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PergamonNeuroscienceand BiobehavioralReviews,Vo i. 18, No. 3, pp. 385-396, 1994Copyright 1994 ElsevierScienceLtdPrinted n the USA. All rights eserved0149-7634/94 $6.00 + .00

0 1 4 9 - 7 6 3 4 ( 9 4 ) E 0 0 0 1 - G

A llostas is, Am ygd ala, and Anticipatory A ngstJ A Y S C H U L K I N , t B R U C E S . M c E W E N A N D P H I L I P W . G O L D

Clinical Neuroendocrinology Branch, National Institute o f Mental Health andDepartment o f Neuroendocrinology, Rockefeller University, Bethesda, MD 20892R e c e i v e d 3 1 A u g u s t 1 99 3

S C H U L K I N , J . , B . S . M c E W E N A N D P . W . G O L D . Aiiostasis, amygdala, and anticipatory angst. N E U R O S C I B I O -BEH AV REV 18(3) 385-396 , 199 4 . -Re gion s o f the amy gdala a re involved in an t ic ipa t ion of nega tive events . Ch ronicant ic ipa t ion of nega tive events l eads to what w e ca l l a l los ta t ic load , o r a rousa l pa tho logy . Two hormones appear to beinvolved in a rousa l pa tho logy; cor t ico t rop in- re leas ing horm one in the bra in and giucocort icoids. W e suggest that increases incor t ico t rop in- re leas inghormon e , by s t ress or g lucocor t ico ids , n the am ygdala may have func t iona l consequences for a l los ta t icload . W hereas , cor t ico t rop in- re leas inghorm one in the parvoce l lu la r reg ion of the p aravent r icu la r nuc leus of the h ypotha la -mus i s decreased by g lucocor t ico ids thereby under negat ive feedback and homeos ta t ic cont ro l , the cen t ra l nucleus of theamy gdala i s to som e ex ten t under pos i t ive feedback and i s increased by g iucocort ico ids , and perhaps under a l los ta t ic cont ro l .The h uman and an imal l i t e ra ture suggest tha t a var ie ty of psychopathologies (e .g . , melanchol ia ) may be t i ed to neurohorm onalsignals act ivating regions of the am ygd ala.Amygdala AI los tas i s Psychopathology

W E p r o v i d e a f r a m e w o r k t h a t i n t e g r a t e s st u d i es i n t h e r e g u l a -t i o n o f c h r o n i c a n x i e t y , f e a r , a n d h o p e l e ss n e s s i n a n i m a l s t u d -i e s, w i th a c l u s t e r o f a n a l o g o u s s y m p t o m s e x p r e s s ed i n h u m a nc l i ni c a l p o p u l a t i o n s . W e t h e n p r o v i d e a n a n a t o m i c a l n e u r o -h o r m o n a l s y s t e m t h a t w e h y p o t h e s i z e u n d e r l ie s t h e se s t a t e s.W e t i e t o g e t h e r t h e f a c t t h a t a c l u s t e r o f p s y c h o l o g i c a l s y m p -t o m s , ( e . g ., f e a r , a n x i e t y , i n a d d i t i o n t o p a t h o l o g i e s s u c h a sa g i t a t e d d e p r e s s i o n , p a n i c d i s o r d e r , p o s t t r a n m a t i c s t r e s s )w h i l e d i s t in c t a n d w i t h d i f f e r i n g m e c h a n i s m s , c a n s t i l l r e s u l ti n a f i x a t i o n o f a n t i c i p a t e d n e g a t i v e e v e n t s . W e a r g u e t h a tb r a i n r e g i o n s l i k e t h e a m y g d a l a ( a n d i ts a s s o c i a t e d s tr u c t u re s )m a y u n d e r n o r m a l c i r c u m s t a n c e s e r v e t o r e g u l a t e t h e i n te r n a lm i l i e u [ r e s p o n s e t o i n t e r n a l s i g n a l s l i k e c o r t i c o t r o p i n - r e l e a s i n gh o r m o n e ( C R H ) a n d g l u c o c o r t i c o i d s ] a n d i n t e g r a te i t w i t he x t e r n a l e v e n t s . M o r e o v e r , w e s u g g e s t t h a t a n t i c i p a t o r y o ra l l o s ta t i c m e c h a n i s m s ( e . g ., r e s p o n d i n g t o m o r e t h a n o n e s i g -n a l a n d p l a n n i n g a h e a d , s e e 1 1 9 ,1 4 5 , 14 6 ) u n d e r l i e s u c h s t a t e s ,a n d t h a t a l l o s ta t i c l o a d a n d " a r o u s a l p a t h o l o g y " ( t o o m u c hi n p u t , c h r o n i c v i g i l a n c e , c o n f l i c t i n g s i g n a l s ) m a y c o n t r i b u t et o t h e d e g e n e r a t i o n o f p h y s i o l o g i c a l t is s u e a n d p s y c h o l o g i c a la d a p t a t i o n ( 1 09 ,1 4 5 ,1 4 6 ). A d d i t i o n a l l y , w e s u g g e st t h a t h o -m e o s t a t i c r e g u l a t i o n a n d n e g a t i v e f e e d b a c k c o n t r o l o f C R Hb y g i u c o c o r t i c o i d s ( e . g . , 2 8 ,1 0 8 ) i s i n c o n t r a s t t o t h e e m e r g i n ge v i d e n c e t h a t C R H c e l l b o d i e s i n t h e a m y g d a l a ( 1 0 4 , 1 5 0 , 1 5 2 )a c t u a l ly i n c r e a se t o h i g h l e v e ls o f g l u c o c o r t i c o i d s , a n d m a y b e

