Effects of Unilateral Entorhinal Cortex Lesion and Ganglioside GM1 Treatment on Performance in a Novel Water Maze Task

Transient deficits have been reported after unilateral entorhinal cortex (EC) lesion. To determine whether there is a more persistent deficit, adult male Sprague–Dawley rats with electrolytic or sham lesions of the left entorhinal cortex were examined on acquisition of a modified working memory task in the Morris water maze. This delayed matching-to-sample task, with a 1-h intertrial interval, reveals a significant deficit in total distance to platform in both presentation (Trial 1) and matching (Trial 2) in the rats with entorhinal lesions. We have also found that this test can be used to assess significant deficits in perseveration (repeated nonproductive movement) in rats with entorhinal lesions. The deficits can be seen up to 16 days postinjury. Administration of ganglioside GM1 resulted in a moderate improvement in performance in both water maze measures analyzed. All groups (sham operated, lesion with saline treatment, and lesion with ganglioside GM1 treatment) were given three other tests, which were used to evaluate possible contributing factors to deficient water maze performance. A one-trial test for exploration of novel objects revealed no significant, simple working memory deficit in any group. Plus maze testing, to assess possible differences in levels of anxiety or increased activity as a component of water maze performance, also revealed no differences in the three groups. All groups were also similar in motor activity, shown by monitoring of activity levels. The worsened water maze performance observed in rats with EC lesion may be related to deficits in working memory ability within the framework of acquisition of a more complex spatial learning task.     

The effects of clozapine on delayed spatial alternation deficits in rats with hippocampal damage

Clozapine is an atypical antipsychotic drug that has been shown to improve spatial memory in some animal models; however its efficacy in reversing spatial memory impairment in rats with hippocampal lesions is unknown. To address this issue, we tested the effects of clozapine on delayed spatial alternation deficits in rats with hippocampal damage in three separate experiments. In each experiment, adult male rats received sham surgery or direct stereotaxic infusions of the excitotoxin, NMDA, into the hippocampus. In the first study, seven days after surgery, the sham control animals received daily saline injections while the lesioned animals were split into two groups that received daily saline or clozapine (2.0 mg/kg, sc) injections. During the fifth week of injections, all animals were tested in a food-motivated delayed spatial alternation task. Saline-treated rats with excitotoxic hippocampal damage displayed significant deficits in delayed spatial alternation. Daily clozapine injections completely reversed this deficit. In a second experiment, it was found that clozapine treatment limited to the testing days only did not improve alternation performance in lesioned rats. Finally, in a third experiment, chronic clozapine treatment did not improve alternation performance in lesioned rats that were pre-trained in the alternation task prior to surgery. These results suggest that chronic, but not acute, clozapine treatment enables rats with hippocampal damage to develop new spatial learning, but can not rescue old spatial learning established prior to damage. These results may have implications for the treatment of cognitive deficits caused by hippocampal dysfunction in disorders such as schizophrenia, Alzheimer's disease, and others.     

Immunotoxic cholinergic lesions in the basal forebrain reverse the effects of entorhinal cortex lesions on conditioned odor aversion in the rat

Conditioned odor aversion (COA) corresponds to the avoidance of an odorized-tasteless solution (conditioned stimulus, CS) previously paired with toxicosis. COA occurs only when the interstimulus interval (ISI) is kept short, suggesting that the memory trace of the odor is subject to rapid decay. Previous experiments have shown that the entorhinal cortex (EC) is involved in the acquisition of COA, since lesion of the EC rendered COA tolerant to long ISI. Because EC lesions induce a septo-hippocampal cholinergic sprouting, the present experiment investigated whether COA tolerance to long ISI may be linked to this sprouting reaction. In a first experiment, male Long-Evans rats subjected to bilateral excitotoxic EC lesions combined to intracerebroventricular infusions of the selective cholinergic immunotoxin 192 IgG-saporin were exposed to odor-toxicosis pairing using a long ISI (120 min). Results showed that EC-lesioned rats displayed COA with the long ISI but not the control groups. In rats with EC combined to 192 IgG-saporin lesions, histological analysis demonstrated no evidence for cholinergic septo-hippocampal sprouting. In a second experiment, animals with 192-IgG saporin lesion showed a marked COA with a short ISI (5 min). These results suggest that the COA with the long ISI found in rats with EC lesions might involve a functional activity related to the EC lesion-induced hippocampal cholinergic sprouting. As the injection of 192 IgG-saporin alone did not affect COA with a short ISI, our data also point to a possible role of hippocampal cholinergic neurons in the modulation of memory processes underlying COA.     

