Regulación neural de las respuestas endocrinas y autonómicas al estrés - Nature Neurosc 2009

7/30/2019 Regulacin neural de las respuestas endocrinas y autonmicas al estrs - Nature Neurosc 2009

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Aaptatin nr cnitins f strss is a prir-ity fr a rganiss. Strss can b bray finas an acta r anticipat isrptin f hstasis ran anticipat thrat t -bing. Strssr-ratinfratin fr a ar snsry systs (frxap, intrcpti cs, sch as b ansarity, an/r xtrcpti cs, sch as th sf a pratr) is cny t th brain, hich rcritsnra an nrncrin systs (ffctrs) tiniiz th nt cst t th ania. Th physigicarspns t strss ins an fficint an highy cn-sr st f intrcking systs an ais t aintainphysigic intgrity n in th st aning fcircstancs.

Th atnic nrs syst (ANS) (BOX 1) pr-is th st iiat rspns t strssr xpsr thrgh its sypathtic an parasypathtic ars,hich prk rapi atratins in physigica stats

thrgh nra innratin f n rgans. Fr xap,th sypath-arnary ar can rapiy (in sc-ns) incras hart rat an b prssr by xcitingth cariascar syst1. Iprtanty, xcitatin f thANS ans qicky ing t rfx parasypathticactiatin rsting in shrt-i rspnss.

Actiatin f th hypthaaic-pititary-arncr-tica (HPA) axis rsts in atins in circating g-ccrticis (BOX 1). Pak pasa gccrtici sccr tns f ints aftr th initiatin f strss2. Tht-stp hrna chanis f HPA inctin (BOX 1)is sggish rati t th atncy f th synaptic cha-niss that ri sypath-arnary actiatin,

an it nsrs that thr is an apifi an ratiyprtract scrtry pis.

Th brain triggrs strss rspnss that ar cn-srat ith th natr f th stis. Physica strssrs sch as b ss, infctin an pain rqir aniiat systic ractin that is triggr by rfx-i chaniss. Th brain as rspns t nn-physicar psychgnic strssrs bas n prir xprinc rinnat prgras3. Ths rspnss rqir prcssingin th frbrain an can ccr in anticipatin f r inractin t strssf nts.

This Ri arsss th brain circits that rgatANS an HPA axis rspnss t strss. Th first sctinris th nrcircitry, fcsing n ascning inptsfr th brainst, scning infncs fr th limbicfrbrain, an hypthaaic chaniss that intgratibic an brainst inpt ith rspct t hstaticfback(FIG. 1). Th scn sctin args that th

strss-cntr circitry is rrganiz in th chronicallystrssd brain, ining th rcritnt f s rginsan iinish infnc f thrs. Th fina sctiniscsss rap f strss circits an ths cntr-ing ry an rar, an anatica arrangntthat pris pprtnity fr ta intractin in thtiat nra intrprtatin f strssr significanc.

Stress triggers: brainstem and hypothalamus

Brainstem systems. Th brainst rcis inpts thatsigna ar hstatic prtrbatins, sch as bss, rspiratry istrss, iscra r satic pain aninfaatin3. Sypathtic rspnss t ths inpts

Department of Psychiatry,

University of Cincinnati,

Cincinnati, Ohio

452370506, USA.

Correspondence to J.P.H.

email:[email protected]

doi:10.1038/nrn2647

Publishd onlin 13 May 2009

Limbic system

Th collction of highly

intrconnctd forbrain

structurs that ar involvd in

procssing motion and

mmory.

Chronic stress

Ongoing or rpatd xposur

to on or mor typs of strss

stimuli ovr a priod ranging

from days to months.

Neural regulation of endocrineand autonomic stress responsesYvonne M. UlrichLai and James P. Herman

Abstract | The survival and well-being of all species requires appropriate physiological

responses to environmental and homeostatic challenges. The re-establishment and

maintenance of homeostasis entails the coordinated activation and control of

neuroendocrine and autonomic stress systems. These collective stress responses are

mediated by largely overlapping circuits in the limbic forebrain, the hypothalamus and thebrainstem, so that the respective contributions of the neuroendocrine and autonomic

systems are tuned in accordance with stressor modality and intensity. Limbic regions that are

responsible for regulating stress responses intersect with circuits that are responsible for

memory and reward, providing a means to tailor the stress response with respect to prior

experience and anticipated outcomes.

REVIEWS

NATuRe RevIewS |NeuroscieNce volume 10 | juNe 2009 |397

f oc us on s tr e s s

2009 Macmillan Publishers Limited. All rights reserved
mailto:[email protected]:[email protected]


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Intermediolateralcolumn (T1L2)

Hindbrain

Sacral spinal cord

Cardiovascular system

Abdominal viscera

Adrenalmedulla

Adrenal cortex

Pituitary

PVN

Medianeminence

CRH, AVP

and others

ACTH

Preganglionic

Rlating to th first nuron in

th two-nuron chains that

mdiat autonomic rsponss.

Postganglionic

Rlating to th scond nuron

in th two-nuron chains that

mdiat autonomic rsponss.

in rfx arcs that cnicat ith aras in tha (fr xap, th rstra ntratra a)an prganglionic sypathtic nrns in th intr-iatra c cn f th spina cr 1(FIG. 2).Crinat atinf th parasypathtic branchf th ANS as ccrs fing strss, t atr th agatn t th hart an ngs1 an t hp cntr th ra-tin f atnic rspnss. This parasypathticrspns t strss is iat by th ncs abigs

an th rsa tr ncs f th ags nr, pssi-by thrgh inpt fr th ncs f th sitary tract(NTS)1(FIG. 2). In aitin, ary an spina crsysts infr highr-rr atnic intgratisits in th hinbrain (fr xap, th raph pais,th atra parabrachia ncs an th Kikr-Fsncs), ibrain an frbrain (fr xap, thrsia hypthaas (DmH))1, hich atth atnic rspns t strssrs in accranc ith

Box 1 | HPA axis and autonomic nervous system responses to stress

The sympatho-adrenomedullary (see the left-hand side of the figure) and hypothalamic-pituitary-adrenocortical (HPA)

(see the right-hand side of the figure) axes are the primary systems for maintaining or reinstating homeostasis during

stress. Stressor exposure results in activation of preganglionic sympathetic neurons in the intermediolateral cell column

of the thoracolumbar (T and L, respectively) spinal cord (shown in blue). These preganglionic neurons project to pre- or

paravertebral ganglia that in turn project to end organs and to chromaffin cells of the adrenal medulla. This sympathetic

activation represents the classic fight or flight response that was first characterized by Walter Cannon and colleagues in

the early twentieth century152; it generally increases circulating levels of adrenaline (primarily from the adrenal medulla)

and noradrenaline (primarily from sympathetic nerves), heart rate and force of contraction, peripheral vasoconstriction, andenergy mobilization. Parasympathetic tone can also be modulated during stress. In the parasympathetic system (shown in

red), activation of craniosacral preganglionic nuclei activates postganglionic nuclei located in or near the end organs that

they innervate; parasympathetic actions are generally opposite to those of the sympathetic system.