u n d e r p o s i t i v e i n d u c t i o n o r a l l o s t a t i c c o n t r o l . T h e s e e f f e c t sm a y b e m o d e s t a n d k n o t t e d t o t h e r e g u l a t io n o f o t h e r n e u r o -p e p t i d e a n d n e u r o t r a n s m i t t e r s y s t e m s , m a y n o n e t h e l es s b e a c -t i v a t e d b y g i u c o c o r t ic o i d s a n d c h r o n i c p a t h o l o g y . W e s u g g e s tt h e l a t t e r c o n d i t i o n i s t i e d t o a n t i c i p a t i o n o f a d v e r s e e v e n t sa n d a l l o s ta t i c l o a d .T h e l o g ic o f t h is p a p e r i s t o d e f i n e w h a t w e m e a n b y a l l o -s t a s i s , t h e n r e v i e w a n i m a l s t u d i e s o n p e r c e i v e d c o n t r o l a n da n t i c i p a t i o n o f a d v e r s i t y a n d t h e h o r m o n e s o f s t re s s , a n d t h e nt o r e v i e w t h e a m y g d a l a a n d i t s r o l e i n a d v e r s i t y . W e t h e nc o n s i d e r t h e i m p l i c a t i o n s t h a t t h i s h a s f o r a c l u s t e r o f p s y c h o -p a t h o l o g i e s b o t h i n te r m s o f h o m e o s t a t i c r e g u l a t i o n a n d a l l o -s t a t i c r e g u l a t i o n , a n d t h e n t o s u g g e s t w a y s i n w h i c h g l u c o c o r t i -c o i d s a n d C R H i n th e a m y g d a l a m a y i n t e r a c t i n m a g n i f y i n gt h e c o n d i t i o n o f a d v e r s i t y , s tr e s s, a r o u s a l p a t h o l o g y a n d a l l o -s t a t i c l o a d .Allostasis

A l l o s t a s is c a n b e d e f i n e d a s f o l l o w s : th e r e g u l a t io n o f m a n yv a r i a b l e s o v e r t im e i n m a i n t a i n i n g s t a b i l it y t o m e e t c h a n g i n gc i r c u m s ta n c e s ; A l l o s t a s i s, a s p r o p o s e d b y S t e rl i n g a n d E y e r ,( 1 4 5 , 1 4 6 ) i s t h e r e g u l a t i o n o f t h e i n t e r n a l m i l i e u t h r o u g h d y -n a m i c c h a n g e i n a n u m b e r o f h o r m o n a l a n d p h y s i c a l v a r i a b le si n w h i c h t h e r e i s a n y t h i n g b u t a s t e a d y s t a t e . W h i l e a l l o s t a s is

Requests for reprints should be addressed to Jay Schulkin, Beh avioral Neuroscience Un it , Clinical Neuroendocrinology Branch, N ationa lIns t i tu te of Menta l H ea l th , Bldg . 10 , 9000 Rockvi l le P ike , Be thesda M D 20892.

