Correct Arm Research Articles

Learning and memory-enhancing effects of Ro 15-4513: A comparison with flumazenil

Synthetic benzodiazepines produce an anterograde amnesia, which can be reversed by selective benzodiazepine antagonists or inverse agonists. It has therefore been suggested that the memory-enhancing effects of the antagonists are due to antagonism of an endogenous “benzodiazepine-like” endocoid. If the memory-enhancing effects of the benzodiazepine antagonists are determined predominantly by the antagonism of such endogenous benzodiazepine-ligands, then it could be hypothesized that administration of an inverse agonist, which produces effects functionally opposite to those of benzodiazepine agonists, may also mimic the effects of benzodiazepine antagonists but not produce effects greater than those of the pure antagonists. The purpose of the present study was therefore to investigate the memory-enhancing effects of the benzodiazepine inverse agonist, ethyl-8-amido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5a] [1,4] benzodiazepine-3-carboxylate (Ro 15-4513) in young HSD:(ICR)BR mice and to compare these effects with those of the benzodiazepine antagonist, flumazenil. Pretraining injections of flumazenil and Ro 15-4513 (2.5 and 10.0 mg/kg) enhanced equally, both the acquisition and the retention of a task for 1 week requiring mice to discriminate the correct arm of a T-maze, to avoid a mild electric shock. Pretreatment with Ro 15-4513 also dose-dependently protected the animals from experimental amnesia, induced by the cholinergic receptor antagonist, scopolamine in a second model of memory, in which mice were required to passively avoid a dark chamber after shock. In contrast, Ro 15-4513, injected prior to daily active avoidance sessions, failed to significantly improve either the acquisition or retention performance. Taken collectively, these results suggest that the benzodiazepine inverse agonist, Ro 15-4513 possessed memory-enhancing effects, approximately equivalent to that of the antagonist, flumazenil. It is therefore concluded that these memory-enhancing effects are related to the ability of these drugs to antagonize the agonistic actions of an endogenous benzodiazepine-like ligand, rather than to any intrinsic activity of their own.

What information is used by rats to update choices in the radial-arm maze?

This study examined the information processed by rats in the radial maze. In Experiment 1, performance in the standard straight-arm radial maze was compared with performance in a angle-arm maze which required a right turn at the end of each radial arm. The results showed that the performance of rats initially trained in the angle-arm maze was much more affected when later tested on the straight-arm maze than was the performance of rats initially trained on the straight-arm maze and then moved to the angle-arm maze. In Experiment 2, two groups of rats were trained in the angle-arm maze and then subjected to two transfer tests during which the location and/or direction of the correct goal arms was manipulated. Both transfer tests produced an increase in errors, but the increase was much more pronounced in rats required to learn a new set of baited locations than in rats tested on the same set of baited locations and required to use new initial travel directions. Together, these experiments demonstrate that rats make complementary use of information about both initial travel direction and goal location.

Impairment of Action to Visual Objects in a Case of Ideomotor Apraxia

Abstract A single-case study is reported of a left-handed patient (GF) who presented with a unimanual left-handed apraxia following lesions of the right temporal and frontal lobes. GF was particularly impaired at making learned left-handed gestures to visual stimuli, and he was rather better at left-hand gestures when given visual and tactile input and when asked to gesture to the name of the object. GF was relatively good at making right-hand gestures to objects irrespective of the modality of presentation. He also had intact proprioceptive and/or kinesthetic knowledge of the correct left arm and hand movements to make. GFs performance improved when he was asked to make an appropriate intervening action with his right hand, or when he had to perform simple repetitive actions with his left hand in between making gestures to a series of objects. GFs case supports the argument for a direct route mapping visual input to action. His impairment is attributed to a problem in inhibiting inappropriate actions wit...

Differential effects of physostigmine and pilocarpine on the spatial memory deficits produced by two septo-hippocampal deafferentations in rats

Rats that had received two kinds of septo-hippocampal deafferentations, medial septum (MS) lesion and fimbria-fornix (FF) transection, were assayed for brain cholineacetyltransferase (ChAT) activity and spatial memory in an 8-arm radial maze task. Both lesions produced profound and long-lasting spatial memory impairments, which were characterized by a reduction in the numbers of correct arm choices and first correct choices, a reduction in the percent of correct choices and an increase in the number of errors. The degree of memory impairment was severer in FF- than in MS-lesioned rats, and paralleled that of decreases in ChAT activity in the hippocampus. MS lesion reduced ChAT activity in the hippocampus by approximately 45%, while FF lesion almost completely depleted the activity. An intraperitoneal injection of physostigmine (0.0032–0.32 mg/kg), an acetylcholinesterase (AChE) inhibitor, significantly ameliorated the spatial memory deficit induced by MS lesion, but hardly affected that by FF lesion. In contrast, intraperitoneal doses (0.032–3.2 mg/kg) of pilocarpine, a muscarinic agonist, showed a significant improvement of both types of memory deficit with bell shaped dose-response curves. The drug was more potent in the FF- than in the MS-lesioned rats. These results suggest that the septo-hippocampal cholinergic system plays a crucial role in the maintenance of spatial memory, and that the degree of septo-hippocampal deafferentation affects the efficacy of cholinergic drugs.

