Quinolinic acid lesion of the rat entorhinal cortex pars medialis produces selective amnesia in allocentric working memory (WM), but not in egocentric WM

ELSEVIER

Behavioural Brain Research 63 (1994) 187-194

BEHAVIOURAL BRAIN RESEARCH

Research Report

Quinolinic acid lesion of the rat entorhinal cortex pars medialis produces selective amnesia in allocentric working memory (WM), but not in egocentric WM Christian HOlscher*, Werner J. Schmidt Z,,,,h,k,t~che~ In,timt der Universttiit "I't'ihin~en...Ihtethm~, .M'un~pharntukohJ.~,W. .tl,hZ~tr. 54 1. "40¢) l~Thin.~en. German~"

Received 15 Jul,, 1993: re',iscd 14 ,\pril 1994: :,cccptcd 14 April l~lt~4

Abstract

l h e functional role of the entorhmal cortex pars medialis in memory formation was investigated b', lesioning this area with quinolinic acid. a select)re agonist of the NMDA-subtypc of glutamate receptors which has neurotoxic properties. With this technique "'en passant'" axons arc spared and only ncurons of the target area are destro) cd. The effects of this lesion on learning abilities in the g-arm maze ~verc tested. Rats in the lesion group showed different exploring behavior: animals did not visit all arms, and previous b visited arms were reentered. When oricnting themselves on distal cues (allocentric tests) the animals showed working mcmor~ (WM) dcticits and reduced speed of acquisition of reference memory (RIM). 'When changing arms that were baited, the test group had difficulties learning the new task. Perforlnancc decreased after introduction of a dela). However, when orienting themsclxes on proprioccptive cues (egocentric tests), no deficits in memor~ formation were detectable. Animals appeared h.~pomotoric in all tests. Kel word~, l.ntorhinal cortex: Quinolinic acid; Memory: N M I ) . \ receptor: Radial maze: Excitotoxicilv

!. Introduction

The h i p p o c a m p a l formation plays a crucial role in the Formation of memory. Patients with lesions in this area display a remarkabl~ complete amnesia of W M and an inability of reference m e m o r y ( R M ) acquisition [1.32,33, 45]. In rats, W M and acquisition of RM is also affected after lesion of the h i p p o c a m p a l formation [21,23,26]. Bridging intratrial delays, a typical W M task, is impaired [27]. When changing the arms that are baited in the 8-arm maze, the rats have difficulties in learning this new task (reversal learning) [ 10, I I ]. The cntorhinal cortex (EC) is considered to be one of the main cortical affe,ent connections o f the h i p p o c a m p a l ftwmation, functioning as an intcrfitce between neocortex and h i p p o c a m p u s [ 3,8,25,28]. Studies of rats with lesions in the cntorhinal cortex shmved learning deficits similar to dclicits after lesions in the h i p p o c a m p u s . Acquisition of a water maze task was possible but impaired, and reversal learning ~ a s ver\ poor [35]. Interestingly, if the EC w a s (orrespondmg author. Present adress: The Open tTni',crsit,.. Brain & Bchaxumr (iroup. Mllh)rl Kcynes. MK7 6.~.A. [TK. [:b,c~icl Scicm..c I,L'~ .S.S'D/ 0 l 6e,-4 3 2 s( ~14 ) 0 0 o ( , 9 - R

lesioned not via mechanical methods but pharmacologicall}, with an excitotoxic agent, the NIMDA agonist ibotenic acid [6]. the m e m o r ) d e l i c i t s were not as pronounced, acquisition of an 8-arm task was normal while reversal learning was impaired. Inactivating the EC bx injecting selective antagonists of the N M I ) A subtype of the glutamate receptor [7.13] or agonists o f the G A B A receptor [7,44] produces learning deficits as well, as do N M D A antagonists when injected into the h i p p o c a m p a l formation [22,34,43]. This suggests thai there is a flow of information from the EC via the perforant path to the dentate gyrus and the h i p p o c a m p u s proper [45] and that any interference with normal function of this sx stem either by lesions or by pharmacological inactivation leads to amnesia. The EC is divided into t~vo areas: pars latcralis (p.[.) and pars lnedialis {p.m.). Each part has its separate topographic projection to the h i p p o c a m p u s [9,36]. There appears to be a functional difl'erencc bet~vecn these two parts o f the EC. Rasmussen et al. [29] fimnd deficits in alloccntric, but not egocentric reversal tests after lesion via electrical current o f the EC p.m. but not p.I. in the rat. Mitchell et al. [20] found impairment m radial maze test

