Bilateral Entorhinal Cortex Lesions Research Articles

Reactive plasticity in the dentate gyrus following bilateral entorhinal cortex lesions in cynomolgus monkeys

Hippocampal structural plasticity induced by entorhinal cortex (EC) lesions has been studied extensively in the rat, but little comparable research has been conducted in primates. In the current study we assessed the long-term effects of bilateral aspiration lesions of the EC on multiple markers of circuit organization in the hippocampal dentate gyrus of young adult monkeys (Macaca fascicularis). Alternate histological sections were processed for the visualization of somatostatin and vesicular acetylcholine transporter (VAChT) immunoreactivity and acetylcholinesterase histochemistry (AChE). The markers revealed the distinct laminar organization of dentate gyrus circuitry for stereology-based morphometric quantification. Consistent with findings in rats, the volume of the somatostatin-immunopositive outer molecular layer (OML), innervated by projections from the EC, was decreased by 42% relative to control values. The inner molecular layer (IML) displayed a corresponding volumetric expansion in response to denervation of the OML as measured by AChE staining, but not when visualized for quantification by VAChT immunoreactivity. Nonetheless, stereological estimation revealed a 36% increase in the total length of VAChT-positive cholinergic fibers in the IML after EC damage, along with no change in the OML. Together, these findings suggest that despite substantial species differences in the organization of hippocampal circuitry, the capacity for reactive plasticity following EC damage, previously documented in rats, is at least partly conserved in the primate dentate gyrus.

Bilateral entorhinal cortex lesions impair acquisition of delayed spatial alternation in rats

Entorhinal cortex lesions induce significant reorganization of several homotypic and heterotypic inputs to the hippocampus. This investigation determined whether surviving heterotypic inputs after bilateral entorhinal lesions would support the acquisition of a learned alternation task. Rats with entorhinal lesions or sham operations were trained to acquire a spatial alternation task. Although the sham-operated rats acquired the task within about 3 weeks postsurgery, rats with bilateral entorhinal lesions failed to learn the task after 12 consecutive weeks of training despite heterotypic sprouting of the cholinergic septodentate pathway and the expansion of the commissural/associational fiber plexus within the dentate gyrus. Thus, heterotypic sprouting failed to ameliorate significantly the effects of bilateral entorhinal lesions. Rather, entorhinal lesions produced a persistent impairment of spatial memory, characterized by a mixture of random error production and perseverative responding.

Involvement of nucleus accumbens dopaminergic transmission in acoustic startle: observations concerning prepulse inhibition in rats with entorhinal cortex lesions.

The relationship between the entorhinal cortex and prepulse inhibition (PPI) as well as the nucleus accumbens dopaminergic participation in acoustic startle were examined in rats. After the entorhinal cortex was damaged bilaterally using ibotenic acid, a microdialysis probe was placed in the nucleus accumbens for detection of dopamine before, during and after acoustic startle stimuli. In rats with bilateral entorhinal cortex lesions PPI was reduced, and extracellular dopamine in the nucleus accumbens was elevated with or without acoustic stimuli. The entorhinal cortex and the sensorimotor gating system thus may be related via dopaminergic connections in the nucleus accumbens, even though dopamine release did not coincide completely with acoustic startle stimuli.

Spatial discrimination deficits by excitotoxic lesions in the Morris water escape task

The effects of the cholinesterase inhibitors (ChEI) metrifonate and donepezil were assessed on spatial performance of rats with bilateral lesions of the entorhinal cortex (EC), which is thought to model early changes in the brains of patients suffering from Alzheimer’s disease. In the present study, we found that spatial discrimination deficits in rats, induced by bilateral ibotenic acid (IBO) lesions of the EC region can partially be antagonised by treatment with the cholinesterase inhibitors metrifonate (30 mg kg −1) and donepezil (0.3 and 3 mg kg −1). Performance was improved in the spatial discrimination task compared with that of the EC-lesioned control group. It is concluded that the rat with bilateral EC lesions is a suitable deficit model for the assessment of effects of putative Alzheimer therapeutics.

Bilateral lesions of the entorhinal cortex differentially modify haloperidol- and olanzapine-induced c-fos mRNA expression in the rat forebrain

Lesions of the entorhinal cortex are now an accepted model for mimicking some of the neuropathological aspects of schizophrenia, since evidence has accumulated for the presence of cytoarchitectonic abnormalities within this cortex in schizophrenic patients. The present study was undertaken to address the functional consequences of bilateral entorhinal cortex lesions on antipsychotic-induced c-fos expression. After a 15-day recovery period, the effect of a typical antipsychotic, haloperidol (1 mg/kg), on c-fos mRNA expression was compared with that of an atypical one, olanzapine (10 mg/kg), in both sham-lesioned and entorhinal cortex-lesioned rats. In sham-lesioned rats, both haloperidol and olanzapine induced c-fos expression in the caudal cingulate cortex, dorsomedial and dorsolateral caudate-putamen, nucleus accumbens core and shell and lateral septum. In addition, olanzapine, but not haloperidol, increased c-fos expression within the central amygdala. In entorhinal cortex-lesioned rats, haloperidol-induced c-fos expression was markedly reduced in most areas. In contrast, the olanzapine-induced c-fos expression was not altered in the nucleus accumbens shell and lateral septum of the lesioned rats. These findings reveal that entorhinal cortex lesions affect c-fos expression in a compound- and regional-dependent manner. Our results further emphasize the importance of the exploration of the mechanisms of action of antipsychotic drugs in the context of an associated cortical pathology.

