze and fear conditioning paradigms. A comparison is made between mice (strain C57BL/6) with ibotenic acid lesioned or vehicle injected hippocampus, two transgenic strains (on CD1 background) overexpressing a calcium binding protein, S100 β, and inbred (C57BL/6, DBA/2, 129/SV and 129/SVEV) and outbred (CD1) strains of mice. This study shows that hippocampal lesioning led to a significant impairment in T-CAT. Furthermore, overexpression of S100 β, which impairs hippocampal LTP, also led to an impairment demonstrating that T-CAT is sensitive to detect hippocampal dysfunction. Analysis of the mouse strains revealed that C57BL/6 and CD1 mice performed well in T-CAT, whereas 129/SV, 129/SVEV and DBA/2 were significantly impaired, a finding that underscores the importance of strain differences in pharmacological or single gene manipulation studies of hippocampal function in mice.