Neuroanatomical Correlates of Sparing of Function After Neonatal

7/29/2019 Neuroanatomical Correlates of Sparing of Function After Neonatal

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24 Bram Research, 568 (1991) 24-34 1991 Elsevier Science Publishers B.V. All rights reserved. 0006-8993/91/$03.50BRES 17270

N e u r o a n a t o m i c a l c o r r e la t e s o f sp a r in g o f fu n c t i o n a f te r n e o n a t a lm e d i a l p r e f r o n t a l c o r t e x l e s i o n s i n r a t s

J.M. de Brabander, C.G. van Eden and J.P.C. de BruinNetherlands lnstuute for Brain Research, Amsterdam (Netherlands)

(Accepted 6 August 1991)Key words . Frontal cortex; Recovery; Brmn damage; Mediodorsal nucleus of the thalamus; Doparmne; Rat

In rats, the possibility of neuroanatomical changes in response to partial medial prefrontal cortex lesions at postnatal day 6, concomitantwith behavioural sparing, was investigated. The projections from the mediodorsal nucleus of the thalamus (MD) and the mesocortlcal do-paminergic (DA) projection were examined. No indications were found for a changed pattern of projection from MD in response to eithera neonatal or an adult medial prefrontal cortex (mPFC) lesion. However, the DA innervatlon was changed after neonatal mPFC lesions. Inthe remainder of the mPFC, the DA fibre network proved to be denser, fibres were thicker, had more varicosities, and often the backgroundstaining was higher. None of these phenomena were seen m operated adult rats or in controls. It ~s postulated that the changes in DAinnervation might contribute to the sparing of function observed in the spatial delayed alternation task.INTRODUCTION

The concept that the immature central nervous systempossesses a great er ability to com pensat e for loss of func-tion after brain damage compared with the adult brainis generally known and often referred to as the ' Kennardprinciple'. Several investigators have reported that afterneonatal damage of the medial prefrontal cortex (mPFC)animals showed sparing of function in the performanceof food hoarding (rat4), spatial delayed alternation be-h a v i o u r (rat6'27"29'31-33'4), and del aye d re spo nding or al-ternation (monkey2'12'14's3). In contrast, damaging themPFC in adult animals resulted in a permanent impair-ment of these behavioural tasks 3'6'13'15'26'29'3'4.

An intriguing question is which neural systems are in-volved in recovery of function. Many hypotheses havebeen proposed to explain behavioural recovery afterneonatal lesions on the basis of neural reorganisation.Several of the proposed mechanisms imply reactive syn-aptogenesis, rerouting of axons, collateral sprouting andthe consolidation of otherwise transient f i br es 8 '12A8'33'35'3 6 , 3 8 , 3 9 , 4 2 , 4 3 . All these mechanisms would lead to achanged projection pattern in combination with func-tional recovery at the behavioural level.

Our earlier studies have demonstrated clear sparing ofspatial delayed alternation behaviour after neonatalmPF C lesions 6. The present study focuses on possiblechanges in two systems which project to the mPFC andwhich might underlie behavioural sparing: the projection

from the mediodorsal nucleus of the thalamus (MD) andthe dopaminergic (DA) projection from the ventraltegmental area (VTA). Both systems have a dense andspecific innervation pattern within the prefrontal corticalar ea s 17'22'34'37'55'56 and both systems are crucial to thefunctioning of the prefrontal cortex.

In the rat, the PFC is defined as the cortical projec-tion area of the MD. Damaging this thalamic nucleus inadulth ood leads to impairmen t of PFC-rel ated tasks 3'24'50 Additionally, the MD is a possible candidate medi-ating the neural reorganisation after PFC damage, sincethe retrograde degeneration in this nucleus frequentlyobserved after mPFC lesions in adult rats could not bedetected after mPF C lesions in neonata l rats t2'29'4. Thismight indicate that the immature MD fibres that weresevered by the lesions are capable of making new con-tacts in an undamaged part of the brain, and thus con-tribute to the survival of the MD cells and possibly tothe observed sparing of function.

Another candidate for mediating neural reorganisa-tion after damage is the dense DA innervation of thePFC, which forms part of the mesocorticolimbic path-way. The cells of origin are situated in the VTA andproject also to limbic structures, such as the nucleus ac-cumbens. Several studies have supported a close func-tional relationship of this DA pathway with the PFC: le-sions of this pathway in adult monkeys and rats resultedin a diminished spatial delayed alternation behaviourwhile in adult rats food hoarding performance was also

Correspondence. J.M. de Brabander, Netherlands Institute for Brmn Research, Melbergdreef 33, 1105 AZ Amsterdam, The Netherlands.


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d e c r e a s e d 4 '5 '2 1'2 3'3 4'4 6'4 7'4 9'5 2, i . e . b e h a v i o u r a l i m p a i r -m e n t s s i m i l a r t o t h o s e r e s u lt i n g f r o m m P F C l e s io n s i na d u l t a n i m a l s . T h e s e o b s e r v a t i o n s a n d t h e f a c t t h a t t r e a t-m e n t w i t h D A a g o n i s ts a f t e r d a m a g e t o t h e n e o c o r t e x i na d u l t r a t s f a c i l i t a t e s b e h a v i o u r a l r e c o v e r y 1 1'1 6'1 9'2 5'5 1m a k e i t w o r t h w h i l e t o i n v e s t ig a t e t h e p o s s i b le i n v o l v e -m e n t o f th i s D A p a t h w a y i n f u n c t i o n a l s p a r i n g a f te r n e o -n a t a l m P F C l e s io n s .

M A T E R I A LS A N D M E T H O D SAnimalsA l l r a ts s t u d i e d ( n = 6 6 ) w e r e m a l e s o f t h e a l b i n o W i s t a r s t r a in( C P B - W U ) . T w o g r o u p s w e r e d i s t i n g u is h e d : t h e f i rs t w a s o b t a i n e df r o m H a r l a n - T N O ( Z e i s t , T h e N e t h e r l a n d s ) a n d a r r i v e d a t o u r i n -s t i t u te a t t h e a g e o f 7 w e e k s ( a v e r a g e b o d y w e i g h t 1 9 0 g ). T h e r a t so f t h e s e c o n d g r o u p w e r e b o r n a t o u r i n s t i t u t e f r o m t i m e d p r e g -n a n t f e m a l e s a l s o o b t a i n e d f r o m H a r l a n T N O . A t b i r t h t h e s e r a t sw e r e c r o s s - f o s t e r e d a n d w e a n e d b e t w e e n P N 2 0 a n d P N 2 2 ( t h e d a yo f b i r th i s p o s t n a ta l d a y 0 , P N O ) . T h e r a t s w e r e h o u s e d i n m a c r o -Ion cages (75 x 55 x 23 e ra ) in g roups o f 4 and kep t a t a 12 hl i g h t -d a r k c y c l e (l i g h ts o n 1 5 . 3 0 - 03 . 3 0 h ) ; t h e a v e r a g e t e m p e r a t u r ew a s b e t w e e n 2 2 C a n d 2 4 *C a n d h u m i d i t y b e t w e e n 5 0 % a n d 6 0 % .J u s t p r i o r t o a n d d u r i n g t h e p e r i o d o f b e h a v i o u r a l t e s t i n g , f o o da v a i l a b il i t y w a s r e d u c e d t o a c h i e v e a b o d y w e i g h t o f a p p r o x i m a t e l y8 5 % o f th a t i n a n a d l i b i tu m f e e d i n g s i t u a ti o n . A f t e r c o m p l e t i o n o fb e h a v i o u r a l t e s t i n g , f o o d w a s a g a i n a v a i l a b l e a d l i b i t u m ( s t a n d a r dr o d e n t p e l l e t s , H o p e F a r m s , W o e r d e n , T h e N e t h e r l a n d s ) .SurgeryNeonatal lesions. N e o n a t a l l e s i o n s w e r e i n f l i c t e d a t t h e a g e o f 6d a y s . T h e a n i m a l s w e r e r a n d o m l y d i v i d e d i n t o a n e x p e r i m e n t a lg roup (n = 13) , a sham-opera ted g roup (n = 12) and a con t ro lg r o u p ( n = 8 ) . U n d e r e t h e r a n a e s t h e s i a , t h e s k u l l o f t h e e x p e r i -m e n t a l a n d s h a m - o p e r a t e d g r o u p s w a s o p e n e d a n d t h e a n t e r i o r s i -n u s s a g i tt a li s s u p e r i o r l i g a tu r e d . I n t h e e x p e r i m e n t a l r a t s , t h e m P F Cw a s s u b s e q u e n t l y b i l a t e r a l l y a b l a t e d b y a s p i r a t i o n ( f o r a d e t a i l e dd e s c r i p t i o n o f t h e s u r g l e a i p r o c e d u r e s , s e e D e B r a b a n d e r e t a l . 6 ) .F r o m e v e r y l i tt e r r a ts w e r e a l l o c a t e d t o a l l 3 g r o u p s a n d a f t e r w e a n -m g e v e r y c a g e c o n t a i n e d a n i m a l s o f e v e r y g r o u p . I n t h e b e h a v -~ o u r a l a n d a n a t o m i c a l r e s u l t s , t h e s h a m - o p e r a t e d a n d c o n t r o l d i dn o t d i f f e r f r o m e a c h o t h e r , t h u s , w e h a v e r e g a r d e d t h e m a s o n eg r o u p , t o b e r e f e r r e d t o a s t h e c o n t r o l s .Young a dult lesions. I n t h i s g r o u p s u r g e r y w a s p e r f o r m e d a t t h ea g e o f 8 w e e k s . T h e r a t s w e r e r a n d o m l y d i v i d e d i n t o t w o g r o u p s :a n e x p e r i m e n t a l g r o u p ( n = 1 9 ) a n d a s h a m - o p e r a t e d g r o u p ( t h econ t ro ls ; n = 14). The su rg ica l p roce dures w ere essen t ia l ly thes a m e a s i n t h e n e o n a t a l g r o u p s , e x c e p t t h a t t h e a d u l t r a t s w e r ea n a e s t h e t i se d w i t h H y p o o r m ( 0. 1 m l / 1 0 0 g b o d y w e i g h t i . m . ; J a n s -s e n P h a r m a c eu t ic . a , B e e r s e , B e l g i u m ) . A s w i t h t h e r a t s t r e a t e d n e o -n a t a l l y , e a c h c a g e c o n t a i n e d a n i m a l s o f b o t h c o n d i t i o n s .Behavtoural testingA t t h e a g e o f 1 5 w e e k s , a l l r a t s w e r e s u b j e c t e d t o t h e s p a t i a l d e -l a y e d a l t e r n a t i o n t e s t . A T - m a z e w a s u s e d c o n s is t i ng o f a s t a r t b o xp l u s m a i n a l l e y (6 5 c m ) a n d t w o s i d e a r m s o f 4 0 c m ( t h e a p p a r a t u sis desc r ibed in de ta i l in S ta re e t a l .47 ) . In th is te s t ra t s mus t a l te r -n a t e b e t w e e n t h e l e f t a n d r i g h t s i d e a r m s t o o b t a i n a r e w a r d ( aN o y e s f o o d p e l l e t , 4 5 n a g ) . T e s t i n g w a s p r e c e d e d b y a p e r i o d o fadap ta t ion and au toshap ing . Dur ing the fas t 10 te s t ing days 16 t r i -a l s p e r d a y w e r e p e r f o r m e d a t i n t e r t r i a l i n t e r v a l s o f 0 s ( I T I 0 ) .T e s t in g w a s c o n t i n u e d f o r a n o t h e r 1 0 d a y s o f 1 6 t r i al s p e r d a y w i t h15 s in te r tna l in te rva ls ( IT I 15) (p rocedures desc r ibed in de ta i l inD e B r a b a n d e r e t a l. 6) . S p a t i a l d e l a y e d a l t e r n a t io n t e s t s w e r e c o n -d u c t e d d u r i n g t h e d a r k p e n o d ( b e t w e e n 0 8 . 3 0 a n d 1 5 . 0 0 h ) . A n i -m a l s w e r e c o n s i d e r e d t o h a v e r e a c h e d c r i t e r i o n w i th m o r e t h a n 8 0 %

