(Techniques in the Behavioral and Neural Sciences 15 Part 2) T. Steckler, N.H. Kalin, J.M.H.M. Reul-Handbook of Stress and the Brain Part 2_ Stress_ Integrative and Clinical Aspects-Elsevier,

7/26/2019 (Techniques in the Behavioral and Neural Sciences 15 Part 2) T. Steckler, N.H. Kalin, J.M.H.M. Reul-Handbook of S

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TECHNIQUES IN THE BEHAVIORAL AND NEURAL SCIENCES

VOLUME 15

HANDBOOK OF STRESS AND THE BRAIN

Part 2" Stress: Integrative and Clinical Aspects


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P r ev i ou s ly p u b li sh e d i n T E C H N I Q U E S I N T H E B E H A V I O R A L A N D N E U R A L S C I E N C E S

Volum e 1 : Feed ing and Drink ing , by F . Toates and N.E. Row land (Eds.) , 1987 , ISBN 0-444-80895-7

Volum e 2 : Dis t r ibu t ion-f ree S tati s tics: Appl icat ion-or ien ted App roach , by J . Kra u th , 1988,

ISBN 0-444-80934-1, Paperback ISBN 0-444-80988-0

Volum e 3 : Mo lecu lar Ne uroan atom y, by F .W. Van Leeuwen, R.M . Bui js , C.W. Pool and O. Pach (Eds.) ,

1989, ISBN 0-444-81014-5, Paperback ISBN 0-444-81016-1

Volum e 4 : M anua l o f Microsurgery on the Lab oratory Ra t , Par t 1 , by J .J . van Dongen , R. Remie,

J .W. R ensem a and G.H .J . van W unnik (Eds.) , 199 0 , ISBN 0-444-81138-9 , Pap erback

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Volum e 6 : Exper im ental Analysis o f Behavior, by I .H. Iversen and K.A . Lat ta l (Eds.), 199 1 , Par t 1 ,

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Volum e 8 : Techniques fo r the Genet ic Analysis o f Brain and Behavior, by D. Goldow itz , D. Wa hls ten

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Volum e 11 : Me thods in Neu ro t ransm it ter and Neuropep t ide Research , by S .H. Parvez (Eds.), 1993 , Par t 1 ,

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Volum e 12: Neglected Factors in Pharmaco logy and Neuroscience Research , by V. Claassen (Ed .) , 1994 ,

ISBN 0-444-81871-5, Paperback ISBN 0-444-81907-X

Vo lu me 1 3: Ha n d b o o k o f M o lecu l a r -Gen e t i c Tech n iqu es for Bra in an d Beh av io r Resea rch, b y W .E . Cru s io

and R.T. Ger lai (Eds.), 1999, ISB N 0-444-50239-4

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Cover image b y T im Teeb k en /Ge t ty Imag es .


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T E CHNIQUE S IN T HE BE HAVIORAL AND NE URAL S CIENCE S

Series Editor

J.P. HUSTON

Dtisseldorf

VOLUME 15

H A N D B O O K O F S T R ES S A N D T H E B R A I N

Part 2" Stress" Integra tive and Clinical As pec ts

Edited by

T . S T E CKL E R

Johnson & Johnson Pharmaceutical Research & Development,

A Division of Janssen Pharmaceutica N.V., Turnhoutseweg 30, 2340 Beerse, Belgium

N . H . KAL IN

Department of Psychiatry and Health Emotions Research Institute, University of Wisconsin Medical School,

6001 Research Park Boulevard, Madison, WI 53719-1176, USA

J . M . H . M . RE UL

Henr y Wellcome Laboratories fo r Integrative Neuroscience an d Endocrinology,

The Dorothy Hodgkin Building, University of Bristol, Whitson Street, Bristol BS1 3 NY , UK

ELSEVIER

A M S T E R D A M - BOS TON - HE IDE L BE RG - L ONDON - NE W YORK- OXF ORD

P ARIS - S AN DIE GO- S AN F RANCIS CO- S INGAP O RE - S YDNE Y- T OKYO

2005


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I. Steckler, T. II. Kalin , N. H. III. Reu l, J.M.H .M.

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List of Contributors, Part 2

J.S. Andrews, Ascend Pharmaceutical Inc., Speakman Drive, Mississauga, ON, Canada

M. Bonacina, Department of Internal Medicine and Medical Therapy, University of Pavia,

Piazza Borromeo 2, 271000 Pavia, Italy

T. Cartmell, National Institute for Biological Standards and Control (NIBSC), Blanche

Lane, South Mimms, Potters Bar, Hertfordshire EN6 3QG, UK

A.R. Cools, Department of Psychoneuropharmacology, P.O. Box 9101, 6500 HB Nijmegen,

The Netherlands

S.C. Coste, Department of Molecular Microbiology and Immunology, L220, Oregon Health

and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098,

USA

L. Cravello, Department of Internal Medicine and Medical Therapy, University of Pavia,


A.C. Dettling, Swiss Federal Institute of Technology Zurich, Schorenstrasse 16, CH-8603

Schwerzenbach, Switzerland

A.Y. Deutch,

Vanderbilt University School of Medicine, Psychiatric Hospital at Vanderbilt,

Suite 313, 1601 23rd Avenue South, Nashville, TN 37218, USA

A.J. Dunn, Department of Pharmacology and Therapeutics, Louisiana State University

Health Sciences Center, P.O. Box 33932, Shreveport, LA 71130-3932, USA

B.A. Ellenbroek, Department of Psychoneuropharmacology, P.O. Box 9101, 6500 HB

Nijmegen, The Netherlands

J. Feldon, Swiss Federal Institute of Technology Zurich, Schorenstrasse 16, CH-8603

Schwerzenbach, Switzerland

E. Ferrari, Department of Internal Medicine and Medical Therapy, University of Pavia,


E.J. Geven, Department of Psychoneuropharmacology, P.O. Box 9101, 6500 HB Nijmegen,

The Netherlands

G. Griebel,

CNS Research Department, Sanofi-Synthelabo, 31 Avenue Paul Vaillant-

Couturier, 92220 Bagneux, France

A.C. Grobin, Department of Psychiatry CB#7160, UNC-Chapel Hill School of Medicine,

7001 Neurosciences Hospital, Chapel Hill, NC 27599, USA

L. Groenink, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht,

Utrecht, The Netherlands

F. Holsboer, Max Planck Institute of Psychiatry, Kraepelinstrase 2-10, 80804 Munich,

Germany

S. Khan, Department of Psychiatry, University of Michigan, VA Medical Center Research

(11R), 2215 Fuller Road, Ann Arbor, MI 48105, USA

S. Levine,

Department of Psychiatry, Center for Neuroscience, University of California at

Davis, Davis, CA 95616, USA


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R.R.J. Lewine, De partm ent of Psychological and Brain Sciences, University of Louisville,

Louisville, KY 40292, USA

L Liberzon,

Dep artmen t of Psychiatry, U niversi ty of Michigan, 1500 E M edical Ctr D r

UH -9D, Box 0118 , Ann A rbor , MI 48109 , USA

J.A. Lieberman,

U N C Chapel Hill School of Medicine, CB #7160, 7025 Neurosciences

Hospita l , Chapel H ill , NC 27599, USA

L. Lu,

Behav io ra l Neurosc ience Branch , IR P/N IDA /NIH , 5500 Na tha n Shock Dr ive ,

Balt imore, M D 21224, USA

F. Magri, Department of Internal Medicine and Medical Therapy, Universi ty of Pavia ,

Piazza Bo rrom eo 2, 271000 Pavia, Italy

M. Marinelli, INSERM U-588, Universit6 de Bordeaux 2, Rue Camille Saint-SaEns,

33077 Bordeaux Cedex, France

C.E. Marx, Duke Universi ty School of Medicine, Durham VA Medical Center , Mental

Health Service l ine 116A, 508 Fulton Street, Du rham , N C 27705, USA

D. Mitchell, Brain Function Research Unit, School of Physiology, University of

W itwatersrand Medical School, York R oad, P arktow n 2193, Johannesburg, South Africa

S. Modell,

Neuroscience, Bristol-Myers-Squibb, Sapporobogen 5-8, D-80809 Munich,

Ge r m a n y

S.E. Murray,

Depar tmen t o f Molecu lar Mic rob io logy and Immunology , L220 , Oregon

Health and Science Universi ty , 3181 SW Sam Jackson P ark Road, Port land, O R 97239-

3098, USA

B. Olivier,

Department of Psychopharmacology, Utrecht Inst i tu te of Pharmaceutical

Sciences, Facu lty of Pharma ceutical Scienc es, Utre cht U niversity, Sorb onne laan 16,

3584 CA Utrecht , The Netherlands

R. Oosting,

Ru dolf M agnus Inst i tu te o f Neuroscience, Universi ty Medical Centre U trecht ,

Utrecht , The Netherlands

P.V. P iazza,

IN SE RM U-588, Universit6 de Borde aux 2, Institut Frangois Mag endie, 1 Rue

Camille Saint-SaEns, 33077 Borde aux C edex, Franc e

C.R. Pryce,

Behavioural Neurobiology Laboratory, Swiss Federal Inst i tu te of Technology

Zurich, Schorenstrasse 16, CH-8603 Schwerzenbach, Switzerland

J.M.H.M. Reul ,

Henry Wellcome Laboratories for Integrat ive Neuroscience and

Endocrinology, The Dorothy Hodgkin Building, University of Bristol, Whitson Street,

