Radial Maze Paradigm Research Articles

Carotid artery disease in post-stroke survivors and effects of enriched environment on stroke pathology in a mouse model of carotid artery stenosis.

Carotid artery disease (CAD) is an important risk factor for stroke. We first evaluated CAD and stroke pathology in elderly post-stroke survivors. To simulate CAD, we assessed long-term consequences of bilateral common carotid artery stenosis (BCAS) in mice and exposed them to environmental enrichment (EE). Histopathological methods were used to determine degrees of CAD (% area stenosis), brain infarct types, sizes and distribution in post-stroke survivors and BCAS mice. Adult male C57BL/6J mice after BCAS or sham surgery were randomly assigned to standard housing (Std) or limited (3h) or full-time (Full) exposure to EE per day for 12weeks. High frequencies of moderate carotid artery stenosis (51-75%) were evident in post-stroke survivors whereas those with severe CAD (>75% stenosis) exhibited greater numbers of cortical rather than subcortical infarcts and, were at higher risk of developing dementia. BCAS in mice reduced cerebral blood flow by 52% (P<0.01) and thickened carotid artery walls, regardless of EE duration. Remarkably, the total and cortical infarcts declined by >50% in BCAS mice exposed to EE compared with BCAS-Std (P<0.01). Frontal lobe and cortical strokes were associated with worsening working memory tested in a radial maze paradigm. Proteomic analysis revealed EE, both BCAS-3h and BCAS-Full attenuated coagulation cascade factors including fibrinogen and von Willebrand factor, markers of blood-brain barrier damage. Small cortical and subcortical infarcts were evident in both post-stroke survivors with CAD and BCAS mice. Experimental evidence suggested that moderate exposure to EE is sufficient to reduce subsequent stroke lesions.

Differential changes in hippocampal CaMKII and GluA1 activity after memory training involving different levels of adaptive forgetting.

Phosphorylation of CaMKII and AMPA receptor GluA1 subunit has been shown to play a major role in hippocampal-dependent long-term/reference memory (RM) and in the expression of long-term synaptic potentiation (LTP). In contrast, it has been proposed that dephosphorylation of these proteins could be involved in the opposite phenomenon of hippocampal long-term synaptic depression (LTD) and in adaptive forgetting. Adaptive forgetting allows interfering old memories to be forgotten to give new ones the opportunity to be stored in memory, and in particular in short-term/working memory (WM) that was shown to be very sensitive to proactive interference. To determine the role of CaMKII and GluA1 in adaptive forgetting, we adopted a comparative approach to assess the relative quantity and phosphorylation state of these proteins in the brain of rats trained in one of three radial maze paradigms: a RM task, a WM task involving a high level of adaptive forgetting, or a WM involving a low level of adaptive forgetting. Surprisingly, Western blot analyses revealed that training in a WM task involving a high level of adaptive forgetting specifically increased the expression of AMPA receptor GluA1 subunit and the activity of CaMKII in the dentate gyrus. These results highlight that WM with proactive interference involves mechanisms of synaptic plasticity selectively in the dentate gyrus.

Influence of age on cognition and scopolamine induced memory impairment in rats measured in the radial maze paradigm

The influence of age on (1) cognition and (2) scopolamine (CAS 51-34-3) induced memory impairment in female rats was measured in the radial maze paradigm (RAM). (1) First training trials were done with 3 and 12 months old rats. Rats were trained to find all eight food baits in the RAM without errors and within 1 min. Both 3- and 12-month old rats need about 15 trials for the first-time learning of the RAM task. After intervals of 3 6 months, respectively, initially young rats were re-trained with an age of 6 and 12 months. Surprisingly, re-trained rats successfully completed the maze runs already after one re-training trial. Thus the phenomenon of preserved spatial memory was approved for female rats. (2) Memory impairment by scopolamine in the RAM was tested for the time in rats with an age of 3 months. first rats with thesame After a control run,the rats received an i.p. injection of either scopolamine hydrochloride (0.05 mg/100 g b. wt.) or saline vehicle. The effect of scopolamine on working memory was measured 20 min after administration. Training procedure and scopolamine administration were repeated at an age of 6, 12, 18, and 24 months in the same manner. The cognition impairment after scopolamine (number of errors: control: <1; scopolamine: 5-6) remains constant between 3 and 24 months of age. The only significant difference was the increase in run time in rats older than 18 months caused by degenerative changes developing with age.

