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Delayed-alternation performance after kainic acid lesions of the thalamic mediodorsal nucleus and the ventral tegmental area in the rat
Bclmvi,,ural Brain Re.~earcll, 3 ( 1981 ) 125 130 ~,, ElsevierNorlh-Holhu~d Biomedical t'res~
125
Short Communication l)elayed-alternatinu performance after kaiuic acid lesions of the thalamic mediodorsal nucleus and the ventral tegmental area in the rat
JOSEF KESSLER and HANS J. M A R K ( ) W I T S ( ' H * l)¢7~artnlent o/ P~ycholo.~.v. Univer.~itv ol Kmls'tan;., P.O.B. 556¢), 1)-7750 Konstanz ' I".R.G. ) I Receivcd October 31st, 1980) I Revised version received I)ecember 101h. 1980) IAccepted January 8th, 19811
Kc.v words: ventral tegmental area lhalanlic mediodorsal nucleus ll~llion prefrontal cortex
kainic acid
delayed-ahcr-
[ h e relative importance of tv, o subcortical structures, projecting to the rat's prefrontal cortex, in mediation of delayed-alternation performance, was tested. These structures, the thalamic mediodorsal nucleus and the ventral tegmental area, v, ere lesioned with kainic acid after lhe rats had learned a spatial delayed-alternation lask. h was found that both struclures are apparently invol,,ed to a similar degree in the perfornlance of this task and that the behavior of both experimenial group~, differed from that of it sham-operated control group of rats.
The prefrontal cortex is most frequently defined as cortical projection area of the thalamic mediodorsal nucleus (MD) [10]. This definition is especially favored in non-primate species such as the rat [8]. Recently. however, a study combining the techniques of retrograde horseradish peroxidase transport and of fluorescense histochemistry, revealed that the cortical afferents from MD closely resemble those from thc ventral tegmental area of the mesencephalon (VTA) [1]. From their results, DNac et al. [1] concluded that "the dopaminergic innervation of the cortex (arising from VTA) might in lhct serve to identify the prefrontal area' (p. 67). This suggestion was tested empirically by Simon et al. [20]. From their 6-hydroxydopamine lesioning of the VTA A10 neurons of rats, trained in a delayed-alternation task, these authors concluded that "the dopaminergic A I0 system could.., be considered as a rather better indicator of frontal system ['unction than the mediodorsal thalamic nucleus" (p. 150). They did not. however, test this statement by lesioning MD neurons in rats trained in a delayed-alternation task. Therefore, we have subjected this statement to direct testing using, as did Simon et al. [20], a delayed-alternation paradigm.
* r o xshom MI correspondence should he addressed.
126 Twenty-five male Sprague--Dawley rats of 220 350 g weighl ~ ere employed They were housed in individual cages and each of them rcceivcd 13 g c,,mmercial rat chow daily alter the testing. The animals were assigned randoml~ I~, 3 group,,. destined to receive either a sham-operation or lesions of V T A or MI). All animals were trained in a modified f-maze (length, breadth alld height: 85, 70 and 10 cm, respectively), similar tt) Ihose mazes used l~rcviousl3 tor guinea pigs [11] and cats [9]. As in the previous expcrimelll [2i. the rats were at first handled extensively and were given time to adapt to lhe tnaz¢ testing situation. Thc tbrmal training procedurc, the number of tlial~ (20). the criteria (3 consecutive sessions of at least 85", correct pertbrmancc~, and the resting periods (10 days) between preoperative and postoperative rctesling were identical to those described previously [2, 9, 11]. Surgery was perlbrmed immediately lbllowing attainment of the criterion in the preoperative relearning test. Animals of the two experimental groups were anesthetized (Equithesin : 3.5 ml/kg i.p.) and then reccived 0.15/~1 oF kainic acid per hemisphere at a concentration of 2.5/~g /al, dissolved in 0.2 M phosphate buffer. The techniquc of injection has bcen described previously [141. (,'oordinares, according to the atlas of Pellegrino ct al. [I 3]. were, lor VTA rats: 3.7 mm posterior to the bregma, 0.7 mm lateral to the midline, and 8.7 mm below the dura and, lbr animals of the M D group: 1.2, 1.0 and 6.0 mm, rc.