Quantitative morphological analysis of subicular terminals in the rat entorhinal cortex

In the present report, we describe a morphological and quantitative analysis of subicular synapses in layer V of the lateral entorhinal cortex (LEA) of the rat. Projections from the dorsal subiculum were labeled anterogradely, and areas in LEA showing high terminal density were randomly selected for ultrathin sectioning. More than 400 terminals in LEA were photographed in the electron microscope, and synapse types and postsynaptic targets were identified and, subsequently, quantified with the unbiased disector method. Most subicular terminals appeared to form asymmetrical synapses. A majority of asymmetrical synapses terminated on spines (67.5%), whereas a smaller fraction of asymmetrical synapses (23.5%) terminated on dendritic shafts. A small fraction of the terminals (7%) had symmetrical features. These symmetrical synapses had an almost equal percentage of spines and dendritic shafts as postsynaptic elements. Labeled synapses on somata or axons were never observed. The findings of this study in conjunction with relevant electrophysiological observations (Jones [1987] Neurosci Left 81:209-214) leads to the conclusion that the subiculo-entorhinal pathway comprises a large excitatory and a smaller inhibitory projection, both making synaptic contacts with presumed principal neurons and interneurons in the entorhinal cortex.     

Some behavioral effects of entorhinal cortex lesions in the albino rat.

Performed 7 experiments on groups of adult male albino Sprague-Dawley rats (N = 74). Ss with lesions in the entorhinal cortex (a) were hyperactive in a novel open field and in activity wheels, (b) were less responsive to punishment than controls, and (c) showed complex changes in several avoidance behaviors. Mild hyperphagia was observed only when the lesions extended into the subiculum. Results support the idea that the entorhinal cortex may relay information from the cingulate cortex and olfactory areas to the hippocampus. It is suggested that entorhinal-midbrain connections demonstrated in other species may serve important functions in the rat. (36 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Entorhinal cortex lesions disrupt the transition between the use of intra- and extramaze cues for navigation in the water maze.

[Correction Notice: An erratum for this article was reported in Vol 117(5) of Behavioral Neuroscience (see record 2007-16848-001). The definitions "Present = intramaze landmark present during Stage 2" and "Absent = intramaze landmark absent during Stage 2" appear incorrectly in the caption to Figure 3. These terms and definitions should appear in the caption to Figure 4.] This study with rats examined the effects of excitotoxic lesions to the entorhinal cortex (EC) and hippocampus (HPC) on using extramaze and intramaze cues to navigate to a hidden platform in a water maze. HPC lesions resulted in a disruption to the use of extramaze cues, but not intramaze cues, whereas EC lesions had no effect on the use of these cues when they were encountered for the fast time. However, prior navigation training in which 1 type of cue was relevant disrupted navigation with the other type in rats with EC lesions. Results show that the EC contributes to the processing of spatial information, but that this contribution is most apparent when there is a conflict between 2 sources of navigational cues in the water maze. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Aging and atropine effects on spatial navigation in the Morris water task.

A recent animal model that has been particularly useful in the neurobiology of aging has been the age-related decline of spatial information processing capacity in Sprague-Dawley rats measured in the place-learning water task developed by Morris (1981). In the first experiment of the present study, place behavior was examined in young (6 months), old (23–24 months), and very old (28 months) rats of another strain, Long-Evans. As an analogue of aging-related cholinergic dysfunction the effects of atropine sulfate (5–50 mg/kg), an anticholinergic drug that is known to disrupt behavior in this task, also was determined. Place navigation was not impaired in undrugged rats, even those in the oldest age group. Rats treated with atropine showed dose-dependent deficits. In a second experiment, young (4–5 months), old (18–20 months), and very old (28 months) Fischer-344 rats were examined. Place navigation was impaired in the old rats. The very old (28 months) rats could not swim well enough to be tested adequately. Although nonspatial deficits associated with aging may be found across most strains tested, there appear to be very large strain-related differences in spatial processing ability as a function of age. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effect of excitotoxic lesions centered on the perirhinal cortex in two versions of the radial arm maze task.

