The effects of delaying reward on choice preference in rats with hippocampal or selective septal lesions

Two experiments are reported in which rats were trained to choose one of two goal arms in a Y-maze, for water reward. In one arm, the rats always received water (the continuously reinforced-CRF-arm). In the other arm the rats only sometimes received water (the partially reinforced-PRF-arm). During the critical test phase in both experiments, we delayed the reward in the CRF arm only by 10 s. Experiment 1 tested intact rats given saline injections, or injections of chlordiazepoxide hydrochloride (Librium, 5 mg/kg), and rats with hippocampal or cortical control lesions. When reward was immediate in both arms all rats preferred the CRF arm. Once reward was delayed, the rats with hippocampal lesions switched their preference to the PRF arm, while the rats in the other treatment groups did not. Experiment 2 tested rats with medial septal lesions, lateral septal lesions or control operations in the same way. The rats with medial septal lesions, and to a lesser extent those with lateral septal lesions, switched their preference to the PRF arm when compared to the sham-operated controls. We conclude that damage to the hippocampus or its afferent pathway from the septum increases rats' sensitivity to temporal discontiguities between the outcome of a response and its emission.     

Characteristics of memory impairment following lesioning of the basal forebrain and medial septal nucleus in rats

Memory impairment in rats with lesions of the basal forebrain (BF) and medial septal nucleus (MS) including cell bodies of the cortical and septohippocampal cholinergic systems, respectively, were compared in order to evaluate the functional contribution of the two cholinergic systems to memory. Biochemical assay revealed that lesioning of the BF and MS resulted in marked and selective decreases in both choline acetyltransferase and acetylcholinesterase activities in the cerebral cortex and hippocampus, respectively. Rats with BF lesions exhibited a severe deficit in a passive avoidance task; acquisition of passive avoidance by repeated training was sluggish, and the acquired response was rapidly eliminated in a subsequent extinction test. However, only slight impairment of passive avoidance was observed in rats with MS lesions. Memory impairment in rats with BF or MS lesions was also investigated using two spatial localization tasks, the Morris water task and the 8-arm radial maze task. Both BF and MS lesions elicited a significant impairment in the Morris water task that required reference memory, as demonstrated by an apparent increase in the latency to escape onto a hidden platform in a large water tank. The impairment was much more obvious in the BF-lesioned rats. In contrast, in the radial maze task primarily requiring working memory, rats with lesions of the MS showed severe disruption, exhibiting a marked increase in total errors, a decrease in the number of initial correct responses, and an apparent change in the strategy pattern. However, corresponding changes in the rats with BF lesions were slight. These results suggest that BF lesions may lead to substantial long-term memory impairment while MS lesions may primarily produce short-term or working memory impairment, indicating a qualitatively different contribution of the two cholinergic systems to memory. It is also suggested that these two experimental animal models may be useful for evaluation of therapeutic drugs for senile dementia of the Alzheimer type.     

The Entorhinal Cortex and a Delayed Non-matching-to-place Task in Mice: Emphasis on Preoperative Training and Presentation Procedure

This study examined the effects of ibotenate lesions of the entorhinal cortex (EC) on performance of a spatial recognition memory task, the delayed non-matching-to-place task (DNMTP), varying in level of difficulty according to the number of interpolated arm visits between sample-place presentation and subsequent recognition in mice. Results of experiment 1, designed to test the rate of acquisition of the task, showed that experimental animals were impaired in the basic non-matching task. However, with further training they were able to learn the task. Impairments were also observed when the amount of interpolating information inserted was gradually increased, and then all problem difficulties were pseudorandomly tested. There was no measurable recovery of function over time when the animals were retested on the task ∼1 month later. Experiment 2 showed that the animals that received extensive training on the task prior to lesions of the EC were only transiently impaired in the DNMTP task. These data suggest that the EC plays an important role in acquisition rather than retention of the spatial recognition memory task.     

Aversive stimulus attenuates impairment of acquisition in a delayed match to position T-maze task caused by a selective lesion of septo-hippocampal cholinergic projections

Infusion of 192 IgG-saporin (SAP) into the medial septum (MS) of rats selectively destroys cholinergic neurons projecting to the hippocampus and impairs acquisition of a delayed matching to position (DMP) T-maze task. The present study evaluated whether introduction of a mild aversive stimulus 30 min prior to training would attenuate the deficit in DMP acquisition caused by the SAP lesions. Male Sprague-Dawley rats received medial septal infusions of either artificial cerebrospinal fluid or SAP (0.22 microg in 1.0 microl). Fourteen days later, all animals were trained to perform the DMP task. Half of the SAP-treated animals and controls received an intraperitoneal injection of saline each day, 30 min prior to training. Results show that intraperitoneal saline attenuated the impairment in DMP acquisition in SAP lesioned rats. These results suggest that a mild aversive stimulus can attenuate cognitive deficits caused by medial septal cholinergic lesions.     