Reduced prepulse inhibition in rats with entorhinal cortex lesions

The relationship between the entorhinal cortex and prepulse inhibition (PPI) as well as dopaminergic participation in this relationship were examined. PPI is an operational measure of sensorimotor gating in which a robust response to a startling auditory pulse stimulus is inhibited when the stimulus is preceded by a weak prepulse. PPI can be measured in various species and is reduced in several neuropsychiatric disorders and in dopamine-activated rats. The entorhinal cortex was damaged bilaterally using ibotenic acid, and acoustic startle experiments were performed during treatment with haloperidol or saline on day 21 after the ibotenic acid injection. Neither this injection nor haloperidol affected the amplitude of the startle movement. Bilateral entorhinal cortex lesions reduced PPI, while haloperidol partially restored it. The entorhinal cortex and the sensorimotor gating system therefore may be related via dopaminergic circuits, possibly including the nucleus accumbens. Further, as the entorhinal cortex provides the major extrinsic synaptic input to the rat hippocampus, disease involvement of this region may severely affect cognition in various disorders including schizophrenia.

Effect of entorhinal cortex lesion on hippocampal cholinergic system in rat in operant learning task as studied by in vivo brain microdialysis

An in vivo microdialysis method was used to study the cholinergic alteration of the hippocampus in entorhinal cortex-lesioned rats performing a positive reinforcement operant learning task. Rats with bilateral entorhinal cortex lesions were implanted with a dialysis probe into the hippocampal CA3 after ten learning sessions. After 7 days, the bilateral entorhinal cortex-lesioned rats showed impaired acquisition of positive reinforcement operant learning. The basal level of the acetylcholine efflux decreased within 30 min before the beginning of a learning session. The hippocampal acetylcholine efflux showed a significantly diminished increase and rapidly returned to the basal level during the 60 min after the beginning of a learning session. These results suggested that enorhinal cortex lesion may cause damage to the hippocampal cholinergic system with disruption of the entorhinal cortex-hippocampus relay passage.

GM1-Ganglioside Suppresses Septodentate Sprouting and Enhances Recovery from Entorhinal Cortex Lesions on DRL Perfomance and Locomotor Behavior in Rats

Administration of gangliosides accelerates recovery of function after entorhinal cortex lesions on open field activity and learned spatial alternation tasks. In the present study, we examined whether GM1 ganglioside might enhance recovery from bilateral entorhinal cortex lesions on a differential reinforcement of low-rate responding tak with a 20 sec delay (DRL-20) as well as on open field activity. Optical densitometry measurements were taken to assess sprouting by the acetylcholinesterase-containing septodentate pathway. Eighteen rats were assigned to sham/GM1, lesion/GM1, or lesion/saline conditions. After preoperative training and testing, the rats received surgery and were then tested post-operatively for thirty days. GM1 injections (20 mg/kg) were given beginning the day before surgery through day 5 postsurgery and then on alternating days. Relative to the lesion/saline group, rats in the lesion/GM1 group showed enhanced recovery on the DRL-20 and the open field tasks. The lesion/GM1 group had significantly less septodentate sprouting than the lesion group treated with saline. GM1 treatment may be facilitating recovery from bilateral entorhinal lesions by reducing the trauma of injury and denervation, reducing heterologous sprouting, or both.

Effects of entorhinal cortex lesions on memory in different tasks.

Lesions of the entorhinal cortex produce retrograde memory impairment in both animals and humans. Here we report the effects of bilateral entorhinal cortex lesions caused by the stereotaxic infusion of N-methyl-D-aspartate (NMDA) in rats at two different moments, before or after the training session, on memory of different tasks: two-way shuttle avoidance, inhibitory avoidance and habituation to an open field. Pre- or post-training entorhinal cortex lesions caused an impairment of performance in the shuttle avoidance task, which agrees with the previously described role of this area in the processing of memories acquired in successive sessions. In the inhibitory avoidance task, only the post-training lesions had an effect (amnesia). No effect was observed on the open field task. The findings suggest that the role of the entorhinal cortex in memory processing is task-dependent, perhaps related to the complexity of each task.

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.