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3 86 S C H U L K I N , M c E W E N A N D G O L Dis s t a b i l i ty th r o u g h c h a n g e , a l lo s t a t i c lo a d i s th e h id d e n p r i c et h e b o d y p a y s f o r c o n t a i n i n g t h e e f f ec t s o f a r o u s i n g s t i m u l i ,a n d o f th e a n t i c ip a t io n s o f n e g a t iv e e v e n t s ( 1 0 9, 1 1 9 ). Th u s ,we b e g in wi th s t a t in g two p r o p o s i t io n s a b o u t a l lo s t a s i s : F i r s t ,a l lo s t a t i c r e g u la t io n d o e s n o t d e p e n d o n s e t p o in t r e s p o n s e sa n d s ig n a l s a r e n o t c o n s ta n t . I n s t e a d , th e r e i s c o n s ta n t e v a lu a -t i o n a n d r e e v a l u a t i o n o f h u m o r a l a n d e n v i r o n m e n t a l s i g n al s .S e c o n d , a l l o s t a t i c m e c h a n i s m s a r e t i e d t o a n t i c i p a t i o n o fn e e d s . B e h a v i o r a l a d j u s t m e n t s a r e m a d e i n a d v a n c e , a n d o r -g a n i s mic c o n t r o l u t i li z e s re s o u r c e s to a d ju s t to c h a n g in g a n t i c -i p a t e d d e m a n d s . B e h a v i o r i s d r i v e n b y a n t i c i p a t o r y a n d n o tju s t r e a c t iv e r e s p o n s e s .H o m e o s t a t i c m e c h a n i s m s , b y c o n t r a s t , a r e v i e w e d ( e . g . ,1 7 , 2 4 ) a s b e in g t r ig g e r e d b y d e v ia t io n s in o n e v a r i a b le a n d as u b s e q u e n t r e s t o ra t i v e r e s p o n s e t o c o r r e c t i t ( f o o d i n t a k e a n da d e v ia t io n o f g lu c o s e l ev e ls ). Ho m e o s ta t i c s y s te ms wi th in l im-i t s a b s o r b d e v ia t io n s f r o m o u t s id e s o u r c e s a n d ma in ta in s t a b i l -i ty a n d s u f f i c i e n c y . Th e y r e v o lv e a r o u n d a c e r t a in s e t p o in tth a t i s th e o p t ima l p o s i t io n f o r a g iv e n p h y s io lo g ic a l s y s te m.Th u s , h o me o s ta t i c r e g u la t io n r e f l e c t s s t a b i l i ty o f c o n s ta n t s .B u t a l l o s t a t i c m e c h a n i s m s i n v o l v e t h e o r g a n i s m i c c o n t r o l o fm a n y v a r i a bl e s , s o m e o f w h i c h a r e i n c o n f l ic t a n d w h i c h m a yle a d to a l lo s t a t i c lo a d ( 1 0 9 ) . A l lo s t a t i c me c h a n i s ms c o mp u tet r a d e o f f s a m o n g v a r i a b l e s , c o m p u t i n g m a n y f a c t o r s a t o n c e .T h e s e i n c l u d e m a n y h o r m o n a l s i g n a l s , w h i c h a r e i n c o n f l i c tw i th o n e a n o th e r ( s ee 1 0 6 , 1 4 5 , 1 4 6 ). A l lo s t a s i s r e fl e c t s s t a b i l ityt h r o u g h c h a n g e , c e n t r a l c o o r d i n a t e d e f f e c t s a n d a n t i c i p a t o r yr e s p o n s e s .P h y s io lo g ic a l ly , o n e e x a mp le o f a l lo s t a t i c lo a d i s e l e v a te dc o r t is o l i n c re a s in g i n s u l in s e c r et i o n a n d b o t h h o r m o n e s c o n -jo in t ly a c c e le r a t in g a th e r o s c le r o s i s ( 1 0 9 ) . Th i s r e p r e s e n t s p h y s -i o l o g ic a l p a t h o l o g y . A l l o s t a ti c l o a d c a n a l s o b e c a s t i n l i g h t o fS e ly e ' s ( 14 1 ) c o n c e p t io n o f a d a p ta t io n to s t r e s s u n d e r e x t r e mec o n d i t i o n s . H e d e f i n e d a " g e n e r a l a d a p t a t i o n s y n d r o m e . " I no n e s t a t e th a t h e c a l l e d " r e s i s t a n c e " ( e . g . , s e c r e t io n o f g lu c o -c o r t i c o i d s ) , a d a p t a t i o n h a s t a k e n h o l d . T h e o t h e r s t a t e t h a tS e ly e c a ll e d " e x h a u s t i o n " ( f r o m p e r h a p s c h r o n i c a n x i e t y a n df e a r) w o u l d i n c l u d e n o t o n l y a d r e n a l a t r o p h y , b u t a l s o ti s su ew e a k e n i n g s u c h a s n e u r o n a l c e ll l o ss f r o m c h r o n i c g l u c o c o r t i -c o id e l e v a t io n (e . g . , 1 1 1 , 1 3 5 ) . Bo t h s t a t e s a r e o n a c o n t in u u m ,a n d b o t h a r e t h e c o n s e q u e n c e s o f e l e v a t e d g l u c o c o r t i c o i d s(108,109,136) .

