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EMORY IMPAIRMENT INDUCED BY AN INTERFERING TASK ISEVERTED BY PRE-FRONTAL CORTEX LESIONS: A POSSIBLE ROLE
OR AN INHIBITORY PROCESS IN MEMORY SUPPRESSION IN MICE
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. COSTANZI,a,c D. SARAULLI,a,c C. ROSSI-ARNAUD,b

. ACETIa,b AND V. CESTARIa,c*

Istituto di Neuroscienze del Consiglio Nazionale delle Ricerche, viael Fosso di Fiorano, 64-00143 Roma, Italy

Dipartimento di Psicologia, Università di Roma “La Sapienza,” via deiarsi, 78-00185 Roma, Italy

Facoltà di Scienze della Formazione, Università LUMSA, piazza delleaschette, 101-00193 Roma, Italy

bstract—Interference theory refers to the idea that forget-ing occurs because the recall of certain items interferes withhe recall of other items. Recently, it has been proposed thatnterference is due to an inhibitory control mechanism, trig-ered by competing memories, that ultimately causes forget-ing [Anderson MC (2003) Rethinking interference theory:xecutive control and the mechanisms of forgetting. J Memang 49:415–4453]. In the present research we study the

nterference process by submitting CD1 mice to two differentippocampal-dependent tasks: a place object recognitionask (PORT) and a step-through inhibitory avoidance taskIA). Our results show a mutual interference between PORTnd IA. To elucidate the possible neural mechanism underly-ng the interference process, we submit hippocampus- andrefrontal cortex-lesioned mice to PORT immediately before

A training. Results from these experiments show that pre-rontal cortex lesions completely revert the impairing effectxerted by PORT administration on IA memory, while hip-ocampus lesions, that as expected impair memory for bothORT and IA, increase this effect.

Altogether our results suggest that interference-induced for-etting is driven by an inhibitory control mechanism throughctivation of hippocampus-prefrontal cortex circuitry.

The hippocampus seems to be crucial for storing informa-ion related to both behavioral tasks. Competition between

emories triggers the inhibitory control mechanism, by activat-ng prefrontal cortex, and induces memory suppression. © 2009BRO. Published by Elsevier Ltd. All rights reserved.

ey words: step-through inhibitory avoidance, place objectecognition task, open field, CD1 mice, hippocampus.

he interference process induces forgetting when similar in-ormation is subsequently presented (Anderson and Neely,996). The classical theory of interference, namely the re-ponse competition theory (McGeoch, 1942), predicts thatorgetting is due to an association of additional memory

Correspondence to: V. Cestari, Istituto di Neuroscienze del CNR, viael Fosso di Fiorano, 64-00143 Roma, Italy. Tel: �39-06-501703274;ax: �39-06-501703304.-mail address: [email protected] (V. Cestari).bbreviations: AP, anterior–posterior; DV, dorso-ventral; Hippo, hip-

2ocampus; IA, inhibitory avoidance; ML, medial–lateral; OF, openeld; PFC, prefrontal cortex; PORT, place object recognition task.

306-4522/09 © 2009 IBRO. Published by Elsevier Ltd. All rights reserved.oi:10.1016/j.neuroscience.2008.08.026

503

races to existing ones. It follows that association of multipleraces to the same cue induces a competition process duringetrieval according to the degree of similarity between stimuli.his process is known as cue-dependent interference (Raa-

imakers and Shiffrin, 1981; Mensink and Raajimakers,988). Alternatively, it has been proposed that interferenceight be a cue-independent process due to an inhibitory

ontrol mechanism in which forgetting arises from suppres-ion between competing memories, rather than from associ-tion of additional traces (Anderson, 2003; Levy and Ander-on, 2002). In this view forgetting arises whenever the re-rieval of memory traces triggers the inhibitory control. Whenhe retrieval does not require interference to be resolved, noorgetting is found even if the nature of the competing stimulis similar. Moreover, forgetting induced by interference isndependent from the strength of the memory trace (seenderson, 2003 for a review).

A number of studies suggest that prefrontal cortex (PFC)lays an important role in response selection and inhibitoryontrol (Winograd-Gurvich et al., 2008; Forstmann et al.,007; Stürmer et al., 2007; de Jong and Paans, 2007; Mayrt al., 2006; Miller and Wang, 2006; van Eimeren et al., 2006;stlund and Balleine, 2005; Lissek and Güntürkün, 2004;idderinkhof et al., 2004; Fuster, 2001; see also Dalley et al.,004; Miller, 2000; Miller and Cohen, 2001 for reviews) asell as in the response-inhibition mechanism necessary to

esolve the interference in working memory tasks (Nee et al.,007; Jha et al., 2004, 2006; Mecklinger et al., 2003;’Esposito et al., 1999). Furthermore, it is interesting toote that suppression of unwanted memories as well asecall of remote memories stored in cortex, requires thectivation of an inhibitory process in which the hippocam-al function is disengaged through PFC activation (Ander-on et al., 2004; Frankland and Bontempi, 2005). Theseesults suggest a role for the PFC in the inhibitory processeading to suppression of hippocampus (Hippo) activity.