Bristol, BS1 3NY, UK

N.M.J. Rupniak,

Clinical Neuroscience, Merck R esearch Labora tories, B L2-5, We st Point,

PA 19486 , USA

D. Rfiedi-Bettschen,

Sw iss Federa l Institute of Technology Zurich, Schorenstrasse 16,

CH-8603 Schwerzenbach, Switzerland

R.R. Sakai, Department of Psychiatry , Universi ty of Cincinnati Medical Center , 2170

E. Galbrai th R oad, B ldg. 43/UC-E, C incinnati, OH , USA

F. Salmoiraghi, Dep artme nt of Internal M edicine and Medical Therapy, Universi ty of Pavia ,

Piazza Bo rrom eo 2, 271000 Pavia, Italy

C. Serradeil-Le Gal, Sanofi-Synthelabo Recherche, Toulouse, France

Y. Shaham, Behavioral Neuroscience Branch, IRP /N ID A /N IH , 5500 Na than Shock Drive,

Balt imore, M D 21224, USA

R. Sinha, Department of Psychiatry, Yale University School of Medicine, 34 Park Street,

Room S110 , New Haven , CT 06519, USA

LE.M. Stec,

Institute of Pathophysiology, University of Innsbruck, Medical School,

Fritz-Pregl-Str. 3/IV, A-6020 Innsbruck, Austria


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vii

T. Steckler, Johnson & Johnson Pharmaceut ica l Research & Development , A Divis ion of

Janssen Pharm aceutica N.V ., Turnho utsewe g 30, 234 0 Beerse, Belgium

M.P. Stenzel-Poore,

Department of Molecular Microbiology and Immunology, L220,

Oregon H eal th and Science Univers ity, 3181 SW Sam Jackson Park Road , Po r t land,

OR 97239-3098, USA

P. Sterzer, Department of Neurology, Johan Wolfgang Goethe-Univers i ty, Theodor-Stern-

ka i 7, D-60590 Frankfur t am Main, Germany

K.L.K. Tamashiro, Department of Psychia try, Univers i ty of Cinc innat i Medica l Center ,

2170 E. Galbra i th R oad, Bldg. 43/UC -E, Cinc innati , OH , US A

M. Van Bogaert, Department of Psychopharmacology, Utrecht Ins t i tute of Pharmaceut ica l

Sciences, Faculty of Pharmaceutical Sciences, Utrecht University, Sorbonnelaan 16, 3584

CA Utrecht , The Nether lands

R. Van Oorschot, Rudolf Magnus Ins t i tute of Neurosc ience , Univers i ty Medica l Centre

Utrecht , Utrecht , The Nether lands

D.M. V~zquez, Univers i ty of Michigan, 1150 Medica l Center Drive , Ann Arbor , M I 48109-

9550, USA

G.J. Wiegers,

Ins t itute of Pa thophysiology, Univers i ty of Innsbruck, Medica l School, Fr i tz-

Pregl-Str. 3/IV, A-6020 Innsbruck, Austria

R. Yehuda,

Psychia try Depar tm ent and D ivision of Traumatic Stress Studies , Mo unt Sinai

School of Medicine and Bronx Veterans Affairs, Bronx, NY, USA

E.A. Young,

Department of Psychia try and Menta l Heal th Research Ins t i tute , 205 Zina

Pitcher Place , Univers i ty of Michigan, Ann Arbo r , M I 48109 , US A


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Preface

St r e s s i s a phe nome non be ing a l l a r ound us , bu t s e e ming ly be ing t oo w e l l know n a nd t oo

l i t t l e unde r s tood a t t he s a me t ime , de sp i t e t he f a c t t ha t t he f i e l d ha s a dva nc e d e nor mous ly

ove r r e c e n t ye a r s . We ha ve l e a r ne d t ha t s t r e s s c a n sha pe va r ious t ype s o f be ha v iour i n

the i nd iv idua l l ong a f t e r e xposur e t o t he s t r e s so r it s e lf ha s t e r m ina t e d . Exp osur e t o a

s t re s s fu l s t imulus dur ing t he pe r ina t a l pe r i od , f o r e xa m ple , c a n ha ve l on g- t e r m c onse que nc e s

ove r w e e ks a nd months , w e l l i n to a du l t hood . Th i s i s a c c ompa n ie d by a va r i e ty o f

c ha r a c t e r i s t i c ne ur oc he mic a l , e ndoc r ine a nd a na tomic a l c ha nge s i n t he b r a in , l e a d ing , f o r

e xa mple , t o c ha nge s i n ne ur a l p l a s t i c i t y a nd c ogn i t i ve f unc t i on , mot iva t i on a nd

e mot iona l i t y .

We have s ta r ted to discover the di f fe rent ia ted e f fec ts of va r ious s t r essors in the bra in and

how e xpr e s s ion o f a w ide va r i e ty o f ge ne p r oduc t s w i l l be a l t e r e d i n t he CN S a s a f unc t i on

of t he t ype a nd dur a t i o n o f t he s t re s so r. A c t i v i ty i n h ighe r b r a in a r e a s i n t u r n w i ll sha pe t he

response to acute and chronic s t r ess and there a re in t r ica te in te rac t ions wi th , for example ,

immune func t ions . Cytokines wi l l access the bra in and a f fec t i t s func t ion a t va r ious leve ls .

I t has become increas ingly c lea r tha t s t r ess se rves as one of the main t r iggers for

psyc h i a t r i c a nd non- psyc h i a t r i c d i so r de r s , i nc lud ing de pr e s s ion , a nx i e ty , p syc hos i s ,

d r ug a buse a nd de me nt i a . Re c ogn iz ing t he se i n t r i c a t e r e l a t i onsh ips ha s i n i t i a t e d a w e a l t h

o f r e se a r c h i n to t he de ve lopme nt o f nove l a n ima l mode l s a nd nove l t r e a tme n t s t r a t e g i e s

a iming a t inf luenc ing s t r ess r esponsivi ty in pa t ients suf fe r ing f rom these diseases .

Mor e ove r , nove l t e c hno log i e s , suc h a s mole c u l a r t e c hn ique s , i nc lud ing ge ne t a r ge t i ng

me thods a nd D N A mic r oa r r a y me thods s t a r t t o un r a ve l t he c e l l u l a r e ve n t s t a k ing p l a c e a s a

consequence of s t r ess and fac i l i ta te the unders tanding of how s t ress a f fec ts the bra in .

Thus , t he t op i c o f s tr e ss , t he b r a in a n d b e ha v io ur ga ins i nc re a s ing r e le va nc e , bo th f r o m a

bas ic sc ient i f ic and c l in ica l pe r spec t ive , and spans a wide f ie ld of exper t i se , r anging f rom

the mole c u l a r a ppr oa c h t o i n - de p th be ha v iour a l t e s t i ng a nd c l i n i c a l i nve s t i ga t i on . Th i s book

a ims a t b r i ng ing t he se d i s c ip l i ne s t oge the r t o p r ov ide a n upda t e o f t he f i e l d a nd a n ou t l ook

to the future . We think these a re exc i t ing t imes in a r apidly deve loping a rea of sc ience

and hope tha t the reader wi l l f ind i t both use ful as an in t roduc tory text as wel l a s a de ta i led

r e fe r e nce bo ok .T he H a nd bo ok o f S t re s s a nd t he Br a in i s p r e se n t e d i n tw o pa r t s , i .e . Pa r t 1:

The Neurobiology of S t ress , and Par t 2 : S t ress : In tegra t ive and Cl inica l Aspec ts .

Th i s pa r t , Pa r t 2 , t r e a t s t he c omple x i t y o f shor t - t e r m a nd l ong- t e r m r e gu l a t i on o f s t r e s s

responsivi ty , the role of s t r ess in psychia t r ic d isorders as based on both prec l in ica l and

c l inica l evidence , and the cur rent s ta tus wi th regard to new therapeut ic s t r a tegies ta rge t ing

s t ress- re la ted disorders .

T h o m a s S t ec k le r

N e d K a l i n

H a n s R e u l


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Contents, Part 2

L is t o f C o n t ri b u to r s, P a rt 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v

P re fac e . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

Section 1. Environmental and Genetic Factors Influencing Stress Reactivity

1.1.

H y p o t h a l a m i c - p i t u i t a r y - a d r e n a l a x i s in p o s t n a t a l l ife

D .M. V f i z que z a nd S . Le v ine ( A nn A r bor , MI a nd D a v i s , CA , U SA )

1.2.

Ea r ly - l i f e e nv i r onme nta l ma n ipu l a t i ons i n r ode n t s a nd p r ima te s :

po t e n t i a l a n ima l mode l s i n de pr e s s ion r e se a r c h

C .R . P r yc e , D . Rf i e d i - Be t t s c he n , A .C . D e t t l i ng a nd J . Fe ldon

( S ch w e rz e nb a ch , S w i tz e rl an d ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 3

1 .3 . G e ne t a r ge t e d a n ima l s w i th a l t e ra t i ons i n c o r t i c o t r op in pa thw a ys : ne w ins igh t s

in to a l l os t a t i c c on t r o l

S .C . Cos t e , S .E . Mur r a y a nd M.P . S t e nz e l - Poor e

( Po rt la nd , O R , US A ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

51

1.4.