ANIMAL STUDIES ON THE LOSS OF PERCEIVED CONTROL:FEAR, ANXIETYCOUPLED WITH ELEVATEDGLUCOCORTICOIDSDe p r e s s e d p a t i e n t s a r e o f t e n in a s t a t e o f c h r o n ic e x p e c ta -t io n s o f n e g a t iv e o u tc o me s ( 9 ) , a n d in th e s e r e s p e c t s ma y b ec o n s i d e r e d t o b e u n d e r a l l o s t a t i c l o a d u n d e r c o n d i t i o n s o fp h y s i o l o g i ca l a n d p s y c h o l o g i c a l p a t h o l o g y . O u r h y p o t h e s i s i s

th a t c o n d i t io n s in wh ic h th e r e i s a lo s s o f p e r c e iv e d c o n t r o lo v e r t h e e n v i r o n m e n t s h o u l d e x a g g e r a t e n o r m a l c o p i n g r e -s p o n s e s . Th a t i s , e x p e c ta t io n s o f a v e r siv e e v e n t s in d u c e a n x i -e t y a n d f e a r a n d c a n a c t i v a t e t h e h o r m o n e s o f s tr e ss . P r o -l o n g e d a c t i v a t i o n a n d c h r o n i c a n t i c i p a t i o n o f a d v e r s it y s h o u l dr e s u l t i n a l lo s t a t i c lo a d . W h a t e x p e r im e n ta l e v id e n c e i s th e r e int h e a n i m a l l i t e r at u r e t o s u p p o r t m o d e l s o f a n t i c i p a t ed n e g a t iv ee v e n t s t h a t a r e a r o u s i n g ? A n d w h a t a r e t h e b i o l o g i c a l a n dn e u r o h o r m o n a l m e c h a n i s m s t o c o p e w i t h i t ?C u r t R i c h t e r a t t h e P h i p p s C l i n i c a t J o h n H o p k i n s d e -s c r i b e d a n a n i m a l m o d e l f o r w h a t h e c a l l e d " h o p e l e s s n e s s "( se e h i s c o l l e c te d wo r k s , 1 2 5) . He h e ld r a t s u n t i l t h e y s to p p e ds t r u g g l i n g o r w e r e i m m o b i l e . T h e n h e p l a c e d t h e m i n w a t e r .R a t s t y p i c a l ly s w i m f o r l o n g p e r i o d s o f t i m e . B u t t h e r a t s t h a tw e r e h e l d d r o w n e d w i t h in m i n u t e s . R i c h t e r s u g g e s te d t h a t t h e ye x p e r i e n c e d h o p e le s s n e s s, a n d a s a c o n s e q u e n c e ju s t g a v e u p .

