Object and place memory in the macaque entorhinal cortex

Lesions of the entorhinal cortex in humans, monkeys, and rats impair memory for a variety of kinds of information, including memory for objects and places. To begin to understand the contribution of entorhinal cells to different forms of memory, responses of entorhinal cells were recorded as monkeys performed either an object or place memory task. The object memory task was a variation of delayed matching to sample. A sample picture was presented at the start of the trial, followed by a variable sequence of zero to four test pictures, ending with a repetition of the sample (i.e., a match). The place memory task was a variation of delayed matching to place. In this task, a cue stimulus was presented at a variable sequence of one to four "places" on a computer screen, ending with a repetition of one of the previously shown places (i.e., a match). For both tasks, the animals were rewarded for releasing a bar to the match. To solve these tasks, the monkey must 1) discriminate the stimuli, 2) maintain a memory of the appropriate stimuli during the course of the trial, and 3) evaluate whether a test stimulus matches previously presented stimuli. The responses of entorhinal cortex neurons were consistent with a role in all three of these processes in both tasks. We found that 47% and 55% of the visually responsive entorhinal cells responded selectively to the different objects or places presented during the object or place task, respectively. Similar to previous findings in prefrontal but not perirhinal cortex on the object task, some entorhinal cells had sample-specific delay activity that was maintained throughout all of the delay intervals in the sequence. For the place task, some cells had location-specific maintained activity in the delay immediately following a specific cue location. In addition, 59% and 22% of the visually responsive cells recorded during the object and place task, respectively, responded differently to the test stimuli according to whether they were matching or non-matching to the stimuli held in memory. Responses of some cells were enhanced to matching stimuli, whereas others were suppressed. This suppression or enhancement typically occurred well before the animals' behavioral response, suggesting that this information could be used to perform the task. These results indicate that entorhinal cells receive sensory information about both objects and spatial locations and that their activity carries information about objects and locations held in short-term memory.     

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)     

Preserved number of entorhinal cortex layer II neurons in aged macaque monkeys

The perforant path, which consists of the projection from the layer II neurons of the entorhinal cortex to the outer molecular layer of the dentate gyrus, is a critical circuit involved in learning and memory formation. Accordingly, disturbances in this circuit may contribute to age-related cognitive deficits. In a previous study, we demonstrated a decrease in N-methyl-D-aspartate receptor subunit 1 immunofluorescence intensity in the outer molecular layer of aged macaque monkeys. In this study, we used the optical fractionator, a stereological method, to determine if a loss of layer II neurons occurred in the same animals in which the N-methyl-D-aspartate receptor subunit 1 alteration was observed. Our results revealed no significant differences in the number of layer II neurons between juvenile, young adult, and aged macaque monkeys. These results suggest that the circuit-specific decrease in N-methyl-D-aspartate receptor subunit 1 reported previously occurs in the absence of structural compromise of the perforant path, and thus may be linked to an age-related change in the physiological properties of this circuit.     

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.     

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)     

Contributions of the entorhinal cortex, amygdala and hippocampus to human memory

Recent studies have indicated that, in the monkey, the rhinal cortex (consisting of the entorhinal and perirhinal cortices) is more important to visual recognition memory than the hippocampus or amygdala. The present study investigated the role of the entorhinal cortex in humans using memory scores from surgical epilepsy patients classified according to their mesial temporal lobe pathology. The temporal lobe removals included 4-5 cm of neocortex, amygdala, rhinal cortex and 2-3 cm of the hippocampus and parahippocampal gyrus. Compared to autopsied control subjects, all of the patients showed significant gliosis in the amygdala, but they differed as to whether or not there were entorhinal and/or hippocampal abnormalities. Both preoperatively and one or more years postoperatively, the patients performed tests of verbal recall (Wechsler Memory Scale Logical Memory), visual recall (Rey Figure), verbal recognition and visual recognition (Warrington Recognition Memory Test: Words and Faces, respectively). Preoperatively, patients with hippocampal pathology showed deficits in visual recall. Postoperatively, a significant drop in verbal and visual recall was seen only for patients who lost intact hippocampal tissue, irrespective of the condition of the excised entorhinal cortex. Together, the results argue that the hippocampus is more important than the entorhinal cortex for the recall of newly learned information.     