For the HPA axis, stressor exposure activates hypophysiotrophic neurons in the paraventricular nucleus of the

hypothalamus that secrete releasing hormones, such as corticotropin-releasing hormone (CRH) and arginine vasopressin

(AVP), into the portal circulation of the median eminence. These releasing hormones act on the anterior pituitary to

promote the secretion of adrenocorticotropic hormone (ACTH), which in turn acts on the inner adrenal cortex (that is, the

zona fasciculata) to initiate the synthesis and release of glucocorticoid hormones (for example, corticosterone in rats and

cortisol in humans). Circulating glucocorticoids then promote the mobilization of stored energy and potentiate numerous

sympathetically mediated effects, such as peripheral vasoconstriction. Moreover, the adrenal cortex is directly innervated

by the sympathetic nervous system, which can regulate corticosteroid release153. Thus, the HPA axis and sympathetic

system have largely complementary actions throughout the body, including energy mobilization and maintenance of

blood pressure during stress.

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Stress signals Experiential factors Innate programmes

Ongoing homeostaticfeedback

Stress signals Homeostatic imbalance Pain Inflammation

Top-down regulationLimbic forebrain

Middle managementBST and hypothalamus

Stress response triggersBrainstemHypothalamusCVO

Output systems

HPA activation (PVN)

SAM activation (ANS)

Subfornical organ

A forbrain circumvntricular

organ that lacks a bloodbrain

barrir.

Preautonomic

Rlating to th CNS nurons

that ar involvd in rgulating

prganglionic sympathtic or

parasympathtic nurons in

th spinal cord and/or

brainstm.

FOS

An immdiat arly gn,

xprssion of which is tightly

linkd to rcnt cllular

xcitation.

scning infratin fr th hypthaas anth ibic frbrain. Athgh a f ths circits par-ticipat in atnic intgratin, thir prcis r(s) instrss-inc rspnss is nt yt fin.

Signas f hstatic ibaanc in th brainstas a t actiatin f th HPA axis: ascning brain-st (an prhaps spina) pathays prct haiyt th parcar iisins f th parantricarncs f th hypthaas (PvN) (FIG. 3). Fr xa-p, catchainrgic (sch as nrarnrgic anarnrgic) prctins t th hypphysitrphic znf th PvN riginat in th NTS an C1C3 rgins4,5an participat in HPA actiatin6. NTS prctins tthis ara ras aitina nracti factrs (inc-ing nrppti Y, gcagn-ik ppti 1, inhibin-,satstatin an nkphain79) that can rgat HPAactiatin. In s bt nt a NTS nrns ths factrsar ccaiz ith nrarnain an arnain8.

Dstrctin f ascning nrarnain an arna-in nrns rcs HPA axis rspnss t stii thatsigna hstatic prtrbatins (fr xap, hypgy-

caia r intrkin 1 inctin)10,11 bt s ntaffct psychgnic rspnss. Ths, it as prps thatascning catchainrgic pathays iat systic-strss rspnss3. Hr, s nn-catchainrgicNTS c grps (fr xap, gcagn-ik ppti 1nrns)12 ar in in gnrating HPA rspnss tbth psychgnic an systic strssrs, sggsting thatthr is s gr f fnctina spciaizatin angNTS an PvN pathays.

Th parcar PvN as rcis srtnrgicinnratin fr th ian raph nci in th i-brain. Srtnin actiats th HPA axis13 by actiatingsrtnin 2A rcptrs n PvN nrns14. Srtnrgic

fibrs prct qay t th PvN an srrningrgins15, raising th pssibiity that srtnin asinfncs ca circit nrns that prct t th PvN.

Circumventricular organs: integration of peripheralsignals. Cpnnts f th aina trinais systin th frbrain (that is, th ian prptic ncs,th subfornical organ an th rgan ascs fth aina trinais) rspn t prtrbatins in fian ctryt baanc an b prssr. This systis ssntia fr th cntra rgatin f b prssrby angitnsin II. Th sbfrnica rgan16 has irctangitnsin II-cntaining prctins t th iaparcar PvN, hr it stiats HPA axis acti-ity by actiating th angitnsin II typ I rcptr 17. Thaina trinais as prcts t thr hypthaaicstrctrs, incing th antrntra prptic ncs,th DmH an th prautonomic PvN18, thrgh hichit can initiat strss-inc changs in cariascaractiity19.

Paraventricular and dorsomedial hypothalamicnuclei. Ang sra hypthaaic nci that arircty in in rgating HPA axis an atnicrspnss t strssrs, th PvN stans t as a princi-pa intgratr f strss signas. Th PvN hss istinctppatins f nrns that prct t th ian i-nnc an t atnic targts in th brainst anspina cr sch as th intriatra c cn,th parabrachia ncs, th rsa tr ncsf th ags nr an th NTS20. Transnrna tracingstis inicat that parasypathtic an sypathticprctin nrns ar intring in th PvN, sg-gsting that ths nrns inpt int bth ars f ANSfnctin21.

Th PvN is haiy innrat by GABA (-ain-btyric aci)-rgic inpts22, hich pri a sbstantiainhibitry tn23,24(FIGS 3,4). S f th GABArgicinnratin t th PvN cs fr nrns in thpri-PvN rgin25, hich in trn is targt by sraibic brain rgins, nabing it t transat ibic infr-atin int atin f th HPA axis r atnicactiatin26.

