A further characterization of the spatial problem-solving deficit induced by lesions of the medial frontal cortex in the rat

Two experiments were conducted to investigate the basis of the spatial impairment displayed by rats with lesions to the medial frontal cortex, using a three-table Y-shaped apparatus. In both experiments, animals were first given an exploratory experience of the maze, followed by a short feeding experience on one of the tables, and were then required to return to the location where they had just been fed. In Expt. 1, a spatial working memory procedure was used in which the location of the goal table was varied from day to day. When compared to normal animals frontal rats showed a marked impairment, despite the addition of (a) distinctive visual cues on the tables and their associated runways, or (b) a conspicuous visual pattern placed directly above the goal. Expt. 2 used a spatial learning procedure, in which the spatial location of the goal table remained constant over days. However, the whole apparatus was daily rotated so that animals could not learn to associate the goal table with specific cues located behind it. This procedure did not prevent frontal animals from learning the consistent location of the food by using the spatial relationships of the environment. These results, together with previous ones, suggest that frontal animals suffer from a specific (though not restricted to the domain of spatial information) working memory deficit, and their spatial reference memory is not impaired.     

Rhinal and dorsolateral prefrontal cortex lesions produce selective impairments in object and spatial learning and memory in canines

To examine the effects of rhinal and dorsolateral prefrontal cortex lesions on object and spatial recognition memory in canines, we used a protocol in which both an object (delayed nonmatching to sample, or DNMS) and a spatial (delayed nonmatching to position or DNMP) recognition task were administered daily. The tasks used similar procedures such that only the type of stimulus information to be remembered differed. Rhinal cortex (RC) lesions produced a selective deficit on the DNMS task, both in retention of the task rules at short delays and in object recognition memory. By contrast, performance on the DNMP task remained intact at both short and long delay intervals in RC animals. Subjects who received dorsolateral prefrontal cortex (dlPFC) lesions were impaired on a spatial task at a short, 5-second delay, suggesting disrupted retention of the general task rules; however, this impairment was transient, and long-term spatial memory performance was unaffected in dlPFC subjects. The present results provide support for the involvement of the RC in object, but not visuospatial, processing and recognition memory, whereas the dlPFC appears to mediate retention of a nonmatching rule. These findings support theories of functional specialization within the medial temporal lobe and frontal cortex and suggest that rhinal and dorsolateral prefrontal cortices in canines are functionally similar to analogous regions in other mammals.     

Cholinergic receptor blockade in prefrontal cortex and lesions of the nucleus basalis: implications for allocentric and egocentric spatial memory in rats

In this study we have examined the involvement of the prefrontal cortex (PFC) along with the Nucleus basalis magnocellularis (NBM) in two types of spatial navigation tasks. We evaluated the effects of excitotoxic (ibotenate-induced) lesions of the NBM in an allocentric and an egocentric task in the Morris water maze, using sham operations for a comparison. In both cases we also assessed the effects of local cholinergic receptor blockade in the PFC by infusing the muscarinic receptor antagonist scopolamine (4 or 20 microg). Anatomically, the results obtained showed that this lesion produced a profound loss of acetylcholinesterase (AChE) positive cells in the NBM, and a loss of AChE positive fibres in most of the neocortex, but hardly in the medial PFC. Behaviourally, such lesions led to a severe impairment in the allocentric task. Intraprefrontal infusions of scopolamine led to a short-lasting impairment in task performance when the high dose was used. In the second experiment, using the same surgical manipulations, we examined the performance in the egocentric task. Like in the allocentric task animals with NBM lesions were also impaired, but with continued training they acquired a level of performance similar to the sham-operated ones. This time, infusions of scopolamine in the medial PFC led to a severe disruption of performance in both groups of animals. We conclude that acetylcholine in the medial PFC is important for egocentric but not allocentric spatial memory, whereas the NBM is involved in the learning of both tasks, be it to a different degree.     

Temporal and spatial context memory in patients with focal frontal, temporal lobe, and diencephalic lesions