The effect of excitotoxic hippocampal lesions on simple and conditional discrimination learning in the rat.

The effect of excitotoxic lesions of the hippocampus on acquisition and reversal of simple and conditional tasks was investigated using a Y-maze. Hippocampal-lesioned rats were severely impaired on acquisition and reversal of a conditional visuo-spatial task (where different pairs of visually distinctive choice arms indicated whether a left or right arm choice was correct on that trial) and were unable to acquire a visuo-visual conditional discrimination (where the appearance of the start arm indicated which of the visually distinctive choice arms was correct irrespective of their left/right position). They were not impaired on acquisition or reversal of a simple spatial left/right discrimination task (where all arms had the same visual appearance) nor on acquisition of a visual discrimination (where the correct, visually distinctive, choice arm varied in its left/right position). Hippocampal-lesioned rats were, however, impaired on reversal of this visual discrimination task and on acquisition and reversal of another visual discrimination task in which the visually distinctive choice arms were less different from each other than in the first version of this task. The degree of impairment in the lesioned rats was related to task difficulty for the sham-operated rats and was not specific to tasks requiring spatial choices, visual discrimination or conditional responding. The impairment on conditional tasks was greater than the impairment on those non-conditional tasks which happened to be matched for task difficulty for the sham-operated rats, suggesting that the conditional demand may target the function of the hippocampus rather closely. Statistically worse than chance performance by hippocampal-lesioned (and sham-operated) rats at the beginning of reversal testing, which was given 24 h after achieving criterion on acquisition of that task, indicated that hippocampal-lesioned rats simultaneously exhibited good memory but impaired learning for the type of information required for those tasks.     

Medial septal lesions, radial arm maze performance, and sympathetic sprouting: a study of recovery of function

Long-Evans rats received septal lesions or sham operations and were tested for performance in a radial arm maze, level of activity and water intake in order to test whether recovery of function was mediated by sprouting of peripheral sympathetic fibers. Animals receiving septal lesions displayed an initial deficit in radial arm maze performance followed by recovery. No critical changes occurred in activity level and no recovery was seen in water intake. Subsequent superior cervical ganglionectomies had no effect on recovery of radial arm maze performance.There was a significant relationship between behavioral recovery and the degree of hippocampal AChE depletion. It is concluded that recovery of radial arm maze performance is not mediated by sympathetic sprouting following septal lesions but might be mediated by residual septohippocampal fibers.     

Towards therapy to relieve memory impairment after anterior thalamic lesions: improved spatial working memory after immediate and delayed postoperative enrichment

Injury to the anterior thalamic nuclei (ATN) is associated with severe amnesia in humans. To test the principle that these deficits may be amenable to intervention, the behavioural effects of postoperative housing in an enriched environment were examined in rats that received neurotoxic lesions of the ATN. As expected, rats with ATN lesions maintained in standard group-housing showed severe, and in this case long-term, deficits in a preoperatively trained non-matching-to-sample spatial working memory task. Thirty days of enriched housing, introduced either at 5 days (Experiment 1) or delayed until 40 days post-surgery (Experiment 2) markedly reduced this working memory impairment, including evidence of improved utilization of spatial cues. The treatment gains found in Experiment 2 were maintained at 4 months post-surgery despite no further enrichment. ATN lesions also retarded the postoperative acquisition of spatial discrimination problems in Experiment 1, irrespective of the separation between target arms, but this impairment was not ameliorated by the prior enrichment. This study provides the first evidence of substantial recovery of severe, and otherwise long-lasting, spatial working memory deficits after ATN brain injury and suggests that further investigation on the extent of possible recovery of function in animal models of diencephalic amnesia is warranted.     