Ra t s t r a in di f fe rences in s t r ess sens i t iv i ty

B .A . E l l e nbr oe k , E . J . G e ve n a nd A .R . Coo l s

( Ni jm e ge n, T h e N e th e rl an d s ) . . . . . . . . . . . . . . . . . . . . . . . . . . . .

75

1.5.

G luc oc or t i c o id hor mone s , i nd iv idua l d i f f e r e nc e s , a nd be ha v io r a l

a n d d o p a m i n e r g i c r es p o n s es t o p s y c h o s t i m u l a n t d r u g s

M . M a r i n e ll i a n d P .V . P i a zz a ( B o r d e a u x , F r a n c e ) . . . . . . . . . . . . .

89

1.6 . Soc ia l h ie ra rch y and s t ress

R . R . S a k a i a n d K . L . K . T a m a s h i r o ( C i n ci n n a ti , O H , U S A ) . . . . . . . 1 13

Section 2. Stress and the Immune System

2.1.

S t r e s s - i nduc e d hype r the r mia

B . O l iv i e r , M. va n Boga e r t , R . va n O or sc ho t , R . O os t i ng

a n d L . G r o e n i n k ( U t r e c h t , T h e N e t h e r l a n d s a n d N e w H a v e n ,

C T , U S A ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135


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xii

2.2.

C y t o k i n e a c t i v a ti o n o f t h e h y p o t h a l a m o - p i t u i t a r y - a d r e n a l a x i s

A . J. D u n n ( S hr ev e po rt , L A , U S A ) . . . . . . . . . . . . . . . . . . . . . . . . 157

2 .3 . Glu co co r t i co id s an d th e imm u n e r e sp o n se

G.J . W ieg e r s , I .E .M. S tec , P . S te r ze r an d J .M.H.M. R eu l ( I n n sb r u ck ,

A u s t r ia , F r a n k f u r t a m M a i n , G e r m a n y a n d B r is to l, U K ) . . . . . . . . 1 75

2 .4 . The mole cular basis o f fever

T . C a r tme l l an d D. Mi tch e l l ( Po t t e r s B a r , UK an d Jo h an n esb u r g ,

S o ut h A fric a) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

Section 3. Stress and Psychiatric Disorders

3.1. An ima l mo d e l s o f p o s t t r au ma t i c s t r e ss d i so r d e r

I . L ib e r zo n , S . Kh an an d E .A. Y o u n g ( An n Ar b o r , MI , USA)

231

3.2.

N e u r o e n d o c r i n e a s p ec t s o f P T S D

R . Y e h u da ( Br on x, N Y , U S A ) . . . . . . . . . . . . . . . . . . . . . . . . . . . 251

3.3.

Depression and ef fec ts o f an t idepressant d rugs on the s t ress systems

S . M o d e l l a n d F . H o l s b o e r ( M f in c h en , G e r m a n y ) . . . . . . . . . . . . . . 2 73

3.4.

A co n temp o r a r y ap p r a i sa l o f t h e r o l e o f s t r e ss in sch izo p h r en ia

R . R . J. L e w in e ( Lo ui sv il le , K Y , U S A ) . . . . . . . . . . . . . . . . . . . . . . 2 87

3.5.

Aty p ica l an t ip sy ch o t i c d r u g s an d s t r e ss

C .E . Mar x , A .C . Gr o b in , A .Y . Deu tch an d J .A . L ieb e r man ( Du r h am,

N C , C h a p e l H i ll , N C a n d N a s h v il le , T N , U S A ) . . . . . . . . . . . . . . . 3 01

3.6.

The ro le of s t ress in op ia te and psychost imulant addic t ion : ev idence f rom

an ima l mo d e l s

L . L u a n d Y . S h a h a m ( B al ti m or e, M D , U S A ) . . . . . . . . . . . . . . . . 3 15

3.7.

S t r e ss an d d r u g ab u se

R . S in ha ( N ew H a ve n , C T , U S A ) . . . . . . . . . . . . . . . . . . . . . . . . . 333

3.8.

S t r e ss an d d emen t i a

E . Fe r r a r i , L . C r av e l lo , M. B o n ac in a , F . Sa lmo i r ag h i an d F . Mag r i

(P av ia , I ta ly ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357

Section 4. Novel Treatment and Strategies Targeting Stress-related Disorders

4.1.

C R F an tag o n i s t s a s n o v e l t r ea tmen t s t r a t eg ie s f o r s t r e ss - r e l a t ed d i so r d e r s

T . S te c kl er (B ee rs e, B e lg iu m ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 73

4.2.

No n p ep t id e v aso p r ess in Vlb r ecep to r an tag o n i s t s

G. Gr ieb e l an d C . Se r r ad e i l - Le Ga l ( B ag n eu x , F r an ce an d To u lo u se ,

F ra nc e) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409


14/484

xiii

4 .3 . Subs t a nc e P ( N K 1 re c e p to r ) a n t a gon i s t s

N . M . J . R u p n i a k ( W e st P o i nt , P A , U S A ) . . . . . . . . . . . . . . . . . . . . 4 23

4.4.

G luc oc or t i c o id a n t a gon i s t s a nd de pr e s s ion

J .S . A n d r e w s ( M is si ss au g a, O N , C a n a d a ) . . . . . . . . . . . . . . . . . . . 4 37

S ub je ct In de x . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451


15/484



16/484

S E C T I O N 1

Envi ronmenta l and Gene t i c Fac to r s

Inf luencing Stress React ivi ty


17/484



18/484

T. Steckler, N.H. Kalin and J.M .H .M. Reul (Eds.)

Handbook of Stress and the Brain, Vol. 15

ISBN 0-444-51823-1

Copyrigh t 2005 Elsevier B.V. All rights reserved

C H A P T E R 1 . 1

Hypothalamic-pituitary-adrenal axis

in postnatal life

Delia M. Vfizquez ~'* and Seymour Levine 2

1Department of Pediatrics, University of Michigan, 1150 Medical Center Drive, Ann Arbor, M I 48109-9550, USA;

2Center for Neuroscience, Department of Psychiatry, University of California, Dav is, Davis, California, 95616, USA

Glossary: M aterna l dep r iva t ion : sepa ra t ion o f mo ther and in fan t du r ing the s t res s -hyporespons ive per iod , wh ich needs

to l as t fo r a t l eas t 8 h fo r imme dia te a nd pers i s ten t e f fec ts on the neu roen docr in e regu la t ion o f the hypo tha lam ic-

p i tu i t a ry -ad rena l ax i s .

S t r e s s-h y p o res p o n s iv e p e r i o d: a p e r i o d o f r e du c e d a d re n a l c o r t i c o s t e ro n e a n d p i t u i ta ry a d re n o c o r t i c o t ro p h i c h o rm o n e

re lease in response to s t res s l as t ing in the ra t f rom pos tna ta l days 4 -14 .

Based p r imar i ly on the p ioneer ing work o f the l a te Han s Se lye , the s t res s response has become som ew hat sy nonym ous

wi th the re lease o f ho rm one s f rom the p i tu i t a ry and ad rena l g lands. Thus , in mos t adu l t mam ma ls s t imu l i p resum ed

to be s t ress fu l resu l t in a sys temat ic re lease o f ad ren ocor t i c o t roph ic ho rm one (A CT H) and the subseque n t secre t ion

of g lucocor t i co ids f rom the ad rena l . Th is s impl i s t i c v iew o f the p i tu i t a ry -ad rena l ax i s as f i r s t descr ibed by Se lye has

been e labora ted on ex tens ive ly . Thus , the regu la t ion o f the so -ca l led s t res s ho rmone c lear ly invo lves spec i f i c pep t ides

syn thes ized and s to red in the b ra in ( i . e . , co r t i co t rop in - re leas ing fac to r ( (CRF) and a rg in ine vasopress in (AVP)) and

bra in -der ived neuro t ransmi t te rs ( i . e . , no rad rena l ine) . Thus the b ra in mus t be inc luded as a c r i t i ca l s t res s - respons ive

sys tem. However , the sequence o f responses observed cons i s ten t ly in the adu l t a re in many ways very d i f fe ren t in the

deve lop ing o rgan ism. Ab und an t ev idence ind ica te tha t the ru les tha t govern the ac t iv ity o f the hypo th a lam ic-p i tu i t a ry -

ad rena l (HPA) ax i s in the adu l t a re very d i f fe ren t in the neona te . Th is i s bes t apprec ia ted in roden t . Thus , in th i s

chap te r , the on tog eny and reg u la t ion o f the roden t H PA i s d i scussed . In add i t ion , de ve lopm en ta l aspec t s o f the huma n

HPA ax is du r ing the f i r s t years o f l i fe a re rev iewed .