Investigation into the in vivo effects of five novel tacrine/ferulic acid and β-carboline derivatives on scopolamine-induced cognitive impairment in rats using radial maze paradigm

Two tacrine-ferulic acid hybrids (1 A, 1 B) and three beta-carboline derivatives (BCs; 2A, 2B, 2C) were tested in vivo on 3-month-old female rats as multi-potent anti-Alzheimer drug candidates. In vitro, the two tacrine-ferulic acid hybrids show higher acetylcholinesterase (AChE) inhibitory activity and comparable butyrylcholinesterase (BChE) inhibitory activity compared to tacrine (CAS 1684-40-8). However, in vivo both substances have no beneficial effect on scopolamine (CAS 51-34-3) induced cognition impairment. On the contrary, 1B even worsen the scopolamine induced cognition impairment. The beta-carboline derivatives 2A, 2B, and 2 C, the inhibitory potency of which at AChE reaching tacrine activity does not antagonize scopolamine induced impairment of cognition in rats measured in radial maze paradigm. Compounds 2A and 1B might act as positive allosteric modulators of scopolamine action at the muscarinic acetylcholine receptors. On the basis of these results it can be concluded that both ferulic acid- (CAS 537-98-4) and BC-derivatives are not qualified as cognition improving drugs and further studies in this field should be focussed on other pharmaceutical leads to find effective anti-Alzheimer drugs.

Evidence for a virtual human analog of a rodent relational memory task: A study of aging and fMRI in young adults

A radial maze concurrent spatial discrimination learning paradigm consisting of two stages was previously designed to assess the flexibility property of relational memory in mice, as a model of human declarative memory. Aged mice and young adult mice with damage to the hippocampus, learned accurately Stage 1 of the task which required them to learn a constant reward location in a specific set of arms (i.e., learning phase). In contrast, they were impaired relative to healthy young adult mice in a second stage when faced with rearrangements of the same arms (i.e., flexibility probes). This mnemonic inflexibility in Stage 2 is thought to derive from insufficient relational processing by the hippocampus during initial learning (Stage 1) which favors stimulus-response learning, a form of procedural learning. This was proposed as a model of the selective declarative and relational memory decline classically described in elderly people. As a first step to examine the validity of this model, we adapted this protocol to humans using a virtual radial-maze. (1) We showed that performance in the flexibility probes in young and older adults positively correlated with performance in a wayfinding task, suggesting that our paradigm assesses relational memory. (2) We demonstrated that older healthy participants displayed a deficit in the performance of the flexibility probes (Stage 2), similar to the one previously seen in aged mice. This was associated with a decline in the wayfinding task. (3) Our fMRI data in young adults confirmed that hippocampal activation during early discrimination learning in Stage 1 correlated with memory flexibility in Stage 2, whereas caudate nucleus activation in Stage 1 negatively correlated with subsequent flexibility. By enabling relational memory assessment in mice and humans, our radial-maze paradigm provides a valuable tool for translational research.

Neuronal Ras activation inhibits adult hippocampal progenitor cell division and impairs spatial short‐term memory

A large number of endogenous and exogenous factors have been identified to upregulate and downregulate proliferation, differentiation and/or survival of newborn cells in the adult hippocampus. For studying neuronal mechanisms mediating the impact of those factors, we used a transgenic synRas mouse model expressing constitutively activated Valin12-Harvey Ras selectively in differentiated neurons. BrdU injections showed significantly reduced proliferation of new cells within the adult hippocampus of transgenic animals compared with their wild-type siblings. In contrast, the relative survival of newborn cells was increased in synRas mice, although this effect did not fully compensate for diminished proliferation. Inhibition of progenitor cell proliferation and enhancement of cellular survival were more pronounced in males compared with females. Double labelling and doublecortin immunostaining verified that specifically newborn neurons were decreased in synRas mice. Reduced cell generation was observed already 2 h after BrdU pulse injections, identifying an early precursor cell population as target of the inhibitory transgene effect. Differences in proliferation remained stable after 24 h and were specific for the subgranular zone of the dentate gyrus, as subventricular cell generation was not affected supporting a non-cell autonomous effect on neural hippocampal progenitors. Transgene expression only starts with synaptic differentiation and therefore reduced proliferation must represent an indirect secondary consequence of synRas activity in differentiated neurons. This was associated with impaired spatial short-term memory capacities as observed in a radial maze paradigm. Our data suggest that constantly high Ras activity in differentiated neurons downregulates hippocampal precursor cell generation in the neuronal lineage, but is modulated by sex-dependent factors.

