Medial septal lesions impair performance on a preoperatively acquired delayed alternation task

Male hooded rats were preoperatively trained to perform an operant delayed alternation (DA) task. The rats were tested, for 10 days each, on DA at 5-, 10-, 20-, and 30-s delays. The rats were then randomly assigned to serve as control subjects or receive a medial septal lesion. Following surgical recovery the rats were retested on DA in the exact manner as they were tested preoperatively. Prior to surgery the groups did not differ, but all rats improved over days of testing, and performed better at short delays than at long delays. In contrast, group differences were obvious following surgery, with the septal-lesioned subjects showing a clear impairment. The control subjects ranged between 85% correct (end of 5-s delay) to 65% correct (end of 30-s delay), while the septal-lesioned rats ranged between 72% correct (end of 5-s delay) to 50% correct (end of 30-s delay). The results are discussed in terms of a working memory impairment produced by the septal lesions.     

Exploring the role of context-dependent hippocampal activity in spatial alternation behavior

In a continuous T-maze spatial alternation task, CA1 place cells fire differentially on the stem of the maze as rats are performing left- and right-turn trials (Wood et al. (2000) Neuron 27:623-633). This context-dependent hippocampal activity provides a potential mechanism by which animals could solve the alternation task, as it provides a cue that could prime the appropriate goal choice. The aim of this study was to examine the relationship between context-dependent hippocampal activity and spatial alternation behavior. We report that rats with complete lesions of the hippocampus learn and perform the spatial alternation task as well as controls if there is no delay between trials, suggesting that the observed context-dependent hippocampal activity does not mediate alternation behavior in this task. However lesioned rats are significantly impaired when delays of 2 or 10 s are interposed. Recording experiments reveal that context-dependent hippocampal activity occurs in both the delay and no-delay versions of the task, but that in the delay version it occurs during the delay period, and not on the stem of the maze. These data are consistent with a role for context-dependent hippocampal activity in delayed spatial alternation, but suggest that, according to specific task demands and memory load, the activity may be generated by different mechanisms and/or in different brain structures.     

Do rats with retrosplenial cortex lesions lack direction?

The retrosplenial cortex is seen as a convergence point for different classes of spatial cue, yet aside from allocentric processing, little is known about other cue types that depend on the integrity of this area. Rats with bilateral retrosplenial cortex lesions were, therefore, trained on a sequence of reinforced spatial alternation tasks designed to isolate different spatial strategies. Using a standard T-maze alternation procedure, which could be solved using multiple strategies, only a marginal lesion effect was observed. Next, by using two T-mazes set side-by-side in the light, and then the dark, it was possible to examine alternation around a fixed bearing (direction alternation). Retrosplenial cortex lesions only disrupted the latter (direction alternation) condition. Direction alternation is of particular interest as it presumably taxes head-direction information, and so provides a way of behaviourally assessing the contribution of this navigation system. Finally, rats were tested on a spatial working memory task in a radial-arm maze. A retrosplenial lesion deficit appeared when the maze was rotated mid-trial, as repeatedly found in previous studies. The pattern of findings in the present study strongly indicates that retrosplenial cortex lesions impair the use of direction cues for alternation, in addition to previously established impairments for allocentric-based navigation and path integration.     

Muscimol infused into the medial septal area impairs long-term memory but not short-term memory in inhibitory avoidance, water maze place learning and rewarded alternation tasks.

These experiments investigated the effects of injections of muscimol (1 or 5 nmol), administered into the medial septal area prior to training, on memory tested at different retention delays after training in 3 tasks: an inhibitory avoidance task, a one-trial place learning task, and a rewarded alternation task. In all 3 tasks, intraseptal injections of muscimol did not impair memory performance at short retention delays, but impaired memory at the longer retention delays. These findings are consistent with the view that GABAergic regulation of the septohippocampal cholinergic system plays a selective role in the establishment of long-term memory.     