Th DmH rgats atnic an prhaps as HPAaxis rspnss t psychgnic stii. lca stiatinf th DmH incrass hart rat, b prssr an HPAaxis rspnss t a psychgica strssr27, hras inhi-bitin attnats strss-inc incrass in hart rat an

b prssr28. Hr, inactiatin f th DmH snt affct cariascar rspnss t harrhag28, ini-cating that hypaic stii ar prcss shr(st iky thrgh brainst rfx pathays). ThDmH ight as b in in gating PvN actiatin:ca inhibitin f th rsa DmH rcs arncrti-ctrpic hrn (ACTH) ras an nra xcitatin(as rfct by actiatin f th iiat ary gnFOS

29) in th parcar PvN t psychgnic bt ntsystic stii30. mrr, th ntra DmH inhibitsnrna actiity in th PvN31, inicating that th DmHcntains anaticay sgrgat nrna ppatinsthat actiat r inhibit HPA axis actiity(FIG. 3).

Figure 1 | Gna hm ban at-t gaty pathway. Stressors

activate brainstem and/or forebrain limbic structures. The brainstem can generate rapid

hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS)

responses through direct projections to hypophysiotrophic neurons in the

paraventricular nucleus of the hypothalamus (PVN) or to preganglionic autonomic

neurons (stress response triggers). By contrast, forebrain limbic regions have no direct

connections with the HPA axis or the ANS and thus require intervening synapses before

they can access autonomic or neuroendocrine neurons (top-down regulation). A high

proportion of these intervening neurons are located in hypothalamic nuclei that are also

responsive to homeostatic status, providing a mechanism by which the descending

limbic information can be modulated according to the physiological status of the animal

(middle management). BST, bed nucleus of the stria terminalis; CVO, circumventricular

organ; SAM, sympathoadrenomedullary system.

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IL

CeA

LC

VLM

aBST

PL

DMX

NA

NTS

PVN

DMH

Preganglionic sympathetic nervoussystem: intermediolateral cell column

Postganglionic parasympatheticnervous system: effector organs

Bradycardic response

A slowing of th hart rat.

Top-down regulation: limbic stress circuits

Bth psychgnic an systic stii ar prcss intip ibic frbrain strctrs, incing th ayg-aa, th hippcaps an th prfrnta crtx. Thsrgins rci assciatina infratin fr sbcrti-ca an crtica aras that ar in in highr-rrsnsry prcssing (fr xap, factry nci, thpirifr crtx an th insar crtx) an ry(th ia spt, th ntrhina crtx an th cing-at crtx). Thy as rci ascning inpts fr sitsin in attntin an arsa (fr xap, th cscrs an raph nci). Th tpt fr ths i-bic strctrs cnrgs n crcia sbcrtica ray sits,aing nstra prcssing f ibic infratin3.Ths ibic rgins rk in para t infnc thactiatin f th HPA axis an prbaby prfr siiarfnctins in th atnic rspnss t strss.

Amygdala. Th aygaa is strctray cpx, ithnrs nstra targts that at atnican nrncrin strss rspnss (FIG. 4). Th cn-

tra ncs f th aygaa (CA) has rci cn-sirab attntin as a ky n fr strss intgratin,ing t its innt in atnic rgatin an itsassciatin ith strss-rat bhairs (spcificay,far rspnss)32. Th CA is iffrntiay actiat

by hstatic isrptin33,34 an systic strssrs35,bt it is nt actiat by psychgnic36,37 strssrs.Nnthss, CA sins ipair bradycardic rsponssring xpsr t psychgica strssrs38,39, sggst-ing that th CA has a r in intgrating th atniccpnnts f psychgnic strss. ora, th r fth CA ss t b spcific t stis aity anight b prfrntiay ight tars atnicrathr than HPA axis rspnss t strss.

Th ia (mA) an basatra (BlA) aygaanci ar prfrntiay actiat by psychgicastrssrs33,40,41: sins f th mA prc sctificits in HPA axis rspnss t psychgnic bt nthstatic strssrs36, an BlA sins apn HPAaxis rspnss t rstraint42. Th ipact f th mAan BlA n HPA rspnss is prbaby iat byxtnsi intractins ith intrning PvN-prctingnrns, as thr ar f irct cnnctins btnth PvN an ths aygaa nci43. Th rs f thmA an BlA in rgating atnic strss rspnssha yt t b finitiy tst; hr, bas n

th pacity f mA an BlA prctins t principaatnic tpt nci, it ss niky that thsrgins ircty at atnic strss rspnsst a significant xtnt.

Hippocampus. Nrs stis ink th hippcapsith inhibitin f th HPA axis3,44. Hippcapa sti-atin crass gccrtici scrtin in rats anhans45,46, hras hippcapa aag incrassstrss-inc an, in s cass, basa gccrti-ci scrtin3,44. Ntaby, sin ffcts ar st pr-nnc ring th rcry phas f strss-incgccrtici scrtin, ipicating th hippcapsin rgating th trinatin f strss-initiat HPArspnss.

Hippcapa rgatin f th HPA axis is rgin-an strssr-spcific. Th inhibitry ffcts f th hip-pcaps n th PvN ar sbsr by a ratiycircscrib ppatin f nrns in th ntrasbic47(FIG. 4). lsins f this ara rst in incrascrticstrn ras fing psychgnic bt ntsystic strssrs47, cnsistnt ith cntxt-spcificatin f strss rspnss by th hippcaps.

Th hippcaps as infncs atnic tn.Hippcapa stiatin crass hart rat, bprssr an rspiratry rat in aak rats, ffcts that arbck by sins f th ia prfrnta crtx (PFC)48.

Th hippcaps has n ar irct prctins t thbrainst bt s cnnct ith NTS-prcting rginsf th PFC, sch as th infraibic crtx49, sggstingthat hippcapa actins n atnic fnctin ightb rt thrgh th PFC.

Medial prefrontal cortex. Th PFC is as cpx,ith iffrnt sbrgins cntribting t iffrntaspcts f strss tpt (FIG. 4). Th pribic PFCprfrntiay inhibits HPA axis rspnss t psych-gnic strssrs5053 an, ik th hippcaps, rgatsth ratin bt nt th pak s f gccrticiscrtin, sggsting that it is in in rspns

Figure 2 | Th ban ty that gat atnm t pn.