A comparison of the effects of fimbria-fornix, hippocampal, or entorhinal cortex lesions on spatial reference and working memory in rats: short versus long postsurgical recovery period.

Using a radial maze task and different postoperative recovery periods, this experiment assessed and compared the reference and working memory performances of adult Long-Evans male rats subjected to entorhinal cortex, fimbria-fornix, and hippocampus lesions. Sham-operated rats were used as controls. In order to see whether the duration of the postsurgical recovery period would influence acquisition of the complex radial maze task, training began 1 month following surgery (Delay 1) for half the rats in each group, while for the other half training was started 6.5 months following surgery (Delay 2). The results indicated that at both recovery periods the entorhinal cortex lesions failed to affect either working or reference memory in the spatial task. Conversely, both fimbria-fornix and hippocampus lesions impaired both reference and working memory. While the reference memory deficit was generally similar in both fimbria-fornix and hippocampal lesion groups, analysis of the results for working memory indicated that at the longer delay rats with fimbria-fornix lesions were still impaired but in animals that had the hippocampus removed, working memory did not differ from that of controls. These results suggest that there was some recovery in those rats with hippocampal lesions (e.g., on the working memory task) but both hippocampal and fimbria-fornix animals were still impaired compared to controls when training was delayed 6.5 months following the operations.     

损毁大鼠双侧内嗅皮质对束缚应激反应的影响

采用大鼠急性束缚应激动物模型,用鹅羔氨酸损毁大鼠双侧内嗅皮质来建立内嗅皮质损伤模型,观察束缚应激1小时后下丘脑室旁核快反应基因c-Fos表达情况以及应激后血浆促肾上腺皮质激素含量的动态变化,并与对照组相比较,探讨内嗅皮质与束缚应激反应的关系。结果表明,损毁内嗅皮质,明显抑制了应激诱导的下丘脑室旁核c-Fos的表达和血浆促肾上腺皮质激素含量的上升。结果提示,内嗅皮质参与调节束缚应激反应时HPA轴功能。     

Effects of Unilateral Entorhinal Cortex Lesion on Retention of Water Maze Performance

In a previous study, adult male Sprague-Dawley rats with unilateral, electrolytic entorhinal cortex lesions showed significant deficits in acquisition of a water maze task that measured working memory. The 10 days of testing used two trials per day with an intertrial interval of 1 h, and the rats with entorhinal damage were impaired in total distance to the platform in both trials. In the present retention study, rats who learned the same task prior to injury and were then retested for 5 days after lesion showed only a first day deficit in total distance to platform in the second trial. Analysis of swim patterns indicated that rats with unilateral entorhinal lesions used an altered strategy in retention testing to find the platform in the second trial of each day and incorporated the use of headings appropriate for Trial 1 only. This altered or compensatory strategy was not the optimum choice for problem solution. Although the rats then were able to switch headings and find the platform without significant impairment in total distance to platform on days 2–5 of testing, the use of an initial incorrect strategy indicated subtle residual deficits in cue integration and use of working memory.     