Basal forebrain lesions produce a dissociation of trial-dependent and trial-independent memory performance

The behavioral effects of lesions in the basal forebrain (BF) of rats were evaluated using two tasks. The BF lesions included both the nucleus basalis magnocellularis (NBM) and the medial septal area (MSA). The first task was a Stone maze, which has 14 consecutive choice points and is a task of complex, trial-independent memory. BF lesions did not impair choice accuracy in this task. The second task was a win-shift spatial discrimination in a radial arm maze, which requires trial-dependent memory. BF lesions produced a significant decrease in choice accuracy in this task. These results demonstrate that BF lesions impair trial-dependent (working) memory but not trial-independent reference memory, and that task difficulty is not the sole factor determining whether BF lesions produce behavioral impairments.     

Galanin and perseveration

Galanin is a 29/30 amino acid neuropeptide that has been shown to impair learning and memory task performance and also have roles in somatosensation, stress responses, sexual behavior, and feeding regulation. However, little is known about galanin involvement in higher cognitive processes, especially executive processes. Perseveration is a classic sign of frontal cortex damage and failure of executive control. Galanin has been shown to disrupt the performance of maze delayed alternation tasks and the operant, spatial delayed nonmatch-to-position (DNMTP) working memory task, tests especially sensitive to perseverative responding. To better understand this potential involvement of galanin in executive control, the present study tested the hypothesis that galanin induces perseveration. The first experiment examined the effects of galanin (10, 20 microg i.c.v.) on the performance of a simple operant response alternation task in which stimuli were assigned to one of two spatially distinct locations to produce extended sequences of presentations to one location, separated by a 10-s intertrial interval. The second experiment looked at the effects of galanin (5, 20 microg i.c.v.) on the performance of non-delayed match-to-position and nonmatch-to-position conditional discrimination operant tasks in which a minimal 1.0 s time interval separated responses. Finally, the effects of galanin (10, 20 microg i.c.v.) on delayed match-to-position (DMTP) performance were examined to determine whether response alternation (i.e., nonmatching) was critical to observing a galanin-induced impairment in this task. Galanin reduced the rate of trial completion in all the tasks, but did not alter simple or conditional discrimination accuracy. Galanin (10 microg) impaired DMTP performance in a delay-independent manner. Together, these data suggest that galanin does not produce perseveration, but are consistent with a galanin-induced decrease in reinforcer strength.     

Comparison of the effects of neonatal and adult medial prefrontal cortex lesions on food hoarding and spatial delayed alternation

Performance in food hoarding, a species-typical task, and spatial delayed alternation, a learning task, was investigated in male rats with bilateral medial prefrontal cortex (mPFC) lesions sustained in adulthood or at the age of 6 days. Animals with adult mPFC lesions hoarded significantly fewer food pellets than their controls. The mPFC lesion effect on hoarding behaviour of the neonatally operated rats was unclear because of the unexpectedly low hoarding score of their controls. In the spatial delayed alternation task, the animals with mPFC lesions in adulthood exhibited a permanent deficit, while the animals with neonatal mPFC lesions showed no significant deficits. It is concluded that a bilateral lesion in adulthood, mainly affecting the frontal area 2 and the dorsal anterior cingulate area of the mPFC, results in a permanent deficit in food hoarding and spatial delayed alternation performance, whereas a similarly restricted mPFC lesion at the age of 6 days shows a complete sparing of the spatial delayed alternation task performance.     

Medial prefrontal and neostriatal lesions disrupt performance in an operant delayed alternation task in rats

An operant version of the classical delayed alternation task is presented and applied to evaluate the effects of bilateral prefrontal and striatal lesions in rats. Retractable levers in a conventional operant chamber control discrete trial opportunities for making sequential choice responses to the two sides, and the rats are required to maintain repeated nose poke responses to a central panel during the delay interval, which is randomly varied. The operant task provides measures of the speed and accuracy of response alternation and side bias; analysis at different delay intervals provides an index of the memory demands of accurate performance; and analysis of accuracy depending on the response on preceding trials provides measures of proactive interference and perseveration. Following pretraining in the task contingencies, both striatal and prefrontal lesions induced profound deficits in task accuracy, with no change in side bias and only small changes in movement times. The deficit in the prefrontal lesion group recovered more rapidly, neither group showed any change in sensitivity to proactive interference, while the rats with striatal lesions alone exhibited an increased tendency to perseverate incorrect responses on either side. We conclude that the operant delayed alternation task should assist analysis of fronto-striatal function in rats as well as be useful for the analysis of strategies for fronto-striatal repair.     