Stress-induced pre-autonomic outflow originates in multiple brain areas. The colours

denote brain regions that are implicated in sympathetic activation (blue),

parasympathetic activation (red) or both (bicoloured). The paraventricular nucleus of the

hypothalamus (PVN) has substantial projections to both sympathetic and

parasympathetic nuclei, including the nucleus of the solitary tract (NTS), the dorsal

motor nucleus of the vagus nerve (DMX), the intermediolateral cell column (IML), thelocus coeruleus (LC) and the ventrolateral medulla (VLM) (the latter two sets of

projections are not shown for clarity). The rostral VLM, LC and PVN directly innervate the

IML and are thought to initiate sympathetic responses. The NTS in turn receives direct

input from neurons in the infralimbic cortex (IL), the central amygdala (CeA) and the PVN.

Other hypothalamic regions, most notably the dorsomedial hypothalamus (DMH),

modulate autonomic nervous system activation through connections with the PVN (and

possibly other descending pathways) (see main text). Parasympathetic outflow is

mediated largely by descending outputs from the DMX and the nucleus ambiguus (NA)

and is under the direct influence of the prelimbic cortex (PL), the PVN and possibly other

descending relays (see main text). Parasympathetic effects of the anterior bed nucleus of

the stria terminalis (aBST) are probably mediated by relays in the PVN or the NTS. The

anatomical complexity of autonomic nervous system integration is underscored by the

mixing of sympathetic and parasympathetic projection neurons in individual nuclei.

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Third ventricle

Third ventricle

mPOA

pPVNOptic chiasm

pBST

avBST

Anteriorcommissure

dmDMH

vlDMH

Arc

C1

NTS

PVNmpd

trinatin. Inhibitin f th pribic PFC rca inctin f nrarnain nhancs hart ratrspnss t psychgica stii54, cnsistnt ith ar fr th pribic PFC in inhibiting atnic strssrspnss.

By cntrast, th infraibic PFC is in in initiat-ingatnic an HPA rspnss t psychgnic sti-i52,55. ectrica stiatin f th ntria PFC(hich ncpasss th infraibic crtx) incrassb prssr in nanasthtiz rats, hras sin-ing r inactiatin f this rgin inhibits cnitincariascar rspnss56,57. Inactiatin f this aras nt affct basin hart rat r b prssr,

sggsting that th infraibic crtx is sctiyin in strss-inc cariascar rgatin,prhaps thrgh ificatin f th parasypathticcpnnt f th barrfx58. Cctiy, th atainicat that th pribic an infraibic crtics haiffrnt rs in crinating strss rspnss, ithtf fr th rsa PFC an th pribic cr-tx cnfrring inhibitin, an that fr th infraibiccrtx cnfrring stiatin. As a rst f its intrcn-nctins ith th hippcaps an th aygaa, thprfrnta crtx is psitin at th tp f th rspns-initiatin hirarchy an ight b a principa, bt nt ths, ibic crinatr f physigica ractiity.

Figure 3 | Th ban ty that gat HPA ax t pn. Stress-induced activation of the dorsal part of

the medial parvocellular paraventricular nucleus of the hypothalamus (PVNmpd) originates in several brain regions

(excitatory inputs are coloured blue with solid lines and inhibitory (GABA (-aminobutyric acid)-ergic) inputs are colouredred with dashed lines). The paraventricular nucleus of the hypothalamus (PVN) receives direct noradrenergic, adrenergic

and peptidergic innervation from the nucleus of the solitary tract (NTS). The dorsomedial components of the dorsomedial

hypothalamus (dmDMH) and the arcuate nucleus (Arc) provide intrahypothalamic stress excitation. The anterior part of

the bed nucleus of the stria terminalis (BST), particularly the anteroventralnucleus of the BST (avBST), activates hypotha-

lamic-pituitary-adrenocortical (HPA) axis stress responses. The PVN also receives a stress-excitatory drive from the dorsal

raphe, the tuberomammillary nucleus, the supramammillary nucleus and the spinal cord, among others (omitted in the

interest of space). Activation of the PVNmpd is inhibited by numerous hypothalamic circuits, including the medial

preoptic area (mPOA), the ventrolateral component of the dorsomedial hypothalamus (vlDMH) and local neurons in the

peri-PVN region (pPVN), encompassing the PVN surround and the subparaventricular zone. The posterior subregions of

the bed nucleus of the stria terminalis (pBST) provide a prominent forebrain inhibition of HPA axis responses; most of these

inputs are GABAergic. Brain sections are modified, with permission, from ReF. 154 (1998) Academic Press.

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ANS and HPA axis(systemic stress)

HPA axis(psychogenic stress)

HPA axis(psychogenic stress)

HPA axis(modality undefined)

ANS andHPA axis(psychogenic stress)

ANS and HPA axis(psychogenic stress)

mPOA, amBST, pmBST,DMH, pPVN, PL, IL and LS

avBST, DMH and NTS

mPOA and BST

BST, CeA and MeA

DRN, PVT, pPVNand BLA

BST, NTS, CeA,MeA and BLA

MeA

Limbic site Neurocircuits Primary action

IL

PL

vSUB

BLA

CeA

a

b

c

Other limbic sites. Thr is as inc f strss-rgatry rs fr thr ibic sits, incing th atraspt, th spraaiary ncs an th antrirthaas40,59,60. Fr xap, th atra spt inhibitsHPA axis an atnic rspnss t act strssrs59 a r it shars ith its principa affrnt src, thhippcaps.

Top-down integration of glucocorticoid negative feedback.Th HPA axis is sbct t fback inhibitin by itsprincipa prct, gccrticis (BOX 2). This fbackis iat at ast in part by ibic frbrain strctrs.Bth gccrtici rcptrs (GRs) an inra-crtici rcptrs (mRs) ar abnanty xprss inth hippcaps an ar prbaby ccaiz in snrns61. mRs an GRs ha iffrnt affinitis frcrticstrn (BOX 2), hich rnrs th hippcapsrspnsi t bth basa an strss-inc atinsf crticstrn62. GRs ar as highy xprss in thPFC, bt th xprssin f mRs is r iit hr,sggsting that th PFC ight b ss rspnsi t

gccrtici s. Ipants f crticstris inth PFC inhibit HPA axis rspnss t rstraint btnt thr51, spprting a pssib r in fback inhi-bitin f psychgnic rspnss. Gin that bth thhippcaps an th PFC attnat strss-incincrass in hart rat an b prssr, it is pssibthat n r bth crticstri rcptrs infnc at-nic tf in aitin t HPA axis actiity, bt this

pssibiity has yt t b instigat.Frbrain GRs ar in in rgating bth

th basa HPA tn an th trinatin f th strssrspns. mic ith scti tin f th GR in thcrtx, th hippcaps an th BlA ha atbasa gccrticis an prng crticstrnrspnss t psychgnic bt nt systic strss63,64.Thy ar as rsistant t th inhibitry ffct fxgns gccrticis n HPA axis actiatin63.orxprssin f GR in th frbrain as t rcpak ACTH an crticstrn s fing strss,sggsting that frbrain GRs ar sfficint t rcstrss ractiity65,66. Frbrain mRs ha a r sbt

Figure 4 | oganzatn mb tpt. Limbic modulation of stress responses occurs predominantly through

oligosynaptic inputs to the paraventricular nucleus of the hypothalamus (PVN) and other preautonomic brain regions.