Effects of anterior or dorsomedial thalamic ibotenic lesions on learning and memory in rats

Sprague-Dawley rats were used to study the effects of ibotenic acid lesions of the anterior (A.Th.) and the dorsomedial (MD) thalamic nuclei on learning and memory. Memory was assessed by employing a temporal alternation task in a straight alley with varying intertrial intervals. In addition, spatial orientation and response flexibility were evaluated on a radial maze and on a spatial reversal task (SSDR). The results indicated that MD rats required more trials to learn the temporal alternation task and exhibited impaired performance compared to A.Th. and control groups at the shortest delay (15 s). In contrast, compared to the control group, A.Th. subjects which required less trials to master the task and exhibited normal performance at the 15-s delay were impaired when the intertrial interval was increased to 45 s. Whatever the lesion, no impairments were found in the SSDR or the radial maze while only MD lesions were found to result in a night hyperactivity associated with greater food and water consumptions. These findings indicate that A.Th. and MD are differentially involved in learning and memory processes. It is suggested that the MD is mostly involved in registering new information while the A.Th. plays a role in the maintenance of information over time.     

Excitotoxic lesions restricted to the dorsal CA1 field of the hippocampus impair spatial memory and extinction learning in C57BL/6 mice

Recent studies in patients with hippocampal lesions have indicated that the degree of memory impairment is proportional to the extent of damage within the hippocampus. Particularly, patients with damage restricted to the CA1 field demonstrate moderate to severe anterograde amnesia with only slight retrograde amnesia. Comparable results are also seen in other species such as non-human primates and rats; however, the effect of selective damage to CA1 has not yet been characterized in mice. In the present study, we investigated the effects of excitotoxic (NMDA) lesions of dorsal CA1 on several aspects of learning and memory performance in mice. Our data indicate that dorsal CA1 lesioned mice are hyperactive upon exposure to a novel environment, have spatial working memory impairments in the Y-maze spontaneous alternation task, and display deficits in an 8-arm spatial discrimination learning task. Lesioned mice are able to acquire an operant lever-press task but demonstrate extinction learning deficits in this appetitive operant paradigm. Taken together, our results indicate that lesions to dorsal CA1 in mice induce selective learning and memory performance deficits similar to those observed in other species, and extend previous findings indicating that this region of the hippocampus is critically involved in the processing of spatial information and/or the processing of inhibitory responses.     

Place and response learning of rats in a Morris water maze: differential effects of fimbria fornix and medial prefrontal cortex lesions

The question examined in this study is concerned with a possible functional dissociation between the hippocampal formation and the prefrontal cortex in spatial navigation. Wistar rats with hippocampal damage (inflicted by a bilateral lesion of the fimbria fornix), rats with damage to the medial prefrontal cortex, and control-operated rats were examined for their performance in either one of two different spatial tasks in a Morris water maze, a place learning task (requiring a locale system), or a response learning task (requiring a taxon system). Performance of the classical place learning (allocentric) task was found to be impaired in rats with lesions of the fimbria fornix, but not in rats with damage of the medial prefrontal cortex, while the opposite effect was found in the response learning (egocentric) task. These findings are indicative of a double functional dissociation of these two brain regions with respect to the two different forms of spatial navigation. When the place learning task was modified by relocating the platform, the impairment in animals with fimbria fornix lesions was even more pronounced than before, while the performance of animals with medial prefrontal cortex lesions was similar to that of their controls. When the task was again modified by changing the hidden platform for a clearly visible one (visual cue task), the animals with fimbria fornix lesions had, at least initially, shorter latencies than their controls. By contrast, in the animals with medial prefrontal cortex damage this change led to a slight increase in escape latency.     

Effects of BIM-22015, an analog of ACTH4-10, on functional recovery after frontal cortex injury.

Male rats, 90-100 days old, with frontal cortex lesions were given either subcutaneous sterile water (SW) as a vehicle control or 1, 10, or 100 micrograms of BIM-22015 every other day for 20 days. Brain-injured subjects tested in the Morris water maze with either 10 micrograms BIM-22015 or SW took significantly more trials than sham-operated rats to locate a submerged platform eight consecutive times within 60 s. The animals given 1 or 100 micrograms BIM-22015 took significantly fewer trials to reach criterion than brain-injured animals in the other drug treatment groups. On a percentage of savings, measured 8 days after reaching criterion, the brain-injured subjects given 1, 10, or 100 micrograms BIM-22015 did not differ from sham-operated rats. In contrast, the brain-injured animals given SW took longer to find the submerged platform than they did during the initial training. To assess long-term effects of the ACTH analog treatment, rats were trained on a delayed spatial alternation task 30 days after receiving the last injection. On this task, brain-injured rats treated with the 10-micrograms dose performed significantly better than those given sterile water. Acetylcholinesterase (AChE)-labeled neurons counted in the nucleus basalis magnocellularis indicated that rats with frontal cortex damage given the 10-micrograms treatment did not differ from the sham controls and had significantly more AChE-positive neurons than injured counterparts treated with SW or 100 micrograms.     