Different patterns of memory impairments accompany short- and longer-term maintenance on a high-energy diet.

Intake of diets high in saturated fat and simple carbohydrates is associated with cognitive impairments in both humans and rodents. Here we report that feeding rats this type of high-energy (HE) diet has different effects on different types of learning and memory processes. Rats were first trained to solve spatial and nonspatial reference (RM) and working (WM) memory problems in a radial maze paradigm. Memory retention was assessed following six durations of free access to an HE or standard chow control diet ranging from 72-hr to 90 days. The results showed that performance on spatial RM and WM was impaired following only 72-hr on the HE diet and that the magnitude of the spatial RM and WM retention deficits were stable across all tests. On the other hand, stable deficits in nonspatial RM and WM emerged only after 30 days on the HE diet. The results suggest that the processes underlying spatial memory may be especially sensitive to disruption following intake of HE diets.

The AMPA modulator S 18986 improves declarative and working memory performances in aged mice

The aim of this study was to further characterize the memory-enhancing profile of S 18986 a positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors. S 18986 was studied in two mouse models of age-related memory deficits, using radial maze paradigms involving long-term/declarative memory and short-term/working memory. Aged mice exhibited severe deficits when compared with their younger counterparts in the two behavioural tests. S 18986 at the dose of 0.1 mg/kg selectively improved aged mouse performance in the test of long-term/declarative memory flexibility and exerted a beneficial effect on short-term retention of successive arm-visits in the short-term/working memory test. This study confirms the memory-enhancing properties of S 18986 and, in line with emerging data on multiple AMPA modulators, highlights the relevance of targeting AMPA receptors in the development of new memory enhancers.

The hippocampus plays a critical role at encoding discontiguous events for subsequent declarative memory expression in mice

The hypothesis that hippocampal activity at encoding is causally related to subsequent declarative memory expression is tested in the mouse, by using lidocaine inactivation of the hippocampus in combination with c-fos neuroimaging analysis. We employed a two-stage radial maze paradigm of spatial discrimination, which was previously shown to dissociate between declarative and nondeclarative expression of memory related to the same acquired material. In Stage 1 (encoding), mice learnt the constant location of food among a set of six arms (three baited, three unbaited) by being submitted repeatedly to discontiguous experiences with each arm separately ("go/no-go" discrimination). In Stage 2 (test-session), they are challenged with novel presentations of the arms, which are either combined into pairs of opposite valence ("two-choice" discrimination), or opened all six together ("six-choice" discrimination). Previous experiments have demonstrated that the "two-choice" situation is a critical test for declarative memory while "six-choice" discrimination may rely on procedural memory. We observed that (i) hippocampal activity measured by c-fos mRNA expression was increased by "go/no-go" learning, and this activation was blocked by pre-training local infusions of lidocaine; (ii) when performed just before each session of Stage 1, such inactivation spared the acquisition of "go/no-go" discrimination but produced, subsequently, a selective deficit in the "two-choice" test (not in the "six-choice" test). This study indicates that the hippocampus is "spontaneously" engaged in encoding processes necessary for long-term storage of discontiguous experiences under a form enabling flexible declarative memory expression.

