Lesions of the rat postsubiculum impair performance on spatial tasks.

Previous studies have identified a population of neurons in the postsubiculum that discharge as a function of the rat's head direction in the horizontal plane (Taube, Muller, & Ranck, 1990a). To assess the contribution of these cells in spatial learning, Long-Evans rats were tested in a variety of spatial and nonspatial tasks following bilateral electrolytic or neurotoxic lesions of the postsubiculum. Compared to unlesioned control animals, lesioned animals were impaired on two spatial tasks, a radial eight-arm maze task and a Morris water task, although the performance scores of both lesion groups improved over the course of behavioral testing. In contrast, lesioned animals were unimpaired on two nonspatial tasks, a cued version of the water maze task and a conditioned taste-aversion paradigm. In addition, lesioned animals showed transient hyperactivity in an open-field activity test. These results support the concept that neurons in the postsubiculum are part of a neural network involved in the processing of spatial information.     

Dose- and delay-dependent working/episodic memory impairments following intraventricular administration of ethylcholine aziridinium ion (AF64A).

The present study examined the effects of intraventricular administration of the cholinergic neurotoxin ethylcholine aziridinium ion (AF64A) on performance of a radial arm maze task. Male Sprague-Dawley rats were trained to perform a delayed-nonmatch to sample radial arm maze task in which a 1-h delay was imposed between the fourth and fifth arm selections. Following acquisition, animals were injected bilaterally with AF64A (1.5 or 0.75 nmol/side) or artificial cerebrospinal fluid into the lateral cerebral ventricles and allowed 7 days to recover before behavioral testing resumed. Significant dose- and delay-dependent impairments in the radial maze performance were observed in AF64A-treated rats as evidenced by fewer correct choices following the delay and by more errors to complete the task. Long-term testing in this task revealed significant recovery of memory performance. These findings indicate dose-dependent impairments in memory following intraventricular administration of AF64A and spontaneous behavioral recovery following such insult.     

Alternation behavior, spatial discrimination, and reversal disturbances following 6-hydroxydopamine lesions in the nucleus accumbens of the rat

The effects of dopaminergic depletion of the nucleus accumbens was tested in various behavioral tasks such as alternation, spatial discrimination, and reversal learning, and in an extinction paradigm in a T maze. Animals with lesions showed impairment of spontaneous alternation behavior, disturbances in the acquisition of spatial discrimination, and great difficulty in reversing previously learned habits. In the extinction phase, experimental animals are unable to adjust their behavior, and continue to choose the previously reinforced arm of the T maze. It is suggested that the nucleus accumbens plays an important role in the transition of motivation into action, and that dopamine has a facilitatory influence on the mediation of these processes.     

Response biases do not underlie the radial maze deficit in rats with mediodorsal thalamus lesions

Previous results indicating that radial maze performance in animals with mediodorsal thalamic lesions is deficient cannot exclude the possibility that these impairments are due to altered motor mechanisms (response biases). The present study sought to eliminate this potentially confounding variable by using a procedure which tests memory for serial position. This procedure involved experimenter-controlled arm entry (number and order) on a radial arm maze. Following this sequence, animals were presented with one previously entered arm along with an arm not yet visited on that trial. Avoidance of the previously entered arm constituted memory for the prior sequence. Thus, this task represents a form of a win-shift or nonmatching-to-sample task. Seven animals were given ibotenic acid lesions of the mediodorsal nucleus and nine others were given sham operations; 2 weeks later testing in the above procedure was conducted. Results indicated that, although control subjects could differentiate between entered and unentered arms without difficulty, animals with lesions were unable to exhibit this distinction. Much of their memory for arms previously entered in a sequence was at chance level, regardless of the placement of the tested arm in the sequence. Some tendency toward increased errors with longer sequences of arm entries was noted. This may indicate that animals with lesions were susceptible to proactive interference from previous choices. Regardless, even without the opportunity to develop or exhibit response biases, animals lesioned in the mediodorsal nucleus were unable to perform this win-shift task reliably. Thus, discrimination among maze arms is impaired after lesion of the mediodorsal nucleus and this impairment is independent of the motor response patterns which emerge during solution of a conventional radial maze task.     