Th e y " e x p e c te d f a i lu r e . " P e r h a p s th e s e n s e o f b e in g o v e r -w h e l m e d p r e d o m i n a t e s . T h i s k i n d o f e x p e ri e n ce m a y c o n t r i b -u te to a l lo s t a t i c lo a d a n d a r o u s a l p a th o lo g y in a s u s c e p t ib leo r g a n i s m .W i th in 1 0 y r , t h e l a n g u a g e s in c e R ic h te r ' s r a t s tu d ie ss h i f t e d f r o m h o p e le s s n e s s to " h e lp le s s n e s s . " Th e mo s t p o p u -la r i z e d a n ima l mo d e l o f h e lp le s sn e s s is th a t in d u c e d b y u n c o n -t r o l l a b le s h o c k . A v a r i e ty o f s p e c ies b e c o m e wh a t in v e s t ig a to r sc a l l " h e lp le s s " wh e n th e y a r e p la c e d in s i tu a t io n s wh e r e th e r ea r e u n c o n t r o l l a b le a n d u n p r e d ic ta b ly a v e r s iv e e v e n t s , t y p i -c a l ly , s h o c k s . Th e y l e a r n th a t th e i r b e h a v io r d o e s n o t a me l io -r a t e th e s i tu a t io n ; th e y e v e n tu a l ly g iv e u p . La te r , i f t h e y c a np e r f o r m a n d d o s o m e t h i n g a b o u t t h e s i t u a ti o n ( e . g ., a v o i d t h es i t u a ti o n b y p e r f o r m i n g a n o p e r a n t ) t h e y g i v e u p , t h o u g h t h e ys t i l l seem anxious and fear fu l ( see rev iews , 101 ,140) . Help lessa n i m a l s l o s e n o t o n l y t h e i n c e nt i v e t o p e r f o r m t h e t a s k i n t h eo p e r a n t s i t u a ti o n i n w h i c h t h e y h a v e p r e v i o u s l y b e e n u n a b l et o c o n t r o l , t h e y a l s o b e c o m e a p a t h e ti c a n d e x p r e s s d e c re a s e dh u n g e r a n d s e x d r iv e s . Th e y lo s e in c e n tiv e a n d d i s e n g a g e ( se er e v ie ws , 4 9 , 1 6 6 ) . Of c o u r s e d i s e n g a g e me n t ma y a l s o b e a na d a p t iv e r e s p o n s e , r e d u c in g b e h a v io r a l a n d p h y s io lo g ic a l r e -sponses (84) .An ima ls t r a c k e v e n t s a n d d r a w c a u s a l r e l a t io n s h ip s ( 3 4 ) .T h i s , w e a s s u m e a l lo w s t h e m t o h a v e s o m e p e r c e i v e d c o n t ro lo v e r th e i r e n v i r o n me n t . Th i s a b i l i ty to d r a w c a u s a l r e l a t io n -s h ip s o c c u r s wh e n e x p e c ta t io n s a r e th wa r te d ; th e d i s c r e p a n c yc a n p r o v o k e l e a r n in g ( 1 2 4 ) . A t t e n t io n i s e n h a n c e d ( 9 9 ) . Bu twi th u n p r e d ic ta b i l i ty , l e a r n in g d e c l in e s a n d a t t e n t io n d i s s i -p a te s ( 1 2 4 ). Av o id a n c e t a k e s p r e c e d e n c e o v e r a p p r o a c h ( 9 1 ).O n e o f t h e m o s t i m p o r t a n t f e a t u r e s i n a n i m a l l e a r n i n g i sp r e d ic t io n a n d p e r c e iv e d c o n t r o l ( 1 0 1 , 1 6 4 ) . Th i s i s a n imp o r -t a n t p s y c h o b i o l o g i c a l a d a p t a t i o n - t h e a b i li t y t o t r a c k e v e n ts .Th i s i s p a r t i c u la r ly t r u e u n d e r s t r e s s . I n th e l a b o r a to r y , s h o c ka n t i c ip a te d b y a s ig n a l r e n d e r s l e s s b o d i ly h a r m th a n u n s ig -h a le d s h o c k ( e . g . , g a s t r i c p a th o lo g y , c e n t r a l c a te c h o la min ed e p le t io n , d e c r e a s e in a p p e t i t e ) . Th e u n s ig n a le d s h o c k i s a n x i-e t y p r o v o k i n g . T h e l a c k o f p e r c e i ve d c o n t r o l , p r e d i c t i o n , a n dd e m a n d , i n a d d i t i o n t o w o r r y , p r o d u c e s a f e a r f u l s t a t e ( 5 1 ,1 6 4) . M a n y m o d e l s o f h e lp le s s n e ss in th e l a b o r a to r y a r e a b o u tth e lo s s o f p r e d ic t a b i l i ty a n d p e r c e iv e d c o n t r o l , a n x ie ty a n df e a r ( 1 0 1 ,1 4 0 , 1 6 3 ). I t is a s t a t e o f p e r p e tu a l a n t i c ip a t io n . Th i ss t a t e o f a n t i c ip a t io n p e r h a p s d r a ws o n s it es in th e b r a in inma in ta in in g v ig i l a n c e to wa r d e v e n t s th a t a r e to o c c u r , o r a r ee x p e c te d , o v e r b o t h s h o r t a n d l o n g p e r io d s o f t im e . T h i s w eh y p o t h e s i z e m a y r e s u l t i n a l l o s t a t i c l o a d a n d p a t h o l o g i c a la r o u s a l .De p r e s s e d o r a n x io u s p e o p le a r e mo r e l ik e ly to in t e r p r e tt h e w o r l d a s m e n a c i n g a n d t o b e a f r a i d . T h e y t y p i c a ll y vi e wo b je c t s a s th r e a te n in g o r d i s a p p o in t in g ( e . g . , d e p r e s s io n , 9 ) .S u c h e x p e r i e n c e s a n d a n t i c ip a t io n s o f a d v e r s e e v e n t s in in d i -v id u a l s wh o h a v e e x p e r i e n c e d a t r a n s ie n t s e n s e o f h e lp le s s n e ssb y u n c o n t r o l l a b le e v e n t s in th e l a b o r a to r y , r e s u l t e d in p i tu -i t a r y - a d r e n a l a c t iv a t io n ( 1 2 ) . I n b o th h u ma n s ( 1 2 ) a n d in r a t sp e r c e iv e d c o n t r o l c a n a f f e c t th e l e v e l o f g lu c o c o r t i c o id s . F o re x a m p l e , w h e n f o o t s h o c k i s p re d i c t ed t h e l e ve l o f g l u c o c o r t i -c o l d s i n ra t s o r m o n k e y s i s l o w e r o v er a l l th a n i n y o k e d c o n -t r o l s wh o a r e u n a b le to p r e d ic t th e s h o c k ( 8 0 , 9 5 , 9 6 , 1 0 6 ;th o u g h s e e , 1 0 2 ). Th e p e r c e iv e d c o n t r o l r e s u l t e d in lo w e r l ev e l so f t h e h o r m o n e ( 1 0 6 ), a n d r e d u c e d a l lo s t a ti c l o a d . M o r e o v e r ,g lu c o c o r t i c o id s a r e s e cr e te d wh e n r a t s a r e p la c e d in n o v e l e n v i -r o n me n ts a n d th e y a r e a l s o s e c r e te d in r a t s , u n d e r a c u te a n x i -e ty ( e . g . , 1 0 2) . I n te r e s tin g ly , r a t s h a n d le d e x te n s iv e ly d u r in gn e o n a ta l d e v e lo p me n t h a v e lo we r c i r c u la t in g l e v e l s o f g lu -c o c o r t i c o i d t h a n n o n h a n d i e d c o n t r o l s , a n d h a v e g r e a t er e x -p l o r a t i o n o f n o v e l e n v i ro n m e n t s ( 1 l l ) . T h o u g h t h e d a t a a r e