Empirical tests of the functional significance of amygdala-based modulation of hippocampal representations: evidence for multiple memory consolidation pathways

This series of experiments evaluated the effects of amygdala damage on the acquisition and long-term retention of variants of the water task, and tested the hypothesis that the amygdala is an essential neural system for consolidation of hippocampal memories. In Experiment 1, rats with large, neurotoxic lesions of the amygdala (AMYG) showed normal acquisition on the standard spatial version of the water task, as well as normal retention and decay rate profiles on the 24-h and 30-day retention probes. In Experiment 2, AMYG rats showed normal one-trial place learning abilities and could retain this one-trial information over a 24 h delay. Experiment 3 showed that the amygdala lesions used in this study were functionally significant because AMYG rats, from Experiment 2, showed impairments in a discriminative fear conditioning to context paradigm. Experiment 4 was a critical test of the idea that the amygdala is a decisive locus for consolidation of hippocampal memories. AMYG rats were trained to sub-asymptotic levels of performance on the standard version of the water task. Following each training session, the subjects were given a post-training peripheral injection of D-amphetamine. A probe test revealed that normal subjects and AMYG rats showed similar post-training memory improvement effects. Taken together, the results show that hippocampal memory consolidation processes do not require amygdala modulation. Arguments for an alternative view are presented suggesting that there are multiple memory consolidation pathways, one of which may depend on amygdala neural circuitry.     

Early life stress impairs social recognition due to a blunted response of vasopressin release within the septum of adult male rats

Early life stress poses a risk for the development of psychopathologies characterized by disturbed emotional, social, and cognitive performance. We used maternal separation (MS, 3h daily, postnatal days 1-14) to test whether early life stress impairs social recognition performance in juvenile (5-week-old) and adult (16-week-old) male Wistar rats. Social recognition was tested in the social discrimination test and defined by increased investigation by the experimental rat towards a novel rat compared with a previously encountered rat. Juvenile control and MS rats demonstrated successful social recognition at inter-exposure intervals of 30 and 60 min. However, unlike adult control rats, adult MS rats failed to discriminate between a previously encountered and a novel rat after 60 min. The social recognition impairment of adult MS rats was accompanied by a lack of a rise in arginine vasopressin (AVP) release within the lateral septum seen during social memory acquisition in adult control rats. This blunted response of septal AVP release was social stimulus-specific because forced swimming induced a rise in septal AVP release in both control and MS rats. Retrodialysis of AVP (1 μg/ml, 3.3 μl/min, 30 min) into the lateral septum during social memory acquisition restored social recognition in adult MS rats at the 60-min interval. These studies demonstrate that MS impairs social recognition performance in adult rats, which is likely caused by blunted septal AVP activation. Impaired social recognition may be linked to MS-induced changes in other social behaviors like aggression as shown previously.     

Long-term effects of immunotoxic cholinergic lesions in the septum on acquisition of the cone-field task and noncognitive measures in rats

In rats, nonspecific mechanical or neurotoxic lesions of the septum impair spatial memory in, e.g., Morris water- and radial-maze tasks. Unfortunately, the lack of specificity of such lesions limits inferences about the role of the cholinergic hippocampal projections in spatial cognition. We therefore tested the effects of septal lesions produced by 192 IgG-saporin in rats, which is highly selective for basal forebrain cholinergic neurons, on home cage activity, noncognitive tests (modified Irwin test, open field and forced swimming tests, and various sensorimotor tasks), and the cone-field spatial learning task. The immunotoxic lesion reduced acetylcholine (ACh) levels in the septum (-61%) and hippocampus (>-75%). Rats with lesions showed mild home-cage hyperactivity at 4 weeks postlesion, but no noncognitive deficits at 13 weeks postsurgery. In the cone-field task, rats with septal lesions made more working- and reference-memory errors than the controls, but acquisition curves were parallel in both groups. The speed of visiting cones was faster in the rats with lesions, indicative of disturbed attention or increased motivation. These data support the growing evidence that involvement of the septohippocampal cholinergic system in spatial learning and memory may have been overestimated in studies that used lesions with poor selectivity.     

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.     

Impulsive choice in hippocampal but not orbitofrontal cortex-lesioned rats on a nonspatial decision-making maze task

Orbitofrontal cortical (OFC) and hippocampal (HPC) lesions in primates and rodents have been associated with impulsive behaviour. We showed previously that OFC- or HPC-lesioned rats chose the immediate low-reward (LR) option in preference to the delayed high-reward (HR) option, where LR and HR were associated with different spatial responses in a uniform grey T-maze. We now report that on a novel nonspatial T-maze task in which the HR and LR options are associated with patterned goal arms (black-and-white stripes vs. gray), OFC-lesioned rats did not show impulsive behaviour, choosing the delayed HR option, and were indistinguishable from controls. In contrast, HPC-lesioned rats exhibited impulsive choice in the nonspatial decision-making task, although they chose the HR option on the majority of trials when there was a 10-s delay associated with both goal arms. The previously reported impairment in OFC-lesioned rats on the spatial version of the intertemporal choice task is unlikely to reflect a general problem with spatial learning, because OFC lesions were without effect on acquisition of the standard reference memory water-maze task and spatial working memory performance (nonmatching-to-place) on the T-maze. The differential effect of OFC lesions on the two versions of the intertemporal choice task may be explained instead in terms of the putative role of OFC in using associative information to represent expected outcomes and generate predictions. The impulsivity in HPC-lesioned rats may reflect impaired temporal information processing, and emphasizes a role for the hippocampus beyond the spatial domain.     