Performance of normal and neurological mutant mice on radial arm maze and active avoidance tasks

The objectives of the present study are to assess the import of gene-imposed structural alterations on behavioral performance and obtain performance data preliminary to studies of experimental mouse chimera behavior. Reeler, staggerer, and weaver neurological mutant, and control B6C3 and ichthyosis mice were tested on radial arm maze and active avoidance tasks. Weaver mice had incapacitating seizures while performing the radial arm maze task and were, therefore, removed from further testing. Staggerer mice displayed a significant deficit on both tasks compared to control mice. Homozygous reeler mice (rl/rl) also had a significant deficit on the active avoidance task compared to +/rl control mice but not significantly poorer than ichthyosis mice. However, their performance on the radial arm maze task, while initially poor, improved so that they performed the task similar to wild-type controls. Three of the reeler mice reached criterion for solving the radial arm maze task. None of the staggerer mice reached criterion. These data are discussed in terms of the value of using neurologically mutant mice in dissecting structural-functional relationships. It is suggested that the behavior of these mutants might point toward specific components of cerebellar involvement in behavioral acts.     

Electrolytic, but not 5,7-dihydroxytryptamine, lesions of the nucleus medianus raphe impair acquisition of a radial maze task

We have previously reported that electrolytic lesions of the nucleus medianus raphe (MR) produce a deficit in the acquisition of an 8-arm radial maze task (Wirtshafter and Asin 1983). In an attempt to determine whether or not this deficit is secondary to serotonin depletion resulting from the lesion, we investigated and compared the effects of electrolytic and 5,7-dihydroxytryptamine (5,7-DHT) lesions of the MR on the acquisition of the radial maze task. Although forebrain serotonin levels after 5,7-DHT injections were reduced as much as those following electrolytic lesions, only rats with an electrolytic MR lesion were impaired on the acquisition of both a free-running maze task and on a related task, where animals were replaced into the same arm between arm choices. In contrast, 5,7-DHT-treated rats were unimpaired on both tasks compared to an ascorbate-injected control group. These findings provide further evidence that most of the profound behavioral deficits shown by rats with electrolytic MR damage are not due to serotonin depletion and are consistent with the results of other studies indicating strong similarities between the behavioral effects of limbic and MR lesions.     

Dorsal striatal dopamine depletion impairs both allocentric and egocentric navigation in rats

Successful navigation requires interactions among multiple but overlapping neural pathways mediating distinct capabilities, including egocentric (self-oriented, route-based) and allocentric (spatial, map-based) learning. Route-based navigation has been shown to be impaired following acute exposure to the dopaminergic (DA) drugs (+)-methamphetamine and (+)-amphetamine, but not the serotoninergic (5-HT) drugs (±)-3,4-methylenedioxymethamphetamine or (±)-fenfluramine. The dopaminergic-rich neostriatum is involved in both allocentric and egocentric navigation. This experiment tested whether dorsal striatal DA loss using bilateral 6-hydroxydopamine (6-OHDA) injections impaired one or both types of navigation. Two weeks following 6-OHDA injections, rats began testing in the Cincinnati water maze (CWM) followed by the Morris water maze (MWM) for route-based and spatial navigation, respectively. 6-OHDA treatment significantly increased latency and errors in the CWM and path length, latency, and cumulative distance in the MWM with no difference on cued MWM trials. Neostriatal DA levels were reduced by 80% at 2 and 7 weeks post-treatment. In addition, 6-OHDA increased DA turnover and decreased norepinephrine (NE) levels. 6-OHDA injections did not alter monoamine levels in the prefrontal cortex. The data support that neostriatal DA modulates both types of navigation.     

