Radial Arm Maze Task Research Articles

Lack of change in CA1 dendritic spine density or clustering in rats following training on a radial-arm maze task

Background: Neuronal plasticity is thought to underlie learning and memory formation. The density of dendritic spines in the CA1 region of the hippocampus has been repeatedly linked to mnemonic processes. Both the number and spatial location of the spines, in terms of proximity to nearest neighbour, have been implicated in memory formation. To examine how spatial training impacts synaptic structure in the hippocampus, Lister-Hooded rats were trained on a hippocampal-dependent spatial task in the radial-arm maze. Methods: One group of rats were trained on a hippocampal-dependent spatial task in the radial arm maze. Two further control groups were included: a yoked group which received the same sensorimotor stimulation in the radial-maze but without a memory load, and home-cage controls. At the end of behavioural training, the brains underwent Golgi staining. Spines on CA1 pyramidal neuron dendrites were imaged and quantitatively assessed to provide measures of density and distance from nearest neighbour. Results: There was no difference across behavioural groups either in terms of spine density or in the clustering of dendritic spines. Conclusions: Spatial learning is not always accompanied by changes in either the density or clustering of dendritic spines on the basal arbour of CA1 pyramidal neurons when assessed using Golgi imaging.

Lack of change in CA1 dendritic spine density or clustering in rats following training on a radial-arm maze task.

Background:Neuronal plasticity is thought to underlie learning and memory formation. The density of dendritic spines in the CA1 region of the hippocampus has been repeatedly linked to mnemonic processes. Both the number and spatial location of the spines, in terms of proximity to nearest neighbour, have been implicated in memory formation. To examine how spatial training impacts synaptic structure in the hippocampus, Lister-Hooded rats were trained on a hippocampal-dependent spatial task in the radial-arm maze. Methods:One group of rats were trained on a hippocampal-dependent spatial task in the radial arm maze. Two further control groups were included: a yoked group which received the same sensorimotor stimulation in the radial-maze but without a memory load, and home-cage controls. At the end of behavioural training, the brains underwent Golgi staining. Spines on CA1 pyramidal neuron dendrites were imaged and quantitatively assessed to provide measures of density and distance from nearest neighbour. Results: There was no difference across behavioural groups either in terms of spine density or in the clustering of dendritic spines. Conclusions:Spatial learning is not always accompanied by changes in either the density or clustering of dendritic spines on the basal arbour of CA1 pyramidal neurons when assessed using Golgi imaging.

A long-term cyclic plus tonic regimen of 17β-estradiol improves the ability to handle a high spatial working memory load in ovariectomized middle-aged female rats

The influence of estrogens on modifying cognition has been extensively studied, revealing that a wide array of factors can significantly impact cognition, including, but not limited to, subject age, estrogen exposure duration, administration mode, estrogen formulation, stress history, and progestogen presence. Less known is whether long-term, extended exposure to estrogens would benefit or otherwise impact cognition. The present study examined the effects of 17β-estradiol (E2) exposure for seven months, beginning in late adulthood and continuing into middle age, using a regimen of cyclic exposure (bi-monthly subcutaneous injection of 10 μg E2), or Cyclic+Tonic exposure (bi-monthly subcutaneous injection of 10 μg E2 + Silastic capsules of E2) in ovariectomized female Fischer-344-CDF rats. Subjects were tested on a battery of learning and memory tasks. All groups learned the water radial-arm maze (WRAM) and Morris water maze tasks in a similar fashion, regardless of hormone treatment regimen. In the asymptotic phase of the WRAM, rats administered a Cyclic+Tonic E2 regimen showed enhanced performance when working memory was taxed compared to Vehicle and Cyclic E2 groups. Assessment of spatial memory on object placement and object recognition was not possible due to insufficient exploration of objects; however, the Cyclic+Tonic group showed increased total time spent exploring all objects compared to Vehicle-treated animals. Overall, these data demonstrate that long-term Cyclic+Tonic E2 exposure can result in some long-term cognitive benefits, at least in the spatial working memory domain, in a surgically menopausal rat model.