Effect of centrally administered atropine and pirenzepine on radial arm maze performance in the rat

The effect of two anticholinergic drugs administered intracerebroventricularly on acquisition of an 8-arm radial maze task was examined in the rat. Increasing doses of atropine (1, 4.5, 22.5, 45 μg/rat) and pirenzepine (4.5, 15, 60, 90 μg/rat) significantly impaired performance in the working-memory components of the task. For both drugs this impairment was linearly related to the log of the administered doses and log-dose-response relationships were parallel. The regression lines calculated for each parameter for both drugs were parallel to each other, thus allowing us to calculate the potency of atropine versus pirenzepine: atropine was 5.4 times more potent than pirenzepine for correct arm entries, 10 times more potent for the number of errors and 4 times more potent for the total time taken to complete the task. The relevance of M 1 and M 2 subtype central acetylcholine receptors in cognitive processes is discussed.

Radial maze performance following hippocampal kindling

The relation between hippocampal epileptiform activity and 8-arm radial maze performance was assessed following repetitive afterdischarges (ADs) evoked by stimulation of the hippocampal CA1 region (kindling). Hippocampal kindling, whether to stage V (generalized) convulsions or to a preconvulsive stage, induced deficits in radial maze performance, evaluated by correct arm entries in 8 choices or total maze run (trial) time. The deficits persisted at least until 21 days after the last AD. Hippocampal interictal spikes (ISs) were induced by kindling, but the rate of ISs declined to near zero in a few days. The rate or presence of ISs was not related to maze performance.

Scopolamine treatment and fimbria-fornix lesions: Mimetic effects on radial maze performance

Long-Evans female rats were “trained” in an 8-arm radial maze and subsequently tested under systemic treatment with physostigmine (0.05 mg/kg, IP), scopolamine methylbromide (MBr) and scopolamine hydrobromide (HBr; 0.5 mg/kg, IP), whose effects were compared to those of aspirative lesions of the fimbria-fornix pathways. During the predrug trials, rats with lesions showed impaired performances compared to those of intact rats. Whereas physostigmine had no significant effect in either group, scopolamine HBr impaired performances of intact rats in a manner closely parallel to all measured behavioral effects of the lesions (errors, “correct arms” and strategies). The scopolamine HBr-induced deficits were not correlated with the percentage of “spatial” strategies. Under scopolamine HBr treatment the performances of rats showing preferences for “spatial” strategies did not differ significantly from those of rats showing preferences for “orientation” strategies. These results provide further support for the involvement of cholinergic processes in working memory and suggest that scopolamine-induced central cholinergic disruption may mimic the effects of fimbria-fornix lesions in an 8-arm radial maze. They also somewhat qualify previous reports on 1) the poor sensitivity of an uninterrupted radial maze testing procedure to pharmacological treatment and 2) the abilities of rats to resist muscarinic blockade depending on the strategies they use in the maze.

The role of homecage environmental stimuli in the facilitation of shock-motivated spatial discrimination learning in rat pups.

In three experiments we examined the role of homecage environmental stimuli on learning an aversively motivated spatial discrimination task in 11-day-old rats. Varying the presence and absence of nest shavings in the correct and incorrect arms of a T-maze in Experiment 1 revealed that nest shavings had both nondirective facilitation and approach-eliciting properties. Training the 11-day-old rats in the presence or absence of shavings over three daily sessions and comparing their performance on the third day of training with that of a maturation control in Experiment 2 indicated that there is a residual training effect of the approach-eliciting property of nest shavings on shock-escape behavior. In Experiment 3, using nest shavings either as an irrelevant stimulus or as a redundant relevant cue in an aversively motivated T-maze reversal task suggested that 11-day-old rats acquire the discrimination task using non-nest spatial or directional cues as well as those provided by nest shavings. Overall, these results suggest that nest shavings introduced into aversively motivated tasks create a learning environment comparable to that of appetitively motivated instrumental tasks utilizing suckling from an anesthetized dam as a reinforcer.