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)     

Visual identification and memory in monkeys with circumscribed inferotemporal lesions.

Reports 2 experiments concerning the role of inferotemporal (IT) cortex in the processing of visual information, using a matching-to-sample procedure. Exp. I studied identification of visual stimuli at 3 levels of delay in 9 monkeys with anterior and posterior IT lesions and in normal controls. Exp. II examined proactive interference effects in the same groups. Results show that the 2 IT inferotemporal areas are involved in directing spatial and temporal attentional mechanisms in visual perception in complementary ways. (22 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Memory impairment in monkeys following lesions limited to the hippocampus.

Investigated the degree of memory impairment produced by a lesion limited to the hippocampus in 13 cynomolgus monkeys (Macaca fascicularis) with circumscribed hippocampal lesions who were tested on the delayed-nonmatching-to-sample task, a test of recognition memory that is sensitive to amnesia in humans. Ss were given no preoperative training and were given no postoperative experience prior to training on the task. A marked deficit was observed. The results, taken together with those from previous studies, also provide information about the role of factors that could potentially influence the level of memory impairment following hippocampal lesions. The level of impairment does not appear to be due to any of the following factors: time of testing after surgery, prior postoperative testing, surgical techniques, species differences, or behavioral training methods. However, preoperative training experience does appear to reduce the severity of the impairment, and this factor may account for the observation that the memory impairment associated with hippocampal lesions is sometimes mild. A recent case of human amnesia is discussed in which a bilateral lesion limited to a portion of the hippocampus produced a well-documented memory deficit. (27 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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)     

Cytoarchitecture of the entorhinal cortex in schizophrenia

OBJECTIVE: The purpose of this study was to determine whether schizophrenia is associated with abnormalities in neuronal migration in the entorhinal cortex. METHOD: Nissl-stained sections through three cytoarchitectonic subdivisions of the entorhinal cortex were examined in postmortem brain specimens from 10 schizophrenic subjects and 10 matched normal comparison subjects. RESULTS: No qualitative differences in cytoarchitecture were observed between the schizophrenic and comparison subjects. CONCLUSIONS: These findings do not replicate previous reports of cytoarchitectural disturbances in the entorhinal cortex of schizophrenic subjects and thus fail to support the hypothesis of abnormal neuronal migration in schizophrenia.     

Comparison of emotional responses in monkeys with rhinal cortex or amygdala lesions.

Four emotionally arousing stimuli were used to probe the behavior of monkeys with bilateral ablations of the entorhinal and perirhinal cortex. The monkeys' behavioral changes were then contrasted with those observed earlier (M. Meunier, J. Bachevalier, E. A. Murray, L. Málková, & M. Mishkin, 1999) in monkeys with either neurotoxic or aspiration lesions of the neighboring amygdala. Rhinal cortex ablations yielded several subtle behavioral changes but none of them resembled any of the disorders typically seen after amygdalectomies. The changes produced by rhinal damage took mainly the form of heightened defensiveness and attenuated submission and approach responses, that is, just the opposite of some of the most distinctive symptoms following amygdala damage. These findings raise the possibility that the rhinal cortex and amygdala have distinct, interactive functions in normal behavioral adaptation to affective stimuli. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Place memory is intact in rats with perirhinal cortex lesions.