Rats with bilateral ibotenic acid lesions centered on the perirhinal cortex and sham-operated controls were tested in 2 versions of a spatially guided radial arm maze task. Lesioned rats made significantly more errors and required more sessions to reach criterion relative to controls in the standard radial maze task. When they were tested in a delayed nonmatch to sample version of this task, lesioned rats made more errors during the predelay phase and at both the 30-s and 10-min delays of the postdelay phase. These findings provide further support for the hypothesis that the role of the perirhinal cortex in object recognition memory may include reference to some spatial aspect of the environment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of NMDA lesions centered on the postrhinal cortex on spatial memory tasks in the rat.

Rats with bilateral N-methyl-D-aspartate lesions centered on the postrhinal cortex (POR) and sham lesions were tested in a series of spatial memory tasks. The POR-lesioned rats were significantly impaired compared with sham rats in the reference memory version of both the water maze and radial arm maze tasks and in the standard radial arm maze working memory task. The POR-lesioned rats displayed a delay-independent impairment in the working memory versions of the water maze and in a delayed nonmatching-to-place (DNMP) version of the radial arm maze task. The POR-lesioned rats were also impaired in a DNMP procedure conducted in the T-maze. These findings indicate that the POR has a delay-independent role in the processing of spatial information. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential effects of cholinergic blockade on performance of rats in the water tank navigation task and in a radial water maze.

Tested the disruptive effect of cholinergic blockade under conditions in which either the working memory or the spatial mapping requirements of the behavioral task were emphasized. In Exp I, 13 male hooded rats were trained in an 8-arm radial water maze to asymptotic performance. When delays of 5, 10, 20, and 40 min were inserted between Choice 4 and Choice 5, incidence of errors in Choices 5–8 increased after pretrial (20 min) intraperitoneal scopolamine (0.2 mg/kg) faster than under control conditions and approached chance level with the 40-min delay. Scopolamine after Choice 4 or pretrial methylscopolamine was ineffective. In Exp II, 30 Ss were trained in a Morris water tank. Acquisition was impaired by pretrial injection (20 min) of 0.1 and 0.2 mg/kg scopolamine, but a higher dose (1.0 mg/kg) was required to impair overtrained performance. In a working memory version of the navigation task, scopolamine administered 20 min before the 1st trial deteriorated retention tested 40 min later at a dose of 1.0 but not at 0.4 and 0.2 mg/kg. It is concluded that the disruptive effect of scopolamine is proportional to the demands on the working memory component of the task, whereas the use of an overtrained mapping strategy is relatively resistant to cholinergic blockade. (35 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of cytotoxic entorhinal lesions and electrolytic medial septal lesions on the acquisition and retention of a spatial working memory task

This study assesses how social desirability affects responses in clinical self-report inventories. Six hundred items gathered from four normal personality questionnaires were adapted to devise a pre-experimental personality questionnaire (pre-EMHQ). Results obtained from administering Ko's Mental Health Questionnaire (KMHQ) and the pre-EMHQ to separate samples were the proportion of individuals answering "true" to each item (i.e., P(t)) and the social desirability scale value (i.e., SDSV) of each item. The Experimental Mental Health Questionnaire (EMHQ) was established from the pre-EMHQ by closely matching the P(t)s and the SDSVs of the two questionnaires. Administering the KMHQ and the EMHQ concurrently to another sample provided results for factor analysis and other statistical analyses. The SDSVs and the P(t)s for each of the KMHQ items certainly displayed a linearly increasing relation. The two sets of corresponding subscales also correlated significantly. By applying the polynomial regression analysis, the tendency to score might be expressed as a quadratic function of SDSVs. Two iterative principal-factor analyses of the two sets of subscales each resulted in two factors, and Factor 1 is similar in both the KMHQ and the EMHQ. In brief, social desirability plays a critical role in affecting responses in a clinical self-report inventory. The factors involved and suggestions proposed will be of value for further research.     

Persistent short term memory deficits in Hebb–Williams maze performance are shown by rats with unilateral entorhinal cortex lesions.

