Perirhinal cortex and anterior thalamic lesions: comparative effects on learning and memory

Three learning and memory tasks were used to compare the effects of neurotoxic anterior thalamic nuclei (ATN) and perirhinal cortex (PRC) lesions in rats. Rats with ATN lesions showed impaired spatial memory in a 12-arm radial maze, whereas rats with PRC lesions showed intact spatial memory, despite the use of minimal pretraining and extensive within-session delays (to 40 rain). PRC, but not ATN, lesions produced impairments on a configural learning task using complex visual-tactile cues in the radial maze. Neither ATN nor PRC lesions consistently affected spontaneous object recognition across extended sample-test delays (to 40 min). These findings confirm the differential involvement of the ATN and PRC in learning and memory.     

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

Rats with lesions either of medial septal nucleus (MSN) or the entorhinal cortex (ECx) were compared postoperatively with unoperated controls in a discrete-trial, delayed matching-to-position (DMTP) task, conducted on an elevated T-maze. A DMTP trial consisted of two consecutive visits to the maze: an information run and a choice run. The animals were first forced to visit a randomly selected choice arm in the information run. In the choice run, the correct response was to match the choice arm that had been visited on the information run, regardless of whether the information run itself had been rewarded or not. MSN animals failed to succeed in this task, performing at close to chance level throughout training. On the other hand, ECx rats consistently perform at a level comparable with that of unoperated controls; both groups attained more than 90% correct after 192 trials. Long-term retention testing was carried out after an intermission of 4 weeks, when the same task was re-administered to the ECx and unoperated control animals. ECx animals showed significantly less saving than controls in the retention test. In contrast, when the retention interval within a DMTP trial was increased by the imposition of a 20-s delay between the information and choice runs, the ECx group was not selectively affected by this manipulation. Received: 17 June 1997 / Accepted: 4 December 1997     

Excitotoxic lesions of the entorhinal cortex leave gustatory within-event learning intact

The ability of rats with ibotenate lesions of the entorhinal cortex to form memories for events was assessed by using a gustatory within-event learning procedure. Rats first received exposure to 2 events, AX and BY, each composed of a pair of flavors. Following this exposure period, Flavor X alone was paired with the delivery of lithium chloride. Lesioned and control rats showed a greater aversion to A than to B and to AX than to BX. These results challenge theories that suppose that the entorhinal cortex plays a general role in forming representations of patterns of stimulation.     

Inputs from the olfactory bulb and olfactory cortex to the entorhinal cortex in the cat

Summary The spatial organization and laminar distribution of projections from the olfactory bulb and the anterior (PPCa) and posterior (PPCp) divisions of the prepiriform cortex to the entorhinal cortex were studied with anterograde (³H-leucine) and retrograde (WGA-HRP) tracing techniques. After ³H-leucine injections into the olfactory bulb transported labeling was seen over the lateral entorhinal area, except its most medial part, and over the rostral part of the medial entorhinal area. The labeling covers exclusively layer Ia. The lateral and medial entorhinal areas are also reached by fibers from the prepiriform cortex. The projection to the medial entorhinal area has not been described previously. Following injections of ³H-leucine into the PPCa transported labeling is present over the entire expanse of the entorhinal cortex and is located over layer Ib with the greatest density in its superficial part. Injections of ³H-leucine into the PPCp give rise to transported labeling over much of the entorhinal cortex. No labeling was found over the most medial parts of the medial subdivision (VMEA) of the lateral entorhinal area and the medial entorhinal area. Labeling occupies layer Ib, especially its middle part, and layers II and III. Both PPCa and PPCp appear to project most heavily to the dorsal (DLEA) and ventral (VLEA) subdivisions of the lateral entorhinal area. From the retrograde experiments it can be inferred that cells of layers II and III of the PPCa project predominantly to the DLEA, whereas those of the PPCp project predominantly to the VLEA. The MEA receives its heaviest projection from layer II of both PPCa and PPCp. In control experiments with ³H-leucine injections into the endopiriform nucleus it was found that this nucleus projects to the entire expanse of the entorhinal cortex. The fibers distribute to all layers with the exception of layer Ia.Abbreviations AI agranular insular cortex - AL lateral nucleus of the amygdala - BL basolateral nucleus of the amygdala - BM basomedial nucleus of the amygdala - C claustrum - CoA cortical nucleus of the amygdala - DLEA dorsal division of the lateral entorhinal cortex - END endopiriform nucleus - H hippocampus - I granular insular cortex - lot lateral olfactory tractus - MCL mitral cell layer of the olfactory bulb - MEA medial entorhinal area - OB olfactory bulb - PPCa anterior part of the prepiriform nucleus - PPCp posterior part of the prepiriform nucleus - VLEA ventral division of the lateral entorhinal cortex - VMEA ventromedial division of the lateral entorhinal cortex - 35 area 35 of the perirhinal cortex - 36 area 36 of the perirhinal cortex     