Stress-hyporesponsive period

In 1 9 5 0 , a r e p o r t a p p e a re d t h a t f i r s t i n d i c a t e d t h a t

t h e n e o n a t a l r e s p o n s e t o s t r e s s d e v i a t e d m a r k e d l y

f r o m t h a t o b s e r v e d i n t h e a d u l t r o d e n t s a n d t h u s ,

c r e a t e d a fi e ld o f i n q u i ry t h a t h a s p e r s i s t e d fo r o v e r

f o u r d e c a d e s . U s i n g d e p l e t i o n o f a d r e n a l a s c o r b i c

a c i d a s t h e i n d i c a t o r o f t h e s t re s s r e s p o n s e , J a i l e r

r e p o r t e d t h a t t h e n e o n a t e d i d n o t s h o w a n y r e s p o n s e

to s t res s ( Ja i l e r , 1950) . By the ear ly 1960s , Shap i ro

p l a c e d a f o r m a l l a b e l o n t h i s p h e n o m e n o n a n d

d e s i g n a t e d i t a s t h e " s t r e s s n o n r e s p o n s i v e p e r i o d "

*Corresponding author: E-mail: [email protected]

(S N R P ) (S h a p i ro e t a l ., 1 9 6 2) . I t i s i m p o r t a n t t o n o t e

t h a t f o r t h e m o s t p a r t t h e b a s i s f o r t h i s d e s c r i p t i o n

w a s t h e i n a b i l i t y o f t h e r a t p u p t o s h o w s i g n i f ic a n t

e l e v a t io n s o f c o r t i c o s t e r o n e ( C O R T ) f o l l ow i n g s t re s s.

Th e re w a s o n e s t u d y t h a t r e c e i v e d l i t t l e a t t e n t i o n a t

t h e t i m e b u t d i d r a i s e i m p o r t a n t q u e s t i o n s c o n c e r n -

i n g t h e v a li d i ty o f t h e n o t i o n o f a n S N R P . I n t h a t

s t u d y , i n a d d i t i o n t o e x p o s i n g t h e p u p t o s t r e s s a n d

d e m o n s t r a t i n g a l a ck o f C O R T r e s po n s e, a n o t h e r

g r o u p w a s i n j e c t e d w i t h a d r e n o c o r t i c o i d h o r m o n e

(A C TH ) (Le v i n e e t a l . , 1 9 6 7 ) . Th e s e p u p s a l s o f a i l e d

t o e l i c i t a C O R T r e s p o n s e , w h i c h i n d i c a t e d t h a t o n e

o f t h e f a c to r s c o n t r i b u t i n g t o th e S N R P c o u l d b e

a d e c r e a s e d s e n s it iv i ty o f t h e a d r e n a l t o A C T H .


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T here fo re , i t was conce ivab le tha t o the r com ponen ts

of the HPA axis might be respons ive to s t ress . The

reso lu t ion o f th i s ques t ion was dependen t on the

avai labi l i ty of re lat ively easy and inexpens ive proce-

dures fo r exam in ing o ther com ponen ts o f the

HPA ax is . T he m ethodo log ica l b reak- th rough , wh ich

a l te red m os t o f the endocr ino logy and had a m ajo r

im pac t on our under s tand ing the on togeny o f the

s tress response, was the development of radio-

im m uneas say (RIA) p rocedures .

T he in i t i a l im pac t o f the RIA was to change

the des igna t ion o f th i s deve lopm enta l pe r iod f rom

the SNRP to the " s t r es s -hyporespons ive per iod"

(SHRP) . T h is change was a r esu l t o f s tud ies tha t

showed a small but s ignif icant r ise in CORT when

m easured by RIA (Sapo lsky and Meaney , 1986) .

A l though the r esponse o f the ad rena l was r educed

m arked ly dur ing the SHRP, the ad rena l i s capab le o f

r e leas ing sm al l am ounts o f CORT when exposed to

cer tain types o f s t ress .

W hen inves t iga to r s began to exam ine o ther com -

ponen ts o f the neona tes ' HPA ax is i t becam e appa-

rent that the SHRP is s t i l l a val id concept . However ,

in order to confront th is ques t ion, we wil l examine

the deve lopm ent o f s evera l com ponen ts o f the HPA

axis . These include the adrenal , the pi tu i tary , and the

brain .

SHRP, the adrenal, and corticosterone

I t is general ly agreed that in response to most

s tressors the neonate fai ls to e l ic i t adrenocor t ical

response, or does so minimally (Walker e t a l . , 2002) .

There are several features that character ize the

func t ion o f the pup ' s ad rena l . T he f i r s t and m os t

obv ious charac te r is t i c o f the ad rena l func t ion dur ing

SHRP i s tha t basa l l eve l s o f CORT are cons ider -

ab ly lower than tha t o bse rved im m edia te ly fo llowing

par tur i t ion and that these low basal levels cont inue to

p redom ina te be tween pos tna ta l days 4 -14 . Fur the r ,

num erous inves t iga to r s have r epor ted tha t the

neonate can el ic i t a s ignif icant increase in plasma

CORT levels (Walker e t a l . , 2002) . However , invar i-

ab ly the m agn i tude o f the r esponse i s sm al l com pared

to o lder pups tha t a r e ou t s ide the SHRP and o f

cour se to the adu l t . T hus , whereas the r epor ted

changes in CORT levels fol lowing s tress in the adul t

can at t imes exceed 50 ~tg/dl, rarely d oes the infan t

reach levels th at exceed 10 ~tg/dl dur in g the SH RP .

These levels are reached only under special c i r -

cumstances , which shal l be descr ibed la ter . Thus ,

the ab i l i ty o f the neona ta l ad rena l to s ec re te CORT

seem s to be im pa i red m arked ly . Morpho log ica l ,

b iochemical , and molecular b iological s tudies sugges t

tha t the deve lopm ent o f the ad rena l co r tex is in pa r t

respons ible for th is phenomenon. Chromaff in cel ls in

the ad rena l m edu l la and m ate rna l f ac to r s a re a l so

important (see Sect ion "Adrenal Sens i t iv i ty") .

T he m atu re ad rena l co r tex in the roden t cons i s t s

of three concentr ic s teroidogenic zones that are

m orpho log ica l ly and func t iona l ly d i s t inc t : the zona

g lom eru losa (ZG) , the zona in te rm ed ia , an d the zona

fasc icu la ta (ZF) / r e t i cu la r i s (ZR) . T he ZG, ZF /ZR

have unique express ion of specif ic s teroidogenic

enzymes that def ines the specif ic s teroid produced

by each zone (Parker e t a l . , 2001) . Thus , cytochrome

P450 a ldos te rone syn thase (P450a ldo) i s p roduced

wi th in the g lom eru losa to p roduce the m inera locor -

t icoid aldo s terone, whereas P450 l l j3-hydroxylase

(P4501113) def ines the glucoco r t icoid p rodu cing zon a

fasciculata/ret icular is . In many mammalian species

the deve lopm ent o f the ad rena l co r t i ca l l ayer s and

s teroidogenic enzyme synthes is pr imar i ly occur

during fetal life (Parker et al. , 2001). However, cells

expressing P4501 l j3 clearly resolve into their cortica l

layer by the th ird da y af ter b ir th (M itani e t a l ., 1997) .

T he deve lopm ent o f ad rena l co r t i ca l zones a re

closely related to the development of the chro-

maff in cel ls of the adrenal medulla (Borns tein and

E hrhar t -Borns te in , 2000). As show n by Borns te in and

co-worker s , a va r ie ty o f r egu la to ry f ac to r s p roduced

and r e leased by the ad rena l m edu l la p lay an im por -

tan t ro le in m odu la t ing ad renocor t i ca l func t ion . I so -

la ted adrenocor t ical cel ls loose the normal capaci ty to

p roduce g lucocor t i co ids , whereas cu l tu re o f ad reno-

cor t ical cel ls with chromaff in cel ls causes marked

upregu la t ion o f P450 enzym es and the s te ro ido-

genic regulatory prote in (STAR ), which m ediates the

t r anspor t o f cho les te ro l to the inner m i tochondr ia l

m em brane where s te ro idogenes i s occur s (Borns te in

and Ehrhar t-Borns tein , 2000) . On the 18th day of

fetal l i fe , cel ls containing tyros ine hydroxylase (TH),

the in i t ia l and rate- l imit ing enzyme of catecholamine

synthes is , and a marker for adrenal medullary cel ls ,

are found intermingled with cor t ical cel ls express ing


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P4501113 in the are a th a t i s l a ter def ined as the Z F/

ZR . Ho wev er , t h e ad ren a l m ed u l l a b eco m es a we l l -

d e f i n ed m o rp h o l o g i ca l r eg i o n a t t h e en d o f t h e f i r s t

week of l i fe (Pignate l l i e t a l . , 1999) , a t a midpoin t

i n t h e SHR P. Wi t h i n t h i s p e r i o d an d u n t i l PND 2 9 ,

the TH enzymat ic ac t iv i ty increases (Lau e t a l . , 1987) .