The spatial abilities of adult, male Sprague-Dawley rats in the Hebb–Williams maze were examined at 6 mo after unilateral electrolytic entorhinal cortex lesions. Compared with sham-operated rats, their performance was impaired in both initial entry and repeat entry errors over 12 consecutive problems, using immediate starting replacement for the 6 trials per problem. The configurations of the 12 maze problems are independent, and deficits were seen over the entire course of the testing. This study indicates that Hebb–Williams maze performance deficits after unilateral entorhinal cortex lesion are persistent and can be seen up to 6 mo after injury. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Impaired processing of local geometric features during navigation in a water maze following hippocampal lesions in rats.

Hippocampal damage impairs navigation with respect to information provided by the shape of an arena. Recent evidence has suggested that normal rats use local geometric information, as opposed to a global geometric representation, to navigate to a correct corner. One implication of this pattern of results is that hippocampal lesions may impair processing of 1 or more of the local geometric features of an environment. The authors therefore investigated the effects of hippocampal cell loss in rats on navigation to a hidden goal with respect to a variety of local cues in an environment with a distinctive shape. Rats with lesions of the hippocampus were impaired in discriminating a right-angled corner from its mirror image. However, they were able to use cues provided by an acute-angled corner (Experiment 1) or a local polarizing cue (Experiment 2). In contrast, lesioned rats were impaired in discriminating long versus short walls (Experiment 3). Results indicate that the hippocampus plays a role in disambiguating locations by processing (metric) information related to the distance between corners. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Entorhinal-perirhinal lesions impair performance of rats on two versions of place learning in the Morris water maze.

The effects of entorhinal–perirhinal lesions in rats were studied with 2 versions of a place learning task in the Morris water maze. These lesions impaired performance on a multiple-trial task (3 days of 6 trials and a probe trial). This assessment was followed by a task in which rats were repeatedly trained to find novel locations with a variable delay (30 sec or 5 min) imposed between each sample trial and retention test. Entorhinal–perirhinal damage produced a delay-dependent deficit in spatial memory: Rats with lesions were impaired at the 5-min delay relative to the control group and to their own performance at 30 sec. These findings are discussed in relationship to memory impairment after entorhinal damage and spatial learning deficits observed after hippocampal damage. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Facilitation of conditioned odor aversion by entorhinal cortex lesions in the rat.

This study examined the role of the entorhinal cortex (EC) in conditioned odor aversion learning (COA). Lateral EC lesions did not impair but rather facilitated COA. In the experiments the delay separating the odor cue presentation from the subsequent toxicosis was varied during acquisition. EC-lesioned rats demonstrated COA for delays up to 2 hr, whereas sham-operated rats displayed COA only if toxicosis immediately followed the odor cue. This facilitation was not dependent on the intensity of the odor and corresponded to a facilitated long-delay learning. EC lesion did not affect conditioned taste aversion, confirming that the facilitation effect does not correspond to a general facilitation of conditioned aversion learning. Taken together, these results indicate that the removal of the EC may allow odor-toxicosis associations across longer delays by extending the duration of the olfactory trace. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Transplantation of hippocampal cell lines restore spatial learning in rats with ventral subicular lesions.

We have demonstrated in our previous studies that ventral subicular lesion induces neurodegeneration of the hippocampus and produces cognitive impairment in rats. In the present study, the efficacy of transplanted green fluorescent protein (GFP)-labeled hippocampal cell line (H3-GFP) cells in establishing functional recovery in ventral subicular lesioned rats has been evaluated. The survival of H3-GFP transplants and their ability to express trophic factors in vivo were also investigated. Adult male Wistar rats were subjected to selective lesioning of ventral subiculum and were transplanted with H3-GFP cells into the cornu ammonis 1 (CA1) hippocampus. The transplants settled mainly in the dentate gyrus and expressed neurotrophic factors, brain-derived neurotrophic factor (BDNF), and basic fibroblast growth factor (bFGF). The ventral subicular lesioned (VSL) rats with H3-GFP transplants showed enhanced expression of BDNF in the hippocampus and performed well in eight-arm radial maze and Morris water maze tasks. The VSL rats without hippocampal transplants continued to show cognitive impairment in task learning. The present study demonstrated the H3-GFP transplants mediated recovery of cognitive functions in VSL rats. Our study supports the notion of graft meditated host regeneration and functional recovery through trophic support, although these mechanisms require further investigation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparison of ventral subicular and hippocampal neuron spatial firing patterns in complex and simplified environments.