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c o r r e c t r e s p o n s e s f o r a t l e a s t 3 c o n s e c u t iv e d a y s . T h e n o n - p a r a m e t -r ic Ch i -Squa re (g2) te st4S was used t o ana lyse th e num ber o f ra t sw h i c h h a d r e a c h e d c r i t e r i o n o n t h e l a s t t e s t i n g d a y s a t I T I 0 a n dI T I 1 5 .AnatomyTracer injections and immunocytochemical staining. F o l l o w i n gT - m a z e t e s t i n g , t h e r a t s w e r e o p e r a t e d a g a i n f o r t h e t r a c e r e x p e r -i m e n t . T h e a n t e r o g r a d e t r a c e r , P h a s e o h i s V u l g a r i s L e u c o a g g l u t i -n i n 1 [ P H A - L , 2 . 5 % d i s s o l v e d i n 0 .0 1 M p h o s p h a t e b u f f e r ( p H 7 . 6 );V e c t o r l a b o r a t o r i e s , U . S . A . ] w a s i n j e c t e d i o n to p h o r e t i c a l l y in t o t h eM D o f t h e f i g h t h e m i s p h e r e , u s i n g t h e f o l l o w i n g c o o r d i n a t e s , w i t hB r e g m a a s r e f e r e n c e p o i n t : A P - 2 . 5 r a m , L + 1 . 7 n u n , V - 5 . 4 r a m ,u n d e r a n a n g l e o f + 1 2 ". T h e t i p d i a m e t e r o f t h e g l as s p i p e t t e w a s5 0 / t m a n d a n a l t e r n a t i n g 6 m A D C c u r r e n t w a s a p p l i e d f o r 3 0 m i n( 5 s o n , 5 s o f f ) . A f t e r a s u r v i v a l p e r i o d o f 7 d a y s , t h e a n i m a l s w e r ei n t r a c a r d i a l l y p e r f n s e d u n d e r d e e p p e n t o b a r b i t a l a n a e s t h e s i a ( 1ml /kg body we igh t , i . p . ) wi th sa l ine fo l lowed by f ixa t ive . The f ix -a t i o n c o n s i s te d o f 5 % g l u t a r a l d e h y d e i n 0 . 0 5 M a c e t a t e b u f f e r ( p H4 . 0 ) . A f t e r p e r f u s i o n t h e b r a i n s w e r e r e m o v e d f r o m t h e s k u l l a n dp o s t f i x e d f o r 3 0 r a i n . T h e n t h e b r a i n s w e r e i m m e r s e d i n 0 . 0 5 MT r i s - b u f fe r e d s a l in e ( T B S ) c o n t a i n i n g 1 % N a z S 2 0 s ( p H 7 . 2 ). U s i n ga v ib ros l ice , co rona l se r ia l sec t ions (50 /~m) were ga the red fo rP H A - L , D A a n d N i s s l s t a in i n g . T h e P H A - L a n d N i s s l - se c t io n sw e r e c o l l e c t e d i n 0 .0 5 M T B S a n d t h e D A s e c t io n s i n T B S c o n -t a i n i n g 1 % N a z S 2 0 5 . A l t e r n a t i n g s e c t io n s w e r e u s e d f o r i m m u n o -c y t o e h e m i e a l s t a in i n g f o r P H A - L a n d D A . A l l a n ti b o d i e s w e r er a i s e d i n o u r i n s t i t u t e a n d t h e s p e c i f ic i ty o f t h e s t a i n in g f o r P H A - La n d D A h a s b e e n d e m o n s t r a t e d p r e v i o u s l y 9 ' 2 . T h e P H A - L a n dD A s e c t i o n s w e r e i n c u b a t e d u s i n g t h e p e r o x i d a s e - a n t i p e r o x i d a s e( P A P ) m e t h o d * s, w i t h 0 .3 % a n d 0 . 5 % a m m o n i u m n i c k e l s u lp h a t e ,r e s p e c t i v e l y , t o e n h a n c e t h e r e a c t i o n w i t h d i a m i n o b e n z i d i n e( D A B ) . F o r t h e N i s s l s t a i n i n g , t h e s e c t i o n s w e r e f i r s t m o u n t e d o ng lass s l ides and d r ied , then r insed in a so lu t ion o f e thano l andc h l o r o f o r m ( 1: 1) t o r e m o v e t h e h p i d s , t h u s b r i g h t e n i n g t h e s t a in i n gw i t h 0 . 5 % t h i o n i n e .T h e D A i n n e r v a t i o n o f c o n t r o l a n i m a l s a n d a n im a l s w i t h n e o n a -ta l and adu l t le s ions was inves t iga ted a t 3 leve ls , co r respond ingw i t h + 3 . 0 , + 2 . 5 a n d + 2 . 0 m m a n t e r i o r o f b r e g m a o f t h e Z i l le s at -l a s 5 9. T o g e t h e r , t h e s e l e v e l s c o v e r t h e e x t e n t o f t h e l e s io n s o f m o s to f the an imals and they a re eas i ly d is t ingu ishab le in the sec t ions .