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in rats and loss of theta rhythm in the EC pars medialis after lesioning the medial septum. The EC pars medialis therefore appears to be more important for learning and memory formation. A similar separation of functions between parts of the hippocampus is observed by several authors: The dorsal part of the hippocampus appears ta be of importance in learning memory' tasks, while the ventral part does not [23,24,41]. There is evidence that the hippocampus is involved in learning allocentric tasks (learning by orientation by external cues) but not egocentric tasks (learning of bodx movements, motor learning). Kesner [16] found a clear involvement of the motor cortex in learning egocentric motor tasks, while the parietal cortex was involved in learning allocentric tasks. In the studies presented here, lesioned animals were tested in both types of spatial learning tasks to investigate if this functional differentiation in learning is visible in rats that have lesions in the EC. Lesions of the hippocampal formation also appear to selectively interfere with allocentric, but not with egocentric memory as is shown by' Squire [39,40] in experiments with rhesus monkeys. It is difficult to deduce the actual role of areas m the brain using mechanical lesions, because these methods destroy not only neuronal cell bodies but also sever "'en passant'" axons passing through the entorhinal cortex. thereby disconnecting other cortical areas of the n e o c o f rex that might directly project to the hippocampus. In the present study the neurotoxin quinolmic acid was used to selectively destroy neuronal cell bodies, but to spare "'en passant'" axons (see [31] for detailed description). Quinolinic acid is a selective N M D A receptor agonist, which most probably activates this receptor subtype to such an extend that it becomes neurotoxic [19]. The purpose of this study was to clarity' the role of the projection of the EC p.m. to the hippocampal formation by means of a pharmacological lesion. Allocentric memor~ and egocentric memory experiments were put to use to distinguish between these different categories of learning. When analyzing the errors made in these experiments, it was differentiated between working memory errors (multiple entries of arms within one run) and RM errors (entry of an unbaited arm). Furthermore. :in intratrial delay x~as introduced to test the animals" ability to retain information in their working memor,,.

2. Materials and methods

2.1. SuhNctx 2() male Sprague-Dawley rats (lnterfauna. Tuttlingen, FRG) weighing between 250 and 300 g were housed in groups of five in macrolon cages. They' were kept in a

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colony room with a room temperature of 22 :t 3 (7 and light turned on from 6.00 to 18.0~1 h. "fhev were fed after the end of daily experiments with 12 g of commercial laboratory chow per animal each dax. Water was frecl~ available.

2.2. Surgery "The animals were pretreated with 0.2 mg'kg atropine sulfate, ten minutes later, they xs.cre anaesthetized with 1.5 ml of a chloralhydrate solution t7",,) in saline gi\'cn i.p.. Rats were then placed into a stereotaxic apparatus (Trem Wells} with the incisor bar 3.3 mm below the interaural line. Due to the curved shape of the entorhinal cortex a special technique had to be employed to ensure maximum efficacy. An adapted version of the method used by Schenk and Morris [30] was used. A hole ~sas drilled on each side with the coordinates 8 mm posterior to bregma and 3.5 mm lateral. A microsyringe v,as used, tilted 15 in the coronal plane, the cannula tip ((t.45 mm outer diameter) pointing to the medial plane. The needle was inserted, and at 6, 7, and 7.5 mm (measured dorsoventrally from brcgma) an injection of quinolinic acid (dissolved in phosphate buffer solution, pH 7.5) or buffer solution (control group) ~as administered. 0.1 ml were injected at the 6 mm coordinate, [).2 ml at the other tx~o. 0.1 ml contained 10 nmole of quinolinic acid. 1his makes a total of 50 nmol quinolinic acid per hemisphere. \fter completion of each injection the cannula was left in place for 5 rain to :dtoxx difl'usion of solution. Control and test grot, p consisted ~1 ten animals each. randomly selected.