D’Esposito (2007), reviewing a number of studies onorking memory, suggests that the ability to maintain the

epresentation of information necessary for goal-directedehavior emerges from a functional interaction betweenFC and other brain structures. In this context, manytudies have shown a role for the interaction between PFCnd Hippo in spatial and nonspatial working memory both

n humans (Piekema et al., 2006; Jonides and Nee, 2006or a review; Scoville and Milner, 1957; Holdstock et al.,995; Eichenbaum, 2000; Kesner and Hopkins, 2001) andodents (Delatour and Gisquet-Verrier, 1996; Floresco etl., 1997; Porter et al., 2000; Fuster, 2001; Izaki et al.,
001; Lee and Kesner, 2003; Touzani et al., 2007).
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M. Costanzi et al. / Neuroscience 158 (2009) 503–513504

If interference were a cue-independent process medi-ted by a memory suppression mechanism, then learningwo different tasks which depend on the same brain struc-ures could trigger suppression of competing memorieshus inducing forgetting during retrieval.

To assess this point we tested memory for a one-trialnhibitory avoidance task (IA) in mice submitted to a placebject recognition task (PORT), as well as the reverse,amely memory for object location in PORT in mice sub-itted to IA. In IA, mice learn to avoid a context in which

hey receive a mild foot shock; memory for this task isapidly acquired and largely depends upon hippocampalunction (Harooni et al., 2007; Tan, 2007; Igaz et al., 2006;alin and McGaugh, 2006; Martí Barros et al., 2004;aubenfeld et al., 2001; Izquierdo et al., 1999b; see also

zquierdo and Medina, 1997 for a review). In PORT, micere exposed twice to an open field (OF) in which they learnn object displacement. Memory for displacement alsoepends upon hippocampal function (Sato and Yamagu-hi, 2005; Mumby et al., 2002; Liu and Bilkey, 2001). Wexpected mutual interference between PORT and IA toccur, thus inducing memory suppression and forgetting.

Moreover, to verify the specificity of PORT in memoryuppression for IA we submitted additional groups of animalso an OF test, as a control condition. The only differenceetween OF and PORT was the object presentation. It isorth noting that although the hippocampal function seems toe crucial for OF habituation when sessions are spaced by4 h interval (Rossi-Arnaud and Ammassari-Teule, 1992;zquierdo et al., 1992; Thiel et al., 1998, 1999; Wolfman et al.,999), pharmacological treatments into CA1 Hippo that affectemory for an IA task have no effect on OF habituation (delivera Alvares et al., 2005; Vianna et al., 2001), suggesting

hat memory formation for OF and IA recruits different neu-onal mechanisms. Moreover, it has recently been shownhat CA1 lesions do not affect habituation when sessions arepaced by short-term time interval (Vago and Kesner, 2008).n agreement with the inhibitory control theory (Anderson,003), we expected that, despite the similarity betweenORT and OF procedures, the OF administration should not

rigger competition between memories. Thus only PORT ad-inistration should induce forgetting for IA throughout an

nhibitory process. Moreover, regarding interference as aue-independent process, we expected IA retention to induceorgetting for object location in PORT. Finally, we hypothe-ized that the inhibitory control process could involve theFC-Hippo circuitry. That is, the PFC was supposed torive memory suppression by inhibiting the activity ofhe Hippo when competing pieces of information (PORTnd IA) were presented. As a consequence, we ex-ected that PFC lesions to prevent the interference ef-ect exerted by PORT on the retrieval of IA, by removinghe inhibitory control. On the other hand, as Hippo is thetructure storing information related to both PORT andA, we expected Hippo lesions to impair memory for bothasks. Thus, in order to investigate the brain structuresnvolved in the inhibitory control of cue-independent in-erference, Hippo- and PFC-lesioned mice were submit-
ed immediately before IA training to either PORT or OF. o
EXPERIMENTAL PROCEDURES

ubjects

ale CD1 mice (Charles River Laboratories, Como, Italy) aged 8eeks and weighing 25–30 g were used in these experiments.pon arrival the mice were housed in groups of four in standardreeding cages (21�21�12 cm) and kept in a 12-h light/darkycle (lights were on from 07:00–19:00 h) at a constant temper-ture of 21 °C, given food and water ad libitum and tested duringhe second half of the light period (between 14:00 and 17:00 h) in

sound-insulated room. The research in this paper was con-ucted according to Italian national laws and regulations on these of animals in research and NIH guidelines on animal care.aximum care was taken to minimize the number of animals usednd to minimize their suffering.