Two experiments compared the effects of bilateral lesions of the hippocampal formation (HPC) or perirhinal cortex (PRh) on rats' performance of an allocentric spatial working memory task—delayed matching-to-place (DMTP) in a water maze. DMTP trials consisted of paired swims, and the hidden platform was moved to a new location on each trial. Performance was assessed with intervals between the first and second swim (i.e., retention delays) of 4, 30, 120, and 300 s. The rats received extensive presurgery training in Experiment 1 and no presurgery training in Experiment 2. In both experiments, rats with HPC lesions displayed DMTP deficits at all delays, taking longer and swimming farther to find the platform on the second swims than did sham-operated controls. By contrast, rats with PRh lesions displayed normal DMTP acquisition and performance. The results suggest that, unlike the functions of HPC, those of PRh are not critical for allocentric spatial working memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A quantitative autoradiographic and electrophysiological study of the reinnervation of the dentate gyrus by the contralateral entorhinal cortex following ipsilateral entorhinal lesions

The post-lesion proliferation of contralateral enthorhinal afferents which occurs in response to ipsilateral entorhinal lesions was quantitatively analyzed with autoradiographic and electrophysiological techniques. In both cases, the extent of the crossed projection to the dentate granule cells was quantified on the basis of a contralateral/ipsilateral (C/I) ratio. Autoradiographic measures of grain density in the entorhinal terminal field indicates that the very sparse crossed entorhinal projection in intact animals proliferates approximately 6-fold following unilateral entorhinal lesions (on the basis of an increased C/I ratio of grain density in animals with long standing unilater entorhinal lesions). Furthermore, the total number of grains in the entorhinal terminal zone (obtained by subtracting background from non-terminal regions) also increases approximately 6-fold, indicating that compression of the neuropil cannot be the factor responsible for the increased grain density. These increases in the anatomical extent of the crossed projection as a consequence of unilateral entorhinal lesions are also reflected electrophysiologically. In operated animals, the C/I ratio of the extracellular population EPSP (a measure of the synaptic current generated by the crossed projections) also increase 5-8 fold. In addition, while in normal animals, no population spikes are observed following stimulation of the contralateral entorhinal area (indicating an absence of synchronous grnaule cell discharge in response to contralateral entorhinal input), such population spikes are quite prominent in the reinnervated dentate gyrus, indicating a large increase in the effective synaptic drive of the proliferated crossed projections.     

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)     

Effects of lesions in the mesial frontal cortex on bimanual co-ordination in monkeys

The hypothesis was tested that the mesial frontal cortex, including the supplementary motor area, is engaged in bimanual co-ordination. Three monkeys, trained in a well-co-ordinated bimanual pull-and-grasp task, were subjected to unilateral or bilateral lesions of the mesial frontal cortex. With unilateral lesions, the deficit consisted in a delay in movement initiation of the contralateral arm. With a bilateral lesion, the deficit was more pronounced with marked bilateral delays in movement onset and slowing in reaching. However, in the three monkeys bimanual co-ordination at the moment of goal achievement remained intact with an excellent temporal co-variation of the two limbs. In the two unilateral cases, an adaptive strategy developed after a few sessions, either by catching up during reaching with the limb contralateral to the lesion (monkey M1) or by delaying movement initiation of the limb ipsilateral to the lesion (monkey M2). This outcome is discussed in terms of Lashley's principle of motor equivalence, i.e. invariant goal achievement with variable means. Bilateral lesions led to a transient and near-total impairment in movement self-initiation when all external cues were absent. It is concluded that in monkeys the mesial frontal cortex does not play a crucial role in bimanual co-ordination but rather in movement initiation, especially when sensory cues are absent.     

Improving effects of huperzine A on spatial working memory in aged monkeys and young adult monkeys with experimental cognitive impairment