Excitatory inputs are coloured blue and inhibitory (GABA (-aminobutyric acid)-ergic) inputs are coloured red. a | Theventral subiculum (vSUB) coordinates hippocampal stress output by providing glutamatergic input to primarily inhibitory

PVN relays, thereby limiting psychogenic stress responses. b | GABAergic projections from the central amygdala (CeA)

regulate responses to systemic stressors, whereas those from the medial amygdala (MeA) preferentially modulate

responses to psychogenic stressors. Through glutamatergic projections in and outside the amygdala, the basolateral

amygdala (BLA) plays a part in both the acute response to psychogenic stress and chronic-stress regulation. | The

prelimbic cortex (PL) inhibits responses to psychogenic stress, and this inhibition is mediated predominantly by

glutamatergic projections to inhibitory PVN relays. By contrast, the infralimbic cortex (IL) activates autonomic and possibly

hypothalamic-pituitary-adrenocortical (HPA) axis responses to psychogenic stress, perhaps through direct projections (to

the nucleus of the solitary tract (NTS)) or indirect projections (to the CeA). amBST, anteromedial BST; avBST, anteroventralBST; BST, bed nucleus of the stria terminalis; DMH, dorsomedial hypothalamus; DRN, dorsal raphe nucleus; LS, lateral

septum; mPOA, medial preoptic area; pmBST, posteromedial BST; pPVN, peri-PVN; PVT, paraventricular nucleus of the

thalamus; vSub, ventral subiculum. Brain sections are modified, with permission, from ReF. 154 (1998) Academic Press.

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Depressor response

A dcras in blood prssur.

Pressor response

An incras in blood prssur.

r in act HPA axis fback rgatin. Dtin

f mRs in th ibic frbrain has n ffct n basaHPA tn r th pak rspns t rstraint (rcryas nt assss)67. orxprssin f mRs prcsa i spprssin f act-strss rspnss ny infa ic68.

Cctiy, th ata ar cnsistnt ith a ibicintrfac btn gccrtici signas an fbackrgatin f th HPA axis. Th rati iprtanc fibic gccrtici signaing pns n th strssaity: it rgats HPA axis rspnss t psychgnicbt nt systic strss an s pris a cntxt-spcificfback signa that ifis HPA axis inhibitin.

Middle management of stress responses

libic strctrs ha itt irct anatica intr-actin ith priary strss ffctr systs. Intrningsynapss ar rqir t ray infratin fr thaygaa, th hippcaps an th PFC t th pri-ary strss ffctr nrns in th PvN, th caaa an th spina cr3(FIG. 4). In gnra, tptfr strss-xcitatry strctrs (sch as th CA, thmA an th infraibic crtx) ixs ith that fstrss-inhibitry rgins (th hippcaps an th pr-ibic crtx)3, priing pprtnity fr ca intgra-tin f ibic infratin bfr priary strss ffctrsar accss.

mst ibicPvN cnnctins ray thrgh GABA-rich c grps in th b ncs f th stria trina-is (BST) an in th hypthaas3. Ths inhibitryrays pri trans-synaptic inhibitin, transatingxcitatry gtaatrgic tf fr th hippcapsan th pribic crtx int inhibitin f th PvN3.Dscning infratin fr th aygaa ss anyf th sa ray sits, bt hr th pstra nrnsin th CA an mA ar GABArgic69. Ths, actiatinf th PvN by ths aygaa strctrs prbabyrsts fr isinhibitin3. S gr f bisynapticintgratin f strss tf trarss xcitatry nt-rks as . Fr xap, th CA an infraibic

crtx prct t th NTS, hich in trn xcits thHPA axis an th ANS70,71.

Bed nucleus of the stria terminalis. Th BST has nr-s sbrgins that iffr arky in thir cntrib-tins t strss intgratin (FIGS 3,4). Antrntrasbrgins ar iprtant in HPA axis xcitatin, assins thr rc HPA axis rspnss an inhibitact actiatin f PvN nrns fing rstraint72,73(FIG. 4). Th antratra BST cntains crtictrpin-rasing hrn (CRH) nrns that prct t thPvN74,75, sggsting a chanis fr cntra xcitatryactins f CRH n th HPA axis. By cntrast, sinsf th pstria BST incras ACTH an crtic-strn scrtin, PvN FOS actiatin an PvN CRHRNA xprssin72,73, cnsistnt ith a ss f inhibi-try inpt t th HPA axis (FIG. 4). Tracing stis ini-cat that PvN-prcting nrns in this rgin arprinanty GABArgic76, sggsting that, in cn-trast t th antratra PvN, pstrir rgins inhibitHPA rspnss t strss.

Th prcis r f th BST in atnic rgatinrains t b fin. In anasthtiz rats, chicar ctrica stiatin f th BST prcs pri-nantydprssor rsponss, particary hn th sti-atin is irct t th antria sbrgin7779.Hr, in aak anias, pharacgica actiatinf this rgin icits a rapi prssor rspons fby braycaria80,81, hras inactiatin xacrbatsrstraint-inc incrass in hart rat82. This inicatsthat BST signaing is ncssary fr inhibiting carias-car rspnss t strss. matin f th hart rat byBST stiatin r inhibitin ss t b iatby th parasypathtic nrs syst80,81.

Hypothalamic nuclei. Sra hypthaaic rgins pr-i th ptntia fr intractin btn scningibic inpt an hstatic intgratin. Hypthaaicrays btn ibic sits an HPA an ANS tptnrns pri a ans t gat rspnss t strssrsith rspct t nging physigica stats.