NADPH oxidase 2 as a potential therapeutic target for protection against cognitive deficits following systemic inflammation in mice

BackgroundResearch indicates that sepsis increases the risk of developing cognitive impairment. After systemic inflammation, a corresponding activation of microglia is rapidly induced in the brain, and multiple neurotoxic factors, including inflammatory mediators (e.g., cytokines) and reactive oxygen species (e.g., superoxide), are also released that contribute to neuronal injury. NADPH oxidase (NOX) enzymes play a vital role in microglial activation through the generation of superoxide anions. We hypothesized that NOX isoforms, particularly NOX2, could exhibit remarkable abilities in developing cognitive deficits induced by systemic inflammation. MethodsMice with deficits of NOX2 organizer p47phox (p47phox−/−) and wild-type (WT) mice treated with the NOX inhibitor diphenyleneiodonium (DPI) were used in this study. Intraperitoneal lipopolysaccharide (LPS) injection was used to induce systemic inflammation. Spatial learning and memory were compared among treatment groups using the radial arm maze task. Brain tissues were collected for evaluating the transcript levels of proinflammatory cytokines, whereas immunofluorescence staining and immunoblotting were conducted to determine the percentage of activated glia (microglia and astroglia) and damaged neurons and the expression of synaptic proteins and BDNF. ResultsCognitive impairment induced by systemic inflammation was significantly attenuated in the p47phox−/− mice compared to that in the WT mice. The p47phox−/− mice exhibited reduced microglial and astroglial activation and neuronal damage and attenuated the induction of multiple proinflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and CCL2. Similar to that observed in the p47phox−/− mice, the administration of DPI significantly attenuated the cognitive impairment, reduced the glial activation and brain cytokine concentrations, and restored the expression of postsynaptic proteins (PSD-95) and BDNF in neurons and astrocytes, compared to those in the vehicle-treated controls within 10 days after LPS injection. ConclusionsThis study clearly demonstrates that NOX2 contributes to glial activation with subsequent reduction in the expression of BDNF, synaptic dysfunction, and cognitive deficits after systemic inflammation in an LPS-injected mouse model. Our results provide evidence that NOX2 might be a promising pharmacological target that could be used to protect against synaptic dysregulation and cognitive impairment following systemic inflammation.

Cognitive performance of the MAM-E17 schizophrenia model rats in different age-periods

Cognitive disturbances are among the most important features of schizophrenia, and have a significant role in the outcome of the disease. However, the treatment of cognitive symptoms is poorly effective. In order to develop new therapeutic opportunities, the MAM-E17 rat model of schizophrenia can be an appropriate implement.In the present study we investigated several cognitive capabilities of MAM-treated rats using radial arm maze (RAM) task, which corresponds to the recent research directives. Because of the diachronic appearance of schizophrenia symptoms and the early appearance of cognitive deficiencies, we carried out our experiments in three different age-periods of rats, i.e. in prepuberty, late puberty and adulthood.The performance of MAM-E17 rats was similar to control rats in the acquisition phase of RAM task, except for puberty. However, after rearrangement of reward positions (in the reverse paradigm) the number of errors of MAM-treated rats was higher in each age-period. In the reverse paradigm MAM-treated groups visited more frequently those non-rewarding arms, which were previously rewarding.Our results suggest that working memory of MAM-E17 rats is impaired. This deficit depends on the difficulty of the task and on the age-period. MAM-E17 rats seem to be more sensitive in puberty in comparison to controls. Diminished behavioral flexibility was shown as well. These behavioral results observed in MAM-E17 rats were similar to those of cognitive deficiencies in schizophrenia patients. Therefore, MAM-E17 model can be a useful implement for further research aiming to improve cognition in schizophrenia.

Anticholinesterase and Antioxidant Potential of Hydromethanolic Extract of Ziziphus mucronata (Rhamnaceae) Leaves on Scopolamine-Induced Memory and Cognitive Dysfunctions in Mice.