~pcctively. Rats of the control group (CG) received the same amount of the vehicle solution either in M D or VTA. After the end of the experiment all animals were pcrfused with ~tline followed by 10!',, buffered lbrmalin in saline. Brains were cut at 50 #m using a freezing microtome. From the lesioned area, every third section was mountcd and stained with cresyl violet. Furthermore, every sixth section of the brain was taken to check tbr remote lesion effects [4, 17. 22]. Extents of lcsioned areas were determined under the light microscope. Non-parametric statistics were used throughout: only significant values are presented. Of the 25 animals, one of the control group and one of group M D had to be discarded during delayed-alternation acquisition because of strong aggressive behavior. Furthermore, 4 of the rats with lesions aimed at VTA and 3 with lesions aimed at M D died during the first 3 postoperative days. Lesion extents for one rat from each of the two experimental groups are shown in Fig. 1. In the other animals of thc two groups the lesions were generally similar in extent. In addition to the local lesions, distant lesion effects were observed in both experimental groups, most consistently in areas CA3 and CA4 of the hippocampus and in the piri|brm cortex. However, none of the animals exhibited complete bilateral destruction of CA3 and CA4 along the entire length of the hippocampus. Aside from the electrode track, no lesions were found in animals of group CG. Behaviorally, the rats of groups VTA and M D were aphagic and adipsic
127
/
- .A~6
i
•
- .6
-.4
i
20 •
l':ig. I. Coronal sections o f lhe rat's brain at indicated anterior posterior levels a d o p t e d from Pellcgrino el al. [13]. Extent o f neuronal damage (black areas) i~, shov,n for a rat ~ith a lesion of the ventral legmental area (A C'), and for a rat with a lesion o f the thalamic mediodorsal I'lticletls ~[) I:).
for 1 3 days. After 6 days at the most, rats of the VTA group behaved normally. MD-lesioned rats, on the other hand, were rather hyperactive in comparison to the other two groups. Delayed-alternation performance did not differ between groups during acquisition and during preoperative relearning. In spite of the small number of animals in groups VTA (n = 4) and M D (n = 5), rats from each of these two groups differed from animals of the control group postoperatively (Mann Whitney t J-tests: U = 6.5 for group VTA and 7.5 for group M D: 0.05 < P < 0.10 for both experimental groups: one-tailed: Fig. 2). Rats of group VTA manifested so-called collateral or irrelevant behaviors (frequent rearing, sniffing, and stopping) [19.20] during delayed-alternation performance. As Fig. 2 shows, there are no differences in the postoperative performance of the animals of the two experimental groups. Furthermore, this figure reveals that the number of errors was rather similar to that of the VTA-lesioned animals
128 I I
~5!
FL:
:
pre post ""-:
[-~
~-2 . . . .
VYA
MD
CG
F i g 2. Comparison of preoperative (pre) and postoperative (post) performance ratc~ ot ntts ~ t h lesions of the ventral tegmental area (VIA). the thalamic mediodorsal nucleus (MI)) :lnd of i~ control group of sham-operated rats {CG). Medians of crrors are presented as column~,.