R E S U L T S

M o r p h o l o g y o f t h e l e si o n s it eM a c r o s c o p i c a l l y t h e r e w a s a r e m a r k a b l e d i f f e r e n c e i n

t h e a p p e a r a n c e o f t h e l e si o n b e t w e e n n e o n a t a l a n d a d u l te x p e r i m e n t a l r a ts . M o s t o f t h e l e s i on s i n fl i c te d n e o n a -t a ll y s h o w e d n o o b v i o u s i n d i c a t i o n o f a l e s io n a t t h eo u t e r c o r t i c al s u r f a c e o f t h e b r a i n , e x c e p t f o r a s c a r , b u ta l l l e s i o n s i n a d u l t r a t s w e r e v i s i b l e a s a c a v i t y ( m o r p h o l -o g y d e s c r i b e d i n d e t a i l i n D e B r a b a n d e r e t a l. 6) . I n p i lo ts t u d ie s ( u n p u b l i s h e d o b s e r v a t i o n s ) , w e f o u n d t h a t a f te ra s u r v i v a l t i m e o f u p t o o n e w e e k , n e o n a t a l a n d a d u l tl e s io n s a p p e a r e d t o b e e s s e n ti a l ly s i m i la r . H o w e v e r , a f -t e r a s u r v i v al t i m e o f 5 - 8 m o n t h s ( p r e s e n t s t u d y ), i n 1 1o u t o f 1 3 r a t s w i t h n e o n a t a l l e s i o ns n o g r o s s m o d i f i c a -t i o n o f t h e b r a i n w a s v i s i b le a n y l o n g e r , w h e r e a s o n l yt w o s h o w e d a ca v i t y i n t h e c e r e b r u m i n r e s p o n s e t o t h en e o n a t a l l e s i o n .

N e o n a t a l l e s i o n . A l t h o u g h m a c r o s c o p ic a l ly m o s t n e o -n a t a l l e s i o n s w e r e n o t v i s i b l e a s a c a v i t y , m i c r o s c o p i c a l l yt h e l o c a t io n o f t h e l es i o n w a s m a r k e d b y t h e p r e s e n c e o f


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Fig. 1. Photomicrographs of coronal N issl-stained sections of the brains of rats with a representative adult (a) me& al prefrontal cortex (mP FC)lesion and neonatal (PN6) mPFC lesion (b) . Note the cawty in the cerebrum m case of the adult lesion. Location and extent of the lesionin the neonatally operated animal are only visible by the scar ( indicated by arrows) and the cytoarchitectonical abnormalities .


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A DULT NEONATAL

1 1

t I

l l

Fig. 2. Reconstructions of the smallest (hatched) and the largest (dotted) adult (left panel) an d neon atal (right panel) mPFC lesions41 of theanimals used fo r behavioural analysis. Both groups ha d comparable lesions: the mPF C subareas frontal area 2 (Fr2) and dorsal anterioreingulate area (ACd) were either completely removed or severely damaged.

10080604020

NEONA TALITI 0

/ ' /3 4 5 6 7 8 9 10

IT115

J3 4 5 6 7 8 9 1 0

10080604020

ADULTITI 0

3 4 5 6 7 8 9 10Sessions

Cont rol o----o Exp erim enta l

IT115

p,/3 4 5 6 7 8 9 1 0

Fig. 3. Cumulative percentage of animals, which had reached thecriterion of more than 80% correct responses in the spatial delayedalternation (SDA ) tests during at least 3 consecutive days with in-tertrial intervals (ITI) of 0 and 15 s.

gl ia l scar t i ssue. Paral le l to the scar , cort ical cel ls formeda t h i n h o m o g e n e o u s b a n d w i t h o n l y c o r t i c a l l a y e r I b e -ing c l ea r ly d i s t ingui shable . F ig . l b shows a photomic ro-g r a p h o f a r e p r e se n t a t i v e s e c t io n o f t h e f r o n t a l c o r t e x o fa ra t w i th a neona ta l l e s ion . Vent ra l and dorsa l o f t hes c a r c y t o a r c h i t e c t o n i c criteria34'54'57'59 c o u l d b e a p p l i e dto iden t i fy remain ing cor t i ca l a reas . For ins t ance , t hepresence of a dysgranula r cor t i ca l l aye r IV , dorso la t e r -a l ly of the s ca r t i ssue , i nd ica t ed tha t t h i s cor t ica l a reaw a s th e f r o n t a l a r e a 1 ( F r l ) a n d , t h e r e f o r e , i m p l i e d th a tt h e f r o n t a l a r e a 2 ( F r 2 ) h a d b e e n r e m o v e d . V e n t r a l o fthe s ca r t i s sue , t he cor t i ca l a rea was iden t i f i ed by thep r o n o u n c e d d i f f e r e n c e s b e t w e e n t h e d o r s a l a n t e r i o r c i n -g u l a t e a r e a ( A C d ) a n d t h e p r e l i m b i c a r e a ( P L ) , s u c h a s ,the d i f fe rence in th i cknes s o f the l aye rs I I / I I I , t he de -g r e e o f e x te n s i o n o f l a y e rs V a n d V I a n d t h e m o r p h o l -o g y o f l a y e r V I . T h u s , l e s io n s i te a n d l o c a t i o n w e r e r e -c o n s t r u c t e d a n d i t a p p e a r e d t h a t i n a ll r at s w i t h n e o n a t a ll e s i o n s t h e s u b a r e a s F r 2 a n d A C d w e r e a l m o s t c o m -p l e t e l y r e m o v e d ; i n t w o a n i m a l s P L a n d i n f r a l i m b i c a r e a( I L ) w e r e a l s o d a m a g e d .

Young adult lesion. I n t h e a d u lt e x p e r i m e n t a l g r o u p(n = 19), les ions wer e c learly vis ible as cavi t ies l ined bygl i a l t i s sue (F ig . l a ) . The f ron ta l a reas tha t were no t re -


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/ / - - I

b. Neonatal les=on

Fig. 4. The injection site in mediodorsal nucleus of the thalamus (MD ) a nd distribution of the transported label in the PFC m a controlanimal (a) and an animal with a neonatal lesion (b). The Phaseolns Vulgaris Leucoaggluunin (PHA-L) spot m the control animal is locatedm the laterocentrai segment of MD (extension from Bregma -2 .5 t o -4.0). Labelled fibres are present in Fr2, AC d and prellmbic area (PL)and the lateral PFC, as expected on the basis of the topograplucal relation of MD projections to the PFC. The PHA-L spot in the animalwith a neonatal lesion includes all 3 segments of MD (extension fro m Bregma -2 .5 to -3.3 ): a larger injection site overlapping the on e in thecontrol animal. Labelled fibres are located in the rostral part of ACd and in the caudal half of Fr2, which are not ablated, PL and in bothsubareas of the lateral PFC . Th e distribution within these PFC areas is as expected on the b asis of the topographical relation o f MD-PFCprojections.

m o v e d s h o w e d n o c h a n g e s i n c y t o a r c h i t e c t u r e a n d c o u l dbe iden t i f i ed a s desc r ibed above . The l e s ions involvedt h e t w o d o r s a l m P F C s u b a r e a s , F r 2 a n d A C d , a n d i n 1 3r a ts a l s o P L , I L , o r p a r t s o f t h e f o r c e p s m i n o r a n d c a u -d a t e p u t a m e n .Observation o f sparing of function

Al l ra t s were t e s t ed in the T-maze to a s ses s the i r ab i l -i t y to l ea rn to a l t e rna te be tween the a rms , f i r s t w i th a 0s inter t r ia l in terval ( IT I 0; 10 sess ions) , th en with a de-l ay of 15 s be tween t r ia l s ( IT I 15 ; 10 s es s ions ) . In o r de rt o c o m p a r e t h e p e r f o r m a n c e o f r at s w it h n e o n a t a l a n dadul t l e s ions , on ly those an ima l s in which the damagew a s r e s t r i c t e d t o t h e t w o d o r s a l m P F C s u b a r e a s F r 2 a n dAC d were used for behaviou ra l ana lys i s (n = 11 and n= 6 for the ra t s w i th neona ta l and adul t l e s ions , r e spec -t ive ly ; s ee F ig . 2 fo r recons t ruc t ion s o f the sma l l e st a ndthe l a rges t l e s ions ) .

On the l a s t ITI 0 t e st ing day , t he c r i t e r ion (m ore tha n80% cor rec t re sponses on 3 consecu t ive t e s t ing days ) wasmet by 100% (n = 20) o f the neon a ta l con t ro l ra ts and79% (11 ou t o f 14) o f the ad ul t con t ro l s (F ig . 3 ) . A f t e r

l e n g t h e n i n g t h e I T I t o 1 5 s t h e n u m b e r o f c o n t r o l a n i-ma l s , which re sponded dur ing the f i r s t 3 days wi th moret h a n 8 0 % c o r r e c t r e s p o n s e s w a s s t ro n g l y r e d u c e d t o a b o u t3 5 % . B u t o n t e s ti n g d a y 6 a g a in m o r e t h a n 5 0 % o f th ec o n t r o l s o f b o t h t h e n e o n a t a l l y a n d a d u l t - o p e r a t e d r a tsreached c r i t e r ion , and on the l a s t t e s t ing day 95% (19o u t o f 2 0 ) o f t h e n e o n a t a l a n d 9 3 % ( 1 3 o u t o f 1 4 ) o f th eadul t con t ro l s had reached c r i t e r ion .