2.3. Histology After completing all experiments rats were killed b\ injecting 50 mg pentobarbital dissolved in 1 ml saline. Brains were removed and kept t\~r 36 h in a 10",, li)rmalin solution. ~tterwards they were washed for 4 h in water and transferred into a 30",, sacharose solution for 2 da.~ s. Brains were then cut on a freezing microtome -26 C into 15-lmHhick slices. Slices were stained with ('res.~l violet [4].

2.4. Apparatus The 8-artn radial maze, made of plastic coated wood ,~as similar to that described by Olton and Samuelson [26]. It consisted of an octagonal central platform with a diameter of 50 cm and of 8 adjoining arms (length 70 cm, width 17 cm, height 35 cm). i-.ach arm was individually marked with a number {not visible to the animal). At the distal end of each arm a food cup was placed. If the ann was to be baited a 45 mg food pellet was put into the cup.

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Behavi,,ural Brain Re~'earch 63:1994. 17¢--194

2.5. StatAtic.~ l ) a t a are presented as mcans ± S.E.M.. They were submitted either to a U-test of M a n n and Whitney (Expts. 1 and 2) or to a mo-xvav analysis of variance {.,\NOVA, multiple measurement [ 1 7 ] ) ( E x p t . 3-6). A P-value < 0.05 was considered to represent a signiiicant difference. Factors were ah~avs A - I degree o f freedom (groups). B = 5 degrees of freedom {trials). Each trial was completed by 1() animals pet" g,oup../'~XOVi;~ ~ ILIs based on raw d a t a scores, not on means of errors per trial. Please note that each d a t a point per day in figures published here is a svmmary of six trials per day (Expts. 3 - 6 ) sincc limited space does not allow for publication of all figures. A N O V A was c o m p u t e d with full extent of d a t a (trial 1-6). not with summaries shown in figures.

2.6. b..~7~eriment 1 ,'&tv I a/h'r .vur¢eo')." exploratory heh(lvl'rlr l h e rat was put into the center of the 8-arm maze and was alloxvcd to freely investigate the maze for ten minutes. Orientation was possible to extramaze cues such as doors and tables. The scquence of arm entries was recorded. The frequency distribution of anglcs between consecutively entered arms was evaluated. One trial per animal was given. "The arms were not baited.

2.7. Experiment 2 ~&lv 2 a/ier .~urgerv). rein/orced altenmti.n The aninlal started in a r a n d o m l y chosen arm. "l-he remaining 7 arms were baited with a food pellet. After all 7 pellets had been collected the trial was terminated. The nvmbcr o f arm visits required per trial to collect all 7 pellets was evaluated. One trial per animal was given.

2.,~. Experiment 3 ~daw 3 - 9 al?er surgery j" allocentric rev~'rA'(I[ e.xperinwnt with intratrial delav F o u r randomly chosen arms were baited. They were not changed Ibr the tirst 3 da~s. On thc fourth day different arms were baited. Starting arms were changed randoml~ among unbaitcd arms after each trial. Oricntation was allocentric b\ external cues in the room visible to the animal (\vindoxv. door. etc.). Egocentric infornlation could not be used duc to change or starting arm (tbr a detailed description see [ 10.1 I J). Each animal completed six trials per day. On day 6 and 7 a l-rain intratrial delay was introduced by. retaining the animal in the second visited baited arm with a d o o r m a d c of plywood. "l'he abilit~ to bridge delays seems to rely on a functioning h i p p o c a m p u s [26]. In order to test ability to

1,~9

relearn (reversal learning), baited arms wcre changed on day 4.