in the study of Simon et al. [20] (average of number of errors: 19.6 in Simon et al. ; median of errors in the present study: 19.5). Our results, theretbre, reveal that the differences in perlbrmance of a cognitive task after lesions of MD and VTA are not so marked as to supporl the suggestion of Simon et al. [20] that VTA should be taken as a better indicator of functions of the prefrontal cortex than MD. We are, however, aware of the fact that the present results have to be considered with caution. Similar deficits need not necessarily have common, underlying causes, and, in addition to the intended, local lesions of either VTA or MD, further lesions were tbund in the hippocampus and piriform cortex, i.e. in structures extremely sensitive to kainic acid [4, 12, 21, 22]. Parts of the deficits observed in our animals from the two experimental groups might be attributable to a mass-action effect [6], caused by the additional lesions remote from the intended locus of the lesion. Alternatively (or combined with a possible mass-action effect), the lesioning of a region critical for spatial delayed-alternation performance might be partly responsible lbr the observed deficits in the rats of groups VTA and MD. The structure most vulnerable to intracerebral injections of kainic acid, whose partial destruction is also most likely to affect performance rates in a delayed-alternation paradigm, is the hippocampus [5, 15]. However, as kainic acid preferentially destroys only certain hippocampal neurons, the long-term effects of remote lesions on the hippocampus would be less severe than those of conventional, mechanical destruction of the respective areas. In support of this statement is an important finding of Leach et al. [7]. Following kainic acid lesions of the lateral hypothalamus, these authors found that. in spite of damage in regions CA3 and CA4 of the hippocampus, hippocampal EEGs regained normal amplitude and frequency within 25 days after the injections. This finding, together with the similarity in the postoperativc average of errors of our study with that of Simon et al. [20], and the similarity of the structures showing distant lesion effects in both of our experimental groups, allow us to conclude that most of the behavioral deteriorations observed postoperatively in the two experimental groups were due to the local chemical
129 lesion. Nevertheless, it appears wise to substitute ibotenic acid [br kainic acid in future lesion work as ibotenic acid. in comparison to kainic acid, has been found to be less toxic and apparently to cause no remote lesions, while still destroying sufficient amounts of nervous tissue [4, 16]. Though the degrees of the behavioral deficits were lbund to be similar ti)r group VTA and group MD rats, the causes underlying these deficits might differ: as in the studies of Simon et al. [19. 20], our VTA-lesioned rats showed various forms of collateral behaviors which would have both detracted from their performance and lengthened the time necessary to mediate the appropriate behavioral response. MD-lesioned rats, on the other hand, appeared hyperactive and, in part, also hyperaggressive. VTA-lesioned rats, therefore, may be characterized by more general changes in attention [3], while more specific emotional changes might constitute the deficit of MD-lesioned rats [18]. Dr. F. Gruber, the University veterinarian, and his staff', deserve special thanks li)r care of the animals. Furthermore, we thank F.M. Wharton for improvement of the English of the manuscript and M. Sugawa for much help in training the animals.
I