The 11 ra t s w i th neona ta l l e s ions pe r formed as we l la s t h e i r c o n t r o l s . T h i s w a s o b v i o u s f r o m t h e n u m b e r o fra t s pe r t e s t ing day tha t had reached c r i t e r ion : bo th a tITI 0 and a t ITI 15 the pe rcen tage was s imi l a r t o thecont ro l an ima l s (F ig . 3 ) . In con t ra s t , t he 6 ra t s w i th adul tl e si o n s p e r f o r m e d p o o r l y d u r i n g t h e I T I 0 a n d I T I 1 5tes t ing days . A t ITI 0 on ly two (33%) an ima l s ma nag edto reach c r i t e r ion on the l a s t t e s t ing day . However , t h i sd i f fe rence jus t f a i l ed to be s ign if i can t . A t I TI 15 on ly on era t w i th an adul t l e s ion (17%) reached c r i t e r ion and th i sdiffered s ignif icant ly (Z2 , P ~ 0 .001) f rom the adul t con -t ro i s . The o the r 5 an ima l s w i th adul t l e s ions , which d idn o t r e a c h t h e c r i t e r i o n , p e r f o r m e d w i t h 6 0 - 7 0 % c o r r e c tre sponses dur ing the l a s t 5 ITI 15 s es s ions .


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Fig. 5. Photomicrog raph of the dopaminergic (DA) innervat ion ofPL a t a s tandard level corresponding wi th Bregma + 2 .5 mm ofthe Zilles atlassg. The boxed areas a , b a nd c indicate the locat ionof the photomicrographs a, b and c in Fig. 6. P, pial surface; W,whi te mat ter . Bar = 0 .2 mm.

29Neuroanatomical correlates o f sparing off'un ction

In order to inves t igate poss ible neuroanatomicalchanges in MD and DA project ion pat tern in responseto the les ions , a combinat ion of an anterograde t racertechnique and immunocytochemical staining was usedfor all rats, following spatial delayed alternation testing.1. Projection from the mediodorsal nucleus

CytoarchitectonicaUy, no signs of gross retrogr ade al-terat ions were observed in the MD in response to e i therneonatal or adul t mPFC les ions . The subnuclei of MDcould be discerned using the cytoarchitec tonic criteria ofGroenew egen ~7 and Kret tek and Pr ice34. The projectionof the MD to the PFC was s tudied by iontophoret icalinjections of the anterograde tracer Phaseolus VulgarisLeucoagglut in in (PHA-L ) aimed at the MD of the f ighthemisphere. After a survival period of 7 days the distri-bution of labelled fibres in PFC and adjacent frontal ar-eas was examined.

C O N T R O L a b c

A D U L T L E S I O N a b c

N E O N A T A L L E S I O N a b c

i

Fig . 6 . Photomicrographs of the D A innervat ion of the PL regions (por t rayed in Fig . 5) of a cont rol ra t, a ra t w i th an adul t mP FC les ion anda rat with a neonatal mPFC lesion: (a) superficial layers I , II and III; (b) layer V; (c) basal layer V and layer VI. Bar ffi 0.05 ram.


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30

Fig. 7. Photormcrograph of DA fibres at the ventral border of theneonatal lesion site. Note the lugh density of DA fibres, which runparallel to the s car, the thickness of the fibres, the number o f var-icosities and the difference in background staining between PL andFrl. Bar = 0.05 mm.

Eight control ra ts with successful injections, i .e . withth e P H A - L sp o t r e s t ri c t e d t o MD , w e r e a n a ly se d . T h e sein jec t ions re su l ted in labe l led f ibres in laye rs I , I I I , V,and V I of the PFC. F ibres in laye rs V and V I had oc -cas iona l branches and va r icos i t ie s , whi le in laye r I I I andin upper laye r V the f ibres te rmina ted in an ex tens ivef ibre p lexus , cons is t ing of numerous f ine axons , whichbranched profuse ly and conta ined many va r icos i t ie s . Thein jec tions wi th PH A- L usua l ly d id not f il l the en t i r e MD ,but the in jec t ions of a l l an ima ls taken toge the r coveredthe en t i r e MD . Most of the in jec t ions were conf ined tothe la te ra l and cent ra l segments of e i the r the ros t ra l ha l fo f t h e MD ( f r o m B r e g m a - 1 . 8 t o - 3 . 3 ; n = 3 ) o r t h ecauda l ha l f (Bregma -2 .5 to -4 .0 ; n = 3) . In two ra tsthe in jec t ion was conf ined to the media l and cent ra l seg-m e n t s o f MD ( B r e g m a - 1 . 8 t o - 3 . 3 ) . W h e n th e sp o t sinc luded the la te ra l and cent ra l segments , labe l led f ibresw e r e p r im a r i ly f o u n d in F r 2 a n d A C d o f t h e m P F C a n din both dorsa l and vent ra l agranula r insu la r a reas (Aidand AIv , r e spec t ive ly) of the la te ra l PFC. When the in-jec t ion s i te involved the cauda l pa r t o f the cent ra l MD,labe l led f ibres were a lso obse rve d in PL (F ig . 4). P HA -Linjec t ions in the media l and cent ra l segments gave r i seto labe l led f ibres in PL and I L (mP FC) and in the agran-u l a r i n su l a r P F C , H o w e v e r , i n tw o r a t s w i th P H A - Lspots r e s t r ic ted to the dorsa l pa r t o f mediocent ra l MDn o l a b e l le d f i b re s w e r e o b se r v e d i n A id . T h e se P H A - Linjec tions in to MD of cont ro l r a ts conf i rmed the topog-r a p h y o f MD p r o j e c t i o n w i th in t h e P F C p r e v io u s ly d e -sc r ibed by Gro enew egen 17, Kre t tek and Pr ice 34 and VanEde n 55. Bes ides these pro jec t ions to the PFC subareassome in jec t ions a lso labe led a f ew f ibres in the s t r ia tum ,both dorsally and ventrally. No clear topographical pattern

of MD projection within the str ia tum could be detected.In 6 ra ts wi th neona ta l mPFC les ions , PHA-L in jec -

t ions were re s t r ic ted to MD. The in jec t ion s i te s involvedthe la te ra l , cen t ra l , and media l segments (be tweenB r e g m a - 1 . 8 t o - 3 . 3 , n = 3 a n d B r e g m a - 2 . 5 t o - 4 . 0 , n= 3) . In none of these cases labe l led f ibres were foundin a reas where they were not expec ted on the bas is ofth e t o p o g r a p h y o f MD p r o j e ct i o n s ( s e e d e sc r ip ti o n o fMD - P F C p r o j e c t io n i n c o n tr o l s) . W i th in t h e u n d a m a g e dP F C a r e a s n o c h a n g e s w e r e o b se r v e d i n t h e t o p o g r a p h -i ca l r e l a ti o n sh ip b e tw e e n P F C su b a r e a s a n d M D su b n u -c le i, nor w ere changes obs e rved in the dens i ty of labe l ledMD f ibres wi th in the PFC. A l thoug h, in th is group a lsosome in jec t ions labe led f ibres in the s t r ia tum, no c lea rd i f fe rences were found in compar ison wi th the cont ro lgroup. In F ig . 4 the re su l t s of ove r lappin g MD in jec tionsa re jux taposed in a cont ro l r a t ( a ) and in a r a t wi th aneona ta l le s ion (b) . In the ra t wi th a neona ta l le s ion , thela rge PHA-L in jec t ion inc luded the middle pa r t o f thec e n t r o l a t e r a l MD se g m e n t s , e n c r o a c h in g u p o n th e m e -dia l segment . Labe l led f ibres were found in the la te ra lP F C a n d in t ho se p a r t s o f t h e m P F C th a t w e r e n o t d a m -aged . None of these te rmina t ion p lexuses were pa r t icu-la r ly dense in compar ison wi th the pro jec t ions in con-t ro is , nor were f ibres obse rved outs ide the PFC.

In 9 ra ts wi th adul t le s ions , PHA-L in jec t ions wereconf ined to the MD. The in jec t ions involved la te ra l , me-d i al a n d c e n t r a l s e g m e n ts o f MD ( B r e g m a - 1 . 8 t o - 4 . 0 ) .In none of these ra ts , p ro jec t ions outs ide the or ig ina lMD p r o j e c t i o n a r e a s ( s e e a b o v e ) w e r e o b se r v e d , n o rwere the re changes in the MD projec t ion pa t te rn wi th inthe s t r ia tum and the remain ing pa r ts of the PFC.2. The dopam inergic innervation of the prefr ontal cortex

Afte r mPFC les ions inf l ic ted e i the r neona ta l ly or inadul thood, sec t ions a t the leve l of the VTA revea led node tec tab le loss of DA ce l l s in tha t a rea .