Activation of the hippocampus and dentate gyrus by working-memory: a 2-deoxyglucose study of behaving rhesus monkeys

The 2-deoxyglucose method was used to examine metabolic activity in the hippocampus, dentate gyrus, and amygdala of rhesus monkeys performing working-memory and control tasks. A working-memory group was tested on 1 of 3 tasks requiring trial-by-trial updating of information: delayed spatial response, delayed spatial alternation, or delayed object alternation. A control group was tested either on an associative memory problem, visual pattern discrimination, or a sensory-motor task that did not have an explicit mnemonic component. Local cerebral glucose utilization (LCGU) in specific layers of the dentate gyrus and the CA1 and CA3 sectors of the hippocampus, as well as in 7 distinct nuclei of the amygdala, was measured and compared across groups. Metabolic rate in specific layers of the dentate gyrus and the CA3 and CA1 fields of the hippocampus was enhanced in the working-memory compared with the control group: LCGU was between 18 and 24% higher in the granule cell and molecular layers of the dentate gyrus and in the molecular and radiatum layers of CA1 and CA3 in the hippocampus. In contrast, no significant group differences in LCGU were found for any of the 7 amygdaloid nuclei examined: the lateral, lateral basal, medial basal, accessory basal, cortical, central, and medial nuclei. These results are consistent with previous evidence showing that lesions of the hippocampus affect memory selectively, producing deficits on some memory problems while sparing others. Our findings further suggest that working-memory may be a common denominator among those tasks that are sensitive to hippocampal damage in monkeys. The contribution of the amygdala to performance on memory tasks, on the other hand, appears to be independent of the specific type of memory process that is engaged.     

Memory-related acetylcholine efflux from rat prefrontal cortex and hippocampus: a microdialysis study

To investigate the relationship between the prefrontal and hippocampal acetylcholine (ACh) systems and working memory, an in vivo microdialysis study was conducted. A group of rats was trained to perform a working memory task, delayed alternation, in an operant chamber for food reinforcement. The rats had to choose one of two response levers in an alternative manner in each trial, with a certain interval between trials. They had to remember which lever they chose in the previous trial without the assistance of external cues. Another group was trained to perform a reference memory task, cued alternation, in which the behavioral sequence was identical, but an external cue was provided. After stable behavior was established, a dialysis probe was implanted into the prefrontal cortex or the hippocampus of each rat. The extracellular concentration of ACh in the dialysates from the prefrontal cortex increased during performance of the delayed alternation task, while the hippocampal ACh showed a more distinct increase during performance of the cued alternation task. These results suggest that the prefrontal ACh is mainly related to working memory, whereas the hippocampal ACh is mainly related to reference memory.     

Pharmacological challenge reveals long-term effects of perinatal phencyclidine on delayed spatial alternation in rats

Administration of the N-methyl-D-aspartate (NMDA) antagonist phencyclidine (PCP) may produce alterations in behavior that resemble those that have been observed in animal models of schizophrenia. This study was designed to examine the effects of early postnatal injection of PCP on later acquisition and performance of a delayed spatial alternation task, a procedure that is sensitive to manipulations of the prefrontal cortex. At the beginning of the study, we injected cross-fostered female rat pups subcutaneously with either saline or 10 mg/kg PCP on postnatal (PN) days 7, 9, and 11. On PN34, the rats began training in a delayed spatial alternation task consisting of 10 daily trials with a 10-s intertrial interval. Although accuracy improved significantly faster in the saline-treated group than in the PCP-treated group, by PN70, both groups had acquired the task with approximately equal accuracies. Pharmacological challenges with the NMDA antagonists, PCP and ketamine, and with the dopamine modulator, amphetamine, decreased accuracy to a similar extent in both groups of rats when intertrial delays were held constant at 10 s; however, nicotine did not decrease accuracy in either group. In contrast, dizocilpine (a high-affinity NMDA open-channel blocker) produced a more pronounced decrease in accuracy in the PCP-treated rats than in the saline-treated rats. When delays were lengthened to 30 s, PCP also decreased accuracy in the PCP-treated rats to a greater extent than in saline-treated rats. These results suggest that perinatal administration of PCP may produce long-term alterations in cognition that are revealed by pharmacological challenge and manipulation of task difficulty.     

