Involvement of septal muscarinic receptors in cholinergically mediated changes in rat rearing activity.

We tested the hypothesis that septal muscarinic receptors of the rat are involved in exploratory behavior control, at least as reflected in the measure of rearing activity. At a dose capable of inducing hippocampal theta rhythm, carbachol injection into the septum significantly increased the number of rearings from the 2nd to the 5th min postinjection. The increase was maximal in the 3rd min and gradually declined until the 9th min postinjection, when it was near the control level. This behavioral effect was blocked by prior injection of atropine. These data, when considered with other findings showing a similar motor response caused by the hippocampal injection of the cholinergic agonist, strongly suggest that the cholinoceptive cholinergic components of the septohippocampal system play a role in the release of exploratory behavior. This role might be mediated via muscarinic receptors at the septal level. Moreover, the time course of behavioral action of carbachol injected into the septum is of particular importance for studies on the effect of the drug on performance of the rat in learning and memory tests requiring contribution of exploratory behavior.

Effects of RU 52583, an alpha 2-antagonist, on memory in rats with excitotoxic damage to the septal area.

The anti-amnesic action of RU 52583, an alpha 2-adrenergic receptor antagonist, was evaluated through performance of spatial tasks in a radial maze by rats with N-methyl-D-aspartic acid (NMDA) lesion of the medial septal (MS) nuclei. Memory performance of lesioned or sham-operated rats was evaluated by measuring reference memory as long-term maintenance of an acquired performance and working memory or memory for recent events. The lesion: a produced significant impairments of the animals' memory performance, b) significantly reduced the sodium-dependent high-affinity choline uptake in the hippocampal formation, and c) deeply disrupted cholinergic hippocampal theta waves. Oral administration of RU 52583 at 1 and 2 mg/kg (tested doses: 1-5 mg/kg) prior to performance of the task markedly reduced memory impairments, whereas idazoxan, another alpha 2-adrenergic receptor antagonist, had no effect at tested doses (2-5 mg/kg). Cholinergic drugs--arecoline at 0.1 and 1 mg/kg (tested doses: 0.05-1 mg/kg) and physostigmine at 0.02 and 0.1 mg/kg (tested doses: 1, 2, and 5 mg/kg)-administered intraperitoneally showed a tendency to alleviate memory deficits. The present results show that the alpha 2-adrenergic antagonist RU 52583 possesses cognition-enhancing properties in rats with damage to the septohippocampal system.

Ameliorating effects of RU 47213, a novel oral and long-lasting cholinomimetic agent, on working memory impairments in rats.

The anti-amnesic effects of RU 47213 [1-(4-chlorophenoxycarbonyl)-1,2,5, 6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime], a prodrug with oral and long-lasting cholinergic activity, were evaluated on working memory impairments, using tasks of unequal levels of difficulty involving the same reinforcement and motivation in rats: a spatial-based task in a radial maze and a delayed reinforced alternation task in a T-maze. Tetrahydroaminoacridine (THA; tacrine), a cholinesterase inhibitor was used as a reference. Groups of rats were trained in an automated radial maze or T-maze until they had attained an asymptotic level of performance. On test days, memory impairment was produced by administration of scopolamine (0.1 mg/kg s.c.) 15 min prior to testing. Both THA (1.3, and 5 mg/kg) and RU 47213 (0.2, 0.5, 1, and 2 mg/kg) given prior to testing markedly reduced or suppressed the scopolamine induced working memory deficits in both tasks. This activity was evidenced by either a significant decrease in the number of errors or an increase in the number of correct responses. These results show that RU 47213 possesses the capacity to reduce memory deficits induced by an impairment of cholinergic transmission in the rat.

Antagonism of scopolamine-induced memory impairments in rats by the muscarinic agonist RU 35,926 (CI-979).