In 20 cont ro l r a ts corona l sec t ions of the f ronta l cor -t e x w e r e im m u n o c y to c h e m ic a l l y s t a in e d f o r D A , t h u svisua l i s ing the pa t te rn of d is t r ibu t ion and morphology ofDA f ibres in the PFC. DA f ibres were seen in a l l sub-a reas of media l and la te ra l PFC. With in the m PFC , thedens i ty of f ibres was cons ide rably h igher in the basa lcor t ica l laye rs (VI and V) than in the more super f ic ia llaye rs I I I , I I and I . In addi t ion , r eg iona l d i f fe rences inf ibre dens i ty were seen wi th in the mPFC, cor respondingwith the cy toa rchi tec tonic subareas PL, ACd and Fr2 .The dens i ty of DA f ibres was h ighes t in PL, in bothbasa l and super f ic ia l cort ica l laye rs . ACd conta ined fewerf ibres in the super f ic ia l laye r s com pare d wi th P L, w hereasthe dens i ty in the basa l laye rs was s imi la r . Of the 3 sub-a reas , the lowest f ibre dens i ty was found in F r2 , in a l l o fi t s cor t ica l laye rs . In th is subarea , f ibres were pr imar i ly


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l i m i t e d t o l a y e r V I a n d t h e l o w e r p a r t o f l a y e r V . F u r -t h e r m o r e , t h e D A f i b r es h a d a sp e c i fi c c o u r se w i t h i n d i f-f e r e n t c o n i c a l l a y e r s : t h e f i b r e s i n l a y e r V I r a n p a r a l l e lt o t h e p i a l su r f a c e a n d i n l a y e r V , I I I a n d I I p e r p e n d i c -u l a r t o t h e p i a l su r f a c e . I n l a y e r I , w h e r e a f e w f i b r e sw e r e f o u n d , t h e y r a n p a r a ll e l t o t h e m e d i a l c e r e b r a l s u r-f a c e i n a v e n t r o d o r sa l d i r e c t i o n .

I n t h e 9 r a t s w i t h l e s i o n s i n f l i c t e d i n a d u l t h o o d t h ed i s t ri b u t io n a n d m o r p h o l o g y o f D A f i b re s w it h in t h e r e -m a i n i n g p a r t s o f t h e P F C w a s s i m i la r t o t h a t o f t h e D Af i b r e s i n c o n t r o l a n i m a l s . F i g s . 5 a n d 6 sh o w p h o t o m i -c r o g r a p h s o f t h e p r e f r o n t a l a r e a P L . W h e n t h e d e n s i tyo f t h e D A f i b r es o f c o n t r o l s a n d a n i m a l s w i t h a d u l t l e -s i o n s w a s c o m p a r e d i n t h e su p e r f i c i a l l a y e r s , i n l a y e r Va n d i n th e b a sa l l a y e r V I ( F i g . 6 ) , n o d i f f e r e n c e s w e r en o t i c e a b l e , e x c e p t f o r t h e t i s su e i n t h e d i r e c t v i c in i t y o ft h e l e s io n s i te . H e r e f e w e r D A f ib r e s w e r e o b s e r v e d i na n i m a l s w i t h a d u l t l e s i o n s c o m p a r e d w i t h t h e c o n t r o l s .H o w e v e r , w h e n a l e s io n w a s i n fl ic t ed a t P N 6 , t h e r e w a sa r e m a r k a b l e c h a n g e i n D A i n n e r v a t i o n i n t h e r e m a i n -i n g m P F C , P L a n d I L ( F i g . 6 ) . I n a l l o f t h e 8 a n i m a l sw i t h n e o n a t a l l e s io n s , i n w h ic h t h e D A i n n e r v a t i o n w a si n v e s t i g a t e d , a n i n c r e a se i n t h e d e n s i t y o f D A f i b r e s w a so b s e r v e d i n a l l c o n i c a l l a y e r s o f t h e r e m a i n i n g P L a n dI L . T h e d o p a m i n e r g i c r e sp o n se w a s h i g h e s t a t a d i s t a n c eo f 2. 5 m m a n t e r i o r o f b r e g m a , w i th a l o w e r r e s p o n s e a tm o r e a n t e r i o r ( + 3 . 0 ) a n d / o r p o s t e r i o r ( + 2 . 0 ) l e v e ls . T h ei n c r e a s e d d e n s i t y w a s a c c o m p a n i e d b y a n i n c r e a s e db r a n c h i n g o f f i b r e s . T h e f i b r e s c o n t a i n e d m o r e v a r i c o s i -t i e s t h a n o b se r v e d i n c o n t r o l a n i m a l s . I n m a n y a n i m a l st h e d i a m e t e r o f b o t h i n t e r v a r ic o s e s e g m e n t s a n d v a r ic o s -i t ie s w a s in c r e a se d . T h e c o u r se o f t h e D A f i b r es in t h eP F C h a d n o t c h a n g e d , e x c e p t f o r t h e f i b r e s a d j a c e n t t ot h e s c a r . A t t h e v e n t r a l b o r d e r o f t h e l e s io n s i t e a n u n -u s u a ll y h i g h d e n s i ty o f D A f ib r e s w a s o b s e r v e d r u n n i n gp e r p e n d i c u l a r t o t h e p i a l su r f a c e , i .e . p a r a l l e l t o t h e s c a r .T h e s e f i br e s w e r e a l s o v e r y th i c k a n d h a d n u m e r o u s v a r -i c o s i t i e s ( F i g . 7 ) . I n m a n y a n i m a l s t h e h i g h b a c k g r o u n ds t ai n in g o f t h e m P F C w a s a ls o r e m a r k a b l e , w h e r e a s t h es t a in i n g o f t h e b a c k g r o u n d i n t h e f r o n t a l a r e a s i n t h esa m e se c t i o n d o r so l a t e r a l t o t h e l e s i o n w a s c o m p a r a b l et o t h a t i n c o n t r o l a n i m a l s . I n o n e r a t a n e x t e n s i o n o f t h es u p r a g e n u a l D A s y s t e m w a s o b s e r v e d . T h e f in e fi b re s o ft h is D A s y s t e m e x t e n d e d r o s t r a l o f th e g e n u o f t h e c o r -p u s c a l l o su m . T h e se f i b r e s t e r m i n a t e d a n d r a m i f i e d i nl a y e rs I I a n d I I I , a n d a p p e a r e d t h i n n e r t h a n i n t h e b a s a ll a y er s . F u r t h e r e x a m i n a t i o n o f o t h e r p a r t s o f t h e b r a i nr e v e a l e d t h a t t h e D A i n p u t m i g h t a l s o b e i n c r e a s e d i nt h e l a t e r a l p a r t o f t h e P F C a n d i n o t h e r b r a i n a r e a s , su c ha s t h e n u c l e u s a c c u m b e n s , M D , s e p t u m , a n d o t h e r c o r -t i c a l a r e a s . H o w e v e r , t h e i n c r e a s e d i n n e r v a t i o n w a s b yf a r t h e m o s t c o n s p i c u o u s i n t h e m P F C .

31DISCUSSIONSparing of function

I n t h e p r e se n t s t u d y i t w a s e s t a b l i sh e d t h a t r a t s w i t hb i l a t e r a l m P F C l e s i o n in f l ic t e d a t p o s t n a t a l d a y 6 sh o w e dsp a r i n g o f sp a t i a l d e l a y e d a l t e r n a t i o n b e h a v i o u r , w h e r e a sr a t s w i t h a s i m i l a r a d u l t m P F C l e s i o n w e r e i m p a i r e d i nt h e p e r f o r m a n c e o f t h is l e a r n i n g t as k . T h i s b e h a v i o u r a ls p a r i n g a f t e r n e o n a t a l l e s i o n s w a s a c c o m p a n i e d b y a ni n c r e as e d D A i m m u n o r e a c t iv i t y i n th e r e m a i n i n g m P F C .

O t h e r i n v e s t i g a t o r s o b s e r v e d s p a r i n g o f f u n c t i o n i nl e a r n i n g t a sk s a f t e r n e o n a t a l P F C l e s i o n s i n r a t s a n dm o n k e y s . I n r a t s , i t w a s s h o w n t h a t l e s io n s o f th e m P F Ci n f l i c t e d b e t w e e n P N 6 a n d P N 2 4 r e su l t e d i n c l e a r sp a r -i n g i n l e a r n i n g t a sk s , w h e r e a s l e s i o n s a f t e r P N 2 4 h a d a ni m p a i r i n g e f f e c t o n t h e p e r f o r m a n c e o f t h e se t a sk s 6 '2 9'3 1'32,40 . I n m o n k e y s t h e a g e o f 1 2 m o n t h s s e e m s t o b e c r it -icalTM. W i t h r e s p e c t t o o t h e r P F C - r e l a t e d t a s k s , e . g .sp e c i e s - ty p i c a l t a sk s , l e ss i s k n o w n a b o u t t h e c r i ti c a l p e -r i o d i n w h i c h sp a r i n g o f f u n c t i o n o c c u r s . R e su l t s d e -s c r i b e d b y N o n n e m a n a n d C o r w i n 4 0 s h o w e d s p a r i n g o ff o o d h o a r d i n g p e r f o r m a n c e w i t h m P F C l e si o n s in f li c te da t P N 9 , b u t w e c o u l d n o t c o n f i r m t h is w i t h s i m i la r le -s ions a t PN66.Neuroanatomical correlates of sparing of function