Activity from ventral subicular and hippocampal CA1 neurons was recorded in rats exploring a 4-arm radial maze in which the local and distal cues could be manipulated. Cells from both regions exhibited place fields, although ventral subicular neurons had larger fields than hippocampal cells. Rotation of the local and distal cues in opposite directions produced movement of the place fields in either direction or a complete change in firing pattern. Simplifying the environment also produced changes in place field location. Despite similarities between regions, subiculum fields decreased in size whereas hippocampal fields increased in the simple environment. These findings suggest that subicular cells may receive converging input from several hippocampal neurons and code more complex configurations of the cues. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effect of combined fluid percussion and entorhinal cortical lesions on long-term potentiation

Among the pathological processes initiated by traumatic brain injury are excessive neuroexcitation and target cell deafferentation. The current study examines the contribution of these injury components, separately as well as their combined effect, on postinjury alterations in the capacity for long-term potentiation and the immunolocalization of N-methyl-D-aspartate receptors and GABA. Adult rats underwent central fluid percussion traumatic brain injury, electrolytic bilateral entorhinal cortex lesions, or a combined injury of both procedures separated by 24 h. At two or 15 days postinjury, the capacity for long-term potentiation of the Schaffer collateral-commissural input to CA1 was measured in acute electrophysiological recordings. Entorhinal cortical lesions resulted in time-dependent increases in the effectiveness of tetanic stimulation to elevate population postsynaptic potentials and population spike amplitudes. These lesions also resulted in a marked intensification in the density of N-methyl-D-aspartate receptors in the CA1 stratum lacunosum-moleculare. All injury conditions that included fluid percussion as a component (alone or in combined injuries) produced a persistent impairment in long-term potentiation of the evoked population postsynaptic potentials. Thus, in combined injuries, the presence of concussion-induced neuroexcitation attenuated deafferentation-induced response increases. Both N-methyl-D-aspartate receptor and GABA immunobinding following combined injuries were also reduced relative to those observed following entorhinal lesions alone. The present results suggest that a process of receptor plasticity, possibly involving reactive synaptogenesis, may contribute to postdeafferentation enhancements of long-term potentiation, and that a traumatic brain insult will attenuate these enhancements. This interaction of different injury components suggests that recovery of function following brain injury may be enhanced by pharmacological reduction of neuroexcitation during postinjury intervals of reactive receptor plasticity.     

A comparison between the effects of medial septal lesions and entorhinal cortex lesions on performance of nonspatial working memory tasks and reversal learning

Two studies explored the relationship between cognitions and long-term symptoms in adult child sexual abuse (CSA) survivors. In Study 1, an American sample of 43 survivors completed questionnaires assessing attributional style and dysfunctional beliefs in cognitive themes affected by victimization, as well as measures of posttraumatic symptoms. Survivors' attributions of negative events were more internal, stable, and global than those of 29 comparison subjects without a history of CSA. However, only the globality scale was significantly related with severity of long-term symptoms. High correlations between dysfunctional beliefs concerning safety, trust, esteem, or intimacy, and posttrauma symptoms were found. The latter finding was replicated in Study 2 with a German sample of 35 CSA survivors, even when controlling for frequency of abuse.     

Reinnervation of the dentate gyrus and recovery of alternation behavior following entorhinal cortex lesions.

Adult male rats were implanted with chronically indwelling recording electrodes in the dentate hilus of one hemisphere and bipolar stimulating electrodes in the contralateral entorhinal cortex (EC). Daily measurements were then made of the amplitude of responses, evoked through the crossed temporodentate (CTD) pathway, while the rats were unanesthetized and unrestrained. The implanted rats were also trained to alternate turns in a T-maze, with the use of a rewarded-alternation procedure. After reaching criterion performance in the alternation task, each rat was given a lesion of the EC ipsilateral to the recording electrode (n?=?14) or a sham lesion (n?=?5). Mean amplitudes of the evoked responses increased over Postlesion Days 4–21, probably due to reactive synaptogenesis in the CTD system, reaching a level that was significantly elevated above prelesion levels by Postlesion Day 6. Rats given EC lesions exhibited a transient impairment in alternation performance, with the mean alternation score significantly below prelesion levels on Postlesion Days 2–6. Although 2 EC-lesioned rats did not show a behavioral deficit, the electrophysiological increases and behavioral recovery were correlated in the remaining 12 cases (Pearson r?=?.73). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Transient memory impairment in monkeys with bilateral lesions of the entorhinal cortex

