Delay-dependent involvement of the rat entorhinal cortex in habituation to a novel environment

Evidence has accumulated that the entorhinal cortex (EC) is involved in memory operations underlying formation of a long-term memory. Because entorhinal-lesioned rats are impaired for long delays in delayed matching and non-matching to sample tasks, it has been proposed that EC contributes to the maintenance of information in short-term memory. In the present study, we asked whether such a time-limited role applies also when learning complex spatial information in a novel environment. We therefore examined the effects of EC lesions on habituation in an object exploration task in which a delay of either 4 min or 10 min is imposed between successive sessions. EC-lesioned rats exhibited a deficit in habituation at 10 min but not 4 min delays. Following habituation, reactions to spatial change (object configuration) and non-spatial change (novel object) were also examined. EC-lesioned rats were impaired in detecting the spatial change but were able to detect a non-spatial change, irrespective of the delay. Overall, the results suggest that EC is involved in maintaining a large amount of novel, multidimensional information in short-term memory therefore enabling formation of long-term memory. Switching to a novelty detection mode would then allow the animal to rapidly adapt to environmental changes. In this mode, EC would preferentially process spatial information rather than non-spatial information.     

Activity and exploratory behavior after lesions of the medial entorhinal cortex in the woodmouse (Apodemus sylvaticus)

The effects of bilateral electrolytic lesions of the entorhinal cortex were studied in male adult woodmice. Experiments were designed to allow separate analysis of the basal activity level and exploratory behavior. Activity recording was conducted in three situations: (a) 24-hr wheel running in the home cage pre- and postoperatively; (b) 24-hr activity composition in a large enclosure over 4 days, 5 to 9 days postoperatively; and (c) sequence and duration of visits in a residential plus maze 11 to 14 days postoperatively. Medial entorhinal cortex lesion involving the para- and presubiculum increased the 24-hr amount of movements in the enclosure (b) without increasing wheel running in any situation (a or b). This lesion also enhanced the locomotor reactivity to being introduced into the plus maze and impaired exploratory behavior. This last effect was equally apparent when the whole situation was new or when part of the familiar maze was modified. Lesioned woodmice did notice the new element but did not show active focalization of their behavior on that element. Data showed that lesion induced hyperactivity and changes of exploratory behavior were not necessarily associated. Novelty detection was performed but it is not clear now on what information this discrimination was based.     

Orienting reaction habituation in chronic alcoholics

A polygraphic study on resistance to habituation of the somatic (EMG), autonomic (finger plethysmogram, galvanic skin reaction, respiration) and EEG (acoustic-evoked potential and EEG-blocking reaction) components of the orienting reaction elicited by a repetitive auditory stimulus was performed in 67 chronic alcoholics and in 70 matched normal subjects (control group). The study showed a significantly lower resistance to habituation of the orienting reaction in alcoholics than in normal control subjects. The severity of this habituation disturbance depended on the patients’ age, type of alcoholism, alcohol consumption intensity and chronicity, as well as the type of resting EEG.     

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

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

Spatial strategy elaboration in egocentric and allocentric tasks following medial prefrontal cortex lesions in the rat

We evaluated the role of the medial prefrontal cortex (mPFC) in the elaboration of egocentric navigation strategies in a water maze (WM). Lesions of mPFC cell bodies was achieved in 21 rats using bilateral injections of ibotenic acid (IA); 13 control rats were injected with saline. After 17 days, rats had to learn an allocentric (using external cues: 10 lesioned, 7 saline rats) or an egocentric WM (using internal/kinetic cues: 10 lesioned, 6 saline rats) over six trials in a same session. The initial trajectory on the sixth trial was used as an index of the elaboration of a navigation strategy. In the egocentric test, lesioned rats were more rarely located in the target quadrant than control rats. No differences were found between lesioned and control rats in the allocentric test. These results show that lesions of the mPFC impairs the capacity to elaborate an egocentric navigation strategy.     

Studies on retrograde and anterograde amnesia of olfactory memory after denervation of the hippocampus by entorhinal cortex lesions

The effect of hippocampal denervation on olfactory memory in rats was tested after interrupting the lateral olfactory tract projections at the level of the entorhinal cortex. When lesioned animals were trained to learn new odors, they showed no evidence of retention 3 h after acquisition. These results confirm earlier data on rapid forgetting in rats after hippocampal deafferentation and are in parallel to the anterograde amnesia typically found in humans with hippocampal damage. On the other hand, preoperatively learned information was minimally impaired after hippocampal deafferentation even if it was acquired within less than 1 h before the lesion. This finding differs from reports on humans as well as monkeys with hippocampal damage where memories formed during a critical time span of months or even years before the lesion are found to be impaired. This may suggest that the consolidation process in humans and rodents has different time scales or that the roles of the human and the rat hippocampal structure in memory formation are somewhat different.     

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.     

The medial prefrontal cortex and memory of cue location in the rat

We developed a single-trial cue-location memory task in which rats experienced an auditory cue while exploring an environment. They then recalled and avoided the sound origination point after the cue was paired with shock in a separate context. Subjects with medial prefrontal cortical (mPFC) lesions made no such avoidance response, but both lesioned and control subjects avoided the cue itself when presented at test. A follow up assessment revealed no spatial learning impairment in either group. These findings suggest that the rodent mPFC is required for incidental learning or recollection of the location at which a discrete cue occurred, but is not required for cue recognition or for allocentric spatial memory.     

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

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

Delayed recall of fear extinction in rats with lesions of ventral medial prefrontal cortex

Extinction of auditory fear conditioning is thought to form a new memory. We previously found that rats with vmPFC lesions could extinguish fear to the tone within a session, but showed no recall of extinction 24 h later. One interpretation is that the vmPFC is the sole storage site of extinction memory. However, it is also possible that lesioned rats were unable to retrieve extinction memory stored in other structures. To determine if a latent extinction memory could be retrieved with additional training, we repeated the experiment but added an additional 5 d of extinction reminder trials. Replicating our previous findings, vmPFC-lesioned rats extinguished normally on day 1, but showed no recall of extinction on day 2. Over the next 5 d, however, lesioned rats showed significant savings in their rate of re-extinction. Thus, the vmPFC is not the only site where extinction memory is stored. Nevertheless, lesioned rats receiving only two extinction trials per day required twice as many days to initiate extinction as controls. Although recall of extinction is possible without the vmPFC, it is significantly delayed. We suggest that the vmPFC accelerates extinction by permitting access to recently learned extinction trials, thereby maximizing behavioral flexibility.     

The entorhinal cortex plays a role in extinction

In this study, we analyzed the participation of the entorhinal cortex in extinction of a learned aversive response. Rats with infusion cannulae aimed to the entorhinal cortex were trained in a one-trial step-down inhibitory avoidance task (IA) and submitted to four consecutive daily test sessions without the footshock, a procedure that induced extinction of the conditioned response in control animals. When infused into the entorhinal cortex immediately after the first extinction session at doses able to block consolidation of IA memory, the NMDA receptor antagonist, AP5 (25 nmol/side), the inhibitor of protein synthesis anisomycin (300 nmol/side) and the inhibitor of CaMKII, KN-93 (10 nmol/side), but not the MEK1/2 inhibitor PD-98059 (5 nmol/side) hindered extinction of the IA response. The same results were obtained when the interval between the first and second test session was 48 instead of 24h. The data indicate that normal functionality of the NMDA receptors, together with CaMKII activity and protein synthesis are necessary in the entorhinal cortex at the time of the first test session to generate extinction. Our results also suggest that the ERK1/2 pathway does not play a role in this process.