Long-term effects of nerve growth factor and neural transplants on behavior of rats with medial septal lesions

The present experiment investigated the interaction between exogenous nerve growth factor (NGF) and intrahippocampal septal grafts on the behavior of rats after a medial septum lesion. Young female rats received a bilateral injection of a fetal septal cell suspension into the dorsal hippocampus either immediately (immediate grafts) or 8 days after the lesion (delayed grafts). For delayed grafts, a higher concentration of endogenous neurotrophic factors can be assumed to be present in the deafferentated host tissue at the time of transplantation. One group of rats with lesions received NGF with the immediate grafts, another group received NGF alone. A sham-operated group and 3 groups with lesions (and given either immediate or delayed intrahippocampal saline injections, or no other treatment) constituted controls. The animals were tested for spontaneous alternation and for performance in a radial 8-arm maze, 1, 5 and 9 months postoperatively. Medial septal lesions reduced spontaneous alternation but, 9 months after surgery, recovery was observed in both lesion-control rats and in rats with delayed grafts (but not with immediate grafts). In the radial maze task, lesions produced a persistent impairment, although both immediate and delayed grafts reduced this deficit several months after surgery (more markedly and rapidly in the case of delayed grafts). NGF, however, increased the maze learning deficit especially 5 months postoperatively. These latter results are in contrast to findings of earlier studies showing transient beneficial effects of NGF administration. It is suggested that the effects of NGF in the present study might be due to an enhanced sprouting of sympathetic fibers into the hippocampal formation.     

Evidence against a role of the rat's dorsal noradrenergic bundle in selective attention and place memory

In Experiment 1,6-hydroxydopamine-induced lesions of the dorsal noradrenergic bundle (DNB) in rats did not impair either acquisition of non-delayed alternation, retention of non-delayed alternation, or performance of alternation with delays in a T-maze, whether or not the goal arms of the maze were visually distinctive. These results were in contrast with those of a previous report indicating that DNB lesions impair learning of spatial alternation. In Experiment 2, the lack of a reliable effect of DNB lesions on learning performance of spatial alternation was confirmed. However, the rats with DNB lesions showed an impairment of spontaneous alternation. The negative results of the present study do not support either the hypothesis that depletion of forebrain noradrenaline impairs selective attention or the hypothesis that such depletion induces an amnesia for past places. On the other hand, the finding of impaired spontaneous alternation is consistent with previous observations suggesting that depletion of forebrain noradrenaline impairs habituation of fear reactions.     

Striatal grafts alleviate bilateral striatal lesion deficits in operant delayed alternation in the rat

In order to assess the capacity of striatal grafts to alleviate cognitive deficits of the frontal type that arise following bilateral striatal lesions, control, lesion and grafted rats were tested in an operant test of delayed alternation. Bilateral striatal lesions induced a marked impairment in choice accuracy, and signal detection analysis indicated that the lesion animals were reliably impaired on both parametric and non-parametric indices of discriminative sensitivity but not of response bias. The impairment was apparent at all intertrial interval delays, including the very shortest, suggesting the deficit is one of frontal-type executive function rather than of short-term memory. The grafted animals exhibited a significant alleviation of the deficit, again apparent at all delays. Histological analyses indicated good graft survival, and injections of a dextran amine anterograde tracer bilaterally into the host prefrontal cortex indicated reformation of extensive projections into the grafted tissues. Since performance of the operant delayed alternation task is dependent upon the integrity of corticostriatal connections, which is disrupted bilaterally by the lesions and restored to the grafts in the transplanted animals, the results corroborate the hypothesis that striatal grafts can alleviate complex cognitive functions of the frontal type by a mechanism that involves functional integration of the grafted neurons into the neural circuits of the host brain.     