Arc length coding by interference of theta frequency oscillations may underlie context-dependent hippocampal unit data and episodic memory function

Many memory models focus on encoding of sequences by excitatory recurrent synapses in region CA3 of the hippocampus. However, data and modeling suggest an alternate mechanism for encoding of sequences in which interference between theta frequency oscillations encodes the position within a sequence based on spatial arc length or time. Arc length can be coded by an oscillatory interference model that accounts for many features of the context-dependent firing properties of hippocampal neurons observed during performance of spatial memory tasks. In continuous spatial alternation, many neurons fire selectively depending on the direction of prior or future response (left or right). In contrast, in delayed non-match to position, most neurons fire selectively for task phase (sample vs. choice), with less selectivity for left versus right. These seemingly disparate results are effectively simulated by the same model, based on mechanisms similar to a model of grid cell firing in entorhinal cortex. The model also simulates forward shifting of firing over trials. Adding effects of persistent firing with reset at reward locations addresses changes in context-dependent firing with different task designs. Arc length coding could contribute to episodic encoding of trajectories as sequences of states and actions.     

The Effects of Hippocampal and Area Parahippocampalis Lesions in Pigeons: II. Concurrent Discrimination and Spatial Memory

Two experiments were conducted to examine the effects of bilateral hippocampus (Hp) and area parahippocampalis (APH) lesions in pigeons on the acquisition of a visual and spatial task. In Experiment 1, pigeons were trained on three successive six-pair concurrent discrimination tasks, each using a novel set of stimuli. There was no difference between control unoperated pigeons and Hp-APH pigeons in terms of the number of sessions required to learn either the first, second, or third concurrent discrimination task. In Experiment 2, the same pigeons were trained on an open-field spatial task similar in many ways to the radial-arm maze task used with rats. In contrast to the absence of impairments on the visual concurrent discrimination task, pigeons with Hp-APH lesions were severely impaired on the acquisition of the spatial task. These findings support the view that the Hp-APH in pigeons is important for the processing of spatial, rather than visual information.     

Frontal cortex grafts have opposite effects at different postoperative recovery times

We studied the effect of different postoperative times on the behavioral recovery following brain implants. Adult male rats received cortical tissue grafts 2 weeks after aspiration of the medial frontal cortex. Either 2 (Immediate Group) or 28 (Delay Group) days after grafting, the performance of these rats on a behavioral battery, comprising the Morris water maze task, forepaw use, and grooming, was compared to that of rats with similar lesions and postoperative recovery times but no grafts. Rats tested immediately after receiving implants performed better on the spatial navigation task than rats with similar lesions but no grafts. This improvement, however, was less than that shown by rats with lesions but no grafts permitted to recover for 28 days before testing. In contrast, in the Delay Group, rats with grafts were more greatly impaired than were their operated controls. Neither lesions nor grafts affected grooming although the Immediate Group with grafts were significantly more impaired in using their forepaws during feeding than were any of the other groups. These results lead us to conclude that differing postoperative recovery times and task requirements may account for some of the inconsistent results of the influence of brain grafts on behavioral recovery reported in the literature. We also conclude that cortical tissue implants can have two effects with different time courses and opposite net behavioral effects.     