tep-through IA task

ice were tested in a step-through IA apparatus as previously de-cribed (McGaugh and Landfield, 1970). A straight alley was dividednto two compartments, one 7.5 cm long and the other 14 cm long.he floor was 2.5 cm wide and the top 10 cm wide. The smallerompartment was made of white Plexiglas. The larger one was madef black Plexiglas and was equipped with a removable cover of theame material to allow the compartment to be in darkness. The twoompartments were separated by a sliding door. A tensor lamp (60, positioned 80 cm above the apparatus) illuminated the small

ompartment. The floor of the larger compartment consisted of twoblique stainless-steel plates separated by 0.5 cm at the bottom and0 cm at the top, through which scrambled constant current could beelivered. The shape of the electrified floor ensured that the mouseade contact with both plates simultaneously in order to receive the

hock. On the training day, each mouse was placed in the lightompartment, facing away from the dark compartment. When theouse turned around, the door leading to the dark compartment waspened. When the mouse had stepped with all four paws intohe dark side, the door was closed, the step-through latencyas recorded, and a foot shock (0.7 mA, 50 Hz, 1 s) waselivered. A maximum step-through latency of 300 s was al-

owed in the test sessions.

F

he OF arena had a square shape (52�52 cm) and walls (high0 cm) constructed of gray Plexiglas. The arena was situated inhe same sound-attenuated cabin in which the IA apparatus wasocated. All mice submitted to this task were positioned into therena twice. In the first trial they were allowed to explore thepparatus for 5 min. Then they were removed and located intoheir home cage for 5 min. Once this time had elapsed the miceere submitted to the second trial in the arena for 3 min.

ORT

or the PORT all mice were positioned in the apparatus used forhe OF task. As recently described (Mumby et al., 2002), the miceere exposed to the arena twice (sample phase and test phase).

n the sample phase two identical objects (black plastic cylinders;0 cm length, 3 cm diameter) were located in two adjacent cor-ers. After 5 min they were removed and located into their homeage for 5 min. In the test phase, one object was moved to a newocation in the opposite corner. The mice were returned to therena and allowed to explore it for 3 min. The time spent by theice exploring the objects was recorded. A mouse was consid-red to be engaged in object exploration when its head wasriented within 45° of an object and within 2 cm of it. Rearing withhe head oriented upward was also counted as object explorationf at least one forepaw was on the object. Climbing over or sitting
n top of the objects was not included. The exploration ratio, i.e.

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M. Costanzi et al. / Neuroscience 158 (2009) 503–513 505

he proportion of total object-exploration in the new location (tnovel/tnovel�tsample]) during the 3-min test phase was considered as theependent variable.

urgery

efore surgery, mice were randomly assigned to one of the threexperimental groups: (1) sham lesion, (2) medial PFC and (3) CA1orsal Hippo lesion. Mice were anesthetized with chloral hydrate400 mg/kg; Sigma-Aldrich, SL, USA) and placed in a stereotaxicpparatus (Kopfe). The scalp was incised, and holes were madehrough the skull above the intended lesion site. The coordinatesere (AP�anterior–posterior to bregma; ML�medial–lateral toregma; DV�dorso-ventral to bregma) taken from Franklin andaxinos’s (1997) atlas of the mouse brain. A cannula (0.25 mm iniameter) was inserted bilaterally to reach the following areas:A1 subregion of dorsal Hippo (AP��2.5; ML��1.9; DV��1.5)nd medial PFC (AP�2.4; ML��0.4; DV��1.9). The lesions wereerformed injecting 1.0 �g of ibotenic acid (Sigma, St Louis, MO,SA) at each site, in a volume of 0.2 �L of phosphate-buffer-saline.

njections were performed at constant flow rate of 0.05 �L/min. Shamesions were performed by inserting the cannula at the same coor-inates but injecting PBS at the same volume. Lesioned and sham-

esioned groups were left in their home cage for a 7-day period toecover before the behavioral analysis.

istology

t the end of the experiments, lesioned and sham-lesioned ani-als were killed by cervical dislocation. The brains were removednd fixed in paraformaldehyde (4%), sectioned coronally (30 �m)nd stained with Toluidine Blue according to Nissl method.

tatistical analysis

tep-through latencies either during the training or the retention,re expressed as medians and interquartile ranges. Since a ceil-

ng of 300 s was imposed during the tests session the step-hrough latencies were analyzed with appropriate nonparametricnalysis of variance (Kruskal-Wallis test), and the differencesetween groups were estimated by individual Mann-Whitney Uest (two-tailed; Siegel, 1956). Data from PORT are expressed asxploration ratios (according to the formula tnovel/(tnovel�tsample)nd are analyzed by one-way ANOVA. Habituation in the OFessions is expressed as percentage of time spent in both loco-otion and rearing and is analyzed by two-way ANOVA. Whenppropriate, post hoc analyses are performed with the PLSDisher test. In all cases P values less than 0.05 are consideredignificant.

xperiment 1

he first experiment was carried out in order to assess the retro-ctive interference effect of a posttraining administration of eitherF or PORT for retrieval of the IA. Immediately after IA training allice were randomly assigned to one of the three experimental

onditions. The first group of mice (n�8) receiving the interferencerocedure was submitted to PORT. The second group of micen�8) was exposed twice to OF. After PORT and OF, all miceere returned to their home cages. Mice of the third group (n�8),onsidered as a control group (Control), were left to their homeages immediately after training in the IA apparatus. All groups ofice were tested in the IA apparatus 30 min after training.