Ziziphus mucronata Willd, also known as “buffalo thorn,” belongs to the family Rhamnaceae. Its bark and leaves are used in folk medicine for the treatment of various deficiencies related to nociception, inflammation, mood, and depression. Still, there is a lack of scientific data regarding its potential effect on learning and memory process. The present study was designed to investigate the neuroprotective potential of Ziziphus mucronata (ZM) on learning and memory impairment in a scopolamine-induced model of dementia in mice. The phytochemical analysis revealed five cyclopeptide alkaloids (sanjoinines) in the extract from Ziziphus Mucronata leaves using LC-HRMS, and the structural characterization of these compounds was determined via MS/MS. Alzheimer-type amnesia was induced by an intraperitoneal injection of scopolamine (1 mg/kg) to mice for 7 consecutive days. ZM (150 mg/kg, 300 mg/kg, and 600 mg/kg) and piracetam (150 mg/kg) were orally administrated to mice daily for a period of 14 days. Memory-related behavioural parameters were evaluated using the radial arm maze task for 7 days, Y-maze, and novel object recognition task. At the end of protocol schedule, animals were sacrificed, and the levels of acetylcholinesterase, malondialdehyde, catalase, and superoxide dismutase were determined in brain homogenates. Histological studies of the hippocampus were subsequently performed. The long-term scopolamine-injected group decreased the spontaneous alternation (Y-maze), the discrimination index, and the time taken to explore the new object (novel object recognition task). These effects were significantly reversed by ZM at all the doses tested. In the radial arm maze task, ZM (300 and 600 mg/kg) significantly decreased the working and reference memory errors when compared with the demented group. Scopolamine-mediated changes in AChE activity were also attenuated by ZM in mice. In addition, extract-treated groups showed a significant increase in the level of CAT and SOD activity and decreased levels of MDA in the mice brains, as compared with the control group. The present study suggests that ZM could have an important role in neuroprotection on this scopolamine-induced model of Alzheimer-type dementia.

Memory-enhancing Properties of Hypericum scabrum Essential Oil in a Rat Model of Dementia

Hypericum species are known to be used in traditional therapies. H. scabrum L. is one of the Hypericum species distributed in Turkey. In this study, we evaluated the effects of Hypericum scabrum essential oil inhalation on spatial memory in scopolamine-induced amnesic rats. The essential oil was characterized by GC-FID and GC-MS system. Male wistar rats were divided into 6 groups: control; scopolamine-alone treated; diazepam-treated (positive control); tramadol-treated (positive control); scopolamine with Hypericum scabrum essential oil 1%-treated; and scopolamine with Hypericum scabrum essential oil 3%-treated group. All rats were tested behaviorally to evaluate spatial memory peformances in Y-maze task and radial-arm maze task. The most abundant component of the essential oil was identified as α-pinene (51.3%). Hypericum scabrum essential oil application significantly improved spatial memory as compared to scopolamine-alone treated rats as evidenced by increases in spontaneous alternation behavior in Y-maze task and decreases in the number of working memory errors and reference memory errors in the radial-arm maze task in this study. Hypericum scabrum essential oil inhalation could be used as a complementary therapy to reduce memory impairments in the patients with dementia and related diseases.

Sex-specific associations between exposure to multiple metals and visuospatial memory skills in adolescents