The promnesic effects of RU 35,926 (CI-979), a muscarinic receptor agonist, were evaluated on memory impairments induced by the muscarinic antagonist scopolamine, using a radial arm maze task, in comparison with tetrahydroaminoacridine (THA), a cholinesterase inhibitor. Groups of rats were trained in a standard version of the radial maze until they had attained an asymptotic level of performance. The animals were then retested with one trial a day. Twenty minutes before each retest, the rats were given subcutaneous administration of 0.1 mg/kg scopolamine. Oral administration of RU 35,926 (0.02, 0.05, 0.1, 0.2, and 0.5 mg/kg) 30 min before memory retest markedly reduced or suppressed the scopolamine-induced deficit. This reduction was evidenced by a significant decrease in the different types of errors and an increase in the number of correct responses. THA (3 mg/kg, intraperitoneally or orally) given 20 min to testing also significantly reduced or suppressed the scopolamine-induced deficits. These results show that RU 35,926 possesses the capacity to reduce memory impairments induced by a deficit of cholinergic transmission in the rat.

Strategy selection in a task with spatial and nonspatial components: effects of fimbria-fornix lesions in rats.

The main purpose of the present research was to investigate the ability of rats to learn a 12-arm radial maze task that requires the concurrent utilization of both spatial and intramaze cue information. The task involves in a single trial both place and cue learning as well as reference memory (RM) and working memory (WM). Since the animal can choose place and cue arms in any order, the strategies employed to learn the task can be studied as well as the kinds of memory errors that are made. The results of Experiment 1 showed that the number of errors made on the place and cue components of the task did not differ, and that more RM than WM errors were made early during learning. As the task was learned, the animals tended to choose the place arms before choosing the intramaze cue arms, thus suggesting that a spatial strategy was employed first followed by a cue strategy. In Experiment 2 lesions of the fimbria-fornix resulted in temporary impairments in both RM and WM that were especially apparent on the spatial component of the task. The lesioned rats also switched from choosing mostly place arms early during the trial to choosing more cue arms. While fimbria-fornix lesioned rats recovered from the memory impairments with training, the change in response strategy persisted throughout postoperative testing. The procedure of combining both spatial and non-spatial components concurrently in the same task should prove of value in studying response strategies in animals.

Effects of medial and lateral septal lesions on acquisition of a place and cue radial maze task.

Rats with lesions limited to either the medial septal (MS) or dorsolateral septal (LS) nuclei were trained on a place and cue version of the radial maze using a procedure that permits determination of both reference memory (RM) and working memory (WM). Following training the presence or absence of hippocampal theta for MS and LS groups was determined. The results showed that both MS- and LS-lesioned rats were impaired in acquisition. Specifically, the pattern of results indicated a general impairment in working memory that was found on both the place and cue tasks together with impaired acquisition of the place (but not the cue) task. While both septal lesion groups evidenced a similar impairment, rats in the MS group made more errors than LS rats on several components of the tasks. Electroencephalographic recordings revealed that hippocampal theta was not affected in the LS group but was abolished in rats with MS lesions. Thus, it appears that the functional role of the septo-hippocampal system cannot be fully described by a single mechanism or process but rather several processes seem to be affected when the septal area is damaged.

The Roman strains of rats as a psychogenetic tool for pharmacological investigation of working memory: example with RU 41656.

This study examined the effects of RU 41656, a dopaminergic D2 agonist, on the differential working memory performances and on the differential activities of the neurochemical systems of the Roman high (RHA) and Roman low (RLA) avoidance strains of rats. Compared with RLA, RHA performed worse in three tests of working memory (spontaneous alternation, radial maze and object recognition) and had higher levels of exploratory locomotor activity. Hippocampal and frontal cortex choline acetyltransferase (ChAT) activities were lower in RHA. Frontal cortex DA and DOPAC levels, hippocampal and striatal 5-HT and NA levels were higher in RHA. RU 41656 induced a significant improvement in working memory performance of RHA, whereas in RLA it had no effect. It decreased exploratory locomotor activity in both strains. ChAT activity in hippocampus was not affected by RU 41656 in either strain, whereas in frontal cortex it was increased in RHA but not in RLA. Hippocampal NA levels were decreased by RU 41656 in RHA but not in RLA. These results confirm previous data concerning the promnesic effect of RU 41656 and extend the finding that the Roman strains are a psychogenetic model for the behavioural, neurochemical and psychopharmacological study of the working memory in rats.