Acute homeostatic imbalances reinstate sensorimotor dysfunctions in rats with lateral hypothalamic lesions

It has previously been demonstrated that rats recovered from aphagia and adipsia after large bilateral electrolytic lesions of the lateral hypothalamic area do not show the normal feeding response to 2-deoxyglucose or drinking response to polyethylene glyol. The present work reveals that such homeostatic imbalances reinstate the profound sensorimotor impairments that are seen in the immediate postoperative period but abate in parallel with the gradual recovery of ingestive behaviors. Administration of alpha-methyltyrosine or spiroperidol produced sensory and motor dysfunctions in rats with lateral hypothalamic lesions that were similar to those observed after 2-deoxyglucose. These results suggest that the residual feeding and drinking deficits of rats with lateral hypothalamic lesions after apparent recovery of function do not reflect specific loss of putative gluco- and volume-regulatory contributions to ingestive behavior. Instead, they may indicate continued impairments in nonspecific activational components of motivation that normally are mediated, in part, by central dopaminergic neurons.     

Spatial navigation in complex and radial mazes in APP23 animals and neurotrophin signaling as a biological marker of early impairment

Impairment of hippocampal function precedes frontal and parietal cortex impairment in human Alzheimer's disease (AD). Neurotrophins are critical for behavioral performance and neuronal survival in AD. We used complex and radial mazes to assess spatial orientation and learning in wild-type and B6-Tg(ThylAPP)23Sdz (APP23) animals, a transgenic mouse model of AD. We also assessed brain content of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3). Performance was alike in wild-type and APP23 animals in the radial maze. In contrast, performance in the complex maze was better in wild-type than APP23 animals. Contrary to the wild-type, hippocampal BDNF levels decreased on training in APP23 animals. Hippocampal and frontal cortex NGF levels in APP23 animals correlated with the time to solve the complex maze, but correlated inversely with escape time in wild-type animals. NT-3 levels were alike in wild-type and APP23 animals and were unchanged even after training. Both types of mazes depend on hippocampal integrity to some extent. However, according to the cognitive mapping theory of spatial learning, the complex maze because of the increased complexity of the environment most likely depends more strongly on preserved hippocampal function than the radial maze in the working memory configuration applied here. Greater impairment in complex maze performance than in radial maze performance thus resembles the predominant affliction of the loss of hippocampal function in human AD. NGF and BDNF levels on maze learning are different in wild-type and transgenic animals, indicating that biological markers of AD may be altered on challenge even though equilibrium levels are alike.     

Intraseptal Flumazenil Enhances, while Diazepam Binding Inhibitor Impairs, Performance in a Working Memory Task

GABA_A/benzodiazepine receptors in the medial septum modulate the activity of cholinergic neurons that innervate the hippocampus. Injection of benzodiazepine (BDZ) agonists into the medial septum impairs working memory performance and decreases high-affinity choline transport (HAChT) in the hippocampus. In contrast, intraseptal injection of the BDZ antagonist flumazenil increases HAChT and prevents the memory deficits induced by systemic BDZs. The present studies attempted to further characterize the behavioral effects of medial septal injections of flumazenil to an endogenous negative modulator of the GABA_A/BDZ receptor complex, diazepam binding inhibitor (DBI). Male Sprague–Dawley rats were cannulated to study the effects of intraseptal injections of these BDZ ligands on spatial working memory, anxiety-related behaviors in the elevated plus maze, and on general locomotor activity. Intraseptal flumazenil (10 nmol/0.5 μl) produced a delay-dependent enhancement of DNMTS performance after an 8-h, but not a 4-h, delay interval. This promnestic dose of flumazenil had no effect on locomotor activity and did not produce changes in measures of anxiety on the plus maze. Intraseptal injection of DBI had no effect (8 nmol/0.5 μl) or slightly impaired (4 nmol/0.5 μl) DNMTS radial maze performance following an 8-h delay, without producing changes in locomotion or plus maze behavior. These data demonstrate that flumazenil has a unique profile of activity in enhancing working memory following intraseptal injection.     