A study of hippocampal structure-function relations along the septo-temporal axis

This study examined structural-functional differences along the septo-temporal axis of hippocampus using radial-maze tasks that involved two different memory processes [reference memory (RM) and working memory (WM)], and the use of two kinds of information (spatial vs. nonspatial cue learning). In addition, retention of the nonspatial cue task was tested nine weeks following completion of acquisition, and the rats then underwent discrimination reversal training. Ibotenic acid lesions limited to either the dorsal pole, intermediate area, or ventral pole had minimal effects on acquisition of the complex place and cue discrimination tasks. The one exception was that rats with lesions confined to the dorsal third of hippocampus made more WM errors on the spatial task (but not the cue task) early in training. Selective lesions of the three hippocampal regions had no effects on either long-term retention or reversal of the nonspatial cue discrimination task. In contrast, rats that had all of the hippocampus removed were severely impaired in learning the spatial task, making many RM and WM errors, whereas on the nonspatial cue task, the impairment was limited to WM errors. Further analysis of the WM errors made in acquisition showed that rats with complete lesions were significantly more likely on both the spatial and nonspatial cue tasks to reenter arms that had been baited and visited on that trial compared to arms that had not been baited. A similar pattern of errors emerged for complete hippocampal lesioned rats during reversal discrimination. This pattern of errors suggests that in addition to an impairment in handling spatial information, complete removal of hippocampus also interferes with the ability to inhibit responding to cues that signal reward under some conditions but not under others. The finding that selective lesions limited to the intermediate zone of the hippocampus produce no impairment in either WM ("rapid place learning") or RM in our radial maze tasks serve to limit the generality of the conclusion of Bast et al. (Bast et al. (2009) PLos Biol 7:730-746) that the intermediate area is needed for behavioral performance based on rapid learning about spatial cues.     

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.     

Neurotoxic lesions of the rat perirhinal and postrhinal cortices and their impact on biconditional visual discrimination tasks

It has been argued that damage to the perirhinal cortex should impair visual discriminations when the stimuli have overlapping features. In Experiment 1, rats with perirhinal cortex lesions were trained on a series of visual discriminations in a water tank, culminating in a biconditional discrimination. No evidence was found of a perirhinal lesion deficit, although the same rats showed an object recognition deficit. In Experiment 2 the lesions were extended to involve both the perirhinal and postrhinal cortices in a new group of rats. An impairment was now found on acquisition of the biconditional task, but this was not specific as impairments were also found on two elemental visual discriminations. Taken together, the study failed to find evidence that the rat perirhinal cortex is necessary for configural visual discriminations and so revealed that some ambiguous visual discriminations can be learnt when this area is removed. Furthermore, there was no evidence that the parahippocampal region is selectively dedicated to configural learning, even though the loss of this area can impair the acquisition of some configural tasks.     

Acquisition and extinction of continuously and partially reinforced running in rats with lesions of the dorsal noradrenergic bundle

Local injection of 6-hydroxydopamine was used to selectively destroy the dorsal ascending noradrenergic bundle (DB) in rats. Two lesion procedures were used, differing in the extent of depletion of forebrain noradrenaline they produced (>90% or 77%). In Experiments 1–3 the rats were run in a straight alley for food reward on continuous (CR) or partial (PR) reinforcement schedules. The smaller lesion reduced and the larger lesion eliminated the partial reinforcement acquisition effect (i.e. the faster start and run speeds produced by PR during training) and the partial reinforcement extinction effect (PREE, i.e. the greater resistance to extinction produced by PR training); these changes were due to altered performance only in the PR condition. Abolition of the PREE by the larger DB lesion occurred with 50 acquisition trials, but with 100 trials the lesion had no effect. In Experiment 4 rats were run in a double runway with food reward on CR in the second goal box, and on CR, PR or without reinforcement in the first. The larger lesion again eliminated the PREE in the first runway, but did not block the frustration effect in the second runway (i.e. the faster speeds observed in the PR condition after non-reward than after reward in the first goal box). These results are consistent with the hypothesis that DB lesions alter behavioural responses to signals of non-reward, but not to non-reward itself. They cannot be predicted from two other hypotheses: that the DB mediates responses to reward or that it subserves selective attention. Since septal and hippocampal, but not amygdalar, lesions have been reported to produce similar behavioural changes, it is proposed that the critical DB projection for the effects observed in these experiments is to the septo-hippocampal system.     