I t i s d u r i n g t h i s t i m e t h a t m o s t o f t h e ad ren o co r t i ca l

ce l lu lar p ro l i fera t ion ac t iv i ty i s observed , bu t l imi ted

t o t h e o u t e r co r t ex : ZG an d ZF . S t u d i e s t h a t u t i l i zed

a s p ec i f i c an t i b o d y t h a t r eco g n i zes an t i g en s fo u n d

speci f i ca l ly in these cor t i ca l ce l l s o f the ra t adrenal

( I Z A g l a n d A g 2 ) s h o w e d f a i n t Z F i m m u n o s t a i n -

ing on the f i rs t day of pos tnata l l i fe . A progress ive

increase in s ta in ing was observed unt i l 18-20 days

p o s t n a t a l l y . T ak en t o g e t h e r , t h e s e d a t a s u g g es t t h a t

t h e l i m i t ed ad ren o co r t i ca l ac t i v i t y i n t h e i n f an t r a t

i s g r ea t l y d u e t o t h e m a t u r i t y o f t h e s t e ro i d o g en i c

e n z y m a t i c p a t h w a y s o f t h e a d r e n a l d u r i n g t h e S H R P

(see Fig . 2 ) . In addi t ion , there i s ev idence that

s u g g es t s t h a t t h e au t o n o m i c n e rv o u s s y s t em t h ro u g h

t h e ad ren a l m ed u l l a i s a l s o an i m p o r t an t co n t r i b u t o r

t o t h e r eg u l a t i o n o f ad ren o co r t i ca l d ev e l o p m en t

through paracr ine ac t iv i ty (Pignate l l i e t a l . , 1999) .

Cort icostero id-b inding globulin

T h e r e i s a n i m p o r t a n t c a v e a t i n m a k i n g t h e

as s u m p t i o n t h a t t h e r ed u ced l ev e l o f C OR T fo l l o wi n g

s t ress ind ica tes a reduct ion in b io logical ac t iv i ty .

C OR T ex i s t s i n t h e c i r cu l a t i o n i n t wo fo rm s , b o u n d

a n d u n b o u n d . T h e l a r g e m a j o r i t y o f C O R T i n t h e

ad u l t i s b o u n d t o co r t i s o l -b i n d i n g p ro t e i n (C B G) an d

o t h e r p l a s m a b i n d i n g p ro t e i n s . On l y a s m a l l f r ac t i o n

exis t s in the f ree form, which i s cons idered to be

the b io logical ly ac t ive form. Fol lowing s t ress , CBG i s

s o m e w h a t d e c r e a s e d, m a k i n g m o r e o f t he c i r c u la t in g

C OR T av a i l ab l e a s f r ee C OR T (F l e s h n e r e t a l . , 1 9 9 5 ;

T a n n en b au m e t a l ., 1 9 97 ). An o t h e r a s p ec t o f t h e

SHR P i n ro d en t s i s t h e r e l a t i v e ab s en ce o f C B G

d u r i n g t h e SHR P (Hen n i n g , 1 9 7 8 ) . T h u s , a l t h o u g h

t h e ab s o l u t e v a l u es o f C OR T , wh i ch n o rm a l l y i n c l u d e

b o t h b o u n d a n d u n b o u n d h o r m o n e , a r e v e r y l o w i n

t h e a b s e n c e o f C B G t h e a c t u a l f r a c t i o n o f C O R T

that i s avai lab le in the f ree form for b ind ing to

co r t i co s t e ro i d r ecep t o r s m ay ac t u a l l y b e h i g h e r t h an

i s observed in the adul t . There are few data on f ree

C O R T i n t h e n e o n a t e f o l l o w i n g s t r e s s o r A C T H

ad m i n i s t r a t i o n . Ho wev er , i n o n e s t u d y a t p o s t n a t a l

day 12 , the ra t io of f ree versus to ta l cor t i cos terone

i s m u ch h i g h e r i n t h e n eo n a t a l r a t t h an i n t h e ad u l t

(Hen n i n g , 1 97 8) . Fu r t h e r , t h e c l ea ran ce o f C O R T

from the c i rcu la t ion i s s ign i f i can t ly s lower than the

pup (Van Oers e t a l . , 1998) . Therefore , as a con-

s eq u en ce , C OR T i s av a i l ab l e fo r a m o re p ro l o n g ed

p e r i o d . T h e b i o l o g i ca l l y ac t i v e C OR T h as a m o re

pro longed per iod of t ime to exer t i t s e f fec t s in the

p e r i p h e ry an d t h e b ra i n .

A d r e n a l

sensitivity

Al t h o u g h t h e re ap p ea r t o b e r a t e - l i m i t i n g f ac t o r s t h a t

ac t d ev e l o p m en t a l l y t o l i m i t t h e s ec re t i o n o f C OR T

i n t h e n eo n a t e , ev i d en ce i n d i ca t e s t h a t t h e ad ren a l

i s ac t i v e l y s u p p res s ed d u r i n g t h e SHR P. I t h a s b een

ex t en s i v e l y d o cu m en t ed t h a t ce r t a i n a s p ec t s o f t h e

r o d e n t m a t e r n a l b e h a v i o r p l a y a n i m p o r t a n t r o l e i n

r eg u l a t i n g t h e n eo n a t e HPA ax i s . I n p a r t i cu l a r , t wo

s p ec i f i c co m p o n en t s o f t h e d am ' s ca reg i v i n g ac t i v -

i t i es seem to be cr i t i ca l ; l i ck ing/s t rok ing and feed ing .

Nu m ero u s s t u d i e s h av e d em o n s t r a t ed t h a t f eed i n g i s

i n p a r t r e s p o n s i b l e fo r t h e d o wn reg u l a t i o n o f t h e

p u p s ' c ap ac i t y t o b o t h s ec re t e an d c l ea r C OR T f ro m

the c i rcu la t ion (Suchecki e t a l . , 1993; Van Oers e t a l . ,

1 9 9 9 ) . T h u s , r em o v i n g t h e m o t h e r f ro m t h e l i t t e r

for 24 h resu l t s in a s ign i f i can t ly h igh er basal l evel

an d a fu r t h e r i n c reas e i n t h e s ec re t i o n o f C OR T

fo l l o wi n g s t re s s o r ad m i n i s t r a t i o n o f AC T H . T h e

au t h o r s h av e p o s t u l a t ed t h a t o n e o f t h e co n s eq u en ces

o f m a t e rn a l d ep r i v a t i o n i s t o i n c reas e t h e s en s i t i v i t y

o f th e ad ren a l t o A C T H (R o s en fe l d e t a l. , 1 99 2) . T h i s

has been demons t ra ted in severa l ways . (1 ) Signi -

f i can tl y l o wer d o s es o f A C T H a re r eq u i r ed t o i n d u ce

t h e ad ren a l t o s ec re t e C OR T . (2 ) A l t h o u g h t h e l ev e l s

o f A C T H a r e e q u iv a l e n t be t w e e n d e p r iv e d a n d

n o n d ep r i v ed p u p s u n d e r ce r t a i n ex p e r i m en t a l co n d i -

t i o n s , t h e l ev e l s o f C OR T a re g rea t e r i n d ep r i v ed

pups . (3) Studies ind ica te tha t fo l lowing mi ld s t ress

( in jec t ion of i so tonic sa l ine) there i s an increase in

c-fos gene express ion in the adrenal cor tex of the

d ep r i v ed n eo n a t e , wh e reas t h e n o n d ep r i v ed p u p

exhib i ted a lmos t no detec tab le l evel s o f c- fos

m R N A (Ok i m o t o e t a l ., 20 0 2 ). I f m a t e rn a l l y d ep r i v ed

p u p s a r e p ro v i d ed w i t h fo o d d u r i n g t h e p e r i o d o f

m a t e rn a l d ep r i v a t i o n , b o t h b as a l an d s t r e s s l ev e l s o f


21/484

C O R T n o l o n g e r d i f f e r f r o m m o t h e r - r e a r e d p u p s .

A l though a c l e a r me c ha n i sm ha s no t be e n e luc ida t e d ,

i t i s pos s ib l e t ha t t he ga s t r o in t e s t i na l - me d ia t e d

a c t i v i t y o f t h e a u t o n o m i c n e r v o u s s y s t e m m a y

r e g u la t e t h is p h e n o m e n o n .

A t t h i s t ime t he phys io log i c a l c onse que nc e s o f

t he se c ha nge s i n t he e xp osur e t o h igh l eve ls o f CO RT

in t he de pr ive d pup a r e no t know n. S tud i e s ha ve

show n tha t e xpo sur e t o h igh l e ve ls o f g luc oc or t i c o ids

dur ing de ve lopme nt ha ve p r o f ound l ong- t e r m e f f e c t s

on t he de ve lop ing b r a in ( Bohn , 1984) . I t shou ld be

no t e d , how e ve r , t ha t ma ny o f t he se s t ud i e s use d

pha r ma c o log i c a l dose s o f a d r e na l s t e r o ids a nd , i n

ma ny c a se s , u se d hor mone s t ha t w e r e a typ i c a l f o r t he

r a t ( c o r t iso l , de xa m e tha sone ) . W i th t he a va i l a b il i ty o f

t he ma te r na l de pr iva t i on mode l , on ly r e c e n t l y ha s

i t be e n poss ib l e t o a c h i e ve e l e va t e d l e ve l s o f CO RT

tha t a r e ge ne r a t e d e ndoge nous ly by t he pup .