Septal transplants restore maze learning in rats with fornix-fimbria lesions

In a study of the capacity of neural grafts to promote functional recovery in rats with fimbria-fornix lesions, 5 groups of rats were studied behaviourally and with acetylcholinesterase (AChE) histochemistry: (1) sham-operated controls; (2) bilateral fimbria-fornix lesions; (3) bilateral lesions plus bilateral solid embryonic septal grafts to the lesion cavity; (4) bilateral lesions plus bilateral embryonic septal suspension injections into the hippocampus; and (5) bilateral lesions plus bilateral solid embryonic locus coeruleus grafts to the lesion cavity. Seven months were allowed for growth of the grafts and reinnervation of the host hippocampus prior to behavioural testing.The control rats were able to rapidly learn a rewarded alternation task, while the performance of animals with bilateral fimbria-fornix lesions alone remained at a chance level. Both types of septal grafts (rich in cholinergic neurones) but not the locus coeruleus grafts (rich in noradrenergic neurones) reversed the impairment. Behavioural recovery correlated significantly with AChE-positive fibre ingrowth from the grafts into the denervated host hippocampus. However, the septal grafts did not ameliorate the lesion-induced disturbances in spontaneous activity or spontaneous alternation. Thus, the observed behavioural recovery appears specific to the conditioned alternation task and dependent upon cholinergic reinnervation of the hippocampus.     

Sympathetic sprouting and recovery of a spatial behavior

After lesions of the medial septum, peripheral sympathetic fibers from the superior cervical ganglion appear in the hippocampal formation. To assess the functional significance of this neuronal rearrangement, we analyzed behavior on a spatial/memory task sensitive to hippocampal dysfunction, the radial eight-arm maze. The procedure allowed evaluation of both working and reference memory. All rats were able to master the task. Half of the rats then underwent either medial septal lesions and ganglionectomy or sham neurosurgery and ganglionectomy, and the other half underwent medial septal lesions or sham neurosurgery followed by ganglionectomy after further behavioral testing. Medial septal lesions in both groups disrupted taks performance with recovery of performance occurring with time. However, the rate of recovery was significantly enhanced in rats which had septal lesions and ganglionectomies simultaneously. Removal of the ganglion after recovery produced no effects on maze performance. Our results suggest that sympathetic ingrowth retards recovery processes.     

The Effects of AMPA-induced Lesions of the Medial Septum and Vertical Limb Nucleus of the Diagonal Band of Broca on Spatial Delayed Non-matching to Sample and Spatial Learning in the Water Maze

These experiments investigated in the rat the impact on spatial delayed non-matching to sample and on acquisition of the Morris water maze of (i) AMPA-induced lesions of the medial septal nucleus, which produced a marked reduction of hippocampal choline acetyltransferase activity and acetylcholine levels (measured using in vivo dialysis) together with lesser reductions in cholinergic markers in the cingulate cortex and (ii) similar AMPA-induced lesions of the vertical limb nucleus of the diagonal band of Broca (vDB), which produced more marked reductions in cholinergic markers in the cingulate cortex than in the hippocampus. Medial septal lesions produced a delay-dependent deficit in spatial working memory, while lesions of the vDB resulted in a delay-independent performance deficit. In addition, rats with vDB lesions adopted biased response strategies during the imposition of long delays. Neither lesion significantly affected the acquisition of a spatial reference memory task, the Morris water maze. The results are discussed in terms of cholinergic- and GABAergic-dependent functions of the hippocampal formation and cingulate cortex in spatial short-term and reference memory.     