Th ia prptic hypthaas (PoA) sp-pis GABArgic innratin t th PvN (FIG. 3). PoAsins nhanc HPA axis rspnss t strssrs83, anca inactiatin nhancs ACTH ras. Bth fths ar cnsistnt ith a ss f inhibitry inpt tth PvN84. mrr, PoA sins bck th xcita-try ffct f aygaa stiatin n crticstrn

ras85, sggsting that th aygaa is an pstraatr f PoA nrns that cntr th HPA axisrspns. In, th PoA is a prinnt targt fprctins fr th hippcaps an th mA an isiprtant in th intgratin f gnaa stri signas,by tpratr an sp86; it ths pris a sit frintractin btn ibic inpts an physigicargatry prcsss.

libic ffrnts as innrat th ibasahypthaas, incing th arcat ncs87(FIG. 3),hich is a ky rgatr f nrgy baanc an ssth PvN as a nstra ffctr t rgat fingan nrgy xpnitr (thrgh nrpptirgic an

Box 2 | Corticosteroid receptors and negative feedback

Glucocorticoids have both genomic and non-genomic actions thoughout the body.

Genomic actions occur following binding to glucocorticoid receptors (GRs) and, in the

case of some tissues, mineralocorticoid receptors (MRs). These receptors act as

ligand-activated transcription factors to affect broad, long-latency and biologically

long-acting changes in gene transcription62. The MR has a high affinity for endogenous

glucocorticoids and is extensively bound even during the circadian nadir of

corticosteroid secretion. The GR has a lower affinity and is extensively bound only atrelatively high levels of corticosteroids, such as those that occur during stress

responses121. The GR seems to be the primary mediator of delayed glucocorticoid

inhibition of stress responses. By contrast, non-genomic effects occur within minutes of

glucocorticoid release and probably involve action at the target cell membrane.

Non-genomic signalling accounts for fast negative feedback-inhibition of the hypo-

thalamic-pituitary-adrenal axis, which occurs within minutes of the rise in circulating

glucocorticoids (far too fast to be mediated by genomic actions in any traditional

sense). It is currently unclear whether this mechanism involves membrane actions of

the known nuclear receptors (GRs and MRs) or an as yet unidentified membrane

corticosteroid receptor.

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Glutamic acid decarboxylase

(GAD). Th nzym that

synthsizs GABA. It xists in

two isoforms, GAD65 and

GAD67.

GABArgic prctins)88. Th nt tpt fr th arc-at t th PvN is cpx, cnicating bth rxi-gnic (nrppti Y an Agti-rat ppti) ananrxic (fr xap, -ancyt-stiating hr-n)88 signas. Ntaby, any f ths pptis actiatth HPA axis, ipying that bth psiti an ngatinrgy baanc rprsnt hstatic strssrs89.

latra hypthaaic nrns ar actiat by strs-srs40 an ths ar psitin t at atnican/r HPA tn. Th atra hypthaas is targt byhippcapa, prfrnta crtica an aygaar ffrntsan is iprtant in crinating ingsti bhairs86.Gtaatrgic, GABArgic an pptirgic nrns arhighy intring in this rgin, aking it iffict tprict its nt ipact n strss rspnss90,91.

Th sprachiasatic ncs (SCN) has a sbstan-tia ipact n basa HPA an atnic tn an nrspnss t psychgnic strssrs9294. Th SCN hasf irct prctins t th PvN bt haiy innratsth ara srrning th PvN95, hr it can intrfacith inpt fr ibic sits. Th SCN is th priary

crinatr f physigica rhyths an is ths psi-tin t at HPA axis tpt in cnnctin ithti-f-ay cs.

Neural control of chronic-stress responses

Chrnic strss xpsr physicay atrs th strctran fnctin f brain rgins in in cntring HPAan atnic rspnss t strss (TABLe 1). In th hip-pcaps an prfrnta crtx, chrnic rstraint cassrtractin f apica nrits an rcs spin nsityin pyraia cs96,97. Cnrsy, incras nriticbranching is bsr in th BlA98. Chrnic strss asincs changs in th PvN, incing incras xprs-sin fCRHan asprssin RNA99,100, rc GRxprssin99,100 an atr xprssin f nrs nr-transittr rcptr sbnits101,102. Finay, nrchicachangs ar sn in nrs strss rgatry pathays

that prct t th PvN, incing incras glutamic aciddcarboxylas xprssin ( ipying incras GABAs) in th hypthaas an th BST103.

Sensitization of stress responses. Nrchica i-nc sggsts that chrnic strss nhancs th xcit-abiity f th HPA an th sypath-arnarysysts. Faciitat ACTH an crticstrn rspnsst n strssrs ccr aftr chrnic ri by ithrhtypica r nprictab strss rgins104,105. Thisrspns faciitatin ccrs spit car inc frnging r cati atin in gccrtici -s, ipying that fback fficacy is iinish an/rri is incras.

Chrnic strss can rcrit pathays that ar istinctfr ths in in act rspnss. Fr xap,sins f th parantricar thaas inhibit thpnt f chrnic-strss-inc faciitatin fHPA axis actiatin bt nt affct rspnss t actstrss106, inicating that this rgin is ngag ringrpat chrnic strss xpsr. By cntrast, sins

f th hippcaps nt affct HPA axis rspnssassciat ith chrnic strss47, sggsting that its rin HPA axis rgatin is iinish by rpat strssxpsr. Th BST ss t b iffrntiay inin act- an chrnic-strss rspnss, as sins f thantratra BST rc HPA axis rspnss t actstrss bt nhanc chrnic-strss-inc faciitatin fHPA axis actiatin107.

Rpat xpsr t c nhancs strss-incnrarnain ras in th frnta crtx an snsitizsth firing rat f cs crs nrns fing an strssr108110. Chrnic c strss as incrassth snsitiity f th cs crs t CRH, sggst-ing that sch strss incrass th rspnsinss t afactr that is ras ring strss109. Finay, chrnicstrss incrass th xprssin f tyrsin hyrxyas,th rat-iiting nzy in nrarnain synthsis, in

Table 1 | Neuroplastic responses to chronic stress

st chn-t-n patty et

Hippocampus Dendritic atrophy and decreasedGRexpression

Decreased HPA feedback and decreasedmemory

Medial prefrontal cortex Dendritic atrophy and decreasedGRexpression

Decreased HPA feedback, decreasedmemoryextinction and decreasedreward

Central amygdala Increased CRH expression and release Increased HPA and autonomic excitability, andanxiety

Basolateral amygdala Increased dendritic branching andincreasedstress excitability

Increased HPA and autonomic excitability,increased emotional memory and decreasedreward

Paraventricular nucleusof the thalamus

Increased stress excitability Increased HPA excitability to novel stress anddecreasedHPA excitability to familiar stress

Locus coeruleus Increased neurotransmitter releaseandincreasedstress excitability of projectionsto the cortex and hippocampus

Increased HPA excitability to novel stress

Paraventricular nucleusof the hypothalamus

Increased secretagogue synthesis,increasedstress responsivenessanddecreasedGR expression

Increased excitability to novel stress

CRH, corticotropin-releasing hormone; GR, glucocorticoid receptor; HPA, hypothalamic-pituitary-adrenocortical; mPFC, medialprefrontal cortex.