OPS 40: Metals: neurological effects, Room 412, Floor 4, August 28, 2019, 10:30 AM - 12:00 PM Background/Aim: In rodents, visuospatial memory deficits following metal exposure have been measured with the radial arm maze (RAM) task. In humans, the virtual radial arm maze (VRAM), is the computerized analogue developed to assess visuospatial memory in children. The goal of this study was to examine associations between exposure to metals and performance on the VRAM among adolecents that can be utilized to plan future translational studies using RAM. Methods: Manganese (Mn), lead (Pb), chromium (Cr) and copper (Cu) were measured in blood, urine, hair, nails and saliva of 184 participants (84 girls; 11-15 years of age) enrolled in the PHIME study (Public Health Impact of Manganese Exposure) who resided near a ferroalloy plant in Italy. VRAM performance was assessed as the time required to complete the task. Using generalized weighted quartile sum (gWQS) regression, we investigated associations between a mixture of four metals in all matrices and VRAM performance, controlling for covariates. We estimated metal mixture weights and effects for the whole cohort and for each sex individually. Results: A higher metal mixture index was associated with poorer VRAM performance (β: 0.28; p=0.02). Upon stratification, this association was observed in girls (β: 0.65; p<0.001) and not boys. Urine Mn and blood Cu contributed 27% and 13% respectively to the overall mixture effect. Mn in all 5 matrices combined contributed to 54% to the overall mixture effect. In post-hoc analyses, no associations were observed between exposure to each metal separately and VRAM performance. Conclusions: Exposure to this metal mixture during adolescence may disrupt visuospatial skill acquisition in females. Our results can inform translational research that may address underlying neurotoxic mechanisms and guide additional studies on which metals to focus in future research.

Dorsal hippocampus not always necessary in a radial arm maze delayed win-shift task.

Spatial working memory is important for foraging and navigating the environment. However, its neural underpinnings remain poorly understood. The hippocampus, known for its spatial coding and involvement in spatial memory, is widely understood to be necessary for spatial working memory when retention intervals increase beyond seconds into minutes. Here, we describe new evidence that the dorsal hippocampus is not always necessary for spatial working memory for retention intervals of 8 min. Rats were trained to perform a delayed spatial win shift radial arm maze task with an 8-min delay between study and test phases. We then tested whether bilateral inactivation of the dorsal hippocampus between the study and test phases impaired behavioral performance at test. Inactivation was achieved through a bilateral infusion of lidocaine. Performance following lidocaine was compared to control trials, in which, sterile phosphate buffered saline (PBS) was infused. Test performance did not differ between the lidocaine and PBS conditions, remaining high in each. To explore the possibility that this insensitivity to inactivation was a result of overtraining, a second cohort of animals received substantially less training prior to the infusions. In this second cohort, lidocaine infusions did significantly impair task performance. These data indicate that successful performance of a spatial win-shift task on the 8-arm maze need not always be hippocampally dependent.

Safranal, an active ingredient of saffron, attenuates cognitive deficits in amyloid β-induced rat model of Alzheimer's disease: underlying mechanisms.

Alzheimer's disease (AD) is the most prevalent neurodegenerative amyloid disorder with progressive deterioration of cognitive and memory skills. Despite many efforts, no decisive therapy yet exists for AD. Safranal is the active constituent of saffron essential oil with antioxidant, anti-inflammatory, and anti-apoptotic properties. In this study, the possible beneficial effect of safranal on cognitive deficits was evaluated in a rat model of AD induced by intrahippocampal amyloid beta (Aβ1-40). Safranal was daily given p.o. (0.025, 0.1, and 0.2ml/kg) post-surgery for 1week and finally learning and memory were evaluated in addition to assessment of the involvement of oxidative stress, inflammation, and apoptosis. Findings showed that safranal treatment of amyloid β-microinjected rats dose-dependently improved cognition in Y-maze, novel-object discrimination, passive avoidance, and 8-arm radial arm maze tasks. Besides, safranal attenuated hippocampal level of malondialdehyde (MDA), reactive oxygen species (ROS), protein carbonyl, interleukin 1β (IL-1β), interleukin 6 (IL-6), tumor necrosis factor α (TNFα), nuclear factor-kappa B (NF-kB), apoptotic biomarkers including caspase 3 and DNA fragmentation, glial fibrillary acidic protein (GFAP), myeloperoxidase (MPO), and acetylcholinesterase (AChE) activity and improved superoxide dismutase (SOD) activity and mitochondrial membrane potential (MMP) with no significant effect on nitrite, catalase activity, and glutathione (GSH). Furthermore, safranal prevented CA1 neuronal loss due to amyloid β1-40. In summary, safranal treatment of intrahippocampal amyloid beta1-40-microinjected rats could prevent learning and memory decline via neuronal protection and at a molecular level through amelioration of apoptosis, oxidative stress, inflammation, cholinesterase activity, neutrophil infiltration, and also by preservation of mitochondrial integrity.