xperiment 2

he second experiment was carried out in order to assess theroactive interference effect exerted by a pretraining administration
f either OF or PORT on IA retrieval. Three groups of mice were 6
andomly assigned to different experimental conditions. The firstroup of mice (n�10), was submitted to PORT procedure and

rained immediately after in the IA apparatus. The second group ofice (n�10) was exposed twice to the OF and trained in the IApparatus immediately after the last exposure. The third group ofice (n�9), control group (Control), was only trained in the IA appa-

atus. All groups of mice were tested in the IA 30 min after training.

xperiment 3

he third experiment was carried out in order to study the interferingffect of IA on memory for object location in PORT. Two groups ofice were submitted to IA training procedure. After entering the dark

ompartment mice of the first group (IA, n�8) received a foot shock,hile mice of the second group (IA-sham, n�8) were removed from

he apparatus without foot-shock delivery. Thirty minutes after train-ng all mice were exposed to the apparatus until 3 min were elapsed;atency to the first step-through was recorded and considered as

emory retention index. Immediately after IA test, both groups ofice were submitted to PORT.

xperiment 4

he fourth experiment was carried out in order to assess the role ofither medial PFC or Hippo lesions in the spatial interference inducedy PORT on IA. For this purpose Hippo-, PFC-, and sham-lesionedSham) mice were randomly assigned to the interference procedurePORT) or to OF as described in the experiment 2.

RESULTS

o significant differences (H(4)�4.78; P�0.31) were foundmong groups of mice in the step-through latencies re-orded during the training.

ost-training PORT interferes with IA memory

he results of the first experiment (Fig. 1) show that post-raining PORT administration impairs memory for the IA.he nonparametric statistical analysis (Kruskal-Wallis test)

or the step-through latencies recorded in the IA test car-ied out 30 min after training shows significant differencesH(2)�7.5; P�0.023) among mice groups (control, PORTnd OF mice). Individual comparisons (Mann-Whitneyest) indicate that mice submitted to the PORT immediatelyfter training show a significant memory impairment inomparison to both control (U�9; P�0.028) and OF miceU�8.5; P�0.024), while no significant differences areound between control mice and OF mice (U�19; P�0.17).

These results indicate that learning of PORT, but nothe mere exposure to a new environment, retroactivelynterferes with IA memory, suggesting that context acqui-ition in IA and displacement learning in PORT trigger aemory competition process thus causing the memory

mpairment observed in the IA test.

re-training PORT proactively interferesith IA memory

he results of the second experiment (Fig. 2) show thatre-training PORT administration impairs IA memory. Theonparametric analysis (Kruskal-Wallis test) carried out onhe step-through latencies recorded during the memoryest show significant differences among groups (H �
(2)
.23; P�0.036). Individual comparisons (Mann-Whitney

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est) show that retention in PORT group is significantlyeduced in comparison to both control and OF miceU�14.5; P�0.024 and U�22; P�0.034). No significantifferences have been found between the performances ofontrol and OF mice (U�38; P�0.86).

This result indicates that PORT, but not OF, proactivelynterferes with IA memory, suggesting that learning of thepatial displacement occurring in PORT competes withontext acquisition in IA thus inducing the retention impair-ent observed during the IA test.

A interferes with memory for object locationn PORT

he results of the third experiment (Fig. 3) show that IAdministration before PORT impairs memory for object

ocation. One-way ANOVA carried out on exploration ratiosn PORT sample phase (Fig. 3B, left panel) shows noignificant differences between IA and IA-sham miceF(1,14)�0.77; P�0.4), indicating that both groups of micepent equal time exploring the two objects. Moreover, aurther one-way ANOVA carried out on the total amount ofime spent exploring objects reveals that both groups ofice do not significantly differ in the object exploration

F(1,14)�1.11; P�0.31), showing that IA does not affectamiliarization with objects (data not shown).

One-way ANOVA carried out on exploration ratios inhe test phase (Fig. 3B, right panel) shows that IA mice doot recognize spatial displacement spending equal amountf time exploring both displaced and non-displaced object

ig. 1. Effect of posttraining administration of both PORT and OF onemory retention for the IA task. (A) Schematic representation of thexperimental procedure carried out in the first experiment. Immedi-tely after training to the IA animals were submitted to the PORT (n�8)r to the OF test (n�8). The control mice were returned to their ownome cage (Control; n�8). Thirty minutes after the IA training all miceere tested (without foot-shock administration) for retention. (B) Step-

hrough latencies (median and interquartile range) recorded duringraining and retention test in control mice (black columns, n�8) and
ice submitted to OF (gray columns, n�8) or PORT (white columns,�7). # P�0.05 vs. all other groups (Mann-Whitney U test, two-tailed).
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ompared with IA-sham mice (F(1,14)�19.03; P�0.001).inally, non-parametric analysis (Mann-Whitney test) car-ied out on the performance recorded in IA test reveals, asxpected, that mice exposed to IA apparatus, without foot-