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th cs crs, as as that f ccaiz nr-pptis (fr xap, gaanin). This is cnsistnt ithan nhanc capacity fr nrarnain ras 111,112(bt s as ReF. 113). Th cs crs s ntha sbstantia prctins t th PvN5, sggstingthat cntribtins t HPA axis rgatin ar i-at by pstra aras (fr xap, th hippcaps,th PFC an th aygaa) r nstra targts(th ntratra a an th spina cr).

Th CA is ipicat in chrnic strss rgatinbcas f its snsitiity t crticstris. High sf gccrticis incras CRHRNA xprssin inth CA114, an ffct that is iick by s chrnicstrss rgins (fr xap, chrnic ibiiza-tin an chrnic pain)115 bt nt thrs (fr xap,chrnic rstraint, chrnic nprictab strss anrpat pratr xpsr)116. In shp, rpatstrss (g xpsr) cass CRH ras in th CA,hich ss t b crcia fr snsitizatin f bthth CRH rspns in th PvN an crtis ras nrpat xpsr117. Th aygaar CRH rspns

t rpat strss is bck by prtratnt ith a GRantagnist, ipying that crticstris ar rqirfr th nhanc CRH ras that ccrs in th CAring rpat strss117,118.

Athgh gccrtici scrtin c b ipr-tant fr strss snsitizatin f th aygaa, chrnicstrss prcs ark rctins in gccrticisignaing in thr brain rgins. Nrs chrnic-strss rgins cas nrgatin f GR an, t assr xtnt, mR RNA, bining an prtin s inth PFC an th hippcaps99,119121. This nrg-atin c b assciat ith a ss f gccrticingati-fback snsitiity, at ast in trs f inhibit-ing th circaian ris in crticstrn s120,121. Ths,chrnic strss ss t b sfficint t bth apnngati-fback signaing by strss-inhibitry path-ays an nhanc psiti ri thrgh rgins schas th CA hich, tgthr r an, c cntribt tan nhanc ri f th PvN.

Snsitizatin f atnic rspnss is bsr ins chrnic strss s. In rats, chrnic i strssprcs xaggrat hart rat an prssr rspnsst a n strssr 122. Hr, th nra sbstrats fANS snsitizatin ar nt knn.

Habituation of stress responses. Rspns habitatinhas bn bsr n rpat xpsr t i strs-

srs. In this cas th agnit f th rspns iin-ishs ith ach xpsr, n as rspnss t nstrssrs ar faciitat104,123. Th cras physi-gica rspnss ar para by a cras in cntrastrss-inc FOS xprssin124. Th habitatin pr-css ss t in mRs, as systic tratnt ithmR antagnists rrss th rc crticstrnrspnss t rpat rstraint125. lsins f th paran-tricar thaas inhibit habitatin f crticstrnrspnss t rpat rstraint126 (hr, s ReF. 127)itht affcting act rspning. In cbinatin ithth ffcts f sins in this rgin n faciitatin106, thparantricar thaas ss t b iprtant in

transcing infratin rgaring th chrnicity fstrss xpsr. Ntaby, this rgin rcis hay pr-

ctins fr th ntra sbic an th PFC76,128,129an prcts haiy t th CA130,131, priing a ps-sib intriary ray btn strss-inhibitry anstrss-xcitatry brain rgins.

Habitatin f atnic rspnss is highy pn-nt n th strss rgin. Chrnic scia strss cassiit habitatin f hart rat rspnss t attack insbissi bt nt inant ic132. Chrnic strssas prcs ng-tr changs in atnic fnctin,incing incras hart rat, cras hart rat ari-abiity (in rats)122 an cras b prssr ariabiity(in ic)133. As is th cas fr rspns faciitatin, thnra chaniss that nri habitatin f at-nic changs by chrnic strss ha yt t b xpr.

Memory, reward and stress responses

Emotional learning and memory. Intrprting th pr-icti significanc f nirnnta stii is crciafr apprpriat cntr f physigica rspnss t

strssrs: th rspns t stii assciat ith a highysaint ngati (r psiti) tc sh b appr-priat fr cping ith ths stii, hras a rspnsgnrat t inncs stii b infficint antabicay csty. Ths, crtain ris ncragrspnss t sitatins that ar iky t ha an arstc an iscrag rspnss t irrant rhabitat stii.

libic sits that rgat HPA an ANS rspnss incing th aygaa, th hippcaps an thPFC ar in in cnitining bhairarspnss t tina stii (ri in ReFS 134137) an ar ths as pis t iat cnitiningf HPA an ANS actiity. In spprt f this, cni-tin HPA actiatin aftr cnitin tast arsin(s Sppntary infratin S1 (bx)) is bck byhippcapcty138, an th xprssin f cnitinHPA rspnss aftr cntxta- r tn-ftshck cn-itining is bck by CA sins139. Cnitin prs-sr an tachycaria rspnss t cntxta ftshckcnitining ar as rc by prtrating th ntraPFC ith CC

2(a nn-scti synaps bckr), an

NmDA (N-thy-d-aspartat) rcptr antagnist rnrna nitric xi synthas inhibitrs57,140.

Thr is as inc fr cnitining f strssrspnss at th f th ray aras t HPA an at-nic ffctrs. lsins f th BST bck crticstrn

rspnss t cntxta bt nt tn cnitining, ps-siby ing t cnnctins btn th BST an thhippcaps139. lsins f th prifrnica hypthaa-s an f th atra hypthaas isrpt s typsf cnitin strss rspnss141144, raising th pssi-biity that cnitin HPA an ANS actiatin ightas b intgrat at th f ibic-hypthaaicray aras, hich in trn sggsts that bth ibic anhstatic signas ar in in gnrating arnrspnss.