Inputs from the olfactory bulb and olfactory cortex to the entorhinal cortex in the cat

Summary Field potentials and unit activity elicited by electrical stimulation of the olfactory bulb (OB) and anterior and posterior prepiriform cortex (PPCa and PPCp) were measured extracellularly in the entorhinal cortex (EC) of the cat. Different topographic distributions of the amplitude and peak latency of average evoked potentials (AEPs) were obtained depending on the stimulated area. The maximal evoked activity in the EC showed a gradient in a latero-medial direction with the extremes corresponding to the stimulation of OB and PPCp respectively. Analysis of firing patterns of units in the EC in response to stimulation of the OB, PPCa and PPCp showed that an appreciable number of units responded to stimulation of different areas, mainly PPC- a and PPCp. It was found that the pathways being stimulated differed in conduction velocities with the PPCp-EC being the slowest. Most responding units lay in layer I and II of the EC. The AEPs to PPCaand PPCp-stimulation presented different types of depth profiles. Stimulation of the PPCa evoked an initial surface-negative depth-positive potential whereas the PPCp evoked a different type of AEP with an initial positive component at the surface and negative in depth. It is assumed that the stimulated fibres have their active synapses at different levels within the superficial layers of the EC. The possibility of direct influence of olfactory inputs on the hippocampus mediated by one synapse in the EC is discussed.     

The role of the entorhinal cortex in two forms of spatial learning and memory

It is generally acknowledged that the rodent hippocampus plays an important role in spatial learning and memory. The importance of the entorhinal cortex (ERC), an area that is closely interconnected anatomically with the hippocampus, in these forms of learning is less clear cut. Recent studies using selective, fibre-sparing cytotoxic lesions have generated conflicting results, with some studies showing that spatial learning can proceed normally without the ERC, suggesting that this area is not required for normal hippocampal function. The present study compared cytotoxic and aspiration ERC lesions with both fimbria fornix (FFX) lesions and sham-operated controls on two spatial learning tasks which have repeatedly been shown to depend on the hippocampus. Both groups of ERC lesions were impaired during non-matching-to-place testing (rewarded alternation) on the elevated T-maze. However, neither of these lesions subsequently had any effect on the acquisition of a standard spatial reference memory task in the water maze. FFX lesions produced a robust and reliable impairment on both of these tasks. A second experiment confirmed that cytotoxic ERC lesions spared water maze learning but disrupted rewarded alternation on the T-maze, when the order of behavioural testing was reversed. These results confirm previous reports that ERC-lesioned animals are capable of spatial navigation in the water maze, suggesting that the ERC is not a prerequisite for normal hippocampal function in this task. The present demonstration that ERC lesions disrupt non-matching-to-place performance may, however, be consistent with the possibility that ERC lesions affect attentional mechanisms, for example, by increasing the sensitivity to recent reward history.     

The effects of entorhinal cortex lesions on type 1 and type 2 theta

The effects of bilateral entorhinal cortex lesions on type 1 and type 2 theta generation in the guinea pig were studied in the chronic preparation. EEG recordings from dentate generator zones demonstrated a decrease in the relationship between ongoing type 1 motor movements and theta generation. Before lesioning theta activity accompanied type 1 behaviors (i.e., walking and head movements) in 100% of the samples, while subsequent to lesioning theta activity was present in only 58% of the samples. In addition, prior to lesioning, type 2 theta was present in 100% of the samples taken during immobile sensory processing, e.g., tactile stimulation, while after lesioning type 2 theta was present in only 34% of the samples. Type 2 theta is selectively sensitive to disruption by atropine sulfate. In the present experiment atropine sulfate eliminated all theta activity after entorhinal lesions. Consequently as no type 1 theta appeared to be present it was argued that the entorhinal cortex is a critical route for type 1 theta. However, as the behavioral and sensory correlates of both type 1 and type 2 theta were disrupted it was suggested that the entorhinal cortex is an integral part of both systems.     

