• Embed Doc
  • Copy Link
  • Readcast
  • Collections
  • CommentGo Back
Download
 
Th prfrnta crtx (PFC) intignty rgatsr thghts, actins an mtins thrgh xtnsivcnnctins with thr brain rgins
(BOX 1)
. It cr-ats a “mnta sktch pa” (t s a phras cin by Aan Bay) thrgh ntwrks f nrns that canmaintain infrmatin in th absnc f nvirnmntastimatin
1
. Nrscintists sch as Patricia Gman-Rakic rfrr t this prcss as wrking mmry: thabiity t kp in min an vnt that has st ccrr,r bring t min infrmatin frm ng-trm strag,an s this rprsntatina knwg t rgatbhavir, thght an mtin
2
. Th PFC is ab tprtct ths fragi rprsntatins frm th intrfr-nc f xtrna r intrna istractins, an is ky frinhibiting inapprpriat actins an prmting task-rvant pratins (s-ca ‘tp-wn’ rgatin)
3–6
.PFC pratins aw th fxib rgatin f bhavirt nab s t prpry rspn t a changing nvirn-mnt — fr xamp, th abiity t shift
attentional set
tnw imnsins an t atr cisin making as rwarcntingncis shift
7,8
. Th PFC as mnitrs rrrs, giv-ing s th insight that w ar incrrct an n t shiftstratgis
9
. A f ths abiitis pn n prpr PFCnrna ntwrk cnnctins, which ar highy snsitivt thir nrchmica nvirnmnt.This Rviw iscsss hw nrmatry changsthat ccr ring strss rapiy isrpt PFC ntwrk cnnctins an marky impair PFC fnctin. Itfcss n th spatia wrking mmry fnctins f thPFC bcas th circitry, physigy an matinf th rsatra PFC nrns that miat wrkingmmry ar th bst charactriz f this brain rgin.Th Rviw first scribs hw xpsr t vn mincntrab strss can rapiy impair PFC fnctinsin hmans an animas. It thn scribs th xtrac-ar an intracar mchanisms that cntribt tPFC ficits, an hw chrnic strss xpsr ast strctra changs in th PFC. Finay, it highightshw gntic an nvirnmnta changs in strss sig-naing pathways ar assciat with mnta inss, anhw an nrstaning f ths pathways might a tbttr tratmnts fr nrpsychiatric isrrs.
Acute stress impairs PFC function
Human studies.
Sm f th first stis n th ffctsf strss n cgnitin bgan aftr th Scn Wr War,bas n bsrvatins that pits wh wr highy skiring pactim ftn crash thir pans in th strssf batt wing t mnta rrrs
10
. Rsarch was initiatt xprimntay manipat strss vs t s hw thisatr prfrmanc an cgnitiv abiitis
11
. Many f ths ary stis shw that strss xpsr impairth prfrmanc f tasks that rqir cmpx, fxibthinking, bt that it c actay imprv th prfrm-anc f simpr an/r w-rhars tasks
10,12
. W nwnrstan that th typs f tasks that wr impair by strss wr ths that rqir PFC pratins
13
, whrasngrain habits that ry n basa gangia circits wrspar r nhanc
14
.Ths ary stis as pint t th ssntia rf th sbct’s sns f cntr vr th strssr. Sbctswh ft in cntr f th sitatin (vn if this was an
Dpartmnt of Nurobology,Yal Unvrsty School of Mdcn, 333 Cdar Strt,Nw Havn, Connctcut 06510, USA.‑mal:amy.arnstn@yal.du
doi:10.1038/nrn2648
 Attentional set
A predisposition to attend toone dimension of a stimuluswhile inhibiting otherdimensions — for example,attending to colour rather thanshape.
Stress signalling pathways thatimpair prefrontal cortex structureand function
 Amy F. T. Arnstn
Abstract | The prefrontal cortex (PFC) — the most evolved brain region — subserves ourhighest-order cognitive abilities. However, it is also the brain region that is most sensitive to thedetrimental effects of stress exposure. Even quite mild acute uncontrollable stress can causea rapid and dramatic loss of prefrontal cognitive abilities, and more prolonged stress exposurecauses architectural changes in prefrontal dendrites. Recent research has begun to reveal theintracellular signalling pathways that mediate the effects of stress on the PFC. This researchhas provided clues as to why genetic or environmental insults that disinhibit stress signallingpathways can lead to symptoms of profound prefrontal cortical dysfunction in mental illness.
REVIEWS
 410
|
juNe 2009
|
VoluMe 10
www.na.m/w/n
 