Patients with focal frontal, temporal lobe, or diencephalic lesions were investigated on measures of temporal (recency) and spatial (position) context memory, after manipulating exposure times to match recognition memory for targets (pictorial stimuli) as closely as possible. Patients with diencephalic lesions from an alcoholic Korsak off syndrome showed significant impairment on the temporal context (recency) task, as did patients with frontal lesions penetrating the dorsolateral frontal cortex, according to MRI (and PET) evidence. Patients with temporal lobe lesions showed only a moderate (non-significant) impairment on this task, and patients with medial frontal lesions, or large frontal lesions not penetrating the dorsolateral cortical margins, performed as well as healthy controls at this task. On the spatial context memory task, patients with lesions in the temporal lobes showed significant impairment, and patients with right temporal lesions performed significantly worse than patients with left temporal lesions. Patients with diencephalic lesions showed only a modest (non-significant) impairment on this task, and the frontal lobe group performed normally. When a group of patients with temporal lobe lesions resulting from herpes encephalitis were examined separately, an identical pattern of results was obtained, the herpes group being significantly impaired on spatial memory and showing a trend towards impairment for temporal context memory. There were strong correlations between anterograde memory quotients and context memory performance (despite the use of an exposure time titration procedure) and a weak association with one frontal/executive task (card-sorting perseverations). It is predicted that correlations between temporal context memory and frontal/executive tasks will be greater in samples of patients all of whom have frontal lesions invading the dorsolateral cortical margin.     

Experimental immune-mediated damage of septal cholinergic neurons

Degeneration of cholinergic neurons in the medial septum and the diagonal band of Broca is a frequent neuropathological feature of Alzheimer's disease. To determine whether an immune process can injure these basal forebrain cholinergic neurons, we serially immunized guinea pigs with septal cholinergic hybrid cells (SN-56). Following immunization, a relatively selective damage of septal cholinergic neurons, reduction in septal choline acetyltransferase (ChAT) activity and decrease in acetylcholine release in hippocampus were detected. Serum IgG from guinea pigs immunized with SN-56 cells and stereotactically injected into the medial septal region of rats produced a loss of ChAT activity in the medial septum, frontal cortex and hippocampus, together with impairment of learning and long term spatial memory. These data suggest that relatively selective damage to septal cholinergic neurons can be caused by an immune-mediated process in experimental animals.     

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.     

Effects of medial septal lesions on operant delayed alternation in rats

The septohippocampal system regulates spatial behavior, memory and response flexibility. This experiment determined which of these functions is disrupted by medial septal lesions which impair operant delayed alternation in rats. Male hooded rats received either medial septal lesions or a control operation. Following recovery, they were reinforced for alternating left and right lever presses in an operant chamber. The effects of various delays (0, 10 and 20 s), and exteroceptive cues were assessed. Medial septal lesions did not impair alternation performance at the 0-s delay, but did produce severe impairments at the 10- and 20-s delays. An exteroceptive light cue which reduced the spatial requirements of the task did not ameliorate this impairment. However, an exteroceptive light cue which reduced the working-memory requirements of the task did ameliorate the lesion-induced deficit on delayed alternation. While the lesioned rats also made more perseverative errors than the controls, statistically removing this influence from the data did not modify the results. These data suggest that medial septal lesions in rats impair operant delayed alternation by disrupting the general process of working-memory rather than spatial behavior or response flexibility.     

Conditional discrimination learning in rats with global ischaemic brain damage

Hippocampal cell loss was induced by the four-vessel occlusion (4VO) method, a model of global ischaemia. Global ischaemia for 15 min induced a selective damage to the CA1 subfield. Occlusion for 25 min produced a larger cell loss within the CA1 and more variably the CA2, CA3, the striatum and cortex. Ischaemic and sham control groups were assessed on two conditional discrimination tasks (presenting the conditional cues either in the choice arms or the start arm) and two spatial tasks (water maze and a simple spatial discrimination task). No significant effects were found on either of the spatial tasks (apart from the speed measure on the water maze). However, on the conditional discrimination task with the cues in the choice arms, animals with 25 min ischaemia learned the task significantly more slowly than the 15 min ischaemic and control groups. Results for the task with cues presented in the start arm differed according to choice of criterion for learning. With a standard criterion of 90% accuracy on one session controls were significantly superior to both ischaemic groups. However, in this task rats with 15 min occlusion showed the greatest impairment, and were significantly worse than both the controls and the 25 min occlusion group. These results suggest that hippocampal ischaemic damage disrupts the learning of conditional discrimination but not simple spatial tasks. No clear relationship between the extent of hippocampal cell loss and behavioural impairment was evident. These results highlight the critical importance of procedural factors in the assessment of cognitive impairment.     

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.     

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.     