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AMYGDALA CHRONIC FEAR AND ALLOSTATIC LOAD 387inconsistent, without perceived control the elevation of gluco-corticoids in rats or monkeys persists for longer periods oftime (see 95,106). Moreover, monkeys who are fearful havehigher levels of ghicocorticoids systemically than those thatare not (e.g., 19,79), as do inhibited children who are also shyand fearful (76). Finally, depressed patients (e.g., 18), perhapsparticularly those with agitated depression (14,48,134) havebeen associated with elevated cortisol. Interestingly, at-tempted suicide has been correlated with elevated cortisol indepressed and panic disorder patients (40).Perceived unpredictability and what might lead to arousalpatho logy and allostatic load reflected in hormonal levels hasalso been demonstrated by Sapolsky (136). Dominant malemonkeys secrete less cortisol under basal conditions than sub-ordinate monkeys (see e.g., 21 for a similar phenomenon inrats). The social stress of being lower down on the peckingorder results in lower testosterone, but higher giucocorticoids.This increase in allostatic load and arousal pathology de-creases the subordinate monkeys prospects in turn for success-ful reproduction. The elevated glucocorticoid level may reflectthe uncontrollable context, though uncontrollability may notbe the only difference between dominant and subordinatemonkeys. Sapolsky's (136) results suggest that the loss of per-ceived control and the response to danger may result in ele-vated cortisol. Certainly fear and perhaps anxiety are tied togiucocorticoid levels in monkeys (19,79).The elevated glucocorticoid level is a biological adaptationfor the subordinate male. If the animal is chronically anxious,however, then a form of arousal pathology and allostatic loadmay emerge. Long term exposure to high levels of giucocorti-coids can result in neuronal cell loss in the hippocampus(74,111,135, but this effect depends upon length of exposure,see 108,110), in addition to the central nucleus of the amyg-dala (168). The central nucleus o f the amygdala is one of thecritical sites we will suggest tha t is involved in the chronic stateof fear and anxiety linked perhaps to what we are callingallostatic load.

A N A T O M I C A L A N D F U N C T I O N A L S T UD I ESO F T H E A M Y G D A L AThe evidence demonstrates that the amygdala is impor-tantiy involved in expectations of adversity and tha t the hor-mones of stress are linked to amygdala function.The amygdala is encephalized hypothalamus ; the amygdalais functionally involved in many of the same events as thehypothalamus (64,114,144). It is involved in appetite, driveand enjoyment (43). The amygdala is also involved in antici-pated fearful and anxiety producing events and perhapschronic arousal (94). It has been linked functionally to long-

term considerations, and not simply to reactive homeostaticevents (46). The activation of the amygdala is known to leadto the anticipation of fearful events (93).Regions of the amygdala can be demarcated in a numberof ways. For our purposes, we want to distinguish between thebasal-lateral and central-medial regions. The lateral is a funnelfor all sensory information (2,92,155,156) and the central-medial for the act ivation fo r behavioral responses (e.g.,29,81,93,138). Both regions contain nuclei which receive andprocess distinct sensory information (156). The central-medialis subcortical, while the lateral complex is considered morecortical presumably because of the input, or connectivity,from neocortical sites (3).The central nucleus of the amygdala (CEA), we believe,may have functional significance for allostatic regulation andperhaps for states such as melancholic depression. It receives

the largest degree of visceral projections from the solitary andparabrachial nuclei in the lower bralnstem; it projects directlyto these regions in addition to other areas of the brainstemimportantly involved in arousal in addition to receiving inputfrom neocortical sites and the lateral hypothalamus (e.g.,2,89,90,139).The CEA receives sensory information from the lateralamygdala (155,156) which is a crucial site within the amygdalafor fear conditioning, perhaps because of the sensory projec-tions to this region (92). The CEA is also continuous with thebed nucleus of the stria terminalis (75; Fig. 1), a site whichis derived embryologically from CEA tissue during neuronaldevelopment and thus can be called "extended amygdala" (3).This anatomical fact suggests that this region may alsobe an impor tant site in the regulation of many of the samebehavioral functions as regions of the amygdala. In fact, ana-tomically the CEA and bed nucleus are both tied to the samesites in the brain (55). They both, for example, project tothe parabrachial nucleus and solitary nucleus (Fig. 2; e.g.,53,139).Functional studies demonstrate that direct electrical orchemical stimulation of the CEA and bed nucleus are knownto arouse the release of hypothalamic CRH and elevate sys-temic circulation of ACTH and giucocorticoids (see recentreviews in 54,129). Lesions, for example, of the CEA caninterfere with the release of ACTH in immobilization-inducedstress (e.g., 8,129). Lesions of the CEA also decrease giuco-corticoid elevation to short term immobilization-inducedstress (157), specifically, the elevation of glucocorticoids inconditioned stress (129). Lateral lesions within the amygdaladid not produce this effect (157). Moreover, lesions of thelateral bed nucleus (extended amygdala that contain CRHneurons and ghicocorticoid receptors) also produce the samedecrement of conditioned giucocorticoid secretion to stress aslesions of the CEA (55; also see, 61,62).