REVIEWS
© 2009 Macmillan Publishers Limited. All rights reserved
 
 
HypothalamusStriatum
Bottom-upattentionEmotionalhabitsEmotionalassociationsEmotionalreflexesDMPFC
•
Reality testing
•
Error monitoring
DLPFC
•
Top-down guidance
of 
attention and thought
rIPFC
•
 
I
nhibition of inappropriate ac
tions
VMPFC
•
Regulating emotion
AmygdalaHypothalamusStriatum
a
Prefrontal regulation during alert, non-stress conditions
b
Amygdala control during stress conditions
 
Loss of prefrontalregulation
NANADA
Amygdala
DA
Trier social stress test
A test in which subjects have togive a speech and performcalculations in front of a panelof people they do not know.Blood or saliva samples andblood pressure measurementscan be taken before, duringand after the test to determinethe physical response to thestressor.
isin) wr ftn nt impair by strss xpsr,whras ths wh ft t f cntr wr impair
15
.Anima stis hav cnfirm th ky r f cntr
16
.Th cntr factr pss a particar prbm fr mrnstrss rsarch in hman sbcts, as thicay a sbctsmst b givn cntr f thir sitatin an b ab t avth xprimnt at any tim. Nnthss, paraigms havmrg that ar ffctiv in crating a sns f ncn-trab strss in an xprimnta stting. Fr xamp,n fnctina imaging sty ha fma sbcts watchmtinay pstting mvis an fn vinc f rc activatin in PFC rgins
17
. emtina istractrscan simiary iminish rsatra PFC activity in sb- cts prfrming a wrking mmry task 
18
. Many stisf hrmna rspnss t strss hav s a pbic spak-ing task as an ffctiv strssr (th
Trier social stress test
).This scia strssr has bn fn t impair cgnitivfxibiity 
19
an wrking mmry 
20
, bth f which rqirPFC fnctin. Intrstingy, this sam scia strssr act-ay imprv cassica cnitining fr ngativ stimi,
Box 1 |
Prefrontal cortical versus amygdala circuits: the switch from non-stress to stress conditions
The prefrontal cortex (PFC) has extensive connections with other cortical and subcortical regions that are organized in atopographical manner, such that regions that regulate emotion are situated ventrally and medially (green area in part
a
of the figure) and regions that regulate thought and action are situated more dorsally and laterally (blue and blue–green areasin part
a
). The dorsolateral PFC (DLPFC) has extensive connections with sensory and motor cortices and is key forregulating attention, thought and action
163
. In humans, the right inferior PFC (rIPFC) seems to be specialized for inhibitinginappropriate motor responses
4
. By contrast, the ventromedial PFC (VMPFC) has extensive connections with subcorticalstructures (such as the amygdala, the nucleus accumbens and the hypothalamus) that generate emotional responses andhabits
164-166
and is thus able to regulate emotionalresponses. Finally, the dorsomedial PFC (DMPFC)has been associated with error monitoring
9
and, inhuman functional MRI studies, reality testing
167
.These PFC regions extensively interconnect toregulate higher-order decision making and to planand organize for the future. Under non-stressconditions (see part
a
of the figure), the extensiveconnections of the PFC orchestrate the brain’sactivity
 