Hippocampus and entorhinal cortex in mild cognitive impairment and early AD

Magnetic resonance imaging (MRI) has been suggested as a useful tool in early diagnosis of Alzheimer's disease (AD). Based on MRI-derived volumes, we studied the hippocampus and entorhinal cortex (ERC) in 59 controls, 65 individuals with mild cognitive impairment (MCI) and 48 patients with AD. The controls and individuals with MCI were derived from population-based cohorts. Volumes of the hippocampus and ERC were significantly reduced in the following order: control > MCI > AD. Stepwise discriminant function analysis showed that the most efficient overall classification between controls and individuals with MCI subjects was achieved with ERC measurements (65.9%). However, the best overall classification between controls and AD patients (90.7%), and between individuals with MCI and AD patients (82.3%) was achieved with hippocampal volumes. Our results suggest that the ERC atrophy precedes hippocampal atrophy in AD. The ERC volume loss is dominant over the hippocampal volume loss in MCI, whereas more pronounced hippocampal volume loss appears in mild AD.     

Acquisition of a complex place task in rats with selective ibotenate lesions of hippocampal formation: combined lesions of subiculum and entorhinal cortex versus hippocampus

The effects of isolating the hippocampus from its neocortical inputs and outputs by damaging the deep layers of entorhinal cortex and subiculum were compared with direct removal of the hippocampus using acquisition of a complex radial maze task. A series of eight problems (four out of eight arms being correct) were learned under either massed (45 s) or distributed (10 min) practice conditions, thus varying contextual information. Performance of rats with subiculum/entorhinal cortex lesions was similar to that of controls in all aspects of the radial maze task; whereas animals with hippocampal lesions were impaired on nearly all dependent measures. Although the effects of varying the intertrial interval were generally small, distributed practice did serve to facilitate the performance of hippocampal rats in terms of working memory. These findings are discussed as they related to recent theorizing in the area.     

Selective lesions of the entorhinal cortex, the hippocampus, or the fimbria-fornix in rats: a comparison of effects on spontaneous and amphetamine-induced locomotion

Using adult Long-Evans male rats, this experiment compared spontaneous (assessed 15 days and 4.5 months after surgery) and amphetamine-induced (assessed from 4.5 months after surgery onwards; 1 mg/kg, i.p., ten injections, 48 h apart) locomotor activity following N-methyl-D-aspartate lesions of the entorhinal cortex, electrolytic lesions of the fimbria-fornix, or ibotenate lesions of the hippocampus. Sham-operated rats were used as controls. Hippocampal and fimbria-fornix lesions, but not entorhinal-cortex lesions induced diurnal and nocturnal hyperactivity, which was attenuated over time, but only in rats with fimbria-fornix lesions. Amphetamine-induced hyperlocomotion was assessed in a familiar environment. Lesions of the entorhinal cortex potentiated the locomotor effects of amphetamine, but not lesions of the hippocampus or interruption of the axons in the fimbria-fornix pathway. Sensitization appeared to be decreased by fimbria-fornix lesions and to be prevented by hippocampal lesions. Rats with entorhinal-cortex lesions behaved as if they had already been sensitized by the lesion. These results clearly show that lesions of the fimbria-fornix, the hippocampus, and of the entorhinal cortex have different effects on spontaneous and amphetamine-induced hyperactivity, as they also have on learning and memory tasks.     