Effects of intraseptal zolpidem and chlordiazepoxide on spatial working memory and high-affinity choline uptake in the hippocampus

Injection of GABA(A)/benzodiazepine receptor ligands into the medial septum (MS) alters the activity of cholinergic neurons that innervate the hippocampus and can produce bidirectional modulation of spatial memory. Recent evidence suggests that two subtypes of the GABA(A) receptor are differentially localized to either GABAergic (alpha(1)/beta(2)/gamma(2)) or cholinergic (alpha(3)/beta(3)/gamma(2)) neurons within the MS. The present studies characterized the dose-related behavioral and neurochemical effects of intraseptal infusions of two benzodiazepine (BDZ) agonists that appear to exhibit different profiles of pharmacological specificity for these receptor subtypes. Male Sprague-Dawley rats were cannulated and then artificial CSF, chlordiazepoxide (CDP: 8 or 12 microg), or zolpidem (4, 8, or 12 microg) was injected into the MS. Spatial working memory was assessed in a delay radial-arm maze task and the activity of cholinergic neurons in the MS was evaluated by high-affinity choline uptake (HA-ChU) in the hippocampus. Intraseptal injection of either CDP or zolpidem produced dose-related impairments in spatial working memory and decreases in hippocampal HAChU. Both BDZ agonists were found to produce retrograde memory deficits and a decrease in HAChU following the highest dose tested (12 microg). However, intraseptal injection of 8 microg of zolpidem produced a behavioral deficit comparable to the high dose of CDP, but did not alter HAChU within the HPC. Although the cholinergic component of the septohippocampal pathway has been shown to be important in modulating hippocampal physiology and spatial memory processes, data from the present experiments suggest that the GABAergic component may also play an important role in the behavioral functions of the septohippocampal pathway.     

Sound sequence discrimination learning motivated by reward requires dopaminergic D2 receptor activation in the rat auditory cortex

We have previously reported that sound sequence discrimination learning requires cholinergic inputs to the auditory cortex (AC) in rats. In that study, reward was used for motivating discrimination behavior in rats. Therefore, dopaminergic inputs mediating reward signals may have an important role in the learning. We tested the possibility in the present study. Rats were trained to discriminate sequences of two sound components, and licking behavior in response to one of the two sequences was rewarded with water. To identify the dopaminergic inputs responsible for the learning, dopaminergic afferents to the AC were lesioned with local injection of 6-hydroxydopamine (6-OHDA). The injection attenuated sound sequence discrimination learning, while it had no effect on discrimination between the sound components of the sequence stimuli. Local injection of 6-OHDA into the nucleus accumbens attenuated sound discrimination learning. However, not only discrimination learning of sound sequence but also that of the sound components were impaired. SCH23390 (0.2 mg/kg, i.p.), a D1 receptor antagonist, had no effect on sound sequence discrimination learning, while it attenuated the licking behavior to unfamiliar stimuli. Haloperidol (0.5 mg/kg, i.p.), a D2 family antagonist, attenuated sound sequence discrimination learning, while it had no clear suppressive effect on discrimination of two different sound components and licking. These results suggest that D2 family receptors activated by dopaminergic inputs to the AC are required for sound sequence discrimination learning.     

Exploration and avoidance learning after ibotenic acid and radio frequency lesions in the rat amygdala