Theobromine Improves Working Memory by Activating the CaMKII/CREB/BDNF Pathway in Rats.

Theobromine (TB) is a primary methylxanthine found in cacao beans. cAMP-response element-binding protein (CREB) is a transcription factor, which is involved in different brain processes that bring about cellular changes in response to discrete sets of instructions, including the induction of brain-derived neurotropic factor (BDNF). Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been strongly implicated in the memory formation of different species as a key regulator of gene expression. Here we investigated whether TB acts on the CaMKII/CREB/BDNF pathway in a way that might improve the cognitive and learning function in rats. Male Wistar rats (5 weeks old) were divided into two groups. For 73 days, the control rats (CN rats) were fed a normal diet, while the TB-fed rats (TB rats) received the same food, but with a 0.05% TB supplement. To assess the effects of TB on cognitive and learning ability in rats: The radial arm maze task, novel object recognition test, and Y-maze test were used. Then, the brain was removed and the medial prefrontal cortex (mPFC) was isolated for Western Blot, real-time PCR and enzyme-linked immunosorbent assay. Phosphorylated CaMKII (p-CaMKII), phosphorylated CREB (p-CREB), and BDNF level in the mPFC were measured. In all the behavior tests, working memory seemed to be improved by TB ingestion. In addition, p-CaMKII and p-CREB levels were significantly elevated in the mPFC of TB rats in comparison to those of CN rats. We also found that cortical BDNF protein and mRNA levels in TB rats were significantly greater than those in CN rats. These results suggest that orally supplemented TB upregulates the CaMKII/CREB/BDNF pathway in the mPFC, which may then improve working memory in rats.

Cocaine conditioning induces persisting changes in ventral hippocampus synaptic transmission, long-term potentiation, and radial arm maze performance in the mouse

The effects of drugs of abuse, such as cocaine, on learning and memory processes are thought to contribute to drug craving and relapse susceptibility. Using an Escalating (Esc) or Double Escalating (2x Esc) cocaine i.p. dosing schedule with the conditioned place preference (CPP) model we investigated the persisting effects of cocaine conditioning on long-term potentiation (LTP) in the CA1 region of the ventral hippocampus (vH), and spatial working memory in a radial arm maze (RAM) task. Interestingly, vH LTP was increased 4 weeks after the last injection day in animals that received only saline vehicle injections. A single pre-treatment with the kappa-opioid receptor antagonist, norbinaltorphimine (norBNI), blocks this stress-like effect of the conditioning protocol on vH LTP without altering the behavioral responses of the animals to cocaine. In animals that received the 2x Esc/norBNI cocaine conditioning, vH LTP was significantly decreased compared to those that received saline vehicle 4 weeks after the last dose. These 2x Esc/norBNI treated animals also exhibited a significant leftward shift in the stimulus-response curve of the baseline field excitatory postsynaptic potential (fEPSP) measurements. A separate group of 2x Esc/norBNI displayed an impaired ability to learn a spatial working memory RAM task compared to saline-conditioned mice following a similar 4 week abstinence period. Together, these results demonstrate that cocaine-induced alterations in synaptic transmission and LTP in the vH are associated with persisting drug-induced impairments in learning and memory performance.