Bilateral entorhinal cortex lesions impair DRL performance in rats

The entorhinal cortex participates in a variety of spatial and locomotor behaviors that are thought to be mediated by the hippocampal formation. The present study examined the possibility that the entorhinal area contributes to the maintenance of an operant behavior in which the hippocampus is also implicated—differential reinforcement of low-rate responding (DRL). Rats with bilateral entorhinal cortex lesions or sham operations were tested for retention of a preoperatively learned DRL (10-sec delay) task. Rats with entorhinal lesions were impaired on measures of response rate, temporal discrimination, and response efficiency for 2 to 3 weeks after surgery. Histological analyses indicated that all the rats sustained complete entorhinal lesions. The entorhinal cortex may be an important component of the hippocampal formation contributing to the performance of DRL tasks.

Impairment in the acquisition of passive and active avoidance learning tasks due to bilateral entorhinal cortex lesions

The relationship between the entorhinal cortex and learning behavior was examined. The initial stage of Alzheimer's disease has been shown to be characterized by neuropathological alteration in the entorhinal cortex, with the appearance of the greatest number of neuronal tangles and severe neuronal loss in comparison with other brain regions involved. This entorhinal cortex, because of its anatomical relationship to the hippocampus, may play a crucial role in memory formation. In this study, rats with bilateral ibotenic acid-induced lesions of the entorhinal cortices were tested for acquisition of passive and active avoidance learning tasks. These animals displayed no sensorimotor disturbances as shown by evaluation of locomotor activity and shock sensitivity. However, they did show impair acquisition of passive and active avoidance responses. On the other hand, when the lesions were induced after training, there was no extinction of the acquired passive and active avoidance responses. The results demonstrate the importance of the entorhinal cortex in learning acquisition and indicate that rats with partial neuronal loss in the entorhinal cortex may be a useful model for studying the memory disturbance of Alzheimer's disease.

Spontaneous EEG spikes in the normal hippocampus. IV. Effects of medial septum and entorhinal cortex lesions

Spontaneous EEG spikes (SPKs) were recorded from the CA1 region of the dorsal hippocampus in normal rats during behavioral states not accompanied by rhythmical slow activity (RSA) such as awake immobility and slow wave sleep. The present experiment was designed to examine the effects of large electrolytic lesions of the 2 major hippocampo-petal systems, medial septum (MS) and entorhinal cortex (EC), on spontaneous SPK activity. MS lesions, while completely abolishing RSA, did not eliminate SPKs or change their behavioral correlates. SPKs were still suppressed during behaviors (walking, head movement, etc.) normally associated with RSA. However, SPK frequency was approximately halved after MS lesions. Total bilateral EC lesions did not, in general, change SPKs or RSA unless abnormal hippocampal activities persisted over the first post-lesion week during which most of the recordings were made. Laminar profiles of SPKs in both MS- and EC-lesioned rats showed a normal pattern; small positivity in stratum oriens, large negativity in stratum radiatum and polarity reversal around stratum pyramidale. These results suggest that (1) neither medial septal input nor entorhinal cortical input to the hippocampus is necessary for the generation of SPKs, and (2) SPK suppression still occurs in the absence of these inputs during behaviors normally associated with RSA. The possibility remains, however, that in intact animals these inputs do influence SPK activity in a behavior-dependent manner.

Effects of postoperative environment on recovery of function after fimbria-fornix transection in the rat

We have previously found that rats given dorsal hippocampus lesions show reduced deficits on maze learning, spontaneous alternation and extinction tasks when housed postoperatively in an “enriched” as opposed to an “impoverished” environment. In contrast, postoperative enriched conditions were ineffective in rats given bilateral entorhinal cortex lesions. In this study, we examined whether postoperative differential housing would reduce the impairment in radial maze performance induced by fimbria-fornix transections. Significant interactions were found between lesion state and housing condition for the total number of errors made, the number of errors on the first eight arms visited and for the number of arms visited before the first error in an 8-arm maze. The interaction was due to the fact that, in sham-operated rats, isolated ones made more errors than enriched counterparts whereas, in rats with lesions, enriched ones showed no improvement of performance in comparison to isolated counterparts. These data suggest that the integrity of fimbria-fornix pathways is an important factor for the expression of facilitated maze peformance in intact enriched rats and in enriched rats with hippocampal system damage.

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 discrupted it was suggested that the entorhinal cortex is an integral part of both systems.