2.9. E vwriment 4 '.days 10-13 after .~z#~gervj, E.weriment 5 fda w 14-18 alter .~urget3'e." egocentric re ver~al experiment.~ In 15xpt. 4. fimr arms were baited...\ fifth arm served as a starting arm. Arrns were r a n d o m l y chosen and remained in the same position relative to each other (e.g. baited arms a t 4 5 - . 135 and 2 2 5 turning right a f t e r l c a v i n g s t a r t i n g arm}. This fixed pattern of baited arms and starting arm was rotated randomly after each trial relative to room coordinates. This ensured that thc animal could not relx on external cues (windo~v, door) for orientation. Instead the egocentric pattern of body turns (45 to the right etc.) had to be remembered. In Expt. 5, three arms x~erc baited, located 9 0 180 :, and 2711 from thc starting arm. On d a \ 5 an intratria[ delay of 1 rain ~ a s introduced b\ retaining the animal in the second visited baited arm with a d o o r made o f plywood.

3. Results and discussion 3. I. HLvtology l,ight microscopy analysis of lcsioned area showed extremely reduced numbers o f stained stcllate and pyramidal cells in laver 11, III. and IV of the EC pars medialis. A p p r o x i m a t e l y 90",, of this area was affected. The EC pars lateralis was not affected as severely. An average of 50",, loss of stained neurons was estimated with a large variation between 30". and 8 0 " , . There was no visible loss in thc subicular and h i p p o c a m p a l ( ' A I areas (Fig. 1).

3.2. Expt. 1 Idav I after .smi~e(vJ. e xpbmtto(v t~ehavior Lesioned animals sho~ved very different explorator.v behavior. They showed a preference for 1 3 5 angles while neglecting 45 : when choosing arms (Fig. 2). As in animals with h i p p o c a m p a l lesion [25], not all arms were visited while others were visited repeatedl,v. This is a first clue that the lesion had an effect on spatial orientation. 3.3. Expt. 2 ;&n" 2 alier sm~eetTJ. remlimed ahermaion There was no significant difference in number of arnl visits required to collect all pellets (data not shown}. ]'his experiment showed that lesioned animals have general motor, cognitive, and sensory abilities sufficient to master this task. Animals a p p e a r e d to have applied an egocentric strategy (see below) to collect pellets, since they tended to always c h o o s e the next arm to the right or left. rather than

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all experiments than controls. Since experiments were ver3 different from each other, and since the lesioned rats perfi)rmed not different from control rats in Expts. 4 and 5, this difference in latency' between groups comes as a surprise. The observed hypomotoric behavior is different from symptoms observed after lesion of the hippocampus formarion, which usually produces hypermotoric behavior [25 ]. This hypermotoric behavior was investigated by Kaplan [ 14] who showed that rats with hippocampal lesions showed no hypermotoric behavior when kept in a dark and sound proof box. l.esions of the hippocampal formation also decrease habituation [14,42]. If animals with hippocampal lesions habituate less, hypermotoric behavior in the presence of stimuli might be the result• The h.xpermotoric behavior seen after lesioning the EC might not simpl 3 be produced by' h~.peractivity ofthe motor svstem. It could be that lesioned animals are more do not habituate to environmental stimuli as controls do. This :-:'(P

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would cause the animals to spend more time completing this particular task by dealing longer with irrelevant stimuli if they' have a learning impairment and habituation is dccreased. On days 1 and 2 a difference in WM errors was detectable between groups, but no difference in RM errors. This indicates that these tx~o types of memories are fi)rmed b v two independent systems. The number of RM errors increased after change of baited arms. The animals showed a tendency to perseverate. The lesioned animals did not adapt to the new task and had problems relearning. This can be explained by the decreased abilit~ to form nex¥ RM, which did not enable the animals to "'override'" the old RM that already was established. Dela) s had an effect on both reference and working memorx. This result is surprising, since lesioned animals performed well befi~re the delays. One possible explanation is that lesioned animals were more confused by the delays than controls. If lesitmed animals habituate less, as has been argued in the expla-

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nation of the hypomotoric behavior, they might bc lnorc distracted and make more RM errors. l a k c n together, thc observed learning deficits resemble effects oflcsions in the hippocampal formation rather well. The main difference is thc comparably slight extent of amnestic symptoms.