Timing of administration mediates the memory effects of intraseptal carbachol infusion

Medial septal neurons innervate the entire hippocampal formation. This input provides a potent regulation of hippocampal formation physiology (e.g. theta) and memory function. Medial septal neurons are rich in cholinergic receptors and thus are potential targets for the development of cognitive enhancers. Direct intraseptal infusion of cholinomimetics alters hippocampal physiology and can produce either promnestic or amnestic effects. Several variables (e.g. age of animal, integrity of septohippocampal circuits, task difficulty) may influence treatment outcome. We have previously demonstrated that intraseptal carbachol (12.5–125 ng) infusion immediately after the sample session of a delayed-non-match-to-sample radial maze paradigm produces a dose-dependent amnesia. The present study examined whether manipulating the timing of intraseptal carbachol infusion with respect to the sample session would alter the amnestic effect. A within-subjects design was used to examine the effect of intraseptal carbachol (125 ng/0.5 μl) in a delayed-non-match to sample radial maze task. During a sample session, rats retrieved rewards from six of 12 maze arms. At the test session (3 h later), only the alternate set contained reward and entries into the sample set arms constituted errors. Intraseptal carbachol was administered: 1) 30 min prior; 2) immediately prior; 3) immediately after and 4) 90 min after the sample session. Intraseptal carbachol prior to the sample had no effect on any index of accuracy. Infusion immediately after the sample, or delayed 90 min into the retention interval, produced an acute amnesia. These findings demonstrate that the timing of treatment is a critical variable in determining the memory effects of septohippocampal manipulations and that dynamic changes in cholinergic tone are important for memory.

Acquisition of dominance status affects maze learning in mice

Learning is likely to be costly and thus subject to trade-off with other components of life history. An obvious prediction, therefore, is that investment in learning, and thus learning performance, will vary with individual life history strategy and the reproductive value of the learning outcome. We tested this idea in the context of social dominance in male laboratory mice, using a simple radial maze paradigm to compare the ability of high- and low-ranking male mice to track changing food location. We tested animals in randomly selected pairs before and after establishing aggressive rank relationships to distinguish intrinsic differences in learning ability from those attributable to acquiring high or low rank. There was no difference in learning between later dominants and subordinates prior to establishing rank relationships. After pairing, however, dominants showed a significantly greater percentage of correct responses, with the difference being greatest earlier in a sequence of trials. The percentage of correct responses also increased with the amount of aggression initiated during pairing. The results thus appeared to reflect a state-dependent change in learning associated with the aggressive social relationships formed during pairing.

Effects of Intracerebroventricular Injection of α-Fluoromethylhistidine on Radial Maze Performance in Rats

The effects of α-fluoromethylhistidine (α-FMH) on spatial cognition were investigated using the eight-arm radial maze paradigm in rats. Intracerebroventricular (ICV) injection of α-FMH resulted in spatial memory deficits characterized by an increase in the number of total errors (TE) and a decrease in the number of initial correct responses (ICR). There was a strong correlation between increases in the number of TE and decreases in histamine contents of the cortex and hippocampus regions of the brain, which are known to participate in learning and memory. On the other hand, both histamine (50–100 ng, ICV) and thioperamide (10 μg, ICV) significantly ameliorated the memory deficit induced by α-FMH. However, metoprine showed no significant effect on the α-FMH–induced memory deficit. Pyrilamine and R-(α)-methylhistamine enhanced the memory deficit induced by α-FMH, at doses that had no appreciable effect when administered alone. In contrast, no significant influence on α-FMH–induced memory deficit was observed with zolantidine.

Effects of histamine on MK-801-induced memory deficits in radial maze performance in rats

The effects of histamine on the spatial memory deficits induced by MK-801 were investigated using the eight-arm radial maze paradigm in rats. Intracerebroventricular (i.c.v.) injection of histamine or thioperamide, and intraperitoneal (i.p.) injection of histidine improved the spatial memory deficits induced by MK-801. Similar results were obtained with 2-thiazolylethylamine. In contrast, 4-methylhistamine showed no significant effect. Based on these observations, it seems likely that the protective effect of histamine on MK-801-induced spatial memory deficit is mediated by H 1-receptors.