Corticosteroid clearance

E v i d e n ce o f r e d u c e d c l ea r an c e o f C O R T w a s o b t a i n e d

in a s t udy t ha t e xa mine d t he on toge ny o f ne ga t i ve

feedback regula t ion (Van Oers e t a l . , 1998) . The

t e c hn ique e mploye d t o s t udy ne ga t i ve f e e dba c k i n

the ne ona t e w a s t o a d r e na l e c tomiz e ( A D X ) t he pup

a n d t o m e a s u r e A C T H f o ll o w i n g A D X . P u p s w e re

t e s t e d w i t h a n d w i t h o u t C O R T r e p l a c e m e n t . W h e n

de pr ive d pups w e r e impla n t e d w i th t he i de n t i c a l dose

of CO RT, t he i r CO RT l e ve l s w e r e i nva r i a b ly h ighe r

tha n t hose obse r ve d i n nonde pr ive d pups . Th i s w a s

in t e r p r e t e d a s i nd i c a t i ng t ha t c l e a r a nc e w a s r e duc e d

a s a c onse que nc e o f r e duc e d b lood f l ow r e su l t i ng

f r om 24 h o f f a s ti ng . Ma te r na l de p r iva t i on t he re -

f o r e al t e rs t he pa t t e r n o f e xposur e t o C O R T a s a

f unc t i on o f e l e va t e d CO RT l e ve l s f o l l ow ing de pr iva -

t i on t ha t pe r s i s t i n t he c i r c u l a t i on a nd p r e suma bly i n

the b r a in o f t he de ve lop ing pup due t o r e duc e d r a t e s

of c lea rance .

S H R P an d A C T H

The c on c e p t o f a n a bso lu t e S H R P r e ga r d ing t he r es -

ponse o f t he p i t u i t a r y f o l l ow ing s t r e s s i n t he ne ona t e

is m u c h m o r e p r o b l e m a t i c . W h e t h e r t h e p i tu i t a r y c a n

show a n i nc r e a se i n A CTH in r e sponse t o s t r e s s i s

d e p e n d e n t o n n u m e r o u s f a ct o rs . A m o n g t h es e a re t h e

a ge o f t he ne ona t e , t he t ype o f s t r e s s impose d , a nd ,

once aga in , mate rna l f ac tor s (Walker e t a l . , 1991;

Wa lke r a nd D a l lma n , 1993) . The e a r l y f i nd ings c on-

c e r n ing t he s t r es s r e sponse o f t he p i t u i t a r y sugge s t e d

tha t the re was a def ic iency in the neona tes ' capac i ty

to syn thes i z e A C TH . Thus a s a re su l t, t he pu p sh ou ld

e x h i b i t a r e d u c t i o n i n t h e m a g n i t u d e o f t h e A C T H

stress r esponse . However , suf f ic ient da ta indica te

tha t t he p i t u i t a r y o f t he ne ona t e doe s ha ve t he c a pa -

c i t y t o syn the s i z e a nd r e l e a se A CTH tha t r e se mble s

the a du l t r e sponse . Wha t s e e ms t o d i s c r imina t e t he

ne ona t e f r om the a du l t i s t ha t f o r t he pup t he

r e sponse o f t he p i t u i t a r y i s muc h mor e s t imulus -

dependent (Walker e t a l . , 1991) . Fur ther , the abi l i ty

to te rmina te the s t r ess r esponse i s a l so not ful ly

de ve lope d a nd doe s no t ma tu r e un t i l qu i t e l a t e i n

de ve lopme nt ( V a z que z a nd A ki l , 1993a ) . Pe r ha ps t he

e a r l i e s t de mons t r a t i on t ha t t he ne ona t e c a n i nde e d

m o u n t a n A C T H r e s p o n s e t o a t l e a s t s o m e t y p e s

of c ha l l e nge s w a s a s t udy t ha t c ha l l e nge d ne ona t e s

w i t h a n i n j ec t io n o f e n d o t o x i n t h r o u g h o u t t h e p e r i o d

f r om b i r t h t o w e a n ing ( Wi t e k - Ja nuse k , 1998) . A t a l l

ages the neona te exhibi ted a s igni f icant e leva t ion of

A CTH tha t , be g inn ing da y 5 , w a s e qu iva l e n t t o t he

a du l t . O f i n t e re s t is t ha t a l t houg h t he r e w a s a r ob us t

A C T H r e s p o n s e , t h e C O R T r e s p o n s e w a s r e d u c e d

m a r k e d l y f r o m d a y 5 a n d d i d n o t b e g i n t o a p p r o a c h

adul t va lues unt i l about day 15. The di f f icul ty wi th

th i s s t udy i s t ha t ve r y l a r ge dose s a ppr oa c h ing t he

l e tha l s e nsi ti v i ty o f youn g r a t s t o b a c t e r i al e n do to x in

( 0. 5 - 30 mg/kg ) w e r e use d . I t h a s be e n r e por t e d mo r e

r e c e n tl y t ha t a dm in i s t r a t i on o f I L- 1 ] 3 e l ic i te d a n

A CTH r e sponse i n pups a s e a r l y a s da y 6 pos tna t a l

(Levine e t a l . , 1994) . The peak of the response

f o l l ow e d a s imi l a r t ime c our se t o t ha t o f t he a du l t ,

a l t hough t he ma gn i tude o f t he r e sponse w a s s i gn i -

f i c a n t l y l ow e r e a r l i e r i n de ve lopme nt . The r e duc e d

r e sponse i n da y 6 ne ona t e s c a nno t , how e ve r , be

in t e r p r e t e d a s a r e duc t i on i n t he ne ona t e ' s c a pa c i t y

t o p r o d u c e A C T H . T h r e e h o u r s f o l l o w i n g A D X ,

a r obus t i nc r e a se i n A CTH oc c ur s a s e a r l y a s da y 5 ,

p r e s u m a b l y d u e t o t h e a b s en c e o f a C O R T n e g a -

t ive feedback s igna l (van Oers e t a l . , 1998) . This

ma gn i tude o f t he A CTH r e sponse i s a s g r e a t a s t ha t

seen in older neona tes a t day 18, which a re wel l out

o f th e S H R P .

I t ha s be e n r e por t e d t ha t t he ne ona t e doe s show a

s igni f icant inc rease in ACTH in response to a var ie ty


22/484

of d i f f e r e n t s t imul i i n a n "a du l t - l i ke ma nne r . " I t i s

n o t e w o r t h y f o r e a ch s t im u l u s e x a m i n e d t h a t a p p e a r s

to be a n i d iosync r a t i c t ime c our se t ha t i s de pe nde n t

on the age and the type of s t imulus (Walker e t a l . ,

1991) . Regardless , i t i s apparent tha t the capac i ty

for a p i tu i ta ry response i s present ea r ly in deve lop-

me n t . U nde r some c i r c ums ta nc e s t he pup c a n show

a g r e a t e r A CTH r e sponse e a r l y i n de ve lopme nt

tha n l a t e r . Fo l l ow ing t r e a tme n t w i th ka in i c a c id t he

A CTH r e sponse o f da y 12 pups e xc e e de d t ha t o f da y

6 and day 18 neona tes (Kent e t a l . , 1996) . The la rges t

A C T H r e s p o n s e t o N - m e t h y l - D - a s p a r t a t e ( N M D A )

w a s a t da y 6 . H ow e ve r , mothe r - r e a r e d pups f a i l e d t o

r e spond t o mi lde r pe r tu r ba t i ons . B r i e f pe r iods o f

ma te r na l s e pa r a t i on , e xposur e t o nove l t y , i n j e c t i ons

of i sotonic sa l ine , and res t ra int for 30 min , a l l f a iled

to e l i c i t a n A CTH r e sponse i n no r ma l ly r e a r e d pups

un t i l t he y e sc a pe d f r om the SH RP ( Suc he c k i e t a l . ,

1993).

Maternal behavior

Why do ne ona t e s d i s c r imina t e be tw e e n d i f f e r e n t

c lasses of s t imul i , whereas older pups tha t have

e sc a pe d f r om the SH RP, a nd a du l t s a ppe a r t o r e s -

pond in a s imi la r manner r egardless of the s t r ess-

i nduc ing s t imulus? Se ve r a l hypo the se s c ou ld a c c oun t

f o r t h i s phe nome non . F i r s t i t c ou ld s imply be a

ma t t e r o f s t imulus i n t e ns i t y . Thus , t he ne ona t e ma y

be less r esponsive to s t imul i of lower in tens i t ie s and

ma y the r e f o r e r e qu i r e a mor e i n t e nse s t r e s so r t o

a c t i va t e t he ne ur oe ndoc r ine c a sc a de t ha t e ve n tua l l y

leads to the re lease of AC TH . Second, i t has been

w e l l doc ume nte d t ha t d i f f e r e n t s t imul i a c t i va t e

d i s t i nc t ne ur a l pa thw a ys t ha t l e a d t o t he r e l e a se o f

CRF a nd t hus A CTH . I t i s c onc e iva b l e t ha t t he

ne ur a l pa thw a ys t ha t r e gu l a t e t he r e sponse t o d i f f e r -

ent c lasses of s t imul i mature di f fe rent ly (Sawchenko

e t a l. , 2000) , and thus i f a pa r t icu la r s t imulus ac t iv-

a t e s a pa thw a y , w h ic h ma tu r e s e a r l y i n de ve lopme nt

then i t i s l ike ly tha t a p i tu i ta ry response wi l l be

manifes t . S t imul i tha t threa ten surviva l , such as

se ve r e i n f e c t i on ( e ndo tox in e xposur e ) o r hypog ly -

cemia , may f i t th i s ca tegory. However , i f the regula t -

i ng pa thw a ys a r e de ve lop ing mor e s l ow ly , suc h a s

s t imul i tha t r equi re some leve l of assoc ia t ive proces-

s ing, these s t imul i may not be able to be processed

n e u r o n a l l y a n d p r o d u c e t h e n e u r o e n d o c r i n e c a s c a d e

r e qu i r e d t o a c t i va t e t he p i t u i t a r y .