ig. 2. Effect of pretraining administration of both PORT and OF onemory retention for the IA. (A) Schematic representation of the experi-ental procedure carried out in the second experiment. Immediatelyefore training to the IA animals were submitted to the PORT (n�10) or

o the OF test (n�10). The control mice were returned to their own homeage (Control; n�9). Thirty minutes after the IA training all mice wereested (without foot-shock administration) for memory retention. (B) Step-hrough latencies (median and interquartile range) recorded during train-ng and retention test in control mice (black columns, n�8) and miceubmitted to OF (gray columns, n�10) or PORT (white columns, n�10).P�0.05 vs. all other groups (Mann-Whitney U test, two-tailed).

ig. 3. Effect of IA on memory retention for object location in theORT. (A) Schematic representation of the experimental procedurearried out in the third experiment. Mice were submitted to either merexposure to the IA apparatus (IA sham, n�8) or to the training proce-ure with foot-shock administration (IA, n�8). Thirty minutes after

raining all mice were submitted to the IA test and remained in thepparatus for 3 min. Immediately after the IA test, both IA-sham and IAice were submitted to the PORT. (B) Mean exploration ratios

�S.E.M.) during the sample phase (left panel) and test phase (right
anel) in the PORT of IA-sham (gray column) and IA mice (whiteolumn). # P�0.05 vs. all other groups.

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hock administration, show significantly lower latencies tohe first step-though in comparison with mice trained andested in IA (U�9; P�0.015, data not shown).

Together, these results indicate that IA test, but not theere exposure to IA apparatus, interferes with the spatialisplacement in PORT.

istology

ig. 4 shows photomicrographs and coronal reconstruc-ions of both the Hippo (A–D) and medial PFC (E–H) of thenimals with ibotenic and sham lesions. The Hippo lesion

s restricted to the CA1 subfield with some involvement ofhe dorsal portion of the dentate gyrus while CA2 and CA3ubfields are spared. In the lesioned area a massive py-amidal cell loss and gliosis can be observed; (C–D). ThePFC lesion is extended down to the medial wall of theFC centered on the prelimbic and anterior cingulatedortices with some involvement of the secondary motorortex (G–H).

FC lesions, but not Hippo lesions, rescue thenterfering effect exerted by the pre-trainingdministration of PORT

further statistical analysis carried out on data obtained inhe first and the second experiment show no significantifferences between IA retention levels of pre-trainingORT and post-training PORT mice (H(2)�22; P�0.2).imilarly, no significant differences have been found be-

ween performances of pre-training OF and post-trainingF mice (H(2)�21; P�0.1). Since both pre- and post-

raining PORT administration, but not OF, impairs memoryor the IA in a similar manner, we chose to study the effectf PFC and Hippo lesions on the interference process byubmitting mice to the pretraining interference procedure.

Fig. 5B shows the IA step-through latencies recordedor control and lesioned mice submitted before training toither PORT or OF in the test carried out 30 min afterraining. The nonparametric statistical analysis (Kruskal-

allis test) reveals significant differences among groups inhe retention levels recorded in the IA test (H(5)�24.68;�0.0002). Individual comparisons show that pretrainingORT administration significantly impairs IA retention inham-lesioned mice when compared with the sham-esioned mice submitted pretraining to the OF (U�8;�0.004). However, no significant differences in memory

etention have been found between PFC-lesioned miceubmitted pretraining to either PORT or OF (U�38.5;�0.86). Moreover, performances of PFC-lesioned miceubmitted to PORT or OF are undistinguishable from thatf sham-lesioned mice submitted pretraining to OFU�36.5; P�0.72 and U�39; P�0.89). These results in-icate that the lesions of PFC completely rescue the im-airing effect exerted by PORT on IA retention.

The Hippo-lesioned mice submitted pretraining to theF show a significant impairment of the latencies recordeduring the test in comparison with that observed in bothham- (U�14; P�0.019) and PFC-lesioned mice (U�15.5;�0.027), indicating that Hippo lesions impair the IA re-

ention. Finally, Hippo-lesioned mice submitted pretraining p

o PORT are impaired in the IA test in comparison toham-lesioned mice submitted to PORT. Moreover, al-hough no significant statistical differences have beenound, the Hippo-lesioned mice submitted to PORT show aower retention performance when compared with theippo-lesioned mice submitted to the OF (U�16;�0.054), suggesting that PORT administration enhances

he impairing effect exerted by the Hippo lesion.Together, these results suggest that the PFC have a

ivotal role in suppressing the competition between mem-ries and that a PFC-Hippo circuitry is involved in theorgetting induced by PORT on IA.