A comparison of the effects of temporary hippocampal lesions on single and dual context versions of the olfactory sequence memory task

In recent years, many animal models of memory have focused on one or more of the various components of episodic memory. For example, the odor sequence memory task requires subjects to remember individual items and events (the odors) and the temporal aspects of the experience (the sequence of odor presentation). The well-known spatial context coding function of the hippocampus, as exemplified by place cell firing, may reflect the "where" component of episodic memory. In the present study, we added a contextual component to the odor sequence memory task by training rats to choose the earlier odor in one context and the later odor in another context and we compared the effects of temporary hippocampal lesions on performance of the original single context task and the new dual context task. Temporary lesions significantly impaired the single context task, although performance remained significantly above chance levels. In contrast, performance dropped all the way to chance when temporary lesions were used in the dual context task. These results demonstrate that rats can learn a dual context version of the odor sequence learning task that requires the use of contextual information along with the requirement to remember the "what" and "when" components of the odor sequence. Moreover, the addition of the contextual component made the task fully dependent on the hippocampus.     

Differential modulatory effects of transcranial direct current stimulation on a facial expression go-no-go task in males and females

The ability to recognize facial expressions has been shown to be different between males and females. Here we aimed to explore further this matter and investigate whether the effects of tDCS applied over the superior temporal cortex differs between males and females during a facial expression go-no-go task. Fourteen healthy subjects were exposed to a facial expression go-no-go task while they received two different conditions of stimulation: anodal tDCS of the left temporal cortex (with cathodal stimulation of the right temporal cortex) and sham tDCS. The order of conditions was randomized and counterbalanced across subjects. During each stimulation session (after 5 min of stimulation), subjects underwent a go-no-go task. The results showed that women had significantly more correct answers when compared to men (p=0.03) that was independent of condition of stimulation and valence of figures. In addition, women made significantly less errors during temporal stimulation when compared to sham stimulation (p=0.009) when responding to sad faces. Similarly, men made significantly more errors during temporal active stimulation as compared with sham stimulation (p=0.004) when responding to sad faces. Our results confirmed the notion that performance to facial expression recognition is increased in females compared with males and that modulation of temporal cortex with tDCS leads to differential effects according to gender.     

Volume reduction of the entorhinal cortex in subjective memory impairment

To examine the biological basis of subjective memory impairment (SMI), defined as the feeling of memory worsening with normal memory performance, we measured the volume of the entorhinal cortex (EC) and the hippocampus in SMI subjects, patients with mild cognitive impairment (MCI), patients with Alzheimer's disease (AD) and healthy controls (CO). Compared with controls, the EC was smaller in the SMI group (left: p = 0.060; right: p = 0.045) and in the other two groups in the following order: CO > SMI > MCI > AD. The same sequence was observed with regard to hippocampal volumes, but the volume reduction of the left hippocampus in the SMI group only reached a trend towards significance (p = 0.072) and the right was not significantly smaller compared with controls (p = 0.37). Compared with controls the average (left/right) volume reduction of the EC was 18% (SMI), 26% (MCI) and 44% (AD). The mean volume reduction of the hippocampus was 6% (SMI), 16% (MCI) and 19% (AD). Our results mirror the temporal sequence of neurodegeneration in AD and support the concept of SMI as the first clinical manifestation of dementia.     

Age effects on atrophy rates of entorhinal cortex and hippocampus

The effects of age, subcortical vascular disease, apolipoprotein E (APOE) epsilon4 allele and hypertension on entorhinal cortex (ERC) and hippocampal atrophy rates were explored in a longitudinal MRI study with 42 cognitively normal (CN) elderly subjects from 58 to 87 years old. The volumes of the ERC, hippocampus, and white matter hyperintensities (WMH) and the presence of lacunes were assessed on MR images. Age was significantly associated with increased atrophy rates of 0.04+/-0.02% per year for ERC and 0.05+/-0.02% per year for hippocampus. Atrophy rates of hippocampus, but not that of ERC increased with presence of lacunes, in addition to age. WMH, APOE epsilon4 and hypertension had no significant effect on atrophy rates. In conclusion, age and presence of lacunes should be taken into consideration in imaging studies of CN subjects and AD patients to predict AD progression and assess the response to treatment trials.     

GM1 produces attenuation of short-term memory deficits in Hebb-Williams maze performance after unilateral entorhinal cortex lesions.