l)i,,ac, 1.. Bj6rklund..A~j, l.indvall, 0 . and Passingham. R.L.. ('c, uvcrgm~ projections from the nlediodorsal nucleus and mesencephalic dopaminergic neurons tc, the neocortex in three species, .I, comp. Neurol.. 180 {1978) 59 72. 2 Divac, I.. Markowitsch. H.J. and Pritzel. M.. Behavioral and anatomical consequences of small intrastriatal injections of kainic acid in t h e r a t , Brain Res., 151 (1978) 523 532. 3 Gale3.. D., Jaffard, R. and Le Moal, M., Alternati,,m behavior, spatial discrimination, and reversal after electrocoagulation of the ventral mesencephalic iegmentunl in the rat, Belnn. .\eural Biol., 26 (1979) 81 88. 4 (;uldin. W.O. and Markov.itsch, HJ.. Epidural kainate, but not ihotenate, produces lesions in local and distant regions of the brain. A conlparison of the intracerebral actions of kamic acid and ibotenic acid, submitted ti~r publication. 5 Ivcrscn. S.D.. Brain lesions and memory in anmlals, In J. r)eutsch It{d.). 77w Physioh>,~i¢al Ba.q.~ ~ I Memm'v. Academic P,css, New York. 1973, pp. 305 364. 6 l,ashle). K.S.. Brain :l,lech,ni.wnsandhztelli,w,me, University of ('hicago Press. Chicago. lt-,~29. 7 Leach, 1,., Whisha,,~,, I.Q. and Kolb. B., I{ffectsof kamic acid Icsicms m the lateral hypothalamte, on beha,.ior and hippocampal and neocortical elcctrocncephalographic [I{EG} activit? m the rat. Belntv. Brain Re.~.. I 11980) 411 431. 8 I,eonard, C.M., l h e prefrontal cortex of the rat. 1. ('orlical projection of the mediodorsal nucleus. II. Efferent connections, Brain Re~., 12 11969} 321 343. 9 Marko,aitsch. H.J.. Pritzel, M.. Kessler, J.. (iuldm, W, and Freem~m. R,B.. Jr., Delayedalternation performance after selective lesions v, ithin the prefrontal cortex of lhe cat, Bchov. Brain Rc~., 1 {19g0) 67-.91. I0 Marko,a itsch, H.J.. Pritzcl. M.. Wilson, M. and Divac, I.. The prefrontal corlcx o f a prosimian
130 /Galago .~enegalensis/ defined a,,, the cortical projection area of tile lhakinli~ rricdiudorsai nucleus. Neuroscience, 5 (1980) 1771 1779. I 1 Markowitsch, H.J. and Riess, R., Delayed-alternation pcrlormancc afler ,,clccn~c Icslnn> ¢~1 the m e d i a / a n d sulcal prefrontal cortex of the guinea pig. Brain Bchav. I:lo/. ~n p~c,~, 12 Nadler, J.V., Perry, B.W., Gentry, ('. and Cotman. C W . . Degeneration of hipp~,~.,mlpzil ( , \ ~ pyramidal cells induced by intraventricular kainic acid. ,l, c,mp. ,,V('ttro[. It)2 (]'}N()) .]33 35o 13 Pellegrino. LJ.. Pellegrino, A.S. and (ushlnarl. A.J...4 ,StvreotavD ,4Ha.~ <,! ,',',c Rat Brain, Plenum Press, New York, 1979. 14 Pritzel, M. and Markowitsch. H.J.. Kamic acid lesions in the cat's thalamus \l,wpho/ogicai and behavioral changes, Brain Re.~. Bull.. 5 (1980) 61 6 7 15 Rosvold, H.E. and Szwarcbart, M.K., Neural structures revolved in delayed-re~r~om,e pcr[i~rmance. In J,M. Warren and K. Akerl (Eds.), rtu, Frontal (;ranukn" ('orlc~ end IIc/lal'lm. Mc(,~raw-Hill. New York. 1964. pp. I 15. 16 Schwarcz. R , H6kfelt. T.. [':uxe, K...Ionsson. (,i.. Goldstein, M. and lcrenlm.. I . Ihotenlc acid-induced neuronal degeneration: ;i morphological and nct,rochemical slud.~. I. xy. Bruin Rex.. 37 (1979) 199 216. 17 .~hw'ob, J.li.. Fuller. T., Price, .1.1.. and ()hie,,..I.W.. Widc~,pread palter,>, of ncul <>l,,ll dama.~c following systemic or intraccrebral injections of kaiim: a d d : a histological ,,lud}. \em',,vciem'e. 5 (19g[)) 991 1(}14. 18 Siegel. A., Edinger. |1. and Koo. A.. Suppression of attack beha, vior m lht ~.:t/ by thc prefrontal cortex: role of the mcdiodc)rsal thalamic nuc]cus. Braun Rc.~.. 127 11977) 1~5 190 19 Simon. t1.. Scatton, B. and Lc Moal. M.. Definiti,,.e disruption of spatial dela',.ed alternation in rats after lesions i11 the ,,'elllral n]esencep'llalic tegmerHum. Nctao.~vt I c/, 15 1197q)
20
319 324. Simon. H.. Scatton, B. and l.c Moal. M., Dopammcrgic AI() netu'nnc', arc m',t,l,.cd lu
21
cognitive functions, Nalurc ,'Lo,,td. ,. 286 (1980) 150- 15 I Smialo~vski, A., l)ifferent sensitivit', of hippocampal ncuron~, to kamic acid in Ihc rabbit.