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.

Contribution of the Roman strains of rats to the elaboration of animal models of memory.

Performances of male rats of the Roman High (RHA)- and Roman Low (RLA)-Avoidance strains were compared along four essential dimensions: working memory, reference memory, spontaneous locomotion and avoidance conditioning. Performances of RLA and RHA rats were significantly different for each dimension. As constantly reported, RHA rats were by far superior to RLA in avoidance conditioning. They had also higher levels of locomotor activity. On the opposite, RLA performed better than RHA in an appetitive working memory task, the delayed reinforced alternation, and were also superior in an appetitive reference memory task, the 5-unit linear maze. These results confirm the fact that RLA rats may acquire positively reinforced learning more rapidly than RHA rats and that the differences in active avoidance behavior between the two strains depend more on differential freezing behavior than on learning or memory capacities. Beyond the problem of the characterization of the Roman strains, these data might give indications on the relationships between behavioral tests widely used in rats, and on their use as memory models.

Roman strains as a psychogenetic model for the study of working memory: behavioral and biochemical data.

Performances of male rats of the Roman High- (RHA), Roman Control- (RCA) and Roman Low- (RLA) Avoidance strains were compared in two working memory tests, a spatial one, the radial maze, and a nonspatial one, an object recognition test. The same rats were subjected to measures of emotional reactivity and of different forms of motor activity and finally to measures of cholinergic and aminergic activities in the hippocampus, frontal cortex and striatum. Compared to RHA, RLA performed better in the two working memory tests, displayed "anxiety" and had also lower levels of exploratory locomotor activity. Hippocampal ChAT activity was higher in RLA than in RHA. Levels of DA and DOPAC in the striatum were higher in RLA compared to RHA, whereas in the frontal cortex they were lower. For most of these measures, RCA were intermediate between RLA and RHA. These results confirm and extend the finding that the Roman strains are not only a genetic model for two-way avoidance conditioning but also for working memory.

Effects of unilateral cerebral ischemia on the hippocampal theta depth profile in the ether-anesthetized Mongolian gerbil.

In gerbils (Meriones unguiculatus) unilateral cerebral ischemia of 5 to 15 min resulted in selective destruction of the ipsilateral hippocampal CA1 stratum pyramidale. It also produced an obvious amplitude reduction in both superficial and deep theta rhythms recorded from damaged hippocampal formation. The presence of normal theta in the left normoxic hemisphere showed that the septohippocampal projections, integrity of which is essential for theta appearance, were spared by ischemia. These data have implications in relation to the two generators hypothesis of theta.

d-Amphetamine enhances memory performance in rats with damage to the fimbria.

Rats were preoperatively trained on a 5-unit linear maze and were then subjected to fimbria lesions. The animals were then retested on the same task with one group of rats with fimbria lesions and a control group being injected daily with 0.5 mg/kg d-amphetamine sulfate prior to testing. Lesions significantly impaired postoperative performance of the task, while amphetamine facilitated performance in fimbria lesioned rats. Due to an optimal learning of the task, performance of control animals was not significantly facilitated. These results raise several important issues including the mechanisms of functional recovery after brain lesions and the role of the hippocampal formation in learning and memory.

Short-term memory, exploration and locomotor activity in aged rats.