M a n y n e u r o a n a t o m i c a l c h a n g e s h a v e b e e n d e s c r i b e din re sp ons e to neo na ta l cor t i ca l l e s ions s '27'31'32. Fo l low-i n g n e o n a t a l m e d i a l f r o n t a l c o r t i c a l l e s i o n s , K o l b a n dcoworkers27'31'32 r e p o r t e d a d e c r e a s e i n t h i c k n e s s a n dn u m b e r o f n e u r o n s i n s e v e r a l p a r t s o f t h e c o r t e x , a l o n gw i t h a n i n c r e a se d d e n d r i t i c a r b o r i s a t i o n . I n a d d i t i o n , r e t -r o g r a d e t r a c e r s i n j e c t e d i n t h e v i su a l a n d so m a t o se n so r yc o r t e x r e v e a l e d p r o j e c t i o n s f r o m s o m e t h a l a m i c n u c l e i ,a m y g d a l a a n d c a t e c h o l a m i n e r g i c n u c l e i (su b s t a n t i a n i g r aa n d V T A ) , w h i c h a r e n o r m a l l y n o t s e e n i n a d u l t h o o d .H o w e v e r , t h e s e a b n o r m a l c o n n e c t i o n s w e r e n o t a cc o m -p a n i e d b y f u n c t i o n a l sp a r i n g 2 s ( B . K o l b , p e r so n a l c o m -m u n i c a t i o n ) . T h e p r e s e n t s t u d y w a s f o c u s e d o n t w o s y s-t e m s k n o w n t o b e c r u c i a l f o r P F C f u n c t i o n i n g : t h ep r o j e c t io n f r o m M D t o t h e P F C a n d t h e m e s o c o r t i c alD A sy s t e m , o r i g i n a t i n g i n t h e V T A 3 '5 '21 '23 '24 '46 '47 '49 '50 '52 .W e u s e d a n t e r o g r a d e t r a c i n g a n d i m m u n o c y t o c h e m i c a lm e t h o d s t o r e v e a l p o s s i b le c h a n g e s i n t h e se a f f e r e n t sy s-t e m s r e s u l t i n g f r o m n e o n a t a l m P F C l e s i o n s . T h e y a l s og a v e u s a n o p p o r t u n i t y t o s e a r c h f o r s u b t l e d i f f e r e n c e si n t h e p r o j e c t i o n p a t t e r n w i t hi n t h e r e m a i n i n g P F C a r -eas .1. Innervation from the mediodorsal nucleus of the thal-amusT h e p r o j e c t i o n f r o m M D t o t h e P F C s u b a r e a s w a s e x -a m i n e d u s in g t h e a n t e r o g r a d e t r a c e r P h a s e o l u s V u l g ar is


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32L e u c o a g g l u t i n i n ( P H A - L ) . I n c o n t r o l r a t s t h e t o p o g r a p h -i c al p r o j e c t i o n f r o m M D t o t h e P F C s u b a r e a s e x t e n s i v e l yd e s c r i b e d b y G r o e n e w e g e n 17, K r e t t e k a n d Price 34 a n dV a n E d e n s5 w a s c o n f i r m e d . I n r a t s w i t h n e i t h e r n e o n a -t a l n o r a d u l t l e s i o n s , P H A - L i n j e c t i o n s i n M D s h o w e d ap r o j e c t i o n d i f f e r e n t f r o m t h a t e x p e c t e d o n t h e b a s i s o ft h e M D p r o j e c t i o n p a t t e r n i n c o n t r o l a n i m a l s . I n n o n eo f th e r a t s o f t h e l e si o n g r o u p s M D f i b re s w e r e o b s e r v e di n o t h e r c o r t i c a l o r s u b c o r t i c a l a r e a s n o r m a l l y d e v o i d o ft h i s i n p u t . A l s o w i t h i n t h e P F C a r e a s , t h e M D p r o j e c -t i o n s s h o w e d n o c h a n g e s i n d e n s i t y o r i n t h e i r l a m i n a rd i s t r i b u t i o n .

W e a l s o p a i d a t t e n t i o n t o t h e p r o j e c t i o n t o t h e s t r i a -t u rn , b e c a u s e t h e s t r i a t u m i s a c o m p o n e n t o f a f u n c t i o n a ls y s t e m , t o g e t h e r w i t h M D a n d P F C 3 3'5 s a n d t h e r e f o r ew a s s u g g e s t ed a s a c a n d i d a t e f o r t a k i n g o v e r t h e P F Cfunc t ion 13'14'27'53. H ow ev er , a l tho ugh the in jec t ion s an a l -y s e d w e r e c o n f i n e d t o M D , w e c a n n o t e x c l u d e t h a ts o m e o f t h e P H A - L w a s t a k e n u p b y c e l l s o f t h e i n -t r a l a m i n a r n u c l e i , s i n c e c e l l s o f i n t r a l a m i n a r a r e a s , e s p e -c i a ll y t h e c e n t r a l l a t e r a l n u c l e u s o f t h e t h a l a m u s , i n t e r -m i n g l e w i t h M D c e l l s . T h e r e f o r e , a c c o r d i n g t o B e r e n d s ea n d G r o e n e w e g e n 1 , i t is p o s s ib l e t h a t t h e s e f e w p r o j e c -t i o n s o r i g i n a t e i n i n t r a l a m i n a r n u c l e i a n d n o t i n M D .W h a t e v e r t h e p r e c i s e o ri g i n o f t h e s e t h a l a m o s t r i a t a l p r o -j e c t io n s m a y b e , n o c h a n g e s i n t h e s e p r o j e c ti o n s b e t w e e na n i m a l s w i t h l e s i o n s o f e i t h e r a g e a n d c o n t r o l s w e r e o b -s e r v e d .

A m o n g s e v e r a l p o s s i b l e m e c h a n i s m s t h a t c o u l d a c -c o u n t f o r s p a r i n g , G o l d m a n a n d G a l k i n 12 a n d K o l b a n dN o n n e m a n 29 c o n s i d e r e d t h e p o s s ib i l it y t h a t M D c o u l d b et h e n e u r o a n a t o m i c a l s u b s t r a t e o f s p a r i n g o f f u n c t i o n f o l -l o w i n g e a r l y P F C l e s i o n s . T h i s h y p o t h e s i s w a s b a s e d o nt h e o b s e r v a t i o n t h a t t h e r e w a s n o s i gn o f d e g e n e r a t e dc e l l s i n t h e t h a l a m u s a f t e r n e o n a t a l l e s i o n s , w h e r e a s a f -t e r a n a d u l t l e s i o n r e t r o g r a d e d e g e n e r a t i o n i n M D w a so b s e r v e d . T h e s e a u t h o r s p o s t u l a t e d t h a t t h e s e c e l l s ,w h i c h h a d n o t d e g e n e r a t e d , m i g h t h a v e e s t a b l i s h e d n e wc o n n e c t i o n s w i t h o t h e r a r e a s i n r e s p o n s e t o t h e l e s i o na n d t h u s h a d c o m p e n s a t e d f o r lo s s o f P F C f u n c t i o n . A l -t h o u g h t h e n u m b e r o f r a t s w i t h m P F C l e s i o ns a n d t r a c e ri n j e c t i o n s i n M D w a s n o t s u f f i c i e n t f o r a s y s t e m a t i c a n a l -y s is o f M D p r o j e c t i o n s , t r a c e r i n j e c ti o n s w i t h in e a c h o ft h e g r o u p s d i d c o v e r t h e e n t i re M D . S i nc e n o n e o f t h e sei n j ec t io n s g a v e r i s e to a p r o j e c t i o n p a t t e r n w h i c h w a s n o tdes c r ib ed pre v io us ly 17'34's5 i t i s un l ike ly , tha t sp ro u t in go r r e r o u t i n g o f M D p r o j e c t i o n s h a d o c c u r r e d , a n d t h e r e -f o r e m a k i n g i t a l s o u n l i k e l y t h a t a c h a n g e i n t h i s s y s t e mw o u l d b e r e s p o n s i b l e f o r t h e o b s e r v e d s p a r i n g o f f u n c-t i o n .2. The dopaminergic innervation of the prefrontal cortex