The Hebb-Williams maze was used to examine spatial abilities of adult male Sprague-Dawley rats with unilateral electrolytic entorhinal cortex lesions. The injured rats were treated for 14 days with either saline or ganglioside GM1. Testing was begun 7 weeks following injury, and involved 12 maze problems with independent configurations, with immediate starting replacement used for the six trials per problem. Compared to sham-operated counterparts, the rats with lesion plus saline treatment were impaired in total number of errors, initial entry errors, and repeat errors over 12 consecutive problems. GM1-treated rats showed improved performance, making significantly fewer total and repeat errors, indicating that this substance may be potentially useful as therapy after entorhinal cortex injury.     

Olfactory learning and memory impairments following lesions to the hippocampus and perirhinal-entorhinal cortex

The role of the hippocampus and perirhinal-entorhinal cortex was examined in an olfactory discrimination paradigm. Small neurotoxic lesions of the hippocampus (21% tissue damage) yielded relatively unimpaired olfactory retention across brief (30 s), intermediate (approximately 5 min), and 24-hr delays, whereas impairments were noted at 5-day retention intervals. Larger hippocampal lesions (63% tissue damage) spared memory at intermediate delays, with no impact at 8-day retention intervals. Aspiration lesions directed at the perirhinal-entorhinal cortex produced a variable performance pattern, with impairments noted at intermediate, 24-hr, and 5-day delays. Results suggest the hippocampus is not specifically involved in retaining olfactory information, with additional consideration given to the relationship between lesion size and memory impairment.     

Efferent connections of the main olfactory bulb in the opossum (Monodelphis domestica): a characterization of the olfactory entorhinal cortex in a marsupial

Olfactory projections have been investigated for decades, but few reports using modern, sensitive neural tracers are available. In marsupials, only lesion-degeneration studies exist and they are restricted to the genera Didelphis and Trichosurus. Some of the territories described as olfactory-recipient such as the upper portion of the rhinal fissure and the vomeronasal amygdala are, however, controversial. Also, the characterization of the olfactory portion of the entorhinal cortex is far from clear in acallosal mammals. The present report investigates, using biotinylated dextran-amine, the olfactory connections in the short-tailed opossum (Monodelphis domestica) and characterizes the olfactory portion of the entorhinal cortex in non-placental mammals. The data indicate that olfactory projections do not reach the upper portion of the rhinal fissure, but partially end in the vomeronasal amygdala, i.e., the medial and posteromedial cortical amygdaloid nuclei; thus, although olfactory and vomeronasal system have largely segregated outputs, areas of overlap should be restudied. The olfactory portion of the entorhinal cortex is much larger than previously described, extending up to the occipital pole of the cerebral hemisphere. Collectively, these data contribute to our understanding of the organization of the hippocampal formation in marsupials.     

Behavioural and electrophysiological studies of entorhinal cortex lesions in the rat.

Bilateral ibotenic acid injections aimed at the entorhinal cortex (EC) lesioned the EC and subiculum in 30% of animals (group EC/S) and caused additional hippocampal damage in 50% (group RH). Both lesions increased acetylcholinesterase (AChE) staining in the intermediate molecular layer of the dentate gyrus. EC/S lesions increased diurnal deep sleep and the incidence of spindles but decreased REM sleep. RH lesions increased nocturnal deep sleep and decreased nocturnal quiet sleep. Both lesions reduced power over the theta frequency range from 6-10 Hz for epochs of REM sleep and quiet waking but not deep sleep. Peak frequency was unaffected. The RH group and a subset of the EC/S group were nocturnally, but not diurnally, hyperactive. Six weeks after the lesion there was no evidence for hyperactivity in a novel open field. The EC/S lesion impaired exploration as indicated by reduced motility and rearing in an open field and by the failure of EC/S-lesioned rats to increase contact time in response to a novel olfactory cue. Place navigation learning in a Morris maze was not affected by EC/S or RH lesions. However, when the spatial location of the hidden platform was shifted EC/S-lesioned rats were impaired. The sprouting response, reduced theta power and exploration deficits resemble those reported following electrolytic lesions, but the lack of effect on place navigation learning contrasts with reports of impaired spatial learning following electrolytic lesions. The data prompt a reexamination of the role which the EC projection to the hippocampus plays in spatial learning.