The septo-hippocampal system and cognitive mapping

Rats were trained on a rewarded alternation task, run as a spatial working memory task on an elevated T-maze. Experiment 1 tested the effects of fornix-fimbria (FOFI) lesions on the acquisition, and of medial septal (MS) lesions on the acquisition and retention of this task, when the rats had to use information provided by being forced to run to a selected goal arm. The FOFI lesion produced an enduring impairment; the MS rats showed a severe impairment initially, but subsequently showed some behavioural recovery, when tested in acquisition or in retention. Experiment 2 similarly tested the effects of lateral septal (LS) lesions on acquisition of the task, and found an impairment which again showed signs of recovery with further testing. Experiment 3 was a transfer test conducted on the rats which had shown recovery in Experiments 1 and 2. The rats were now forced to use information provided by simply being placed on a selected goal arm. Both control animals and lesion animals showed identical choice accuracy, lower than that seen in Experiments 1 and 2. Experiment 4 tested acquisition of the task used in Experiment 3, and acquisition of a task in which the rat had to use information provided by running to the goal arm via a different route. Control rats again performed poorly, and scarcely differed from MS rats. It was concluded that rats have difficulty in using information about ‘places’, and that controls and lesion rats learn the tasks in the same way. The implications for ‘cognitive mapping’ hypotheses are discussed.     

Serial position curves for item (spatial location) information: role of the dorsal hippocampal formation and medial septum

Animals were trained on an item recognition memory task for a list of 5 spatial locations. After reaching criterion performance the animals sustained small or medium-size dorsal hippocampal formation lesions, small or large medial septal lesions, or served as sham-operated or cortical controls. Following recovery from surgery, animals were retested for item recognition memory. Sham-operated and cortical control animals showed no deficits in performance. In contrast, animals with small dorsal hippocampal formation or medial septal lesions displayed a deficit for the early items, but had excellent memory for the last item of the list. Animals with medium-size dorsal hippocampal formation or large medial septal lesions displayed a deficit for both early and late items within the list. Because residual short-term memory capacity can be seen only with small hippocampal formation or medial septal lesions, it is suggested that the hippocampal formation and cholinergic input into the hippocampal formation via the medial septum code spatial information within a continuous extended time frame.     

Failure of chronic physostigmine to ameliorate working memory deficits after medial septal lesions

To assess the potential usefulness of chronic acetylcholinesterase inhibition in the treatment of learning/memory disorders arising from central cholinergic deficient states, physostigmine was administered chronically to rats with medial septal lesions and the retention of a spatial/working memory task investigated. Three dose levels of physostigmine (0.025, 0.05, 0.075 mg/kg) were administered three times per day following medial septal lesions. Retention of a standard radial 8-arm maze task was assessed. Although the lesions transiently disrupted task performance, physostigmine therapy did not improve either daily performance or total recovery time. Our results suggest that chronic acetylcholinesterase inhibition is not effective in ameliorating the working memory deficits that occur after medial septal lesions.     

Cognitive mapping in rats: The role of the hippocampal and frontal systems in retention and reversal

These experiments determined the extent to which the hippocampal system and the medial frontal cortex are selectively involved in cognitive mapping in spatial environments.Rats were trained to discriminate between two 3-dimensional objects based on either the location of the objects in the test environment, or on the stimulus characteristics of the objects themselves. Following the acquisition of one of these discrimination tasks, each rat was given a series of transfer tests to determine the extent to which a cognitive mapping strategy had been used to solve the task. Each rat was then given a lesion in the fimbria-fornix or the medial frontal cortex, or a control operation. In the location discrimination, rats with fimbria-fornix lesions, as compared to control rats: (a) performed poorly at the beginning of retention testing; (b) relearned the task to criterion performance; (c) performed normally during the transfer tests indicating that they used a cognitive mapping strategy, and (d) performed poorly in the discrimination reversals. In the object discrimination, these rats performed as well as controls during retention and transfer tests, but had a slight impairment during discrimination reversals. The performance of rats with lesions in the medial frontal cortex was worse than that of the controls during the retention of both discriminations, and during the reversal of the location, but not the object discrimination. These results are related to predictions of current theories implicating the hippocampus and medial frontal cortex in spatially organized behaviors, particularly those behaviors requiring cognitive mapping.     

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.     

Abnormal brain activity patterns during spatial working memory task in patients with end-stage renal disease on maintenance hemodialysis: a fMRI study

Hemodialysis (HD) is associated with cognitive impairment in patients with end-stage renal disease (ESRD). However, the neural mechanism of spatial working memory (SWM) impairment in HD-ESRD patients remains unclear. We investigated the abnormal alterations in SWM-associated brain activity patterns in HD-ESRD patients using blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) technique during n-back tasks. Twenty-two HD-ESRD patients and 22 well-matched controls underwent an fMRI scan while undergoing a three-load n-back tasks with different difficulty levels. Cognitive and mental states were assessed using a battery of neuropsychologic tests. The HD-ESRD patients exhibited worse memory abilities than controls. Compared with the control group, the HD-ESRD patient group showed lower accuracy and longer response time under the n-back tasks, especially in the 2-back task. The patterns of brain activation changed under different working memory loads in the HD-ESRD patients, showing decreased activity in the right medial frontal gyrus and inferior frontal gyrus under 0-back and 1-back task, while more decreased activation in the bilateral frontal cortex, parietal lobule, anterior/posterior cingulate cortex and insula cortex under 2-back task. With the increase of task difficulty, the activation degree of the frontal and parietal cortex decreased. More importantly, we found that lower activation in frontal cortex and parietal lobule was associated with worse cognitive function in the HD-ESRD patients. These results demonstrate that the abnormal brain activity patterns of frontal cortex and parietal lobule may reflect the neural mediation of SWM impairment.