Enhancement of learning and memory in mice by a benzodiazepine antagonist.

Benzodiazepines, a class of drugs widely employed as anxiolytics and anticonvulsants, can induce impairments of learning and memory. The purpose of the present investigation was to determine if a benzodiazepine receptor antagonist, flumazenil (Ro 15-1788), could enhance learning and memory. Pretraining injection of flumazenil (2.5 to 40.0 mg/kg) was found to enhance both learning and memory in a test requiring young mice to discriminate the correct arm of a T-maze to escape mild electric shock. In a second test, which required mice to passively avoid a dark chamber after shock, flumazenil pretreatment prevented the occurrence of amnesia induced by the cholinergic receptor antagonist scopolamine. It is hypothesized that flumazenil may facilitate learning or memory processes by reversing a negative modulatory influence of endogenous diazepam-like ligands for benzodiazepine receptors.

Differential effects of drugs on the behaviour of rats with selective fimbria-fornix lesions and intrahippocampal septal cell transplants

Rats that had received two kinds of septo-hippocampal deafferentations, medial septum (MS) lesion and fimbria-fornix (FF) transection, were assayed for brain cholineacetyltransferase (ChAT) activity and spatial memory in an 8-arm radial maze task. Both lesions produced profound and long-lasting spatial memory impairments, which were characterized by a reduction in the numbers of correct arm choices and first correct choices, a reduction in the percent of correct choices and an increase in the number of errors. The degree of memory impairment was severer in FF- than in MS-lesioned rats, and paralleled that of decreases in ChAT activity in the hippocampus. MS lesion reduced ChAT activity in the hippocampus by approximately 45%, while FF lesion almost completely depleted the activity.An intraperitoneal injection of physostigmine (0.0032–0.32 mg/kg), an acetylcholinesterase (AChE) inhibitor, significantly ameliorated the spatial memory deficit induced by MS lesion, but hardly affected that by FF lesion. In contrast, intraperitoneal doses (0.032–3.2 mg/kg) of pilocarpine, a muscarinic agonist, showed a significant improvement of both types of memory deficit with bell shaped dose-response curves. The drug was more potent in the FF- than in the MS-lesioned rats.These results suggest that the septo-hippocampal cholinergic system plays a crucial role in the maintenance of spatial memory, and that the degree of septo-hippocampal deafferentation affects the efficacy of cholinergic drugs.

Single unit activity in the rat hippocampus during a spatial memory task

Single unit activity was recorded from complex spike cells in the hippocampus of the rat while the animal was performing a spatial memory task. The task required the animal to choose the correct arm of a 4 arm plus-shaped maze in order to obtain reward. The location of the goal arm was varied from trial to trial and was identified by 6 controlled spatial cues which were distributed around the enclosure and which were rotated in step with the goal. On some trials these spatial cues were present throughout the trial (spatial reference memory trials) while on other trials they were present during the first part of the trial but were removed before the rat was allowed to choose the goal (spatial working memory trials). On these latter trials the animal had to remember the location of the cues and/or goal during the delay in order to choose correctly. 55 units were recorded during sufficient reference memory trials for the relationship between their firing pattern and different spatial aspects of the environment to be determined. 33 units had fields with significant relations to the controlled cues while 16 had significant relations to the static background cues, those cues in the environment which did not change position from trial to trial. Of 43 units which could be tested for their relation to the shape of the maze arms themselves, 15 showed such a relationship. Therefore the place units can be influenced by different aspects of the spatial environment but those related to the task requirement appear to be more potent. Interaction effects between the different spatial factors also influenced the firing pattern of some units. Of particular interest was the interaction between the controlled cues and the static background cues found in some cells since this might shed some light on how the hippocampus enables the rat to solve the memory task. 30 units with place fields related to the controlled cues were recorded during successful performance on spatial working memory trials as well as during spatial reference memory trials. The place fields of 90% of these units were maintained during the retention phase of the memory trials. During the recording of some units, other types of trial were given as well. On control trials, the cues were removed before the rat was placed on the maze. These trials provided controls for the potential influence of information left behind by the controlled cues and for the influence of the animal's behaviour on the unit activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Blocking and Overshadowing between Intra-Maze and Extra-Maze Cues: A Test of the Independence of Locale and Guidance Learning