22
.%"euro.sciem'c. 5 (1980) 1475 147g. Zaczek, R., Simonton. S. and ('oylc. J.T., Local and distant neuronal degeneration lolh~wing mtras/riatal injection of kainic acid. J. Ncuropalh. c\p..Vcuro].. 39 (1980) 245 2(,4
125
Short Communication l)elayed-alternatinu performance after kaiuic acid lesions of the thalamic mediodorsal nucleus and the ventral tegmental area in the rat
JOSEF KESSLER and HANS J. M A R K ( ) W I T S ( ' H * l)¢7~artnlent o/ P~ycholo.~.v. Univer.~itv ol Kmls'tan;., P.O.B. 556¢), 1)-7750 Konstanz ' I".R.G. ) I Receivcd October 31st, 1980) I Revised version received I)ecember 101h. 1980) IAccepted January 8th, 19811
Kc.v words: ventral tegmental area lhalanlic mediodorsal nucleus ll~llion prefrontal cortex
kainic acid
delayed-ahcr-
[ h e relative importance of tv, o subcortical structures, projecting to the rat's prefrontal cortex, in mediation of delayed-alternation performance, was tested. These structures, the thalamic mediodorsal nucleus and the ventral tegmental area, v, ere lesioned with kainic acid after lhe rats had learned a spatial delayed-alternation lask. h was found that both struclures are apparently invol,,ed to a similar degree in the perfornlance of this task and that the behavior of both experimenial group~, differed from that of it sham-operated control group of rats.
The prefrontal cortex is most frequently defined as cortical projection area of the thalamic mediodorsal nucleus (MD) [10]. This definition is especially favored in non-primate species such as the rat [8]. Recently. however, a study combining the techniques of retrograde horseradish peroxidase transport and of fluorescense histochemistry, revealed that the cortical afferents from MD closely resemble those from thc ventral tegmental area of the mesencephalon (VTA) [1]. From their results, DNac et al. [1] concluded that "the dopaminergic innervation of the cortex (arising from VTA) might in lhct serve to identify the prefrontal area' (p. 67). This suggestion was tested empirically by Simon et al. [20]. From their 6-hydroxydopamine lesioning of the VTA A10 neurons of rats, trained in a delayed-alternation task, these authors concluded that "the dopaminergic A I0 system could.., be considered as a rather better indicator of frontal system ['unction than the mediodorsal thalamic nucleus" (p. 150). They did not. however, test this statement by lesioning MD neurons in rats trained in a delayed-alternation task. Therefore, we have subjected this statement to direct testing using, as did Simon et al. [20], a delayed-alternation paradigm.
* r o xshom MI correspondence should he addressed.
126 Twenty-five male Sprague--Dawley rats of 220 350 g weighl ~ ere employed They were housed in individual cages and each of them rcceivcd 13 g c,,mmercial rat chow daily alter the testing. The animals were assigned randoml~ I~, 3 group,,. destined to receive either a sham-operation or lesions of V T A or MI). All animals were trained in a modified f-maze (length, breadth alld height: 85, 70 and 10 cm, respectively), similar tt) Ihose mazes used l~rcviousl3 tor guinea pigs [11] and cats [9]. As in the previous expcrimelll [2i. the rats were at first handled extensively and were given time to adapt to lhe tnaz¢ testing situation. Thc tbrmal training procedurc, the number of tlial~ (20). the criteria (3 consecutive sessions of at least 85", correct pertbrmancc~, and the resting periods (10 days) between preoperative and postoperative rctesling were identical to those described previously [2, 9, 11]. Surgery was perlbrmed immediately lbllowing attainment of the criterion in the preoperative relearning test. Animals of the two experimental groups were anesthetized (Equithesin : 3.5 ml/kg i.p.) and then reccived 0.15/~1 oF kainic acid per hemisphere at a concentration of 2.5/~g /al, dissolved in 0.2 M phosphate buffer. The techniquc of injection has bcen described previously [141. (,'oordinares, according to the atlas of Pellegrino ct al. [I 3]. were, lor VTA rats: 3.7 mm posterior to the bregma, 0.7 mm lateral to the midline, and 8.7 mm below the dura and, lbr animals of the M D group: 1.2, 1.0 and 6.0 mm, rc.