     

Functional role of rat prelimbic-infralimbic cortices in spatial memory: evidence for their involvement in attention and behavioural flexibility

The involvement of the medial prefrontal cortex (mPFC), and more particularly the prelimbic and infralimbic cortices (PL-IL area), in spatial memory remains controversial. The present study investigates the effects of neurotoxic lesions restricted to the PL-IL area of the mPFC in rats trained in two different spatial tasks. In experiment 1, PL-IL lesioned rats showed normal acquisition of a delayed non-matching to position task. They were also able to plan their responses for a prospective strategy but were transiently disrupted when the initial delay was extended. In experiment 2, rats were trained to locate one baited box among 13 identical boxes distributed on a circular arena. Lesioned rats performed normally when trained from a single start position but were severely disrupted when four start positions were used. A probe trial showed this deficit was not due to failure to learn the goal location. The addition of a proximal cue signalling the goal box helped lesioned rats to directly open the goal box, but did not compensate for greater distances that they travelled to reach it. Results from both experiments indicate that the PL-IL area is directly involved neither in allocentric spatial representations nor prospective memory and is not specifically involved in working memory. This area seems more likely to be involved in both attentional processes and behavioural flexibility that may be important for processing information for working memory as well as for spatial memory.     

Passive-avoidance learning after medial septal lesions: Effect of experience and the peripheral sympathetic nervous system

Prior studies from our laboratory suggest that peripheral sympathetic ingrowth, which occurs in the hippocampus following medial septal lesions, is detrimental to the reaquisition of a spatial learning/memory task. To assess the generality of this finding we studied step-through passive-avoidance learning in animals with a medial septal lesion with or without superior cervical ganglionectomy under two experimental conditions. In the first condition, in which no prior experience with the task occurred, animals with a lesion demonstrated facilitation of learning. In the second condition, in which animals received pretraining with no shock prior to surgical manipulation, the behavior of animals with the lesion was similar to that of controls. No effect of ganglionectomy or initial sympathetic ingrowth was found in either condition. The results suggest that the effects of medial septal lesions on passive avoidance behavior are determined by the experimental condition and that early peripheral sympathetic ingrowth does not contribute either in a detrimental or beneficial fashion to passive avoidance learning.     

The temporal dynamics of medial and lateral frontal neural activity related to proactive cognitive control

The neural correlates of proactive cognitive control were examined in two experiments using the counting Stroop task and a computerized Blackjack task in combination with event-related brain potentials (ERPs). The primary objective of the study was to determine whether slow wave activity related to proactive control would be observed in the two tasks. Consistent with the existing literature, transient components of the ERPs (i.e., medial frontal negativity and feedback related negativity) were observed over the medial frontal region in both tasks that were related to stimulus congruency and feedback processing, respectively. The medial frontal ERPs in both tasks were modeled with a pair of equivalent current dipoles placed along the anterior to posterior axis of the cingulate. Most importantly, slow wave activity was observed that differentiated incongruent trials from congruent trials after the response in the counting Stroop task, and losses from wins and ties in the Blackjack task. In the Blackjack task, a pair of dipoles in the left lateral frontal and posterior regions modeled the slow wave activity. These data reveal that updating goal representations that support proactive cognitive control may require several 100 ms in contrast to conflict or outcome monitoring that is associated with transient medial frontal neural activity.     

Amnesia following left medial frontal subcortical hemorrhage: a case report]

There has been a controversy as to the contribution of the frontal lobe to human memory function. We describe a 49-year-old right-handed patient with memory disturbance following a left medial frontal subcortical hematoma. Her amnesia was characterized by (1) predominant anterograde amnesia, (2) difficulty in both voluntary recall and recognition tasks, (3) a great number of false-alarm responses in a recognition task, and (4) no confabulation. An MRI demonstrated that her lesion was restricted to the left medial frontal area and anterior cingulate gyrus. This case represents a rare instance of amnesia following damage to the frontal lobe. We speculated that the unique feature of her memory impairment resulted from combined lesions in the medial frontal subcortical white matter and anterior cingulate gyrus. It seems that Papez's circuite participated in the development of these symptoms.