A th i r d f a c to r a ppe a r s t o c on t r i bu t e t o t he r e duc e d

c a p a c i t y o f t h e m o t h e r - r e a r e d p u p t o r e s p o n d

to mi lde r s t r e s s - i nduc ing p r oc e dur e s . The r o l e o f

mothers ca regiving ac t iv i t ie s on the deve loping adre -

na l was discussed ea r l ie r . Evidence shows tha t mate r -

na l f ac tor s can a lso ac t ive ly inhibi t the re lease of

ACTH (Suchecki e t a l . , 1993; Van Oers e t a l . , 1998;

van O ers e t a l ., 1998). Pups dep r ived of ma te rn a l

c a r e f o r 24 h sow e d a n i nc r e a se in A C TH f o l l ow ing

an injec t ion of sa l ine as ea r ly as day 6 . The e f fec ts

o f m a t e r n a l d e p r i v a t i o n w e re e v en m o r e a p p a r e n t a t

da ys 9 a nd 12 . A l though i n subse que n t e xpe r ime n t s

the response a t day 6 was not r e l iable , s igni f icant

increases in ACTH were repl ica ted in 9- and 12-day

old neona tes . These inc reases a re a l so observed

f o l l ow ing 30min o f r e s t r a in t . I n c on t r a s t , nonde pr i -

ve d pups f a i l ed t o sho w a n a c u t e r e l e ase o f A C TH

fol lowing s t ress . Whereas feeding was requi red in

order to r educe the sens i t iv i ty of the adrena l , ano-

ge n i t a l s t r ok ing c a n r e ve r se t he i nc r e a se d A CTH

secre t ion fol lowing depr iva t ion (Suchecki e t a l . ,

1993) . Thus , d i f f e r e n t c ompone n t s o f t he mothe r ' s

be ha v io r a p pe a r t o be i nvo lve d i n r e gu l a t i ng d i ff e re n t

c ompone n t s o f t he e ndoc r ine s t r e s s r e sponse . I n pups

t h a t w e r e s t r o k e d a n d f e d , b o t h A C T H a n d C O R T

are suppressed ( see F ig . 1) . In pups tha t r ece ived only

s t r o k i n g , A C T H w a s d o w n r e g u l a t e d b u t C O R T

was s t i l l e leva ted. These da ta would sugges t tha t the

da m' s be ha v io r w a s a c t i ve ly i nh ib i t i ng t he ne ur o -

e ndoc r ine c a sc a de t ha t u l t ima t e ly r e su l t s i n t he

per iphera l endocr ine responses to s t r ess . Thus , the

c a pa c i t y t o r e spond i s p r e se n t e a r l y i n de ve lopme nt

bu t i s on ly obse r va b l e i f t he ma te r na l i nh ib i t o r y

f a c to r s a r e no t p r e se n t . I t i s impor t a n t t o no t e ,

h o w e v e r , t h a t a l t h o u g h t h e p u p c a n b e i n d u c e d

to show a n e ndoc r ine r e sponse t o s t r e s s du r ing t he

SH RP, ma te r na l i nh ib i t i on i s no t t he on ly r a t e -

l imi t i ng f a c to r . I f one e xa mine s t he body o f da t a on

the A CTH r e sponse s i n pups , w ha t e me r ge s i s t ha t

e ve n w he n t he i n f a n t r e sponds t o mi ld s t r e s s du r ing

the SH RP, t he ma gn i tude o f t he r e sponse i s a lw a ys

c ons ide r a b ly l ow e r i n t he SH RP tha n t ha t o f t he

older pups (day 18) and adul t s (Dent e t a l . , 2000a) .

I t h a s b e e n c o n c l u d e d t h a t d u r i n g t h e S H R P

t h e n e u r a l p a t h w a y s r e g u l a t i n g t h e A C T H r e s p o n s e

to t he se mi lde r s t imul i a r e no t a s ye t ma tu r e o r t ha t


23/484

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F i g . 1 . D i f f e r en t i a l e f fec t o f f e ed i ng and anog en i t a l s t r ok i ng on H PA r e s pons e i n i n f ancy . P l a s m a A C T H and C O R T l evel s i n 12 - day

o l d pups a r e dep i c t ed on pane l A , bo t h unde r ba s a l cond i t i on ( N T ) and 30m i n a f t e r a s a l i ne i n j ec t i on ( ST R E SS) . B as a l C R F ,

s t r e s s - i nduced ( 30m i n a f t e r s a l i ne i n j ec t i on ) c - f o s , and ba s a l G R m R N A exp r e s s i on i n t he PV N o f 12 - day o l d pups a r e s how n i n

pane l B . L i t t e r s w e r e dep r i ved f o r 24 h on pnd 11 , du r i ng w h i ch t i m e t hey w e r e le f t und i s t u r b ed ( U N D ) , s t r oked , o r s t r oked and f ed

e p i s o d i c a l l y ( n = 1 0 - 1 2 / g r o u p ) . N D E P a n i m a l s s e r v e d a s c o n t r o l s . * S i g n i f i c a n t f r o m N D E P c o u n t e r p a r t s , p < 0 . 0 5 . A d a p t e d f r o m

van Oer s e t a l . ( 1999) .


24/484

t he de f i c i e nc y ma y e x i s t i n t he ne ur ona l c ommunic a -

t i on be tw e e n t he b r a in a nd t he p i t u i t a r y . The se

def ic i t s could occur in a number of s i tes of ac t ion

a m o n g w h i c h i s t h e p r o d u c t i o n a n d t r a n s p o r t o f

c r i t i c a l a c t i va t i ng ne ur ope p t ide s , t he p r oduc t i on o f

ACTH secre tagogue(s) , the re lease of these pept ides

f r om the ne r ve t e r mina l s o f t he me d ia n e mine nc e ,

a nd /o r some de f i c i e nc y i n de ve lop ing CRF r e c e p to r s

in the pi tu i ta ry .

I t i s d i f f icul t to view the body of da ta on the

on toge ny o f t he p i t u i t a r y r e sponse t o s t r e s s a nd c on-

c lude t he r e i s a n a bso lu t e SH RP. The a u thor s do no t

a g r e e t ha t t he ne ona t e ' s p i t u i t a r y A CTH r e sponse

to s t r ess i s "adul t - l ike ." The neona te i s d i f fe rent

i n ma ny w a ys t ha t ha s be e n a l r e a dy d i sc us se d . F i r s t ,

there is the issue of st imulus specif ici ty. Second,

in genera l the leve ls of ACTH secre ted tend to be

r e duc e d c ompa r e d t o o lde r pups a nd a du l t s . Th i r d ,

the re i s a major def ic iency in the abi l i ty of the infant

to te rmina te the response once i t i s in i t ia ted. The

pup i s "a du l t - l i ke " i n on ly one r e ga r d . I t c a n , unde r

c e r t a in c ond i t i ons , c l e a r l y moun t a n A CTH r e sponse

dur ing t he so - c a l l e d SH RP.

S H RP an d th e b ra i n

CRF

The bra in i s c lea r ly a s t r ess- sens i t ive organ. I t i s not

the purpose of th is a r t ic le to r eview a l l of the changes

in the b r a in t ha t ha ve be e n show n to oc c ur i n r esponse

to stress. For this review the focus is on specif ic

neura l markers tha t have a di rec t e f fec t on the regu-

la t ion o f the pi tu i ta ry . In th e i r 1992 review, Rosenfe ld

a nd c o l l e a gue s c onc lude d t ha t " t he l ow ba sa l a nd

s t r e s s - i nduc e d l e ve l s o f CRF ma y be due t o t he

imma tur i t y ( e spe c i a l l y o f t hose ne ur a l pa thw a ys t ha t

p r o v i d e s t i m u l a t o r y i n p u t t o t h e h y p o p h y s i o t r o p i c

c el ls ) a nd pe r ha p s t o c h r on i c m a te r na l i nh ib i t i on . The

me c ha n i sm( s ) unde r ly ing t h i s i nh ib i t i on ha s ( ha ve )

no t ye t be e n e xa mine d . The on toge ne t i c c ha nge s i n

s t imulus spec i f ic i ty of the s t r ess r esponse may re f lec t

c onc ur r e n t ma tu r a t i on i n t he spe c i f i c pa thw a ys t ha t

me d ia t e t he e f f e c t s o f e a c h pa r t i c u l a r s t imulus . " N o t

muc h ha s c ha nge d s i nc e t ha t r e v i e w w a s pub l i she d .

Thus , the genera l consensus based on severa l s tudies

is tha t ea r ly in deve lopment the re i s a de f ic iency in

the ne ona t e s c a pa c i t y t o i nc r e a se ge ne t r a nsc r ip t i on

a nd pe p t i de e xpr e s s ion o f A C TH se c r et a gogue s , eve n

though there i s a s t r ik ing increase in ACTH re lease .

Th i s ha s be e n de mons t r a t e d us ing t h r e e d i s t i nc t

a nd po t e n t s t imul i t ha t a l l i nduc e c ha nge s i n t he

pe r iphe r a l ma n i f e s t a t i ons o f i nc r e a se d H PA a c t i v i t y .