Behavioral profiles of young (3-6 months) and aged (24-27 months) rats were compared in three respects: (1) short-term memory, (2) exploration and (3) locomotor activity. Compared to young rats, aged rats were impaired in the 8-arm radial maze acquisition, but not in the delayed reinforced alternation acquisition. They had lower scores of spontaneous alternation, of exploration of a novel object and of a novel environment. Their exploratory activity was lower in a simple environment but similar in a complex environment. Their spontaneous locomotor activity was lower during the dark part of the cycle (8 p.m.-8 a.m.) but not different during the light part of the cycle (8 a.m.-8 p.m.). These results suggest that with respect to short-term memory and exploration, differences between aged and young rats may be influenced by a "complexity" factor and may be secondary to differences in motivation and reactions to novelty.

Effects of selective lesions of fimbria-fornix on learning set in the rat.

The effects of selective partial lesions of the Fimbria-Fornix (FiFx) on reversal and place learning sets were investigated in rats by using a T-maze and a semi-circular multiple discrimination apparatus. Lesions restricted to the Fimbria (Fi) produced a significant deficit in reversal and place learning set, whereas lesions to the Fornix (Fx) only disturbed the learning set based on a reversal procedure. Combined Fi + Fx lesions resulted in impairment in the retention of spatial discrimination tested in the two mazes. Ventral Hippocampal Commissure (vhc) had no significant effect on reversal learning set. These results confirm previous data that the hippocampal formation is involved in learning transfer, and suggest that the Fi and the Fx may play a role in learning set. Our data also confirm previous demonstrations of the ability of rats to rapidly acquire place learning set.

Temporal changes in hippocampal theta activity following twenty minutes of forebrain ischemia in the chronic rat.

The present study was designed to examine the temporal changes in the theta (theta) rhythm recorded from the dorsal hippocampal formation of the chronic rat following 20 min of cerebral ischemia. Recordings were made during both wakefulness and paradoxical sleep. The experimental results show that ischemia resulted in a drastic amplitude reduction in both superficial and deep theta. Amplitude reduction occurred between days 1 and 4 postischemia and was maintained across the subsequent survival period. This EEG alteration was associated with an excessive loss of pyramidal cells in the hippocampal CA1 area, as observed by light microscopy. The above data strongly support our previous conclusions that neural components of the CA1 area may be of fundamental importance for the appearance and the maintenance of not only superficial theta but also deep theta. Moreover, they suggest that the preparation used in the present study may be a useful model for investigations on the neuroanatomophysiological effects of transient cerebral ischemia.

Selective lesions of the fimbria and the fornix in the rat: differential effects on CA1 and dentate theta.

The effects of electrolytic lesions of the dorsal fornix and the dorsomedial fimbria on the CA1 and the dentate theta rhythms (theta s) recorded from the dorsal hippocampal formation were investigated in the ether-anesthetized rat. The results showed that (i) fornix lesions mainly affected CA1 theta, (ii) fimbrial lesions mainly affected dentate theta, and (iii) combined fornix-fimbria lesions suppressed both CA1 and dentate theta s. When considered in connection with other observations, these data suggest that the septal projections pacing the CA1 theta may course essentially within the dorsomedial fornix whereas those pacing the dentate theta may pass essentially within the dorsomedial fimbria. Moreover, our data provide new support for the hypothesis that at least two septohippocampal neural systems are anatomically and functionally independent and capable of controlling the theta activity of the dorsal hippocampal formation of the anesthetized rat.

Decrease in both choline acetyltransferase activity and EEG patterns in the hippocampal formation of the rat following septal macroelectrode implantation.

A decrease in both choline acetyltransferase (CAT) activity and theta (theta) rhythm were observed in the hippocampal formation of rats implanted with a macroelectrode in the dorsomedial part of the septum. The decrease in CAT activity and in theta occurred simultaneously and in parallel, and there was no instance where the two parameters were uncoupled. These observations suggest that a common neurophysiological mechanism is involved in both CAT activity control and theta rhythm production in the hippocampal formation. From a methodological point of view, these observations should be borne in mind in septohippocampal investigations using septal electrode implantation procedures.