Time-dependent effect of oligomeric amyloid-β (1–42)-induced hippocampal neurodegeneration in rat model of Alzheimer’s disease

ABSTRACTObjective: Alzheimer's disease (AD) is characterized with an abnormal deposition of insoluble amyloid-beta (Aβ) peptide plaques, tangles formation and synaptic dysfunction. These result in impaired functioning of neuronal circuits and alter the behavioral response owing to activation of neurotransmitter receptors. Recently, it has been implicated that Aβ influences N-methyl d-aspartate (NMDA) receptor activation in AD; however, the molecular mechanism underlying remains unclear. Thus, emerged specific aim to study the time-course effect of oligomeric Aβ(1–42) (oAβ1–42) on the mRNA expression of genes encoding NMDA and acetylcholine receptors in the rat model of AD.Methods: Aggregated forms of synthetic Aβ peptides were injected bilaterally into the intrahippocampal region of rat brain using stereotaxic surgery. Behavioral analysis was performed using eight-arm Radial Arm Maze task at the end of experimental period. Euthanized rat brain hippocampal tissue was used to study the mRNA expression of glutamatergic and cholinergic receptor using semiquantitative reverse transcription–polymerase chain reaction.Results: oAβ1–42 decreased the gene expression level of α7-nicotinic acetylcholine receptor and increased the mRNA expression of NMDA receptor 2A, and -2B subunits. In particular, oAβ1–42 aggregates increased the retention time and altered the behavioral response in rats after 15 days of injection. Further, amyloid-β1–42 are highly expressed in 15 days after postinjection in hippocampus of adult rats.Conclusion: Acute exposure of oAβ1–42 modulated differential gene expression of glutamatergic and cholinergic receptors in hippocampus of adult rats and is duration dependent reflecting changes in hippocampal circuitry system underlying learning and memory impairments.Abbreviations: AD: Alzheimer’s disease, Aβ: amyloid-β; oAβ1–42: oligomeric amyloid-β 1–42 full length peptide; CAM: calmodulin; CNS: central nervous system; CR: Congo red; DG: dentate gyrus; EC: entorhinal cortex; HFIP: 1,1,1,3,3,3-hexafluoro-2-propanol; IBO: ibotenic acid; NMDA: N-methyl d-aspartate; NMDAR: N-methyl d-aspartate receptor; NR2A: N-methyl d-aspartate receptor 2A; NR2B: N-methyl d-aspartate receptor 2B; ACh: acetylcholine; α7-nAChR: α7-nicotinic acetylcholine receptor; PBS: phosphate buffered saline; RAM: Radial Arm Maze; ThT: thioflavin T.

Memory Enhancing, Anxiolytic and Antidepressant Effects of Achillea biebersteinii (Asteraceae) Essential Oil on Scopolamine-Induced Rats

The objective of this study was to evaluate the effects of inhaled Achillea biebersteinii Afan. (Asteraceae) essential oil on memory, anxiety and depression in scopolamine-induced amnesic rats. Six groups of adult female Wistar rats (3 months old) were used. These are, control group, Scopolamine - alone- treated group, diazepam alone-treated group, tramadol alone treated group, Sco + A. biebersteinii essential oil 1 % administrated group and Sco + A. biebersteinii essential oil 3 % administrated groups. Memory performances were assessed by Y-maze task and radial-arm maze task. Anxiety and depressive-like behavior were evaluated by elevated plus-maze and forced swimming tasks, respectively. The scopolamine-only administrated group showed impaired spatial memory as evidenced by decrease of the spontaneous alternation percentage in Y- maze test, and increase of the number of working and reference memory errors in the radial arm-maze test. In addition, scopolamine-only administrated group displayed increased anxiety and depressive-like behavior as evidenced by decrease of the exploratory activity, the percentage of the time spent and the number of entries in the open arm within elevated plus-maze test and decrease of swimming time and increase of immobility time within forced swimming test. Achillea biebersteinii essential oil significantly improved memory formation, and reduced anxiety and depression-like behavior in scopolamine-induced rats as compared to scopolamine-alone induced rats. The essential oil of this plant could be a good candidate for complementary therapy against neurological diseases like Alzheimer’s disease.

Inositol 1,4,5-trisphosphate 3-kinase A overexpressed in mouse forebrain modulates synaptic transmission and mGluR-LTD of CA1 pyramidal neurons.