I n c on t r a s t t o da y 25 a n ima l s t ha t i nc r e a se d CRF

mRN A , hypog lyc e mia f a i l e d t o i nduc e c ha nge s i n

C R F m R N A i n d a y 8 p u p s ( P a u l m y e r - L a c r o i x e t a l. ,

1 9 9 4 ) . H o w e v e r , a s u b p o p u l a t i o n o f C R F n e u r o n s

tha t c oe xpr e s s A V P d id r e spond a t da y 8 . I t w a s

a r gue d t ha t d i f f e r e n t pa thw a ys r e gu l a t e d i f f e r e n t

pop u la t i ons o f c ell s. Pups e xpose d t o "m a x im a l t o l e r-

a t e d c o ld" show e d a s i gn i f i c a n t i nc r e a se i n CO RT

secre t ion (Yi and Baram, 1996) . However , a t day 6

n o c h a n g e s i n C R F m R N A c o u l d b e d e t e c t e d . B y

day 8 , inc reases in CRF message did occur . In th is

e x p e ri m e n t , C R F a n t i se r u m w a s a d m i n i s t e re d t o p u p s

a t a l l ages and, surpr i s ingly , the ant i se rum was able

to d imin i sh t he CO RT r e sponse i n da y 6 pups ( Yi

a n d B a r a m , 1 9 9 6 ) . T h u s , a l t h o u g h C R F m R N A d o e s

no t a ppe a r t o be a l t e r e d by t he s e ve r e e xposur e t o

c o ld , t he pe r iphe r a l r e sponse a ppe a r s t o be CRF-

d e p e n d e n t . N o c o m p e n s a t o r y c h a n g e s i n C R F a n d

A V P ge ne e xpr e s s ion w e r e obse r ve d f o l l ow ing A D X ,

a l t hough t he r e w e r e ma r ke d i nc r e a se s i n c i r c u l a t i ng

l e ve l s o f A CTH tha t w e r e obse r ve d i n o lde r pups

(days 14-19) . Thus , dur ing the f i r s t 10 days of l i f e ,

w i t h i n t h e a d r e n a l S H R P , h y p o t h a l a m i c C R F a n d

A V P ne ur ons a r e no t s e ns i t i ve t o g luc oc or t i c o id

f e e dba c k a nd ba sa l A CTH se c r e t i on a ppe a r s t o be

r e l a t i ve ly i nde pe nde n t f r om hypo tha l a mic i npu t .

Ba se d on t he e x i s t i ng da t a , t he c onc lus ion t ha t CRF

is a l so not involved in the s t r ess r esponse would a lso

be w a r r a n t e d . H ow e ve r , t he r e is r e a son t o be l ie ve t ha t

s u c h a c o n c l u s i o n m i g h t b e p r e m a t u r e . T h e C R F

system seems to be involved in the response to severe

c o l d . S h a n k s a n d M e a n e y ( 1 9 9 4 ) h a v e d e m o n s t r a t e d

t h a t t h e A C T H a n d C O R T r e s p o n s e s t o e n d o t o x i n

a l so a pp e a r t o be r e gu l a te d by C RF in the r a t ne ona t e .

I n t h e a d u l t , i n c r e a s e s i n C R F m R N A d o n o t

b e c o m e a p p a r e n t u n t i l a p p r o x i m a t e l y 3 - 4 h a f t e r

t he onse t o f s t r e s s ( Ma a nd L igh tma n , 1998) . I n

some ins t a nc e s , e ve n t hough a pe r iphe r a l e ndoc r ine

r e s p o n s e i s e v i d e n t , c h a n g e s i n C R F m R N A a r e n o t

de t e c t e d in t he a du l t . D a t a sugge st t ha t t he dyna m ic s

of t he CRF sys t e m in t he ne ona t e a r e ve r y d i f f e r e n t

t ha n t ha t r e por t e d f o r t he a du l t . The a u thor s f ound


25/484

10

t h a t t h e n e o n a t e m a y i n d e e d b e s h o w i n g c h a n g e s i n

C R F g e n e e x p r e s s i o n m u c h m o r e r a p i d l y t h a n h a s

ever been seen in the adul t (Dent e t a l . , 2000b) .

t h e co n c l u s i o n t h a t t h e i n f an t i s p e rh ap s h y p e r -

r e s p o n s i v e r a t h e r t h an h y p o res p o n s i v e t o ch a l l en g es

(see Fig. 1).

Immediate early genes

On e o f t h e t ech n i q u es b e i n g u s ed t o i n v es t i g a t e t h e

re s p o n s e t o s t r e s s h as b een t o ex am i n e ch an g es i n

t h e ex p res s i o n o f s o m e o f t h e i m m ed i a t e ea r l y g en es

( IE G) . In p a r t i cu l a r , c - fo s h as b een u s ed a s a m ark e r

o f i n c reas ed n eu ro n a l ac t i v it y i n r e s p o n s e t o s tr e s s.

I t i s i m p o r t an t t o n o t e t h a t i n c reas es i n t h es e

s t r e s s - r e s p o n s i v e g en es s h o u l d n o t b e i n t e rp re t ed

as an y i n d i ca t i o n o f t h e ex p res s i o n o f t h e n eu ro p ep -

t i d es . B o t h c - fo s an d n e rv e g ro wt h f ac t o r i n d u c i b l e

g en e (NGFI -B ) were fo u n d s i g n i f i can t l y e l ev a t ed i n

t h e p a r a v e n t r i c u l a r n u c l e u s ( P V N ) o f th e n e o n a t e

fo l lowing the mi ld s t ress of a sa l ine in jec t ion (Smi th

et a l . , 1997) . The express ion of these genes occurs in

m o t h e r - r e a r e d p u p s i n t h e a b s e n c e o f o t h e r i n d i c at o r s

o f st r es s . M a t e rn a l l y d ep r i v ed p u p s s h o w a s ig n i f ican t

e n h a n c e m e n t o f t h e e x p r e s s i o n o f t h e s e t w o I E G s .

I f t h e an o g en i t a l r eg i o n o f t h e p u p i s s t ro k ed fo r

t h ree , 4 5- s p e r i o d s d u r i n g t h e 2 4 -h d ep r i v a t i o n p e r i o d ,

t h e ex p res s i o n o f t h es e n eo n a t a l s t r e s s m ark e r s i s

ob l i t era ted in response to s t ress . This f ind ing leads to

C o r t i c o s t e r o i d f e e d b a c k

N e g a t i v e f e e d b a c k h a s t w o m o d e s o f o p e r a t i o n :

(1 ) T h e "p ro ac t i v e" m o d e t h a t i n v o l v es t h e m a i n -

t en an ce o f b as a l l ev e l s o f HPA ac t i v i t y an d i s m ed i -

a t ed b y t h e h i g h -a f f i n i t y m i n e ra l o co r t i co i d r ecep t o r s

( M R ) f o r C O R T i n h i g h e r b r a i n r e g i o n s a n d ( 2 ) t h e

" reac t i v e" m o d e t h a t f ac i l i t a t e s t h e t e rm i n a t i o n o f

s t r e s s - i n d u ced HPA ac t i v i t y , wh i ch i n v o l v es t h e

l o wer -a ff i n it y g l u co co r t ico i d r e cep t o r s (GR ) l o ca l ized

i n t h e P V N a n d t h e p i t u i ta r y c o r t i c o t r o p h s ( d e K l o e t

e t a l . , 1998b) . GR are widely d i s t r ibu ted in the

l i m b i c -m i d b ra i n s t r e s s c i r cu i t ry i n n e rv a t i n g t h e PVN,

wh ere i t ex e r t s f ac i l i t a t o ry an d i n h i b i t o ry i n f l u en ces

o n t h e H P A a x i s . B o t h f e e d b a c k m o d e s a r e o p e r a -

t ive dur ing the SHRP (van Oers e t a l . , 1998) . The

p r o a c t i v e m o d e s e e m s p r o m i n e n t , a s A D X r e s u l t s

i n a h i g h l ev e l o f c i r cu l a t i n g AC T H. T h e r eac t i v e

feed b ack s eem s t o b e a l a t e d ev e l o p i n g p ro ces s , a s

d u r i n g n eo n a t a l l i f e t h e s t r e s s - i n d u ced AC T H l ev e l s

a re n o t t e rm i n a t ed a s e f f i c i en t l y a s i n ad u l t h o o d .

~D

O

4 -

3 -

2 -

1 -

0 -

- - "O" - - Zo n aGlomerulosa

Zona Fasciculata

i i i i

1-8 days 1O-18 days 20-38 days 40-60' days 65-90 days

Fig. 2. Postnatal adre nal cortex func tion in the rat . P ane l A depicts expression of adrena l cortex enzyme 3-13-hydroxysteroid

dehydrogenase that is requir ed for bo th m ineralocorticoid and glucocorticoid synthesis in the z on a glomerulosa and fasciculata,

respectively. (Adap ted from Parke r and Shimm er, 2001). Panels B and C show the on togenic progression of plasm a aldosterone (B)

and corticosterone (C) levels postnatally. * p < 0.05. Ad apte d from P ignatelli et al. (1999).


26/484

11

1000 -

. 9

9

(D

r~

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