T h e m a i n f i n d i ng o f o u r s t u d y i s t h a t t h e D A i n n e r -v a t i o n i n r e s p o n s e t o a n e o n a t a l m P F C l e s i o n i s i n -

c r e a s e d c o m p a r e d w i t h t h e i n n e r v a t i o n i n c o n t r o l r a t s .I n t h e e n t ir e p a r t o f t h e n o n - a b l a t e d m P F C a r e a s ( m a i n l yP L a n d I L ) , m o r e a n d t h i c k e r fi b r e s w i t h m o r e v a r i c o s -i t i e s w e r e o b s e r v e d o f t e n a l o n g w i t h a n i n c r e a s e d b a c k -g r o u n d s t ai n i n g . A m o r e d e n s e i n n e r v a t i o n o f th e r e -m a i n i n g p r e f r o n t a l a r e a ( P L a n d I L ) c o u l d b e t h e r e s u l to f a t h i n n i n g o f t h e c o r t i c a l t h i c k n e s s ( s e e e . g . K o l b a n dW h i s h a w a 2 ) . S u c h a d i f f e r e n c e i n c o r t i c a l t h i c k n e s s o f P La n d I L d o e s n o t e x p l a i n t h e t h i c k e n i n g o f t h e f i b re s , th em o r e a n d l a r g e r v a r i c o s i t i e s a n d t h e h i g h e r b a c k g r o u n d .T h e s e m o r p h o l o g i c a l c h a n g e s i n d i c a t e c h a n g e s i n t h eD A s y s t e m , i n r e s p o n s e t o n e o n a t a l b u t n o t t o a d u l t l e -s i on s . T h e s e i m m u n o c y t o c h e m i c a l c h a n g e s c a n n o t b ee l u s iv e w i t h r e g a r d t o t h e s t a t e o f a c t iv i t y o f t h e s y s t e m .T h i c k e n i n g o f f i b re s a n d v a r i c o si t ie s c a n b e a n i n d i c a t i o no f a h i g h e r a c t iv i t y a s w e l l a s o f a n a c c u m u l a t i o n o f p r e -s y n a p t i c D A . B i o c h e m i c a l m e t h o d s a r e n e e d e d f o r f u r-t h e r d e t e r m i n i n g t h e s t a t e o f a c t iv i t y o f th e D A s y s t e m .

T h e i m p o r t a n c e o f th e D A s y s te m in P F C f u n c ti o n in ga p p e a r s f r o m s t u d i e s i n m o n k e y s 4 a n d r a t s T M inw h i ch t h e D A i n n e r v at i o n o f th e P F C w a s d e p le t e d b y6 - h y d r o x y d o p a m i n e . T h e D A - d e p l e t e d a n i m a l s s h o w e da n i m p a i r e d p e r f o r m a n c e o f P F C - r e l a t e d b e h a v i o u r . A l s oe l e c t r o p h y s i o l o g i c a l s t u d i e s i n d i c a t e t h a t D A p l a y s a ni m p o r t a n t r o l e b y f a c i l i ta t i n g ~ a s k - s p e ci f i c n e u r o n a l a c -t i v i t y i n t h e P F C 44 . A d d i t i o n a l l y , t h e r e i s e v i d e n c e t h a tt h e D A s y s t e m c o u l d p la y a r o l e in b e h a v i o u r a l s p a r i n g :a m p h e t a m i n e , w h i c h l e a d s t o a n i n c r e a s e d e x t r a c e l l u l a rD A c o n c e n t r a t i o n , a n d a p o m o r p h i n e , w h i c h a c t s a s ap o s t sy n a p t ic D A a g o n is t, c a n b o t h i m p r o v e r e c o v e r y a f -t e r ne oco r tex l e s ions in ad u l th oo d x1'16"19'25'51. F u r th e r -m o r e , n e o n a t a l l e s i o n s o f V T A c e l l s r e s u l t i n a l a s t i n gi m p a i r m e n t o f P F C f u n c t i o n z x, i n d i c at i n g t h a t w h e n t h ism e s o l i m b o c o r t i c a l D A - s y s t e m i s a b s e n t n o s p a r i n g o c -curs .

T h e r e f o r e , t h e p r e s e n t ly r e p o r t e d r e s p o n s e o f t h e D As y s t e m in t h e P F C a f t e r n e o n a t a l l e si o n s , c o u l d v e r y w e llb e c a u s a l l y r e l a t e d t o c o n c o m i t a n t b e h a v i o u r a l s p a r i n g .T h i s m e c h a n i s m c a n a c t m o s t e f f ic i e n tl y i n a n a r e a f u n c -t i o n a l l y r e l a t e d t o t h e a b l a t e d a r e a s ( F r 2 a n d A C d ) : t h ei n f r a li m b i c a n d p r e l i m b i c a r e a s o f t h e m P F C . H o w e v e r ,f u r t h e r s t u d i e s a r e n e c e s s a r y t o p r o v e t h a t t h e D A a c -t i v it y i s i n c r e a s e d i n r e s p o n s e t o n e o n a t a l m P F C l e s io n sa n d t h a t i t i s o f f u n c t i o n a l s i g n i f i c a n c e f o r b e h a v i o u r a ls p a r i n g .

Acknowledgements.We hank E lhs Jansen, Nora Geerts and A n-net Lo uwerse for their assistance in behavioural testing, Eileen vanVulpen and Ria M atthijssen for their h istological assistance Wealso wan t to thank Wendy van Noppen and Dinie K ok-Noormanfor hngm stlc and other corrections, Henk Stoffels for drawing thefigures and G erben van der M eulen for preparing the photographs.The com ments of Harry Uyhn gs and Dick Swaab are gratefully ac-knowledged.


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R E F E R E N C E S1 B e r e n d s e , H .W . a n d G r o e n e w e g e n , H . J . , O r g a n i z a t i o n o f t h etha lamos t r i a ta l p ro jec t ions in the ra t , w i th spec ia l emphas i s ont h e v e n t r a l s t r ia t u m , J. Comp. Neurol., 299 (1990) 187-228.2 B o w d e n , D .M . , G o l d m a n , P .S . a n d R o s v o l d , H .E . , F r e e b e -hav io r o f rhesus monkeys fo l lowing le s ions o f the dorso la te ra l

and o rb i ta l p re f ron ta l co r tex in in fancy , Exp. Brain Res. , 12(1971) 265-274.3 B r i to , G .N .O . , T h o m a s , G . J . , D a v i s , B . J . a n d G i n g o l d , S . I .,P r e l im b i c c o rt e x , m e d i o d o r s a l th a l a m u s , s e p t u m , a n d d e l a y e da l te rna t ion in ra t s , Exp. Brain Res. , 46 (1982) 52-58.4 B r o z o s k i, T . J. , B r o w n , R .M . , R o s v o l d , H .E . a n d G o l d m a n ,ES . , Cogni t ive de f ic it caused by reg iona l dep le t ion o f dopa min ein p re f ron ta l co r tex o f rhesus monkey , Science, 205 (1979) 929-932.5 B u b s e r , M . a n d S c h m i d t, W . J . , 6 - H y d r o x y d o p a m i n e le s i o n o fthe ra t p re f ron ta l co r tex inc reases locomotor ac t iv i ty , impa i r sacqu is i t ion o f de layed a l t e rna t ion t a sks , bu t does n o t a f fec t un-in te r rup ted t a sks in the rad ia l maze , Behav. Brain Res., 37(1990) 157-168.6 D e B r a b a n d e r , J .M . , D e B r u i n , J .P .C . a n d V a n E d e n , C .G . ,C o m p a r i s o n o f t h e e ff ec ts o f n e o n a t a l a n d a d u l t m e d i a l p r e f r o n -ta l co r tex l e s ions on foo d hoa rd ing an d spa taa l de layed a l t e rna -t i o n , Behav. Brain Res., 42 (1991) 67-75.7 D e B r u i n , J .P .C . , O r b i t a l p r e f ro n t a l c o rt e x , d o p a m i n e a n d s o -c ia l -agon ist i c behav io r o f ma le Lo ng Ev ans ra t s , Aggress. Be-hay., 16 (1990) 231-248.8 F i n g e r , S . a n d A l m l i , C .R . , B r a i n d a m a g e a n d n e u r op l a sl a c it y :m e c h a n i s m s o f r e c ov e r y o r d e v e l o p m e n t ? , Brain Res. Rev., 10(1985) 177-186.9 G e f f a r d , M . , B n i j s , R .M . , S e g u e la , P . , P o o l, C .W . a n d L eMoal , M. , F i r s t dem ons t ra t ion o f h igh ly spee tf ic and sens i t ivea n t i b o d i e s a g a in s t d o p a m i n e , Brain Research, 294 (1984) 161-165.1 0 G e r f e n , C .R . a n d S a w c h e n k o , P .E . , A n a n t e r o g r a d e n e u r o a n -a t o m i ca l t ra c i n g m e t h o d t h a t s h o w s t h e d e t a i le d m o r p h o l o g y o fn e u r o n s , t h e i r a x o n s a n d t e r m i n a ls : i m m u n o h i s t o e h e m i c a l l o c al -i za t ion o f an axona l ly t r anspor ted p lan t l ee t in , Phaseo lus vu l -ga r i s - l eucoaggh i t inm (PHA-L) , Brain Research, 290 (1984) 219-238.11 Gl ick , S .D . and Z im merb erg , B . , Pharmaco log ica l modt f ica t iono f b r a i n l e s i o n s y n d r o m e s . I n S . F i n g e r ( E d . ) , Recovery fromBrain Damage, Research and Theory, P l e n u m , N e w Y o r k , 1 9 7 8,pp . 281-296 .1 2 G o l d m a n , P .S . a n d G a l k i n , T .W . , P r e n a t a l r e m o v a l o f f r o n t a lassoc ia t ion cor tex m the fe ta l rhesus monkey : ana tomica l andfunc t iona l consequences m pos tna ta l l i f e , Brain Research, 15 2(1978) 451-485.13 G oldm an , P .S . and Rosvo ld , H .E . , Th e e f fec ts o f se lec tive can-d a t e l e s i o n s i n i n f a n t a n d j u v e n i l e rh e s u s m o n k e y s , Brain Re-search, 43 (1972) 53-66.1 4 G o l d m a n , P .S ., R o s v o l d , H .E . a n d M i s h k i n , M . , S e l ec t iv e s p a r -i n g o f f u n c t i o n f o ll o w i n g p re f r o n t a l l o b e c t o m y i n i n f a n t m o n -keys , Exp. Neurol. , 29 (1970) 221-226.1 5 G o l d m a n , P .S ., R o s v o l d , H .E . , V e s t , B . a n d G a l k i n , T .W . ,Ana lys t s o f the de layed a l t e rna t ion de fici t p roduce d by dorso-la te ra l p re f ron ta l l e s ions in rhesus monkey , J. Comp. PhysioLPsychol., 77 (1971) 212-220.16 Golds te in , L .B . and D av is , J .N . , In f luence o f l e s ion s ize andloca t ion on am phe tam ine- fac i l i t a ted recovery o f beam-walk ingin ra t s , Behav. Neurosci., 104 (1990) 320-327.1 7 G r o e n e w e g e n , H . J . , O r g a n i z a t i o n o f t h e a f f e r e n t c o n n e c t i o n s o ft h e m e d i o d o r s a l t h a la m i c n u c l e u s i n t h e r a t , r e l a t e d t o t h e m e -d iodorsa l -p re f ron ta l topography , Neuroscience, 24 (1988) 379-431.1 8 H i c k s , S .P . a n d D ' A m a t o , C . J . , M o t o r - s e n s o r y a n d w s u a l b e -h a v i o r a f t e r h e m i s p h e r e c t o m y i n n e w b o r n a n d m a t u r e r a t s ,Exp. Neurol., 29 (1970) 416-438.19 Ive rsen , S .D . , The e f fec t o f su rg ica l l e s ions to f ron ta l co r tex