ippo lesions, but not PFC lesion, impair placebject recognition

ig. 5C shows the exploration ratio of the PFC-, Hippo- andham-lesioned mice in PORT. The one-way ANOVA car-ied out on the PORT performance shows a significantifference among the groups (F(2,23)�19.54; P�0.0001).LSD Fisher post hoc test shows that Hippo-lesioned micere significantly impaired in comparison to both PFC-P�0.0001) and sham-lesioned mice (P�0.0001) while noignificant differences are found between PFC- and sham-

esioned mice. These results are in agreement with find-ngs by Mumby et al. (2002) indicating that the hippocam-al function is essential for learning and retention of thebject displacement in PORT.

ippo and PFC lesions do not affect exploration inhe OF

he role of PFC and Hippo in the exploration behavior inhe OF is evaluated by analyzing the percentage of timepent by PFC-, Hippo- and sham-lesioned mice in locomo-ion and rearing recorded during both the first and theecond session of the test (Fig. 5D).

The two-way ANOVA shows that Hippo- and PFC-esioned mice are not significantly different from sham-esioned mice in the amount of time spent both in locomo-ion (F(2,24)�0.36; P�0.05) and rearing (F(2,24)�1.66;�0.05). Moreover, all mice groups show a statisticallyignificant decrease in the percentage of time spent in

ocomotion when the first and the second sessions of theest are compared (F(1,24)�48.58; P�0.0001).

Together, these results indicate that PFC and hip-ocampal function do not play a pivotal role in the OFabituation.

DISCUSSION

he main finding of the present study is that PFC lesionsrevent the interfering effect exerted by the learning of twoonsecutive hippocampal-dependent tasks (PORT and IA).

The inhibitory control theory predicts that interference-nduced forgetting is a cue-independent process. In thisase interference is independent from the similarity be-ween stimuli to be learned and forgetting is induced byemory competition through an inhibitory control process

Anderson, 2003). Here we propose a model of cue-inde-
endent interference in which forgetting seems to be due

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o an inhibitory control process mediated by PFC. In ourrocedure the only difference between OF and PORTonsists in the presence and displacement of two objectsn the latter task. Consequently, all the contextual cuesransferable to IA are common to OF and PORT. Thus, theossibility of a cue-dependent interference can be ruledut. Our data show that the displacement learning in PORT

nduces impairment in IA retention, while no memory effects observed when OF is administered. Further, the IAearning experience, but not the mere exposure to the IApparatus, interferes with learning in PORT showing autual interference between IA and PORT. These data

uggest a competition between memories for PORT andA, able to trigger the inhibitory control process. Moreover,FC lesions prevent the memory impairment for IA, thusuggesting a pivotal role for this structure in the inhibitoryontrol process.

etroactive and proactive interference

he results of the first experiment indicate that learning ofpatial displacement in PORT, but not the mere exposureo a new environment in OF, retroactively interferes with IAetention. This finding is in agreement with recent results

ig. 4. Coronal view reconstruction of the dorsal Hippo (left) and PFChree AP levels is shown. (A–D) Photomicrograph of Cresyl Violet–stbotenic-lesioned (C, D) mice. (B, D) High magnification of the areaespectively. (E–H) Photomicrograph of Cresyl Violet–stained sectioagnification of the areas reported into the black square of the sham

howing that the immediate post-training exposure to a d

otential new learning situation (nose-poke habituation)mpairs long-term memory for an IA task (Boccia et al.,005). Regarding OF and IA retention, there are data in the

iterature showing that a single OF administration 1 h afterA training impairs long-term memory (Izquierdo et al.,999a) while the OF administration immediately, 1 and 2 hefore testing increases retention in an avoidance taskIzquierdo et al., 2001). These data apparently seem toontradict our results. However, it should be noted that, dif-erently from ours, in both the abovementioned studies theest timing is set to investigate long-term but not short-termemory formation. In fact, Medina et al. (1999), using a

imilar procedure, fail to show an amnesic effect of the OFhen short-term memory is investigated. Further, a doubledministration of the OF (resembling our procedure) does notffect memory for the IA (Izquierdo et al., 1999a, 2001).

The results of the second experiment show thatORT, but not OF, proactively interferes with IA mem-ry. The observation that a mere pre-training exposure

o a new environment, like the OF arena, does not affect IAhort-term memory is consistent with results obtained byzquierdo et al. (1999a). In particular, these authors showedhat exposure to a new environment 5 min before training didot affect memory consolidation in rats submitted to a step-

he maximal (gray) and minimal (black) extension of brain damage atctions of CA1 subfield of the dorsal Hippo of both sham- (A, B) andd into the black square of the sham- and ibotenic-lesioned tissuesFC of sham- (E, F) and ibotenic-lesioned (G, H) mice. (F, H) Hightenic-lesioned tissues respectively.

(right). Tained ses reporte

own IA task (Izquierdo et al., 1999a).