DP-VPCPu

CoreShell

~ " ~ ~ BSTM

FIG. 1. The bed nucleus of the stria terminalis (BSTM, BSTL) andthe central nucleus of the amygdala (CEA), CPu caudate putamen,DP-VP dorsal and ventral palladium, EA, extended amygdala (e.g.;BNST), 1o, lateral olfactory tract, ac anterior commisure, [Heimerand Alheid, (58)].

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388 SCHULKIN, McEWEN AND GOLD

J

FIG. 2. An anatomical circuit that may underlie states such as melancholic depression and adversity. AC: AnteriorCommission, CE: central amygdalanucleus, BST: bed nucleus of the stria terminalis, LH: lateral hypothalamus, ZI: zonaincerta, PBN: parabrachial nucleus, NTS: solitary nucleus.

Other functional work has shown that the CEA, in particu-lar, seems to play a role in conditioned arousal and attentionand learning (45,68,69), and anticipatory anxiety (80). More-over, CEA damage abolished conditioning to a fearful stimu-lus, without disrupting the unconditioned response (29,82,92).Interestingly, CEA lesions impair extroreceptive aversive fearconditioning without interfering with positive oral-faciai ex-pression to intra-oral infusions of gustatory stimuli (44). Inaddition, CEA lesions reduced freezing behavior associatedwith inescapable shock or paradigms of hopelessness (50).Moreover, lesions of the CEA, and to some extent the lateralnucleus of the amygdaia, interfere with the hypoalgesic re-sponse to conditioned fearful stimuli, but not unconditionedstimuli (59,161), in addition to reducing the fear (55,60,103).These results extend earlier results that damage to this regionof the amygdala reduces fear and anxiety (10). Conversely, itsactivation increases fear and anxiety which reflects arousalpathology and perhaps eventually aliostatic load. The activa-tion of the CEA sets the stage for the anticipation of adversity.This suggests that allostatic regulation may be operative andarousal pathology may be one result.

CORTICOTROPIN-RELEASINGFACTOR AND GLUCOCORTICOIDREGULATION IN HOMEOSTASISAND ALLOSTASISThe hypothaiamus is the principle site in the brain thatmaintains endocrine, and in many instances behavioral (vege-tative) homeostasis (e.g., 144). Hypothalamic releasing hor-mones under negative feedback regulation and set point con-trol strongly influence pituitary regulation of the thyroid,gonadal and adrenal axes (28). Corticotropin-releasing hor-mone activates corticotropin (ACTH), which then activatesglucocorticoids from the adrenal glands (e.g., 125,158), andits inhibition by giucocorticoids in the parvocellular region ofthe paraventricular nucleus (PVN) of the hypothalamus as thehormone inhibits the response to stress and the elevation ofCRH in maintaining homeostasis (e.g., 28,136). Glucocorti-

coids restrain CRH elevation at the level of the PVN (e.g.,

11,108), as it is well known to restrain other physiologicalprocesses (112). In other words, regulation of CRH is undernegative feedback control at the level of regions of the hypo-thalamus.Hypothalamic disturbances in systems that regulategrowth, reproduction, hunger and the regulation of the princi-ple neuroendocrine systems are called into play during threat-ening situations (e.g., 30,108,112). It has been suggested bya number of investigators that the inhibition of vegetativefunctions and the hyperarousal are mediated through the ac-tions of CRH, in part because intracerebroventricular admin-istration of CRH sets into motion a coordinated series ofbehavioral and physiological responses such as enhancedarousal and inhibition of vegetative functions (e.g., 78,87).Along with the well known restraint on physiological pro-cesses by giucocorticoids (e.g., inflammation) and the regula-tion and maintenance of a variety of neuropeptides and neuro-transmitters (e.g., enkephalin mRNA (20), GABA receptors(105) 5-HT receptors mRNA (22,108), some literature suggeststhat giucocorticoids induce positive effects, for example,upregulation of vasopressin receptors (27). Glucocorticoidsinduce an increase of angiotensinogen mRNA (6) in the brainwhich results in potentiating centraily-delivered angiotensin-induced thirst (147). Glucocorticoids also induced the uptakeof mineraiocorticoids in select regions of the brain and therebypotentiating mineraiocorticoid-induced sodium appetite (100,138). More germane in the present context, glucocorticoidsalso facilitate amphetamine-induced self administration (122),in addition to cocaine-induced-kindiing (83) . Because CRHalso facilitates kindling (38,165), and CORT facilitates CRH-induced kindling (131) perhaps the giucocorticoids effects onkindling are due to the activation of extrahypothalamic CRH.Given the above, thus, while giucocorticoids restrain CRHin the paraventricular nucleus in the regulation of homeostat icregulatory functions, glucocorticoids may be facilitating CRHexpression in the amygdala potentiating conditioned fear, anx-iety and cautious avoidance. This formulation about thepotential coordinating roles of hypothalamic and extrahypo-