Our previous studies demonstrated that huperzine A, a reversible and selective acetylcholinesterase inhibitor, exerts beneficial effects on memory deficits in various rodent models of amnesia. To extend the antiamnesic action of huperzine A to nonhuman primates, huperzine A was evaluated for its ability to reverse the deficits in spatial memory produced by scopolamine in young adult monkeys or those that are naturally occurring in aged monkeys using a delayed-response task. Scopolamine, a muscarinic receptor antagonist, dose dependently impaired performance with the highest dose (0.03 mg/kg, i.m.) producing a significant reduction in choice accuracy in young adult monkeys. The delayed performance changed from an average of 26.8/30 trials correct on saline control to an average of 20.2/30 trials correct after scopolamine administration. Huperzine A (0.01-0. 1 mg/kg, i.m.) significantly reversed deficits induced by scopolamine in young adult monkeys on a delayed-response task; performance after an optimal dose (0.1 mg/kg) averaged 25.0/30 correct. In four aged monkeys, huperzine A (0.001-0.01 mg/kg, i.m.) significantly increased choice accuracy from 20.5/30 on saline control to 25.2/30 at the optimal dose (0.001 mg/kg for two monkeys and 0.01 mg/kg for the other two monkeys). The beneficial effects of huperzine A on delayed-response performance were long lasting; monkeys remained improved for about 24 h after a single injection of huperzine A. This study extended the findings that huperzine A improves the mnemonic performance requiring working memory in monkeys, and suggests that huperzine A may be a promising agent for clinical therapy of cognitive impairments in patients with Alzheimer's disease.     

Memory of monkeys (Macaca mulatta) with lesions in prefrontal cortex.

Three studies with 9 rhesus monkeys examined whether removal of the tissue of sulcus principalis affected Ss' memory for a list of spatial locations. Findings show that 3 Ss whose tissue in the sulcus principalis had been removed were no longer able to search effectively for food, relative to 3 unoperated controls, when given 25 spatial locations to remember. A less marked deficit was apparent in 3 Ss whose superior prefrontal convexity had been removed. Ss with sulcus principalis lesions learned as quickly as other Ss to choose between locations on the basis of a spatial cue, and they did not take significantly longer to shift from a previously rewarded location. Findings are considered in relation to the deficits observed in humans with unilateral frontal lesions and the possibility that frontal mechanisms operate on information in working memory. (55 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of bilateral lesions of auditory cortex in mice on the acoustic startle response

The acoustic startle response (ASR) was used to investigate the effects of auditory cortical lesions on a brain stem-mediated auditory behavior. The ASRs were obtained longitudinally from young adult C57BL/6J mice before bilateral ablation of auditory cortex, 1 day after ablation, and 1 month later. Control mice received lesions of nonauditory cortex. For some mice, averaged brain stem-evoked responses (ABR) were obtained, and these indicated no effects of lesions on auditory sensitivity. One month after surgery, mice with auditory cortex ablations were statistically indistinguishable from controls on all suprathreshold measures of ASR. However, 1 day after ablation of auditory cortex, experimental animals (but not controls) exhibited a change in ASR amplitude (but not threshold or latency). When a noise burst of 80 dB SPL was used to elicit the ASR, the amplitude was diminished, but with a 110 dB stimulus, amplitude was enhanced. The findings can be interpreted in one of two ways: temporary interference with modulation of the ASR normally performed by auditory cortex; or a general effect of auditory cortex ablation on brain stem auditory circuits not specific to the ASR. In any event, if auditory cortex plays a modulatory role with regard to the ASR, it is apparently nonessential and/or readily compensated for after ablation.     

Visual discrimination impairments in rhesus monkeys with combined lesions of superior colliculus and striate cortex.

To test the hypothesis that posterior inferotemporal cortex and the adjoining foveal prestriate cortex contribute to vision by combining inputs from striate cortex and superior colliculus, a total of 18 rhesus monkeys with combined collicular and partial striate lesions, foveal prestriate-posterior inferotemporal lesions, or subcortical lesions (controls) were tested in a series of visual discrimination tasks. Prestriate-inferotemporal lesions, unlike striate-collicular lesions, consistently impaired retention of a pattern discrimination and produced partial impairments in a size discrimination test. However, prestriate-inferotemporal and striate-collicular lesions produced similar deficits in pattern discrimination learning and no deficits in brightness discrimination learning. The deficits of the striate-collicular monkeys are discussed with regard to the "input-combining" hypothesis and alternative views. (39 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)