~pcctively. Rats of the control group (CG) received the same amount of the vehicle solution either in M D or VTA. After the end of the experiment all animals were pcrfused with ~tline followed by 10!',, buffered lbrmalin in saline. Brains were cut at 50 #m using a freezing microtome. From the lesioned area, every third section was mountcd and stained with cresyl violet. Furthermore, every sixth section of the brain was taken to check tbr remote lesion effects [4, 17. 22]. Extents of lcsioned areas were determined under the light microscope. Non-parametric statistics were used throughout: only significant values are presented. Of the 25 animals, one of the control group and one of group M D had to be discarded during delayed-alternation acquisition because of strong aggressive behavior. Furthermore, 4 of the rats with lesions aimed at VTA and 3 with lesions aimed at M D died during the first 3 postoperative days. Lesion extents for one rat from each of the two experimental groups are shown in Fig. 1. In the other animals of thc two groups the lesions were generally similar in extent. In addition to the local lesions, distant lesion effects were observed in both experimental groups, most consistently in areas CA3 and CA4 of the hippocampus and in the piri|brm cortex. However, none of the animals exhibited complete bilateral destruction of CA3 and CA4 along the entire length of the hippocampus. Aside from the electrode track, no lesions were found in animals of group CG. Behaviorally, the rats of groups VTA and M D were aphagic and adipsic
127
/
- .A~6
i
•
- .6
-.4
i
20 •
l':ig. I. Coronal sections o f lhe rat's brain at indicated anterior posterior levels a d o p t e d from Pellcgrino el al. [13]. Extent o f neuronal damage (black areas) i~, shov,n for a rat ~ith a lesion of the ventral legmental area (A C'), and for a rat with a lesion o f the thalamic mediodorsal I'lticletls ~[) I:).
for 1 3 days. After 6 days at the most, rats of the VTA group behaved normally. MD-lesioned rats, on the other hand, were rather hyperactive in comparison to the other two groups. Delayed-alternation performance did not differ between groups during acquisition and during preoperative relearning. In spite of the small number of animals in groups VTA (n = 4) and M D (n = 5), rats from each of these two groups differed from animals of the control group postoperatively (Mann Whitney t J-tests: U = 6.5 for group VTA and 7.5 for group M D: 0.05 < P < 0.10 for both experimental groups: one-tailed: Fig. 2). Rats of group VTA manifested so-called collateral or irrelevant behaviors (frequent rearing, sniffing, and stopping) [19.20] during delayed-alternation performance. As Fig. 2 shows, there are no differences in the postoperative performance of the animals of the two experimental groups. Furthermore, this figure reveals that the number of errors was rather similar to that of the VTA-lesioned animals
128 I I
~5!
FL:
:
pre post ""-:
[-~
~-2 . . . .
VYA
MD
CG
F i g 2. Comparison of preoperative (pre) and postoperative (post) performance ratc~ ot ntts ~ t h lesions of the ventral tegmental area (VIA). the thalamic mediodorsal nucleus (MI)) :lnd of i~ control group of sham-operated rats {CG). Medians of crrors are presented as column~,.
in the study of Simon et al. [20] (average of number of errors: 19.6 in Simon et al. ; median of errors in the present study: 19.5). Our results, theretbre, reveal that the differences in perlbrmance of a cognitive task after lesions of MD and VTA are not so marked as to supporl the suggestion of Simon et al. [20] that VTA should be taken as a better indicator of functions of the prefrontal cortex than MD. We are, however, aware of the fact that the present results have to be considered with caution. Similar deficits need not necessarily have common, underlying causes, and, in addition to the intended, local lesions of either VTA or MD, further lesions were tbund in the hippocampus and piriform cortex, i.e. in structures extremely sensitive to kainic acid [4, 12, 21, 22]. Parts of the deficits observed in our animals from the two experimental groups might be attributable to a mass-action effect [6], caused by the additional lesions remote from the intended locus of the lesion. Alternatively (or combined with a possible mass-action effect), the lesioning of a region critical for spatial delayed-alternation performance might be partly responsible lbr the observed deficits in the rats