for intelligent regulation of behaviour,thought and emotion. The PFC
 
also has direct andindirect connections to monoamine cell bodies inthe brainstem, such as the locus coeruleus (LC)(where noradrenaline projections arise) and thesubstantia nigra (SN) and ventral tegmental area(VTA) (where the major dopamine projectionsoriginate), and thus can regulate itsown catecholamine inputs. Optimal levels of catecholamine release in turn enhance PFCregulation, thus creating a ‘delicious cycle’. Underconditions of psychological stress (see part
b
of thefigure) the amygdala activates stress pathways inthe hypothalamus and brainstem, which evokeshigh levels of noradrenaline (NA) and dopamine(DA) release. This impairs PFC regulation butstrengthens amygdala function, thus setting up a‘vicious cycle’. For example, high levels of catecholamines, such as occur during stress,strengthen fear conditioning mediated by theamygdala
168
. By contrast, stress impairshigher-order PFC abilities such as working memoryand attention regulation. Thus, attention regulationswitches from thoughtful ‘top-down’ control by thePFC that is based on what is most relevant to thetask at hand to ‘bottom-up’ control by the sensorycortices, whereby the salience of the stimulus (forexample, whether it is brightly coloured, loud ormoving) captures our attention
5
. The amygdala alsobiases us towards habitual motor responding ratherthan flexible, spatial navigation
14
. Thus, duringstress, orchestration of the brain’s responsepatterns switches from slow, thoughtful PFCregulation to the reflexive and rapid emotionalresponses of the amygdala and related subcorticalstructures.
REVIEWS
NATuRe ReVIeWS
|
 
NeuroscieNce 
VoluMe 10
|
juNe 2009
|
 
 411
focu
 
S on StRESS
© 2009 Macmillan Publishers Limited. All rights reserved
 
Learned helplessnessparadigm
A paradigm developed morethan 30 years ago in which ratswere exposed to inescapableshock, and supposedly learnedthat they were helpless torespond. Research hasdebunked this interpretationand instead determined thatuncontrollable stress can causecognitive deficits.
 Y-maze task
A task in which rats must learnto escape from a Y-shapedmaze by making the correctdecision. Exposure touncontrollable stress and thepresence of task-irrelevantcues in the maze has beenfound to impair performance.
Spatial delayed alternationtask
A test of spatial workingmemory for primates orrodents in which the subject isrequired to make alternateresponses on successive trials,with a delay period interposedbetween trials.
Tuned persistent firing of neurons
The neuronal representation of a specific stimulus — forexample, a cue in a specificspatial location. Owing tonetwork connections, a cell cansustain firing withoutstimulation from theenvironment, but the sustainedfiring (in this example) occursonly following a cue to aspecific location in space; thusthe neuron is ‘tuned’ to thatdirection.
as w as hippcampa spatia mmry 
20
. Ths fin-ings in hmans ar highy cnsistnt with anima stisshwing that act mi strss impairs prfrnta fnctinbt actay imprvs th fnctining f th amygaaan hippcamps (s bw). othr stis hav fnimpair PFC fnctin in sbcts sing mnta imagry f thir wn vrwhming xprincs
21,22
an in micastnts as thy sti fr th Bars
23
.Th rctin in PFC fnctining that ccrs ringstrss is highy rvant t nrstaning hman mntaan physica hath. lss f sf-cntr ring strss xp-sr can a t raps f a nmbr f maaaptiv bhav-irs, sch as rg aictin, smking, rinking achan vrating
22
. Prng strss is a mar risk factrfr prssin
24,25
, an xpsr t tramatic strss cancas pst-tramatic strss isrr (PTSD)
26
. Strsscan as xacrbat th symptms f schizphrnia
27,28
 an bipar isrr by, fr xamp, switching patintsfrm a pri f nrmacy (thymia) int a manicstat
29
. Givn ths pwrf ffcts n hman hath, itis imprtant t hav anima ms f th strss rspnst hp s nrstan th mchanisms that rnr s vnrab.
 Animal studies.
eary stis f th ffcts f strssn prfrmanc in rnts s th s-ca
learnedhelplessness
 
paradigm
. Ths stis wr amng th firstt shw that ncntrab strss (that is, inscapabshck) bt nt cntrab strss impair prfrmancn a
 Y-maze task
wing t ficits in sctiv attntin
16
.Mr rcnt stis sing this paraigm hav shwn thatwhn th anima prcivs itsf as bing in cntr thPFC is ky fr spprssing strss rspnss triggr inth brainstm
30
.
 