Rats were trained on an elevated maze where the rewarded alternative was defined either in terms of intra-maze cues (rubber or sandpaper flooring on rewarded and unrewarded arms, regardless of their position) or in terms of extra-maze cues (the correct arm always pointed toward a particular corner of the room, and was sometimes covered with rubber and sometimes with sandpaper), or where both sets of cues were simultaneously relevant. In Experiment 1 rats pretrained with either intra-maze or extra-maze cues alone relevant learned less about the other set of cues than non-pretrained control groups, when, in a second phase of the experiment, both sets of cues were simultaneously relevant. Experiment 2 confirmed that intra-maze cues could block extra-maze cues, and ruled out one alternative explanation of the results of Experiment 1. Experiment 3 showed that extra-maze cues overshadowed intra-maze cues, but that there was no reciprocal overshadowing of extra-maze by intra-maze cues. This was despite the fact that animals learned the intra-maze discrimination significantly faster than the extra-maze discrimination. Experiment 3 also suggested that rats did not solve the extra-maze discrimination by learning to approach or avoid specific extra-maze cues, but rather by locating the correct arm by reference to the entire set of extra-maze cues. The results suggest that locale or place learning and cue or guidance learning, in O'Keefe and Nadel's (1978) terminology, interact with one another in much the same way as does learning about any pair of stimuli in a Pavlovian conditioning experiment.

Stimulus perseveration in a water maze following exposure to controllable and uncontrollable shock

When placed in a water-filled maze, mice display a pronounced preference for the illuminated over the nonilluminated arm of the maze. Exposure to inescapable shock increased the time spent in the illuminated arm of the maze, and decreased the frequency of entries into the nonilluminated arm. When animals that had received shock entered the nonilluminated arm they exhibited more activity per second than nonstressed animals. Controllability over the stressor enhanced the preference for the illuminated arm; however, the contribution of this variable was dependent on the number of shock trials mice received. Following 180 escapable or inescapable shock presentations the preference for the illuminated arm was enhanced. The propensity to approach the illuminated arm declined following a greater number (360) of escapable shock trials, while the preference for the illuminated arm did not decline in mice that received inescapable shock. Both escapable and inescapable shock were also found to produce a transient disruption of discrimination performance in a task where animals were required to emit a contraprepared response (swim to dark), whereas these treatments were without effect on performance of the highly prepared response of approaching the illuminated arm. It is provisionally suggested that enhancement of the perseveration represents an innate response to stressful stimuli, but as animals learn mastery over the response contingencies, the persistence in adopting such a response strategy wanes. Moreover, despite the differential effects of escapable and inescapable shock on the perseverative tendency, discrimination accuracy may not be differentially affected by these treatments in a task where acquisition progresses quickly and where explicit cues are associated with the correct and incorrect arms of the maze.

Stimulation parameters influence response involvement in reinforcing brain stimulation

Rats pressed a lever for brain stimulation in the start box of a T-maze. Pulse trains of stimulation were available under various temporal schedules. Periods of self-stimulation (SS) alternated with intervals of experimenter-administered stimulation (EAS) during which identical stimulation was automatically delivered at the same average rate as during SS periods. Rats could terminate the ongoing EAS by traversing the maze and making a turn into the correct arm, thereby reinstating the availability of a SS period. Experiments 1 and 2 demonstrated that manipulations of either the intertrain interval or the train duration, which are parameters that regulate the temporal density of stimulation, influenced the latency to terminate intervals of EAS. Experiment 3 showed that omitting the stimulation during the EAS period of the standard SS-EAS cycle disrupted the resetting behaviour of the experienced rats. They required as many sessions as naive rats to learn the behaviour required to circumvent the EAS-free period. The data suggest that the behaviour patterns exhibited are dependent upon the buildup of activity that is largely influenced by the total neural activity summated across pulse train(s) of stimulation. The behaviour to terminate the EAS occurs as a consequence of an aversive effect which is concurrently produced by the rewarding stimulation. This aversive effect is attenuated by responding.

Effects of ethanol on enforced spatial variability in the 8-arm radial maze

Previous work has indicated that ethanol is a potent stereotypy-inducing agent. At least this is the case for spontaneously emitted instrumental behavior. The present experiments were undertaken to determine if spatial variability could be generated by drugged rats when it was enforced by reward contingencies. With a reward nonreplacement rule in force, four arms of an 8-arm radial maze were baited on every trial. Rats injected with 0, 0.75, 1.5, or 2.0 g/kg ethanol were required to run to the same set of arms from trial-to-trial and session-to-session. Efficient performance depended upon their running to the correct set of arms as well as meeting a “win-shift” demand which proscribed returning to previously visited arms during a given trial. Although all groups were eventually able to run to the correct set of arms, alcohol, especially at higher doses, promoted repetition. The inability to refrain from reentering arms prevented many alcohol-injected animals from obtaining the four rewards in the allotted time. In Phase 2 of Experiment 1, the baited arms were rotated 45°. Now the formerly empty arms contained pellets and rewards were withdrawn from the previously correct arms. Adjustment to this shift was rapid for 0 and 0.75 g/kg groups, but an increasingly severe perseveration was observed across the higher ethanol groups. Experiment 2 reproduced the results of Experiment 1 under different circumstances. While trained as before to run to a specific set of four arms in Phase 1, Phase 2 presented the rats with rewards in all eight arms of the maze. With higher doses of alcohol an increasing persistence in running to the original four arms was observed. Saline-injected animals, on the other hand, rapidly doubled the number of pellets taken. Taken together, and in view of earlier findings, the results suggest that alcohol interacts with previous training as well as recent choices with the result that spatial dispersion is restricted in spite of explicitly opposing reward contingencies.