Rats use a sense of direction to alternate on T-mazes located in adjacent rooms

Lister hooded rats were trained on a forced-sample T-maze alternation task in an environment lacking spatial landmarks. An early study of spontaneous alternation on the T-maze had shown that rats use a "spatial sense" to select alternate maze arms across mazes. As this phenomenon may provide a useful tool for studying the neural substrates of a directional sense, we wished to confirm this finding on a different version of the T-maze task, with well-trained animals. We found that rats successfully selected the appropriate maze arm when the choice phase of the task was presented on a second maze, oriented in the same direction, and located in an adjacent room. However, choice performance fell to chance level when the second maze was oriented 90° relative to the first. This result suggests that the rats do not simply alternate turns across the two environments, but rather that they rely on a sense of direction that is carried across environments. Electronic Publication     

The residual spatial abilities of hippocampally lesioned rats can be enhanced by peripheral sympathetic-adrenal interventions

In order to test the possible effectiveness of peripheral interventions with the adrenergic system for the alleviation of certain disorders that typically follow bilateral hippocampal lesions, rats with bilateral lesions of the hippocampus, the overlying neocortex, or sham operations were tested at two postoperative times in the Morris water maze, a frequently used "spatial task." Half of the animals in all groups were exposed to the adrenergic manipulations, i.e., a chronic, 7-day, systemic bretylium regime (5 mg/kg) and, in addition, a peripheral injection of norepinephrine (4 micrograms/kg) 30 min before the start of each training day. The other half received saline chronically and a single saline injection before each training day. Five days of training were given at each of the two training periods. The first began 7 days after surgery while the second began 33 days after surgery. As expected, the hippocampally lesioned animals were severely impaired in the task. The adrenergic treatment produced enhanced performances in the rats with hippocampal lesions at both training sessions, although the improvement was greatest at the later period. Although the animals receiving the pharmacologic treatment located the general area of the hidden platform better than the saline-treated animals with hippocampal lesions, the treated animals were still impaired, swimming directly to the hidden platform on fewer trials than did animals in the other groups.     

Dissociation of Hippocampal and Striatal Contributions to Spatial Navigation in the Water Maze

Two experiments were conducted to compare the effects of fornix/fimbria and caudate-putamen lesions in Long–Evans hooded rats (Rattus norvegicus) trained on two water maze tasks that differed in the type of spatial localization required for optimum solution. In Experiment 1, the lesioned rats and surgical controls were trained on the standard place task in the water maze (Morris, 1981) and given two postacquisition tests (a platform removal probe and platform relocation test). In Experiment 2, rats with similar lesions and control rats were trained on a modified cue navigation task. Fornix/fimbria lesions impaired a late stage of place task acquisition but did not impair acquisition of the cue task. Caudate-putamen lesions resulted in a severe place acquisition impairment and a transient cue acquisition impairment, both of which were characterized by an initial tendency to swim near the wall of the pool. Post-hoc analyses of the direction and angles of departure from the start points suggested that rats with fornix/fimbria lesions used non-allocentric spatial strategies to solve the place task. These rats also demonstrated a significantly weakened spatial bias for the former training quadrant on the platform removal probe and reduced flexibility in navigating to a novel platform location on the platform relocation test. In contrast, rats with caudate-putamen lesions showed a significant spatial bias for the former training quadrant but failed to cross the exact location within the quadrant where the platform was formerly positioned. The results suggest that the hippocampus mediates the allocentric spatial component of the water maze place task while the dorsomedial striatum may play an important role in the acquisition of the procedural aspects of both place and cue versions of the task.     

Contributions of dorsal striatal subregions to spatial alternation behavior

Considerable evidence has shown a clear dissociation between the dorsomedial (DMS) and the dorsolateral (DLS) striatum in instrumental conditioning. In particular, DMS activity is necessary to form action-outcome associations, whereas the DLS is required for developing habitual behavior. However, few studies have investigated whether a similar dissociation exists in more complex goal-directed learning processes. The present study examined the role of the two structures in such complex learning by analyzing the effects of excitotoxic DMS and DLS lesions during the acquisition and extinction of spatial alternation behavior, in a continuous alternation T-maze task. We demonstrate that DMS and DLS lesions have opposite effects, the former impairing and the latter improving animal performance during learning and extinction. DMS lesions may impair the acquisition of spatial alternation behavior by disrupting the signal necessary to link a goal with a specific spatial sequence. In contrast, DLS lesions may accelerate goal-driven strategies by minimizing the influence of external stimuli on the response, thus increasing the impact of action-reward contingencies. Taken together, these results suggest that DMS- and DLS-mediated learning strategies develop in parallel and compete for the control of the behavioral response early in learning.     