Visual discrimination impairments after lesions in zona incerta or lateral terminal nucleus of accessory optic tract

Possible visual functions of zona incerta (ZI) and lateral terminal nucleus of the accessory optic tract (LTN) in rats were investigated by comparing the effects of localized lesions on a series of discrimination learning tasks. In Experiment 1 animals with ZI lesions were impaired on a simultaneous black versus white (BW) discrimination but not on a simultaneous horizontal versus vertical (HV) task. Animals with LTN lesions were impaired on HV but not on BW. Rats with ZI lesions were impaired on a successive bright versus dim but not a successive HV discrimination when subsequently tested in Experiment 2. Animals with LTN lesions were impaired on both tasks. The results are related to the possibility that visual intensity information gains access to the motor system through a pathway running from the ventral lateral geniculate nucleus to the basal ganglia via ZI. Since LTN lesions impaired acquisition of a HV discrimination, a task highly susceptible to the effects of geniculostriate ablation, it is suggested that such lesions impair the use of visual information without destroying the sensory channels mediating the discrimination.     

Prenatal protein malnutrition and working memory performance in adult rats

The performance of prenatally protein malnourished rats was examined in 2 different tasks of learning and memory beginning at 90 or 160 days of age. In Experiment 1, a rewarded alternation task, run as a spatial working memory procedure on an elevated T-maze, revealed no differences between the formerly malnourished (6/25) and control (25/25) rats when either a minimal or a 20-s inter-trial delay was used. Neither was there a difference when an additional, and conflicting, 'information' run was given to provide a source of proactive interference. In extinction, the 6/25 rats required significantly more sessions to abolish their learned alternation response than the controls. In Experiment 2, an operant equivalent of the T-maze task was applied which allowed greater control over the delay interval and task difficulty. Each trial consisted of a forced information response, for which a randomly selected lever was presented, followed by a free-choice stage, when both levers were presented. The rats were rewarded for pressing the lever not presented at the information stage. The inter-trial interval was always 30 s. When the information response requirement was 10 presses no group differences were found in acquisition of the alternation response or in task performance at delays of 5, 10, 15 or 30 s between information and choice stages. As task difficulty was increased, the performance of the 6/25 rats improved more than that of the 25/25 rats, such that they performed significantly better at the longest delay when the information response requirement was 2 presses. This superior performance of the experimental animals is discussed. No differences in reversal were detected. It was concluded that there is no straight-forward 'hippocampal syndrome' in prenatally malnourished adult rats. Working memory appears largely unaffected, whereas susceptibility to interference and extinction may be modified, depending upon the test parameters employed.     

Buspirone impairs performance of a three-choice working memory water escape task in rats

Two studies were conducted to assess the effects of buspirone and alprazolam on a three-choice working memory water escape task. Both studies involved giving rats three daily trials, each trial consisting of an information run during which guillotine doors forced the rats to swim into the correct escape alley and a test run during which the rats could enter any of the three alleys but escape only on entering the same alley to which they had been forced on the information run. In the first experiment, rats were trained to a 70% correct choice criterion with 5-min interrun intervals and then tested for performance with 5, 20, 20 with distraction, and 60-min interrun intervals. In the second experiment, rats in each of the drug groups were tested after receiving one of three different doses of their respective drug. Results suggest that 1.0, 3.0, and 10.0 mg/kg buspirone but not 0.5, 1.0, and 2.0 mg/kg alprazolam impaired performance of rats on a three-choice working memory water escape task.     

Excitotoxic basolateral amygdala lesions potentiate the memory impairment effect of muscimol injected into the medial septal area

In rats, the septo-hippocampal system is important for memory encoding. Previous reports indicate that muscimol, a specific GABAergic agonist induces learning and memory deficits when infused into the medial septal area. The basolateral nucleus of the amygdala (BLA) modulates memory encoding in other brain areas, including the hippocampus. To explore the interactions between the septo-hippocampal system and amygdala in memory, we studied the effects of intra-medial septal infusions of muscimol in rats with BLA lesions. Animals received sham surgery or excitotoxic BLA lesions and were given infusions of either vehicle or muscimol (5 nmol) into the medial septal area 5 min prior to training sessions in inhibitory avoidance and water maze tasks. In the inhibitory avoidance task, muscimol-induced memory impairment was potentiated by BLA amygdala lesions. Additionally, in the water maze task, BLA-lesioned rats given muscimol infusions into the medial septal also showed memory impairment. These findings indicate that the MSA interacts with the BLA in the processing of memory storage.