Open-field activity, avoidance behavior, and plasma corticosterone levels were studied after intraamygdala injections of 3.0 micrograms ibotenic acid (IBO) and radio-frequency (RF) lesions in the amygdala complex of male Wistar rats. The experiments were undertaken to evaluate the importance of amygdala neurons versus axons of passage in fear-motivated behavior. The IBO lesions led to increased open-field activity, but no impairments in active avoidance learning, nor changes in basal or experimental levels of plasma corticosterone. The RF lesions, on the other hand, led to an increase in experimental plasma corticosterone levels. In the one-way avoidance task the RF lesions, in contrast to the IBO lesions, led to significant impairments in the acquisition of the avoidance response. Although the long-term axon-sparing effect of IBO is questioned since cavities were detected in the affected areas 8 weeks after the injections, the differences in avoidance learning and in corticosterone levels between the RF and the IBO lesions indicate that the axons were functionally active at the time of testing (14-26 days postoperatively). The increase in open-field activity is attributed to the destruction of amygdala neurons and neurons in the overlying cortex, while an avoidance deficit seem to depend on the destruction of axons. On the basis of the behavioral results and the corticosterone data in these experiments, it is suggested that the behavioral changes are not attributable to a general reduction in the arousal of fear. However, since the IBO lesions did not affect the most medial parts of the amygdala complex including the central amygdala nucleus, the role of this nucleus in fear arousal has to be investigated further.     

Selective fimbria and thalamic lesions differentially impair forms of working memory in rats.

Several series of experiments were designed to compare the effects of selective lesions of the fimbria or of thalamic nuclei on three different tasks involving working memory in rats: object recognition, place recognition, and the radial arm maze test. The main effects of fimbria lesions were as follows: they produced deficits in the radial maze; object recognition was spared or even facilitated, whereas place recognition was impaired. Electrolytic lesions of either centromedian-parafascicularis (CM-Pf) or dorsomedialis (DM) nuclei produced highly significant deficits in the radial maze test but spared object and place recognition. Ibotenate lesions of the CM-Pf had no effect on any test, which means that the critical structure in the effects of the electrolytic lesions of the CM-Pf was the fasciculus retroflexus (FR). These data may contribute two main points to animal models of hippocampal and thalamic amnesia: (1) different forms of working memory in rats might have different neural bases and (2) the FR may be involved in learning and memory processes.     

Behavioral measurements in nutritional studies

Studies on the effects of dietary deficiencies have shown marked behavioral impairments in rats deprived of adequate quantities of specific vitamins. In at least one study, such impairment was evident even when body weight did not differ from vitamin-supplemented but pair-fed controls. Recently, experiments have demonstrated that restriction of maternal dietary intake during gestation and lactation results in a variety of physiological and behavioral abnormalities in the progeny. These offspring are stunted, retarded in neuromotor development, impaired in ability to learn a maze, slow in extinction of the conditional reflex and show a low level of exploratory activity, a high degree of emotional behavior and marked anti-social interaction. Furthermore, patterns of change with increasing age in some of these measurements also distinguish these experimental animals from controls born of adequately-fed dams.     

Wistar rats with high versus low rearing activity differ in radial maze performance

Substantial work has shown that rats although identical in stock, sex, age, and housing conditions can differ considerably in terms of behavior and physiology. Such individual differences, which can be detected by specific behavioral screening tests, are rather stable, that is, they probably reflect a behavioral disposition or trait. Here, we asked whether and how such differences might affect performance in a task of spatial learning and memory, the radial maze. As in our previous work, we used the degree of rearing activity in a novel open field to assign male adult outbred Wistar rats into those with high versus low rearing activity (HRA/LRA rats). They were then tested in a plus-maze for possible differences in anxiety-related behavior. Finally, and most importantly, they were food deprived and underwent maze training using an 8-arm radial maze with four non-baited and four baited arms. One of these arms consistently contained a larger bait size than the other three. In the open field, HRA rats not only showed more rearing behavior, but also more locomotor activity than LRA rats. In the plus-maze, HRA rats again showed more locomotion, but did not differ in open arm time or percentage of open arm entries, that is, conventional measures of anxiety-related behavior. In the radial maze, HRA rats consistently needed less time to consume all pellets than LRA rats, which was due to faster locomotion on the arms and less time spent at the food pits (especially in baited arms) of HRA rats. During the initial days of training, they were also more efficient in obtaining all food pellets available. Furthermore, HRA rats visited more arms and made relatively less reference memory errors than LRA rats. This allowed them to forage food quickly, but was paralleled by more working memory errors than in LRA rats. In general, working memory errors were more frequent in the arm with the large bait size, but there were no indications that HRA and LRA rats responded differently dependent on reward size. Finally, LRA rats lost slightly more weight than HRA rats during the period of food deprivation. These results are discussed with respect to the role of cognitive and motivational mechanisms, which as subject-inherent factors can contribute substantially to inter-individual variability in the radial maze.     