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ig. 5. Effect of pretraining administration of the PORT and OF on memory retention for the IA in control mice (SHAM) and mice with hippocampalHippo) and PFC lesions. (A) Schematic representation of the experimental procedure carried out in the third experiment. SHAM-, Hippo- andFC-lesioned animals were submitted to PORT immediately before training to the IA. The retention memory test was carried out 30 min after IA

raining. (B) Step-through latencies (median and interquartile range) recorded during training and memory retention test in SHAM-, Hippo- andFC-lesioned mice pretraining submitted to either OF (gray columns; SHAM n�9; Hippo n�9; PFC n�9) or PORT (white columns; SHAM n�9; Hippo�8; PFC n�9). (C) Mean exploration ratios (�S.E.M.) during retention test in the PORT of SHAM- (white columns, n�9), Hippo- (gray columns, n�8)nd PFC- (hatched columns, n�9) lesioned mice. In all cases the ratio represents the proportion of object-exploration time that was spent exploringhe displacement object. (D) Percentage of time spent in locomotion (left panel) and rearing (right panel) in the first and the second session of the OFy SHAM- (white columns, n�9), Hippo- (white columns, n�9) and PFC-lesioned mice (hatched columns, n�9). # P�0.05 (Mann-Whitney U test,
wo-tailed). * P�0.001 vs. all other groups (PLSD Fisher post hoc test).

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The results of the third experiment show that the re-ention of an aversive experience in the IA, but not theere exposure to the apparatus, impairs PORT perfor-ance. Furthermore, the aversive experience in IA doesot affect familiarization with objects since both groups ofice spend an equal amount of time exploring objectsuring the sample phase in PORT.

Taken together, the results of these experiments indi-ate a mutual interference between IA and PORT, support-ng the idea that forgetting is due to a competition between

emories regarding both tasks. Indeed, the collected datare consistent also with an alternative interpretation refer-ing to detection of (and/or reaction to) novelty per se as aotential trigger for the interference effect. Actually, owingo the object displacement occurring in the recognitionhase, PORT represents a twofold source of novelty inomparison with OF (the latter consisting of a double ex-osure to the same environment). It has been observed,owever, that object presentation in an open arena has alight impact on both behavior and neurotransmitter re-ease associated to the arousal induced by novelty expo-ure (Giovannini et al., 1998, 2001). Together with datahowing that novelty exposure does not affect IA short-erm memory (Izquierdo et al., 1999a), these results sug-est that detection of, and/or reaction to, novelty mayardly constitute, by themselves, the real underpinnings ofhe interference effect we observe.

Supported by evidence pointing to a role for the Hippon the acquisition and retention of both IA (Pereira et al.,007; Giovannini et al., 2005; Schaeffer and Gattaz, 2005;artí Barros et al., 2004; Martinez et al., 2002; Babar et al.,002; Izquierdo et al., 1999) and PORTs (Sato andamaguchi, 2005; Mumby et al., 2002; Liu and Bilkey,001), we suggest that in our experiments the acquisitionf these two tasks induces memory competition by activat-

ng the CA1 region in Hippo, with a possible involvement ofhe same intracellular pathway. Intriguingly, previous stud-es have shown a role for the protein kinase A (PKA)ntracellular pathway in memory formation for object dis-lacement (Malleret et al., 2001) and in both short- and

ong-term memory for IA (Izquierdo et al., 1999b; Vianna etl., 2001), but not in OF habituation (Izquierdo et al.,999b; Vianna et al., 2001). Although further studies areeeded to elucidate the mechanisms through which mem-ry competition induces forgetting, it seems plausible that

nterference may rely on competition between memoryrocesses at molecular/neuronal level. Furthermore, it isossible that competition between memory traces can trig-er the inhibitory control mechanism through the PFCctivity. This interpretation is supported by a number oftudies showing the existence of a functional relationshipetween Hippo and PFC (Rosene and Van Hoesen, 1977;wanson, 1981; Goldman-Rakic et al.,1984; Jay et al.,989) and its role in the organization of behavior in rodentsFloresco et al., 1997; Lee and Kesner, 2003; Gisquet-errier and Delatour, 2006) as well as in humans (Stern etl., 2001). Further evidence comes from electrophysiolog-

cal studies showing that an increase in CA1 stimulation
odifies the activity of PFC pyramidal cells that, in turn, i
esults in changes of the inhibitory phase of the hippocam-al responses. These data suggest that changes in theFC activity are responsible for the temporal filtering of

nformation (Degenetais et al., 2003).

ffects of PFC and Hippo lesions on interference

o assess the role of PFC and Hippo in the interferencerocess we have submitted PFC- and Hippo-lesioned miceo PORT before IA training. The results of the third exper-ment show that bilateral lesions of PFC rescue the mem-ry impairment in IA induced by PORT administration.oreover, lesions of PFC do not affect memory retention

or IA when mice are submitted to OF. On the other hand,ippo-lesioned mice submitted to OF show a memory

mpairment in the IA test, indicating that this structure, asxpected, has a crucial role in acquisition and retention ofA (Harooni et al., 2007; Tan, 2007; Igaz et al., 2006; Malinnd McGaugh, 2006; Martí Barros et al., 2004; Taubenfeldt al., 2001; Izquierdo et al., 1999b). Finally, a clear in-rease in the memory deficit, although not statisticallyignificant, is observed in Hippo-lesioned mice submittedo PORT when compared with that of Hippo-lesioned miceubmitted to OF. Our lesion data are consistent with thosebtained in other studies showing that Hippo and PFCrocess information in parallel, although the former seemso be better suited to process and store spatial informationor a longer period of time (Lee and Kesner, 2003). It ishus possible to envisage that in our experiments the en-oding of PORT and IA information requires the activationf the same Hippo-PFC circuitry.