33

a n d s u b s ta n t aa n i g r a o n a m p h e t a m i n e r e s p o n s e s i n r a t s , BrainResearch, 31 (1971) 295-311.2 0 J h a m a n d a s , J .H . , R a b y , W . , R o g e r s , J . , B u i j s , R .M . a n dR e n a n d , L .P . , D i a g o n a l b a n d p r o j e c t i o n t o w a r d s t h e h y p o t h a .l amic supraop t ie nuc leus : l igh t and e lec t ron m ic roscop ic obse r -va t ions in the ra t , J. Comp. Neurol., 282 (1989) 15-23.2 1 K a l s b e e k , A . , D e B r u i n , J .P .C . , F e e n s t r a , M .G .P . a n d U y l i n g s ,H .B .M . , A ge-de pend en t ef fec ts o f l e s ion ing the mesocor t i ca ld o p a m i n e s y s t e m u p o n p r e f r o n t a l c o r t e x m o r p h o m e t r y a n dP F C - r e l a t e d b eh a v i o r s. I n H .B .M . U y l i n g s , C .G . v a n E d e n ,J .P .C . D e B r u i n , M .A . C o r n e r a n d M .G .P . F e e n s t r a ( E d s . ) ,The Prefrontal Cortex: Its Structure, Function and Pathology,Progress In Brain Research, Vol. 85, E l s e v i e r , A m s t e r d a m ,1990, pp. 257-283.2 2 K a l s b e e k , A . , V o o r n , P ., B n i j s, R .M . , P o o l , C .W . a n d U y l i n g s ,H .B .M . , D e v e l o p m e n t o f t h e d o p a m i n e r g i c i n n e r v a t i o n i n t h epre f ron ta l co r tex o f the ra t , J. Comp. Neurol., 269 (1988) 58-72 .2 3 K e l l e y , A .E . a n d S t m u s , L . , D i s a p p e a r a n c e o f h o a r d i n g b e h a v -io r a f t e r 6 -hydroxydopamine l e s ions o f the meso l imbic dope-m i n e n e u r o n s a n d i t s r e i n s t a t e m e n t w i th L - D o p a , Behav. Neu-rosci., 99 (1985) 531-545.

24 K ess le r , J . and M arkowl t sch , H .J . , D e layed-a i t e rna t ion pe r fo r -man ce a f te r ka l rt ic l e s ions o f the tha lam ic mediodorsa l nuc leusand the ven t ra l t eg rnen ta l a rea in the ra t , Behav. Brain Res., 3(1981) 125-130.25 King , V . and Corwin , J .V . , Neg lec t fo l lowing umla te ra l ab la -t i o n o f t h e c a u d a l b u t n o t t h e r o s t r a l p o r t i o n o f m e d i a l a g r a n -u l a r c o r te x o f t h e r a t a n d t h e t h e r a p e u t i c e f fe c t o f a p o m o r p h i n e ,Behav. Brain Res., 37 (1990) 169-184.26 Kolb , B . , P re f ron ta l l e s ions a l t e r ea t ing and hoard ing behav io rin ra t s , Physiol. Behav., 12 (1974) 507-511.27 Kolb , B . a nd G- ibb , R . , An a tom ica l co r re la tes o f behav io ura lc h a n g e a f t e r n e o n a t a l p r e f ro n t a l l e si o n s i n r a t s. I n H .B .M . U y l -h ag s, C .G . V a n E d e n , J .P .C . D e B r u i n , M .A . C o r n e r a n dM .G .P . F e e n s t r a ( E d s . ) , The Prefrontal Cortex: Its Structure,Function and Pathology, Progress in Brain Research, Vol. 85,Elsev ie r , Amste rdam, 1990 , pp . 241-256 .2 8 K o l b , B . a n d G i b b , R . , S p a r in g o f fu n c t i o n a f t e r n e o n a t a l f r o n -ta l l e s tons cor re la tes wi th inc rea sed cor t i ca l dendr i t i c b ranchmg:a poss tb le mechan ism fo r the Kennard e f fec t , Behav. BrainRes. , 43 (1991) 51-56.2 9 K o l b , B . a n d N o n n e m a n , A . J . , S p a r i ng o f f u n c ti o n i n r a ts w i t hea r ly p re f ron ta l co r tex l e s ions , Brain Research, 151 (1978) 135-148.3 0 K o l b , B . , N o r m e m a n , A . J . a n d S i n g h , R .K . , D o u b l e d i s s o c i a -t ion o f spa t i a l impa i rments and pe rsevera t ion fo l lowing se lec -t ive p re f ron ta l l e s ions in ra t s , J . Comp. Phystol. Psychol., 87(1978) 772-780.3 1 K o l b , B . a n d W h i s h aw , I .Q . , N e o n a t a l f r o n t a l l e s io n s i n t h e r a t :spa r ing o f l ea rned b u t n o t spec ies - typ ical behav io r in the p res -ence o f r educed b ra in we tgh t and cor t t ca l th ickness , J. Comp.Physiol. Psychol., 95 (1981) 863-879.32 Kolb , B . and Whishaw, I .Q . , Ear l i e r i s no t a lways be t t e r : be -hav io ra l dys func t ion and abnormal ce rebra l morphogenes i s fo l -lowing neona ta l co r t i ca l l e s ions in the ra t , Behav. Brain Res.,17 (1985) 25-43.33 K olb , B . and W hishaw, I .Q . , P las t i c i ty in the neocor tex : mech-a n i sm s u n d e r l y i n g r e co v e r y f r o m e a r ly b r a i n d a m a g e , Progr.N e u r o b to l , 32 (1989) 235-276.34 Kre t tek , J .E . and Pr ice , J .L . , The cor t i ca l p ro jec t ions o f themediodorsa l nuc leus and ad jacen t tha lamic nuc le i in the ra t , J .Comp. Neurol., 171 (1977) 157-192.3 5 L a n d , P .W . a n d L u r i d, R .D . , D e v e l o p m e n t o f th e r a t ' s u n -c rossed re t ino tec ta l pa thway and i t s r e la t ion to p las t i c i ty s tud-ies , Science, 205 (1979) 698-700.36 Leon g , S .K . , P las t i c i ty o f ce rebe l la r e f fe ren ts a f t e r neon a ta l l e -s ions in a lb ino ra t s , Neurosci. Lett., 7 (1978)281-289.3 7 L m d v a l l , O . , B j 6 r k l n n d , A . a n d D i v a c , I . , O r g a n i z a t i o n o f c a -techo lamine neurons p ro jec t ing to the f ron ta l co r tex in the ra t ,


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