Activation-induced restoration of sensorimotor functions in rats with dopamine-depleting brain lesions.

Bilateral electrolytic lesions of the lateral hypothalamus or intraventricular 6-hydroxydopamine injections produced substantial depletions of striatal dopamine in rates. All animals with brain damage showed marked sensorimotor impairments. However, they began to move and respond appropriately to environmental stimuli when placed in a sink of water, in a shallow ice bath, or among a colony of cats or rats. A reversal of the sensorimotor dysfunctions was still apparent shortly after the animals were removed from each activating situation. However, the terapeutic effects dissipated rapidly, and by 4 hr after an exposure the rats responded as poorly as they had prior to activation. These findings are strikingly similar to the "paradoxical kinesia" seen in parkinsonism, a clinical disorder attributed to degeneration of central dopamine-containing neurons. Collectively, they suggest the importance of activation in maintaining responsiveness to senory stimuli in rats following dopamine-depleting brain lesions.     

Memory for frequency in rats: role of the hippocampus and medial prefrontal cortex

On a radial arm maze rats were tested for frequency memory of specific spatial locations, a task that presumably involves the coding of temporal information. On any trial during the study phase rats were allowed to visit three different spatial locations only once and one spatial location twice. During the test phase the rats were given a choice between a spatial location that had been visited once and spatial location that had been visited twice. The rats were reinforced for selecting the twice-visited spatial location. The number of spatial locations between a repetition (lag) was varied from one to three. After extensive training rats displayed memory for frequency only for a lag of three spatial locations, i.e., they displayed a repetition lag effect. Animals then received control, medial prefrontal cortex, or hippocampal lesions. Upon subsequent retests control rats continued to display frequency memory, but animals with medial prefrontal cortex or hippocampal lesions displayed a marked impairment. These data support the idea that both the hippocampus and medial prefrontal cortex code temporal order information.     

Working memory deficits in transgenic rats overexpressing human adenosine A2A receptors in the brain

Adenosine receptors in the central nervous system have been implicated in the modulation of different behavioural patterns and cognitive functions although the specific role of A(2A) receptor (A(2A)R) subtype in learning and memory is still unclear. In the present work we establish a novel transgenic rat strain, TGR(NSEhA2A), overexpressing adenosine A(2A)Rs mainly in the cerebral cortex, the hippocampal formation, and the cerebellum. Thereafter, we explore the relevance of this A(2A)Rs overexpression for learning and memory function. Animals were behaviourally assessed in several learning and memory tasks (6-arms radial tunnel maze, T-maze, object recognition, and several Morris water maze paradigms) and other tests for spontaneous motor activity (open field, hexagonal tunnel maze) and anxiety (plus maze) as modification of these behaviours may interfere with the assessment of cognitive function. Neither motor performance and emotional/anxious-like behaviours were altered by overexpression of A(2A)Rs. TGR(NSEhA2A) showed normal hippocampal-dependent learning of spatial reference memory. However, they presented working memory deficits as detected by performance of constant errors in the blind arms of the 6 arm radial tunnel maze, reduced recognition of a novel object and a lack of learning improvement over four trials on the same day which was not observed over consecutive days in a repeated acquisition paradigm in the Morris water maze. Given the interdependence between adenosinic and dopaminergic function, the present results render the novel TGR(NSEhA2A) as a putative animal model for the working memory deficits and cognitive disruptions related to overstimulation of cortical A(2A)Rs or to dopaminergic prefrontal dysfunction as seen in schizophrenic or Parkinson's disease patients.