Again, an alternative explanation may account for theehavioral data. That is, both PFC and Hippo lesions could

nduce non-specific alterations in the freezing responsehich would appear to be memory-related, deceptively.

ndeed, a general decrease in the expression of freezingehavior has been shown, after hippocampal lesions, inversive situations and/or contextual fear conditioningBlanchard et al., 1977; McNish et al., 1997); conversely,FC lesions have been demonstrated to increase freezing

Morgan and Ledoux, 1995; Baratta et al., 2008). However,ontrasting results are present in the literature, dependingn the time and size of the lesions or the procedure usedo assess freezing behavior (Morgan and LeDoux, 1995;organ et al., 1993; Lacroix et al., 2000; Sacchetti et al.,002; Baratta et al., 2008; Gisquet-Verrier et al., 1999 andcNish et al., 1997, 2000; Pentkowski et al., 2006; Frank-

and et al., 1998; Wiltgen et al., 2006; Phillips and LeDoux,994; Quinn et al., 2008). Concerning the PFC, it is worthoting that lesions comparable, for size, to the ones found

n our sample, have been shown not to affect either mem-ry acquisition or retention in rats submitted to an IA taskMuir et al., 1996; Deacon et al., 2003). Besides, lesionsestricted, as ours, to the CA1 region of the Hippo dompair memory retention but not the expression of freezinguring the acquisition of a contextual fear conditioningRogers et al., 2006). Moreover, there exists evidence of aole for the ventral, but not dorsal, Hippo in modulatingnxiety-like behavior in conditioned and unconditioned an-

mal models of defense (Pentkowski et al., 2006). To-

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ether, these results converge in suggesting a specific roleor the dorsal Hippo in the storage of contextual informa-ion, rather than the modulation of memory-unrelated com-onents of the aversive experience. Thus, although non-pecific effects of lesions administered in our study cannote definitively ruled out, such an issue does not seem toontradict the main conclusions we draw from our experi-ents: that is, the involvement of the Hippo in the short-

erm maintenance of spatial feature for both PORT and IA,nd a putative role for the PFC in the temporal integrationf information, driving the inhibitory control process thatauses forgetting for IA in the interfering condition.

This interpretation is also consistent with results bynderson et al. (2004) concerning the mechanism of sup-ression of unwanted memories. In particular, humansubmitted to the think/no-think paradigm show a higherFC activation when they have to voluntarily suppressemories for items previously presented. This PFC acti-

ation corresponds to a decrement in hippocampal activity,uggesting that suppression of unwanted memories re-uires PFC recruitment to disengage hippocampal pro-essing (Anderson et al., 2004).

An alternative explanation refers to a possible inhibi-ory role exerted by PFC on other brain structures involvedn memory processes. For example, Goto and Grace2005a,b), using in vivo electrophysiological recording inats, found that PFC and Hippo have reciprocal connec-ions and exhibit converging projections to the nucleusccumbens. On the basis of their results, the authorsuggest that after strong hippocampal stimulation (Hippo24 PFC information flow) the information processing de-ending on nucleus accumbens goes under the main con-rol of the Hippo. In this condition convergence of both PFCnd Hippo inputs to the nucleus accumbens results in annhanced activity of the latter. On the contrary, when theFC is stimulated (PFC 224 Hippo information flow) the

nformation processing depending on nucleus accumbensoes under PFC dominance. In the latter condition, nu-leus accumbens activity is suppressed (Goto and Grace,005a,b; see also Grace et al., 2007 for a review). In thisrame, a PFC overload, being derived from interfering stim-li in our procedure, can be hypothesized.

Here we propose a procedure that can be useful toetter elucidate the effective role of PFC in the inhibitoryontrol process induced by interference. This aspect cane particularly interesting if one considers schizophrenia. Itas recently been observed that visuo-spatial short-termemory is more susceptible to spatial interference in

chizophrenic patients (Cellard et al., 2007). In this con-ext, the experimental procedure we used in the presentesearch might be a useful tool in the study of animalodels of schizophrenia (Cabungcal et al., 2007;’Tuathaigh et al., 2007a,b) and could help to better clarify

he mechanisms underlying the short-term memory dys-unction observed in schizophrenic patients.

cknowledgments—This work was supported by PRIN 2006roject 2006050725_003 (V.C.). M.C. was supported by FILAS
egione Lazio.
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(Accepted 17 August 2008)(Available online 22 August 2008)

Memory impairment induced by an interfering task is reverted by pre-frontal cortex lesions: A...

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