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AMYGDALA CHRONIC FEAR AND ALLOSTATIC LOAD 389thalamic CRH in mediating different components o f glucocor-ticoids activation is one of the theoretical underpinnings ofour perspective. If we are right about arousal pathology beingtied to amygdala function and the hormones of stress, thenboth functional, anatomical and endocrine studies should sup-port the hypothesis.There is a high density of CRH in the CEA, bed nucleus,PVN, parabrachial and solitary nucleus of the lower brain-stem (e.g., 32,33,128,142), in addition to the dorsal motornucleus and the central gray, and Barrington's nucleus adja-cent to the locus coeruleus (23,52,107,137,149,150). These re-gions (Fig. 3) constitute part of the limbic circuit and arereciprocally connected with one another, many of which con-rain both TYPE I and TYPE II corticosteroid receptor sites(30,31,108,109). Moreover, there is colocalization of CRHmRNA and glucocorticoids receptors in several of these re-gions (e.g., CEA, parabrachial nucleus, 70,77). In otherwords, they contain CRH receptors and cells and corticoste-roid receptor sites, and constitute CRH fibers that are recipro-cally connected with one another (e.g., 52) and are well consti-tuted to underlie autonomic and affective responses.We now know that glucocorticoids not only decrease CRHin sites in the brain, in reducing the well known stress re-sponse, as we indicated, but can also increase CRH mRNA(104,150,162). For instance, glucocorticoid hormones increaseCRH in placenta but also in magnocelhilar neurons of thePVN, while decreasing CRH production in parvocellular neu-rons in the paraventricular nucleus of the hypothalamus (28,108,127,150). Thus, while vegetative or homeostatic functionssuch as food intake are inhibited by elevated CRF (e.g., 78),other functions such as hyperarousal are being generated(65,88). Perhaps this reflects one CRH mRNA system thatregulates the pituitary adrenal axis (15,158,167) and the con-trol o f vegetative funct ions and another system (CEA) thatregulate behavioral functions, such as fear and anxiety. Inter-estingly, while adrenalectomy elevates CRH mRNA in the

PVN, it reduces CRH mRNA in the CEA; this is reversedby corticosterone (Palkovits et al, personal communication;Makino, Gold, and Schulkin, unpublished observations). Thissuggests differential regulation of glucocorticoids on CRHmRNA in different neural sites (see e.g., 73). Moreover , recentevidence suggests more generally the phenomenon of differen-tial regulation on target tissue by glucocorticoids and putativemechanisms that may be responsible for this (113).In contrast to the parvocellular region of the PVN, differ-ing levels of glucocorticoids have been reported to induce dif-fering changes of CRH mRNA in the CEA; in other words,the greater the degree of glucocorticoid activation of the CEAthe greater the degree of CRH mRNA being synthesized (150;Fig. 4). This occurs in adrenalectomized rats treated with cor-ticosterone (150) and in adrenally intact rats treated with highlevels of corticosterone (104,162). Given the results, notedearlier, o f increased fear when glucocorticoids are elevated(79,136), perhaps glucocorticoids are magnifying CRH CEA,and one result may be expectations of adversity (e.g., fear oranxiety). This finding is modest, and needs to be expandedto both measure the peptide itself, and also the receptors.Nonetheless, our hypothesis is that the activation of CEACRH may set the context for expecting adverse events, andperhaps the induction o f chronic arousal pathology over longperiods of time and allostatic load.A further important relationship between the CEA andCRH has been revealed recently by Koob's laboratory (123).As measured by micro dialysis, CRH was increased in theCEA during immobilization-induced-stress (123) as is norepi-nephrine (117). This is a condition in which glucocorticoidsare elevated (e.g., 108,110) and in which glucocorticoids maybe activating CRH and other neuropeptides and neurotrans-mitters in the CEA and perhaps other sites in the CRH circuitin the brain (bed nucleus of the stria terminalis, parabrachialand solitary nucleus in the lower bralnstem; see also 73) inarousing anxiety and fear and the expectation of adversity.

BBS

ZI

O e

FIG. 3. CRH sites in the brain, BBS; bed nucleus of the stria terminaiis; Ce, central nucleus of the amygdala; PVN,paraventricular nucleus of the hypothalamus; PB, parabrachiai nucleus [Gray, (52)].

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390 SCHULKIN, McEWEN AND GOLD