Inositol 1,4,5-trisphosphate 3-kinase A (IP3K-A) regulates the level of the inositol polyphosphates, inositol trisphosphate (IP3) and inositol tetrakisphosphate to modulate cellular signaling and intracellular calcium homeostasis in the central nervous system. IP3K-A binds to F-actin in an activity-dependent manner and accumulates in dendritic spines, where it is involved in the regulation of synaptic plasticity. IP3K-A knockout mice exhibit deficits in some forms of hippocampus-dependent learning and synaptic plasticity, such as long-term potentiation in the dentate gyrus synapses of the hippocampus. In the present study, to further elucidate the role of IP3K-A in the brain, we developed a transgenic (Tg) mouse line in which IP3K-A is conditionally overexpressed approximately 3-fold in the excitatory neurons of forebrain regions, including the hippocampus. The Tg mice showed an increase in both presynaptic release probability of evoked responses, along with bigger synaptic vesicle pools, and miniature excitatory postsynaptic current amplitude, although the spine density or the expression levels of the postsynaptic density-related proteins NR2B, synaptotagmin 1, and PSD-95 were not affected. Hippocampal-dependent learning and memory tasks, including novel object recognition and radial arm maze tasks, were partially impaired in Tg mice. Furthermore, (R,S)-3,5-dihydroxyphenylglycine-induced metabotropic glutamate receptor long-term depression was inhibited in Tg mice and this inhibition was dependent on protein kinase C but not on the IP3 receptor. Long-term potentiation and depression dependent on N-methyl-d-aspartate receptor were marginally affected in Tg mice. In summary, this study shows that overexpressed IP3K-A plays a role in some forms of hippocampus-dependent learning and memory tasks as well as in synaptic transmission and plasticity by regulating both presynaptic and postsynaptic functions.

Contrasting effects of pre-training on acquisition of operant and radial armmazetasks in rats.

Performing multiple tasks either simultaneously, in rapid alternation or in succession, is routine in daily life. Further, testing rodents in a battery of tests is common both in drug discovery and behavioral phenotyping research. However, learning of new tasks can be influenced by prior experience(s). There has been some research on 'switching cost' involved in the transition from one behavior to another. However, there has been no specific assessment of the effect of learning an operant paradigm on performance in a spatial memory task and vice versa. Accordingly, we evaluated task switching between two forms of learning paradigms, operant conditioning and radial arm maze (RAM) tasks. In experiment 1, rats were trained for operant conditioning with food reward followed by a partially baited RAM task. In experiment 2, rats were trained first on a RAM task followed by operant learning. Pre-training on the operant task, impaired the acquisition of the RAM. On the contrary, pre-training on the RAM enhanced operant performance. Our study reveals significant effects of the test order on task-switching in rats. This knowledge can be useful when framing test sequences in test batteries for drug discovery research and screening genetically modified mice.

Environmental enrichment improved cognitive deficits more in peri-adolescent than in adult rats after postnatal monosodium glutamate treatment.

Exposure to enriched environment (EE) is known to promote sensory, cognitive, and motor stimulation with intensified levels of novelty and complexity. In this study, we investigated the positive regulatory effect of short-term exposure to EE on establishing functional recovery in monosodium glutamate (MSG)-induced obese rats. Unless treated, MSG rats exhibited peripheral insulin resistance, cognitive deficits, and a reduction in the total hippocampal volume with decreased neuron count in the DG, CA3, and CA1 subfields. These MSG rats were exposed to short-term EE for 15 days for a period of 6h/day, beginning either at 45 or at 75 days of age. EE exposure has improved insulin sensitivity, yielded a significant increase in total hippocampal volume along with increase in neuron number in the CA1 subfield of the hippocampus in both age groups. However, as assessed by radial arm maze task, which relies upon the positive reinforcement to test spatial memory, and the Barnes maze task, which utilizes an aversive learning strategy, a complete recovery of cognitive function could be achieved in 2-month-old rats only and not among 3-month-old rats, thus highlighting the importance of critical window period for EE interventions in restoring the memory functions. These results suggest the therapeutic potential of EE paradigm in prevention of cognitive disorders.