Sparing and recovery of spatial alternation performance after entorhinal cortex lesions in rats

Groups of adult rats were first trained on a spatial alternation task and then subjected to unilateral entorhinal cortex lesions, unilateral entorhinal cortex lesions followed by dorsal psalterium transections, or bilateral entorhinal cortex lesions. After this surgery, the rats were then tested for retention of spatial alternation. Neither unilateral lesions alone nor unilateral lesions followed by dorsal psalterium transections resulted in long-term spatial performance deficits; however, animals with bilateral lesions exhibited severe impairments from which they eventually recovered. The results from animals with bilateral entorhinal damage indicate that extensive postoperative training may facilitate the recovery of spatial alternation performance. Histological analyses indicated that the crossed entorhinal projection proliferated in the dentate gyrus after unilateral entorhinal lesions and such anomalous growth occurred independently of any changes in alternation performance.

Behavioral effects of bilateral entorhinal cortex lesions in the balb/c mouse

Balb/c mice with small bilateral electrolytic lesions of the entorhinal cortex were compared with both sham and nonoperated subjects in spontaneous and learned behaviors. The operated mice were hyperactive in an open field 1 week but not 6 weeks after surgery; locomotor activity was slightly increased during the night hours 2–3 weeks after lesion. Learning was tested between 2 and 6 weeks postsurgery. Retention of a CRF appetitive operant conditioning task was improved after the lesion, as well as retention of a one-way active avoidance task. In contrast, operated animals were disturbed in an operant task using a discriminative schedule and in passive avoidance conditioning. The observed increase in activity was not sufficient to explain the findings. Considering the connections of the entorhinal cortex with the hippocampal system, we suggest some kind of inhibitory function for this cortex. Because the entorhinal cortex provides multimodal sensory information to the hippocampus, it could be involved in postlearning modulation of information and thus in memory processes.

Effects of postoperative environment on functional recovery after entorhinal cortex lesions in the rat

Young rats (31 days old) sustained bilateral entorhinal cortex lesions and were then housed in different conditions (“enriched” or “impoverished”) to assess the contribution of the postoperative environment to recovery from the effects of the lesion. They were subsequently tested on spontaneous alternation and Hebb—Williams maze learning tasks. In both of these tasks, the performance of rats bearing entorhinal cortex lesions was inferior to that of sham-operated controls. Environmental enrichment improved performance only in sham-operated rats and this only at the level of initial errors in the Hebb—Williams task. There was no evidence for an interaction between lesion and environmental factors. It is suggested that the effects of differential rearing are dependent, in part at least, on the integrity and on the neural and perhaps glial organization of the entorhinal cortex.

The time course of changes in open field activity following bilateral entorhinal lesions in rats and cats

The open field behavior of Sprague-Dawley rats and mongrel cats was tested daily prior to and following bilateral entorhinal cortical lesions. The subjects were tested postoperatively from Days 2 to 17 and the time course of behavioral changes following the lesions was assessed. Total activity and decline (habituation) in activity across successive minutes of each test session were recorded as the measures of open field behavior. Rats with bilateral entorhinal cortex lesions exhibited a dramatic increase in total activity which peaked on Day 4, paralleled by a slower habituation of activity within single test sessions. The increased total activity and slower habituation across minutes were most pronounced during the early postlesion interval, exhibiting some return toward control levels with time, but never attaining control values. To determine whether the return toward control levels was time dependent or a result of the repeated testing design, other groups of rats with bilateral EC lesions were tested beginning 10 and 14 days postlesion. These rats exhibited lower levels of total activity and a more rapid habituation across minutes than was observed in the group tested between 2 and 8 days postlesion. Thus, the return toward control levels was time dependent and not a result of the repeated testing. Cats with bilateral entorhinal cortex lesions also exhibited an increase in total activity and a slower habituation in successive minutes of a test session. Again, both effects were most pronounced during early postoperative intervals, approaching but not attaining control levels with time. The nature and time course of these changes were virtually identical in the two species. The similarities in the nature and time course of the behavioral changes in the rat and the cat are discussed with regard to the possible relationship between reactive changes in the brain and the time-dependent behavioral changes.

Entorhinal cortical lesions in rats and runway alternation performance: changes in patterns of response initiation

To determine whether bilateral lesions of the entorhinal cortex result in generalized performance deficits in tasks which require the recollection of previous trial events, we analyzed patterning behavior in runway alternation tasks. Under conditions of alternate trials of reward (four pellets) and nonreward, rats developed discriminative response patterns; responding with shorter latency and running faster on rewarded trials. Bilateral entorhinal cortex lesions resulted in pronounced reductions of latencies to start on nonreinforced trials to levels statistically indistinguishable from levels associated with reinforced trials; however, response differentiation on the run-time measures was comparable to that found with sham-operated animals. When subjects were shifted to alternation schedules of large (eight pellets) and small (two pellets) reward, operated animals immediately developed differential latencies to the two reward conditions, although longer latencies to start on small reward trials were observed for control subjects. The availability of short-term memory to operated animals for the recollection of previous trial events is indicated by the response differentiation in run measures on both reinforcement schedules. We propose that entorhinal cortex lesions elevate activity levels and thus disrupt response initiation patterns normally associated with contrasting reward conditions.