Increasing acetylcholine levels in the hippocampus or entorhinal cortex reverses the impairing effects of septal GABA receptor activation on spontaneous alternation

Intra-septal infusions of the γ-aminobutyric acid (GABA) agonist muscimol impair learning and memory in a variety of tasks. This experiment determined whether hippocampal or entorhinal infusions of the acetylcholinesterase inhibitor physostigmine would reverse such impairing effects on spontaneous alternation performance, a measure of spatial working memory. Male Sprague-Dawley rats were given intra-septal infusions of vehicle or muscimol (1 nmole/0.5 μL) combined with unilateral intra-hippocampal or intra-entorhinal infusions of vehicle or physostigmine (10 μg/μL for the hippocampus; 7.5 μg/μL or 1.875 μg/0.25 μL for the entorhinal cortex). Fifteen minutes later, spontaneous alternation performance was assessed. The results indicated that intra-septal infusions of muscimol significantly decreased percentage-of-alternation scores, whereas intra-hippocampal or intra-entorhinal infusions of physostigmine had no effect. More importantly, intra-hippocampal or intra-entorhinal infusions of physostigmine, at doses that did not influence performance when administered alone, completely reversed the impairing effects of the muscimol infusions. These findings indicate that increasing cholinergic levels in the hippocampus or entorhinal cortex is sufficient to reverse the impairing effects of septal GABA receptor activation and support the hypothesis that the impairing effects of septal GABAergic activity involve cholinergic processes in the hippocampus and the entorhinal cortex.     

Selective lesions in the temporal-hippocampal region of the rat: effects on acquisition and retention of a visual discrimination task.

The first purpose of this study was to investigate whether lesions in the temporal region may affect acquisition or retention of a discrimination task. In Experiment 1, rats with lesions of the temporal cortex (TC), the lateral entorhinal cortex (LEC), or their interconnections were tested postoperatively in simultaneous brightness discrimination. The results show that neither TC lesions nor LEC lesions affected acquisition of the task, and only LEC lesions impaired retention. TC/LEC transections impaired both acquisition and retention. The second purpose was to investigate effects of hippocampal lesions and perforant path transections on the discrimination task (Experiment 2). Both hippocampal and perforant path lesions impaired acquisition of the task, whereas retention was unaffected. It is suggested that TC and LEC are primarily involved in information storing and that hippocampal function is primarily involved in information processing.     

A neural circuit analysis of visual recognition memory: role of perirhinal, medial, and lateral entorhinal cortex

Using a continuous recognition memory procedure for visual object information, we sequentially presented rats with eight novel objects and four repeated objects (chosen from the 8). These were selected from 120 different three-dimensional objects of varying sizes, shapes, textures, and degree of brightness. Repeated objects had lags ranging from 0 to 4 (from 0 to 4 different objects between the first and repeated presentation). An object was presented on one side of a long table divided in half by an opaque Plexiglas guillotine door, and the latency between opening the door and the rat moving the object was measured. The first presentation of an object resulted in reinforcement, but repeated presentations did not result in a reinforcement. After completion of acquisition training (significantly longer latencies for repeated presentation compared with the first presentation of an object), rats received lesions of the perirhinal, medial, or lateral entorhinal cortex or served as sham operated controls. On the basis of postsurgery testing and additional tests, the results indicated that rats with perirhinal cortex lesions had a sustained impairment in performing the task. There were no sustained deficits with medial or lateral entorhinal cortex lesions. The data suggest that recognition memory for visual object information is mediated primarily by the perirhinal cortex but not by the medial or lateral entorhinal cortex.