Inactivation of the medial prefrontal cortex of the rat impairs strategy set-shifting, but not reversal learning, using a novel, automated procedure

The medial prefrontal cortex (mPFC) of the rat plays an essential role in behavioral flexibility, as lesions or inactivations of this region impair shifting between strategies or attentional sets using a variety of different behavioral tests. In the present study, we assessed the effects of inactivation of the mPFC on strategy set-shifting and reversal learning, using a novel, automated procedure conducted in an operant chamber. In Experiment 1, inactivation of the mPFC with bupivacaine did not impair the initial learning of a visual-cue (i.e.; always press the lever with a cue light illuminated above it) or a response (i.e.; always press the left lever) discrimination. Control rats required greater number of trials to shift from using a visual-cue to a response strategy than the opposite shift. mPFC inactivation impaired performance of a visual-cue-response set-shift, but not the easier response-visual-cue shift. In Experiment 2, pre-exposure to the visual-cue stimulus lights increased the difficulty of the response-visual-cue shift, reflected by a greater number of trials required by control rats to achieve criterion relative to those in Experiment 1. Under these conditions, inactivation of the mPFC did impair performance of this set-shift. In contrast, mPFC inactivation did not affect reversal learning of a response discrimination. These findings highlight the utility of this automated procedure for assessing set-shifting mediated by the mPFC. Furthermore, they reveal that the relative difficulty of the type of shift rats are required to perform has a direct impact on whether or not the mPFC contributes to this form of behavioral flexibility.     

Impairments in the acquisition, retention and selection of spatial navigation strategies after medial caudate-putamen lesions in rats

Using the Morris swimming pool test of spatial navigation, medial caudate-putamen lesions in rats produce impairments in the acquisition and retention of both place and cue tasks, and impair the selection of normal navigation strategies. Also described are some novel features of spatial navigation behaviour displayed by control animals in cue and place tasks that provide insights into the performance of the caudate-putamen rats. Analyses of the swim patterns on postacquisition probe trials, in which the target platform was removed or relocated, showed that the strategy used by the caudate-putamen lesioned rats was dependent upon the task that they were required to solve. Control rats used a place strategy and distal visual cues to identify the location of the start points, the routes from the start points to the platform, and the location of the platform on both the cue and place tasks. The caudate-putamen lesioned rats used distal visual cues and a place strategy only to acquire the place task. They solved the cue task using a taxon strategy consisting of a combination of proximal and position response cues. The results suggest that when necessary, medial caudate-putamen lesioned rats, like normal rats, can use place strategies for spatial navigation, but if an alternate, perhaps simpler, taxon solution is available they seemingly ignore place information and navigate using the simpler strategy. The deficit, which has features of a neglect rather than a loss of ability per se, suggests that medial caudate-putamen neural systems are involved in the selection of alternative strategies in spatial navigation tasks.     

Parallel information processing in the dorsal striatum: relation to hippocampal function.

We investigated the effects of localized medial and lateral CPu lesions and fornix/fimbria lesions on responses to a local cue and to behavior based on cognitive-spatial information in the water maze. Rats were trained concurrently on the cue (visible platform) and spatial (submerged platform) components of the task, followed by a test in which responses to the two types of information were dissociated by a measure of competing response tendencies. Bilateral lesions of lateral CPu did not affect acquisition of either cue or spatial responding but produced a preference for the spatial response on the competition test. Bilateral lesions of the medial CPu retarded but did not prevent learning both components and produced a preference for the cue response on the competition test. The latter effect was accompanied by increased thigmotaxis (swimming in the periphery of the pool), primarily during the early acquisition trials, which was attributed to an impaired ability to respond to learned spatial information. Fornix/fimbria lesions prevented spatial but not cue learning and produced a preference for the cue response on the competition test. Asymmetric lesions (unilateral hippocampus and contralateral medial CPu) produced mild retardation of acquisition of both the cue and spatial tasks and a preference for the cue response on the competition test. These findings dissociate the functions of the lateral and medial CPu and suggest that the hippocampus and medial CPu may be parts of a system that promotes responding based on learned cognitive-spatial information, particularly in competitive cue-place response situations.