Stress and reward. Thr ss t b a rciprcaratinship btn rar an strss prcssing

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in th brain. expsr t natra rars bffrs thffct f strssrs n HPA actiity, an strss incrassrar-sking bhair (fr xap, intakf paatab f r rinstatnt f rg-takingbhair). exprincs ith raring stii gn-ray k strss-ik HPA an ANS rspnss (sSppntary infratin S2 (bx)). Th ffcts

ary pning n hthr th rar is natra (frxap, sxa bhair, ntary h rnning rpaatab f intak) r pharacgica (fr xa-p, rgs f abs), an n hthr th xprincsr sf-ainistr (fr xap, by r prss) rinstigatr-ir.

Th priary brain rar circit cnsists fpainrgic prctins fr th ntra tgntaara t th ncs accbns (NAc) an has xtnsicnnctins ith th BlA an PFC (ri in ReFS145147). Th NAc, BlA an PFC ar iy rcg-niz as ky iatrs f rspnss t natra rarsan rgs f abs145147. As th PFC an BlA rg-at strss rspnss an ar in in cnitining t

saint tina stii, ths strctrs ar ikyt rgat HPA an ANS rspnss t bth ncni-tin an cnitin rar xpsr. It is nt carhthr th NAc as rgats HPA axis an ANS acti-ity, bt prctins fr th NAc cr an sh t brainrgins sch as th atra hypthaas, th BST, thatra prptic ara an th parabrachia ncs148,149pri an anatica sbstrat fr ptntia physigi-ca ffcts n th HPA axis an ANS. Ths, thr is cn-sirab anatica rap ang th brain rginsthat sbsr rar prcssing, tina arning anstrss rspnss.

Overlapping circuits that mediate stress, memory andreward: functional significance. Strss rspnss ath ania t cp ith arsi stii that rprsntra r anticipat thrats t hstasis, bt ntinga strss rspns is nrgticay aning. Ths, thris an aantag t arning hn a particar sitatin isnt a thrat an t pr-ptiy rcing an nsingstrss rspns; rr, it is aantags t b abt assciat spcific nirnnta cs ith a partic-ar strssr s that strss rspnss can b nt inanticipatin f prict strssrs, thrby iniizinghstatic isrptin.

Raring stii (particary ths that ar n,nprict an/r nt sf-ainistr) can b cn-

sir strssf bcas thy isrpt hstasis. Inparticar, rgs f abs icit strng ncnitinan cnitin actiatin f th HPA axis an ANSthat ar ink t th aictin prcss150,151. Hr,raring stii pri fnantay iffrntxprincs fr thr typs f strssrs bcas ani-as ar tiat t btain th. In fact, chrnic -ntary ngagnt in natray raring bhairs,sch as paatab f intak, rcs strss rspnss;ths fnantay pasrab xprincs s tha anti-strss ffcts. Ths, th brain can tair strssrspnss bas n th ccti xprincs f aniniia.

Conclusions and future directions

Nra cntr f strss is a cpx prcss thatrqirs th intgratin f infratin rgaring bthacta an ptntia tcs. Highr-rr prcssingf strss ins stiating th ptntia significanc fa gin stis. Th pysynaptic rganizatin fstrss pathays frthr sggsts that inpts that rayinfratin n th physigica stats f th aniacan cntribt t th nta ncrin r atnicrspns t th strssr.Th ast arity f ci-sins rgaring th initiatin f physigica strssrspnss s t b a at th f ibic strc-trs, hich cnicat infratin t sbcrticasits psitin t intrfac ith nging hstaticfback.

onging fnctina stis sggst that thr is acnsirab iisin f abr ang ibic sits.Cnnctins btn th infraibic crtx, th CA,th ntratra BST, th PvN an th NTS an at-nic ffctrs sggst a ans by hich th iprtantiiat ffctr th sypath-arnary

syst

is brght nin. Rspnss f th thrffctr th HPA axis in a ntrk that cn-ncts th pribic crtx, th mA, th hippcaps,th pstrir BST, th prptic ara an thr hyptha-aic nci ith hypphysitrphic nrns f thPvN; ths cnnctins sr t initiat as as tr-inat gccrtici ras in rspns t nra anhrna fback. Th physica sparatin f at-nic an HPA strss ffctr circits prts sgr f inpnnc f th t strss-atrycascas, aing fr apprpriat tning f nra anhrna rspnss t spcific an charactristicsf th acta r anticipat nt. Hr, ths tphysigica systs as rk tgthr, bth in trsf rap in thir nrying nra circitry an intrs f thir physigica fnctins. Ftr grthf th strss physigy fi i n t inc rrk that brigs th prrbia HPA rss ANSii, thrby priing a r cpt pictr fh an iniia arns t anticipat an thriscp ith strss.

whras th ffctr circits that cntr strss arprbaby har-ir, th ra ighting f infra-tin is sbct t cnsirab iniia ariatin. It isiky that ysfnctins f infratin prcssing acrssths circits, rsting fr nirnnta arsityan/r gntic factrs, i at th rt f aaapti

strss ractins that can cinat in affcti isas(fr xap, prssin an pst-traatic strss isr-r) an physica infiritis. Iprtanty, strss rsarchgnray fcss n th s f ngati stii as strs-srs (that is, sitatins that iniias ai ifpssib). Hr, psiti stii (sch as nrars) can cas cparab physigica strssrspnss spit th fact that iniias ar tiatt btain th. An nrstaning f h an hy thisapparnt cntraictin ccrs is ncssary t apprciathy iniias ak th chics that thy , an hth brain an by cp ith th cnsqncs f thrsting actins.

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One of an excellent series of papers from the

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AcknowledgementsThe authors thank present and past members of the Herman

laboratory for their contributions to this work, and S. Woods

for his comments on the Review. The authors work c ited in

this Review was supported by US National Institutes of Health

grants MH049698, MH069860, MH069725, AG12962

and DK078906.

DATABASESez G:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene

FOS

FURTHER INFORMATION

Jam P. Hma hmpag:www.psychiatry.uc.edu/hermanlab

SUPPLEMENTARY INFORMATIONs li ail:S1 (box) | S2 (box)

All liNks Are AcTive iN THe oNliNe Pdf

r e V I e W s f oc us on s tr e s s
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Regulación neural de las respuestas endocrinas y autonómicas al estrés - Nature Neurosc 2009

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