Eicosanoyl-5-hydroxytryptamide (EHT) prevents Alzheimer's disease-related cognitive and electrophysiological impairments in mice exposed to elevated concentrations of oligomeric beta-amyloid.

Soluble forms of oligomeric beta-amyloid (Aβ) are thought to play a central role in Alzheimer’s disease (AD). Transgenic manipulation of methylation of the serine/threonine protein phosphatase, PP2A, was recently shown to alter the sensitivity of mice to AD-related impairments resulting from acute exposure to elevated levels of Aβ. In addition, eicosanoyl-5-hydroxytryptamide (EHT), a naturally occurring component from coffee beans that modulates PP2A methylation, was shown to confer therapeutic benefits in rodent models of AD and Parkinson’s disease. Here, we tested the hypothesis that EHT protects animals from the pathological effects of exposure to elevated levels of soluble oligomeric Aβ. We treated mice with EHT-containing food at two different doses and assessed the sensitivity of these animals to Aβ-induced behavioral and electrophysiological impairments. We found that EHT administration protected animals from Aβ-induced cognitive impairments in both a radial-arm water maze and contextual fear conditioning task. We also found that both chronic and acute EHT administration prevented Aβ-induced impairments in long-term potentiation. These data add to the accumulating evidence suggesting that interventions with pharmacological agents, such as EHT, that target PP2A activity may be therapeutically beneficial for AD and other neurological conditions.

Lesions within the head direction system reduce retrosplenial c-fos expression but do not impair performance on a radial-arm maze task

The lateral mammillary nuclei are a central structure within the head direction system yet there is still relatively little known about how these nuclei contribute to spatial performance. In the present study, rats with selective neurotoxic lesions of the lateral mammillary nuclei were tested on a working memory task in a radial-arm maze. This task requires animals to distinguish between eight radially-oriented arms and remember which arms they have entered within a session. Even though it might have been predicted that this task would heavily tax the head direction system, the lesion rats performed equivalently to their surgical controls on this task; no deficit emerged even when the task was made more difficult by rotating the maze mid-way through testing in order to reduce reliance on intramaze cues. Rats were subsequently tested in the dark to increase the use of internally generated direction cues but the lesion rats remained unimpaired. In contrast, the lateral mammillary nuclei lesions were found to decrease retrosplenial c-Fos levels. These results would suggest that the head direction system is not required for the acquisition of the standard radial-arm maze task. It would also suggest that small decreases in retrosplenial c-Fos are not sufficient to produce behavioural impairments.

Chronic traumatic stress impairs memory in mice: Potential roles of acetylcholine, neuroinflammation and corticotropin releasing factor expression in the hippocampus

Chronic stress in humans can result in multiple adverse psychiatric and neurobiological outcomes, including memory deficits. These adverse outcomes can be more severe if each episode of stress is very traumatic. When compared to acute or short term stress relatively little is known about the effects of chronic traumatic stress on memory and molecular changes in hippocampus, a brain area involved in memory processing. Here we studied the effects of chronic traumatic stress in mice by exposing them to adult Long Evan rats for 28 consecutive days and subsequently analyzing behavioral outcomes and the changes in the hippocampus. Results show that stressed mice developed memory deficits when assayed with radial arm maze tasks. However, chronic traumatic stress did not induce anxiety, locomotor hyperactivity or anhedonia. In the hippocampus of stressed mice interleukin-1β protein expression was increased along with decreased corticotropin releasing hormone (CRH) gene expression. Furthermore, there was a reduction in acetylcholine levels in the hippocampus of stressed mice. There were no changes in brain derived neurotrophic factor (BDNF) or nerve growth factor (NGF) levels in the hippocampus of stressed mice. Gene expression of immediate early genes (Zif268, Arc, C-Fos) as well as glucocorticoid and mineralocorticoid receptors were also not affected by chronic stress. These data demonstrate that chronic traumatic stress followed by a recovery period might lead to development of resilience resulting in the development of selected, most vulnerable behavioral alterations and molecular changes in the hippocampus.