of groups VTA and MD. The structure most vulnerable to intracerebral injections of kainic acid, whose partial destruction is also most likely to affect performance rates in a delayed-alternation paradigm, is the hippocampus [5, 15]. However, as kainic acid preferentially destroys only certain hippocampal neurons, the long-term effects of remote lesions on the hippocampus would be less severe than those of conventional, mechanical destruction of the respective areas. In support of this statement is an important finding of Leach et al. [7]. Following kainic acid lesions of the lateral hypothalamus, these authors found that. in spite of damage in regions CA3 and CA4 of the hippocampus, hippocampal EEGs regained normal amplitude and frequency within 25 days after the injections. This finding, together with the similarity in the postoperativc average of errors of our study with that of Simon et al. [20], and the similarity of the structures showing distant lesion effects in both of our experimental groups, allow us to conclude that most of the behavioral deteriorations observed postoperatively in the two experimental groups were due to the local chemical
129 lesion. Nevertheless, it appears wise to substitute ibotenic acid [br kainic acid in future lesion work as ibotenic acid. in comparison to kainic acid, has been found to be less toxic and apparently to cause no remote lesions, while still destroying sufficient amounts of nervous tissue [4, 16]. Though the degrees of the behavioral deficits were lbund to be similar ti)r group VTA and group MD rats, the causes underlying these deficits might differ: as in the studies of Simon et al. [19. 20], our VTA-lesioned rats showed various forms of collateral behaviors which would have both detracted from their performance and lengthened the time necessary to mediate the appropriate behavioral response. MD-lesioned rats, on the other hand, appeared hyperactive and, in part, also hyperaggressive. VTA-lesioned rats, therefore, may be characterized by more general changes in attention [3], while more specific emotional changes might constitute the deficit of MD-lesioned rats [18]. Dr. F. Gruber, the University veterinarian, and his staff', deserve special thanks li)r care of the animals. Furthermore, we thank F.M. Wharton for improvement of the English of the manuscript and M. Sugawa for much help in training the animals.
I
l)i,,ac, 1.. Bj6rklund..A~j, l.indvall, 0 . and Passingham. R.L.. ('c, uvcrgm~ projections from the nlediodorsal nucleus and mesencephalic dopaminergic neurons tc, the neocortex in three species, .I, comp. Neurol.. 180 {1978) 59 72. 2 Divac, I.. Markowitsch. H.J. and Pritzel. M.. Behavioral and anatomical consequences of small intrastriatal injections of kainic acid in t h e r a t , Brain Res., 151 (1978) 523 532. 3 Gale3.. D., Jaffard, R. and Le Moal, M., Alternati,,m behavior, spatial discrimination, and reversal after electrocoagulation of the ventral mesencephalic iegmentunl in the rat, Belnn. .\eural Biol., 26 (1979) 81 88. 4 (;uldin. W.O. and Markov.itsch, HJ.. Epidural kainate, but not ihotenate, produces lesions in local and distant regions of the brain. A conlparison of the intracerebral actions of kamic acid and ibotenic acid, submitted ti~r publication. 5 Ivcrscn. S.D.. Brain lesions and memory in anmlals, In J. r)eutsch It{d.). 77w Physioh>,~i¢al Ba.q.~ ~ I Memm'v. Academic P,css, New York. 1973, pp. 305 364. 6 l,ashle). K.S.. Brain :l,lech,ni.wnsandhztelli,w,me, University of ('hicago Press. Chicago. lt-,~29. 7 Leach, 1,., Whisha,,~,, I.Q. and Kolb. B., I{ffectsof kamic acid Icsicms m the lateral hypothalamte, on beha,.ior and hippocampal and neocortical elcctrocncephalographic [I{EG} activit? m the rat. Belntv. Brain Re.~.. I 11980) 411 431. 8 I,eonard, C.M., l h e prefrontal cortex of the rat. 1. ('orlical projection of the mediodorsal nucleus. II. Efferent connections, Brain Re~., 12 11969} 321 343. 9 Marko,aitsch. H.J.. Pritzel, M.. Kessler, J.. (iuldm, W, and Freem~m. R,B.. Jr., Delayedalternation performance after selective lesions v, ithin the prefrontal cortex of lhe cat, Bchov. Brain Rc~., 1 {19g0) 67-.91. I0 Marko,a itsch, H.J.. Pritzcl. M.. Wilson, M. and Divac, I.. The prefrontal corlcx o f a prosimian
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