Performance on five behavioral tasks was assessed post-operatively in Macaca fascicularis monkeys prepared with bilateral lesions of the entorhinal cortex (E group). Three of the tasks were also readministered 9-14 months after surgery. Initial learning of the delayed nonmatching-to-sample (DNMS) task was impaired in the E animals relative to unoperated control monkeys. On the delay portion of DNMS, the performance of E animals was nearly at control levels at short delays (up to 60 sec) but was impaired at 10 min and 40 min retention intervals. On the retest of DNMS, the E animals performed normally at all retention intervals. The E animals were unimpaired on the four other memory tasks. Neuroanatomical studies revealed a significant transverse expansion of the terminal field of the perirhinal cortical projection in the CA1 region of the hippocampus. Compared to unlesioned, anatomical control monkeys, the transverse length of the perirhinal terminal field in CA1 increased approximately 70% in the E monkeys. Although this was a striking morphological alteration, it is not known whether the sprouting of this projection influenced the behavioral recovery. The results of these studies suggest that the entorhinal cortex may normally participate in the learning and performance of tasks that are dependent on the medial temporal lobe memory system. However, recovery of normal DNMS performance demonstrates that the entorhinal cortex is not, by itself, essential for learning and performance of such tasks.     

Involvement of entorhinal cortex or parietal cortex in long-term spatial discrimination memory in rats: Retrograde amnesia.

Twenty-four rats assigned to 1 of 3 matched groups (control, entorhinal cortex [EC], and parietal cortex [PC]) were trained on 6 successive discrimination problems (2 in an 8-arm for pretraining and 4 in a 12-arm radial maze for training per se). The training on the 12-arm maze started 6, 4, 2 and 0.5 weeks before surgery. On the day after the rats learned the last problem, they were given surgery according to groups. Postoperative retention was measured by presenting 16 trials per session for each of the problems during 4 sessions. Results indicate that the EC lesions produced a retention deficit for problems learned immediately and up to 4 weeks before surgery, but not for the problem acquired 6 weeks before the lesions. The PC lesions produced a significant retrograde amnesia that was not temporally graded. Results demonstrate that the EC and PC make important, albeit distinct, contributions to spatial memory storage and retrieval in rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Direct projections from the entorhinal cortical layers to the dentate gyrus, hippocampus, and subicular complex in the cat

Projections from each layer of the entorhinal cortex (EC) of the cat were traced to the dentate gyrus (DG), Ammon's horn (CA), prosubiculum (ProSb), subiculum (Sb), presubiculum (PreSb) and parasubiculum (ParaSb); the anterograde or retrograde labeling method was used after stereotaxic injection of wheat germ agglutinin-horseradish peroxidase, cholera toxin B subunit, or Phaseolus vulgaris leucoagglutinin. On the side ipsilateral to the tracer-injection, layer II of the EC projected most abundantly to the outer half of the molecular layer (ML) of the DG, less abundantly to the almost entire thickness of the stratum lacunosum-moleculare (SLM) of CA2-3, moderately to the almost entire thickness of the SLM of CA1, and less to the outer part of the ML of the ProSb and Sb. Layer III projected abundantly to the almost entire thickness of the SLM of CA1 and outer part of the ML of the ProSb and Sb, and sparsely to the SLM of CA2-3. Layer IV projected sparsely to the pyramidal cell layer of the ProSb and Sb; Layer IV of the medial part (toward the ParaSb) of the EC projected further to the ML of the DG. Layer VI projected sparsely to the outer part of the ML of the DG, almost entire thickness of the SLM of CA1-3, and outer part of the ML of the ProSb and Sb. More temporal parts of the hippocampal region received the projections from progressively more medial and more rostral parts of layers II and III, and from progressively more rostral parts of layers IV and VI. The ML of the PreSb and ParaSb received projections from all layers of the medial part of the ipsilateral EC. The SLM of CA1 and ML of the ProSb, Sb and ParaSb received projections from layer II and/or III of the contralateral medial entorhinal area.