Calcium channel blockers potentiate the analgesic effect of acetaminophen in mice

The effects of α-fluoromethylhistidine (α-FMH) on spatial cognition were investigated using the eight-arm radial maze paradigm in rats. Intracerebroventricular (ICV) injection of α-FMH resulted in spatial memory deficits characterized by an increase in the number of total errors (TE) and a decrease in the number of initial correct responses (ICR). There was a strong correlation between increases in the number of TE and decreases in histamine contents of the cortex and hippocampus regions of the brain, which are known to participate in learning and memory. On the other hand, both histamine (50–100 ng, ICV) and thioperamide (10 μg, ICV) significantly ameliorated the memory deficit induced by α-FMH. However, metoprine showed no significant effect on the α-FMH–induced memory deficit. Pyrilamine and R-(α)-methylhistamine enhanced the memory deficit induced by α-FMH, at doses that had no appreciable effect when administered alone. In contrast, no significant influence on α-FMH–induced memory deficit was observed with zolantidine.

Chronic infusion of GABA and saline into the nucleus basalis magnocellularis of rats: II. Cognitive impairments

In order to assess sensorimotor and/or cognitive modifications following chronic inhibition of nucleus basalis magnocellularis (NBM) neurons, rats trained in two radial maze paradigms (the classical version of the test and a modified version introducing a one-hour delay between the fourth and the fifth choice) received chronic infusion of γ-aminobutyric acid (GABA) into the NBM area. GABA (10 and 50 μg/μl/h) was infused for 3 days into the NBM contralateral to their preferred turning direction in the radial maze. Simultaneously, saline (NaCl 0.9%; 1 μl/h) was infused into the contralateral NBM. GABA and saline infusions were alternated for the subsequent 3-day period. One week later, we investigated the rats' ability to learn a multiple trial passive avoidance task. At the dose of 50 μg/μl, GABA infusion produced (1) a turning bias ipsilateral to the side first infused with GABA, (2) transitory cognitive impairments in radial maze tasks and (3) a deficit in the acquisition of the passive avoidance task. At the dose of 10 μg/μl, the same behavioral deficits were observed except that (1) the turning bias was reversed by the contralateral GABA infusion and (2) cognitive impairments in the radial maze were observed only when a delay was inserted between the fourth and the fifth choice. Histologically, we found a dose-dependent gliosis in the NBM area first infused with GABA. These data suggest a reactivity of the NBM to GABAergic manipulations and the intervention of this structure in both sensorimotor and cognitive processes involved in the radial maze paradigms.

Effects of age on antidepressant kinetics and memory in Fischer 344 rats

Experiments were conducted in young (3–4 months) and old (24–25 months) male Fischer 344 rats to assess the effects of amitriptyline, scopolamine, and zimelidine on short term memory using an eight arm radial maze paradigm. Kinetic analyses employing serial blood sampling were also conducted for amitriptyline and zimelidine in an attempt to determine if age-related deficits in performance could be related to changes in pharmacokinetics. In the maze, acquisition of performance was significantly decreased in old rats compared to young. Amitriptyline (5 mg/kg) produced a significant decrement in maze performance on day four of a five day testing period in both young and old rats, while scopolamine (1 mg/kg) produced an initial decrement on day one, followed by a return towards pre-treatment levels in these two age groups. Zimelidine (5 mg/kg) produced no performance decrement in either young or old rats. Kinetic analyses revealed an increased half-life, slower plasma clearance, and a larger volume of distribution of amitriptyline and zimelidine in old rats. Although the kinetic parameters in aged rats exhibited a change in the direction of a decreased ability to metabolized both drugs, this change was not of sufficient magnitude to produce an additive detrimental effect on maze performance.

Effects of tunnel maze complexity on caffeinic hyperactivity in the rat

The study investigated effects of caffeine on spontaneous tunnel locomotion without consummatory reward. The stimulant effects consisted in delayed intrasession habituation, and they differed in magnitude according to dosage and the complexity of the tunnel arrangements. In a simple hexagonal tunnel without choice points, 16 mg/kg BW produced greater stimulation than other doses, and this most efficient dose became less effective if tunnels were arranged according to the radial maze paradigm. No stimulation was obtained if an open field was incorporated into the maze. Caffeine also had no effect on open field behavior, but it tended to improve the efficiency of radial arm maze patrolling, and it significantly depressed exploration of short tunnel arms branching from the radial arms in favor of exploration of the more distant radial tunnel ends.