Simultaneous colour discrimination in chicks is improved by brief exposure to light

Dark-reared chicks were exposed to white light for 1 h at age 24 h. At 48 h these chicks, and others kept in the dark throughout, were given the opportunity to obtain a heat reward by choosing the correct arm in a Y maze. The discriminanda were red and blue illuminated circles, each being the positive stimulus for half the chicks. Light-exposure resulted in faster learning, especially when the positive stimulus was blue. This is taken as further support for the view that brief exposure to light activates the visual system non-specifically, affecting many kinds of visually guided behaviour.

Pavlovian aversive to instrumental appetitive transfer: Evidence for across-reinforcement blocking effects

Rats received Pavlovian aversive (shock) conditioning in which white noise was established for different groups as a CS+, CSO, or CS−. Then, in an appetitive T-maze discrimination, the CSs were presented contingent upon a designated correct response for which food reinforcement was factorially varied at 0, 1, 2, or 4 pellets. Although the CS+ suppressed and the CS− facilitated speed of running in the correct arm at the start of discrimination training, these effects extinguished rapidly and did not interact with reward magnitude. Furthermore, choice learning was faciltated by the CS+ and retarded by the CS−, with these effects being comparable for the 1- to 4-pellet reinforcement conditions, but absent for the 0-pellet condition. These findings are difficult to reconcile with a transfer interpretation positing a general signaling property of the CS and are better interpreted as across-reinforcement blocking effects: By predicting a preferred outcome (safety) comparable to the preferred outcome of food reinforcement, the CS− blocks (retards) the association of reinforcement and the SD; conversely, by predicting a nonpreferred (shock) outcome discrepant from the preferred food outcome, the CS+ “counterblocks” (enhances) the association of reinforcement and the SD.

Secondary reinforcement property of a stimulus paired with morphine administration in the rat

Rats learned to run to the correct arm of a Y-maze. Correct responses were reinforced with morphine injection paired with a conditional tone stimulus. After the maze response was well established, extinction trials were run. During extinction half of the animals received neither morphine nor tone as a consequence of a correct response, while the other half received the tone but no morphine. Rats receiving the tone during extinction required significantly more trials to reach the extinction criteria than rats not receiving tone presentations. Extinction with the tone also facilitated relearning of the maze response. The results support the view that morphine is a potent reinforcer, and that stimuli paired with morphine administration acquire the properties of a secondary reinforcer.

Chemoreception in Aplysia californica. I. behavioral localization of distance chemoreceptors used in food-finding

The importance of rhinophores and tentacles to distance food localization by Aplysia californica was investigated using a Y-maze. When food algae was placed in one arm of the maze, a normal animal placed in the stem almost invariably entered the correct arm in search of food. Performance was compared before and after removal of tentacles, rhinophores, and both structures. Only the distal portion of each organ, containing a darkly pigmented groove, was removed. Loss of rhinophores did not affect maze performance if tentacles were intact. Loss of tentacles, however, resulted in an increase in errors even when rhinophores were present. A significant decline in performance occurred only after removal of both structures. Rhinophores are well situated to detect odors carried by passing currents, and could be used initially to alert Aplysia californica to the presence of food upstream. Tentacles, which are closer to the substrate and more widely separated, may then play the dominant role in locating food.

Response perseveration in the hippocampal lesioned rat

Hippocampal lesions were found to affect a rat’s relearning a previously learned correct arm from a new starting position in a T-maze situation. Hippocampal-damaged rats (HIPP group) perseverated turning responses by entering into the opposite arm from the correct one more than did sham-operated rats (SHAM group). This perseveration phenomenon was seen only for HIPP rats that were required to choose between two similar choice arms. When side arms were differentiated by brightness cues, no differences in relearning the correct arm were found between groups. Greater resistance to extinction of the position habit was also found in HIPP rats, but only in the situation with both side arms similar in color.