,?.5. Expt. 4 r&n,,s 10-13 after surgetT). Expt. 5 t&n's 14-18 a[h,r .~urgerl'J." egocentric reversal experimenr~ -ks in Expt. 3, lesioned animals needed more time to colnplete trials (Fig. 3). No difference in numbers o f \ V M and RM was detectable (data not shown). In Expt. 5, number of WM errors was higher in the lesion group after delay (Fig. 6). The results of the egocentric experiments differ drastically from results obtained in the allocentric experiments. In the egocentric Expts. 4 and 5, control and test groups slowly learned the location of baited arms. In contrast to learning the allocentric task, learning the egocentric task proved to be no problem for lesioned animals at all, numbers of errors made were virtually identical in most days. The intratrial delay, however, caused lesioned animals to make more WM errors after the delay as compared to controls. Since lesioned animals did not make more WM errors in trials without delay, this finding is difficult to interpret. The bridging of delays could be a especially demanding task that needs the support by the hippocampal-entorhinal system.

4. General discussion The deficits induced b) a lesion of the entorhinal c o l tcx pars medialis resemble those of a lesion of the hippocampal formation. Long term RM is little affected while

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WM memory is poor in lesioned aninlals, and the abilit,, to bridge delays is impaired ltowever, the extent of deficits is not as large as after lesioning the hippocampus. This confirms pre,,ious findings [6.13.44] and supports the theor\ that the E(" is the main afferent connection of the luppocampus, yet the residual learning capabilities suggest that different afferent connections exist besides the kit'. Animals lesioned b\ qumolinic acid seemed to learn the tasks as well as the control group did after some trials. ,naybe because of gaining experience and adapting to the task. After 3 days (t-xpt. 3)even WM was not significantly different from controls. This compensation was not due to axon~.ll sprouting which might occur from neurons in other areas to the EC or to the hippocampus [37,38] and n o t d u e It') compensation after incomplete lesion, because changing baited arms on day 4 caused lesioned animals to again make significantly' more WM errors than controls. In animals with mechanical lesions of the entorhinal cortex, acquisition is severely hampered, pcrscveration is highly dc,,eh)ped and ma~ last for ~ecks without signs of compensation [18]. WM is severel~ impaired over long periods of time without compensation [2.12,28]. The resuits therefore sho~ that the entorhinal cortex is important for memor~ formation. Possible direct projection of primary and secondar,, association area,', to the hippocanipal forum,,on without relay' in the cntorhinal cortex might also exist in the rat and could be o1" importance for proper acquisition of allocentric memory. It is surprising that lcsioning the t'i(7 p.m. (and affecting some of the EC p.l.) is sufficient to cause the observed cfl'ects. This confirms previous rcsuhs [291 and supports the theory that The EC-hippocampal system consists of two subsystems, with the EC p.m. and the dorsal part of the hippocampus on one side and the EC p.l. and the ventral part of the hippocampus on the other side [9,301. The selective impairment t)("allocentric memory bx thi,,, axon sparing lesion is quite remarkable. Squire [39,40] suggests that thci'e arc at least t~.o different memory .,,ysterns. ()no x~otild be responsible for sensory (allocentric) inli)rmation (tteclarative memor.~ ), the other (me ~ ould bc responsible fi)r acquisition of egocentric inlbrmation (proccdural incn~ory). Kesner ct ,ll [ 15,16] propc)sed a siniilar model after tinding selective deficits of egocentric mclnorv after lesion of the medial prefrontal cortex and selective impairntcnt of alloccntric memoi') after parietal cortex lesions in animal studies {till lesions b~ aspiration of tissue). The role t)l' the EC-hippocampat sv,,,tem scelns t() bc the retention of sensor? information over some time (,e.g. in bridging delays), sufficiently to citable long-tcrnl memor', formation. Problems m reversal learning demonstrate this ,,'erx well. since in this task the animals have tt) encode a

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Behavu,ural Brain Re~ean'h 63 • 1994. 18--194

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formalion.

References [ I] Baddcle). \.1).. 7he P',l~ h,,b~.~r <~I ,lh'moO. Basic Books. [.ondon.

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