In, th PFC an th hippcampsar th tw brain strctrs that ar psitin t inhibitth gccrtici strss rspns
31
.Svra stis hav s tasks that xpicity ry n PFC fnctin t xamin th ffcts f mi strss ncgnitiv prfrmanc. Ths stis s spatiawrking mmry tasks in rats an mnkys an fnthat qit mi act strss impair th accracy f rspning an ftn prc a prsvrativ pattrnf rspns that is cnsistnt with PFC ysfnctin
32–34
.Fr xamp, a whit-nis strss that impairs cgni-tiv abiitis in hmans was fn t as impair spatiawrking mmry in mnkys
33
. Cnvrsy, prfrm-anc f cntr tasks with simiar mtr an mtivatinamans bt n n fr PFC rgatin was nt atrby mi strss xpsr. Simiary, rats xps t actstrssrs wr impair n a
spatial delayed alternationtask
that rqirs mia PFC fnctin, bt wr ntimpair n a nn-PFC-riant spatia iscriminatintask in th sam maz
32
.By cntrast, act mi strss xpsr has n ffct nr can actay imprv th mmry cnsiatin fnc-tins f th hippcamps an th amygaa
35,36
. (Nt thatth vntrmia PFC rgats th far rspnss mi-at by th amygaa; s
REF. 37
fr a rcnt rviw.) Mrsvr act strssrs impair hippcampa fnctins
38
btcntin t strngthn th mtina assciatins anmtr habits carri t by th amygaa an striatm,rspctivy 
14,39
. Ths, act ncntrab strss impairsPFC-miat cgnitiv fnctins in hmans an ani-mas an switchs th cntr f bhavir an mtint mr primitiv brain circits.
Catecholamines mediate acute-stress effects
Hw  nrchmica changs vk by xpsr tact strss impair PFC fnctin? PFC wrking mmry abiitis crciay pn n th prcis activity f intr-cnnct nrna ntwrks. Th micrcircitry thatsbsrvs spatia wrking mmry in primats has bnan attractiv m fr sty, as th anatmy, physigy an nrmatin f ths ntwrks ar w charac-triz wing t th pinring wrk f Gman-Rakican cags
40
. This Rviw fcss n catchaminmatin f spatia wrking mmry circits, as thisis crrnty th arna whr w bst nrstan hwstrss-ik atratins in th chmica nvirnmnt atrnrna rspns pattrns in primat prfrnta nt-wrks that ar activy ngag in a cgnitiv pratin.It is hp that ftr stis wi xtn this appracht thr crtica rgins, aitina cgnitiv pratinsan thr ky nrmatrs.Th circits that nri spatia wrking mmry hav bn mapp in grat tai. In th primat crtx,highy prcss visa spatia infrmatin is f fr-war frm th parita assciatin crtics t th prin-cipa sca crtx in th rsatra PFC
40
. This ara iscrcia t spatia wrking mmry, as sins in this arabt nt in th srrning tiss prc prfn anprmannt ficits n spatia wrking mmry tasks
40
.Micrcircits in th PFC can maintain rprsntatins f  visspatia infrmatin in th absnc f nvirnmn-ta stimatin — fr xamp, ring th ay priin a wrking mmry task. Fnahashi
et al.
41
vpa task t prb th spatia wrking mmry circitry,ca th cmtr ay rspns (oDR) task 
(FIG. 1)
. In this task, th mnky has t rmmbr a pr-cis spatia catin vr a ay pri bfr mvingits ys t th rmmbr catin t rciv a icrwar
(FIG. 1a)
. each sssin cnsists f hnrs f tri-as, with th crrct spatia psitin changing btwntrias. Ths, th cntnts f wrking mmry mst bcnstanty pat. Sing nits ar rcr frm thPFC
(FIG. 1b)
whi th mnky prfrms th oDR task.In this rgin many nrns shw highy 
tuned, persistentactivity
ring th ay pri; this activity rprsntsspatia psitin in th absnc f nvirnmnta stim-atin (fr xamp, s
FIG. 1c
). Th prsistnc f n-rna activity ring th ay pri is thght t arisfrm rcrrnt xcitatin btwn PFC pyramia cswith shar inpts frm th parita crtx — that is,btwn pyramia cs with simiar spatia charactr-istics
(FIG. 1d).
Ths xcitatry rcrrnt
 
cnnctinsprbaby invv NMDA (
N 
-mthy-d-aspartat) anAMPA (α-amin-3-hyrxy-5-mthy-4-isxaz pr-pinic aci) rcptr synapss nt nritic spins. By cntrast, th high gr f spatia tning ariss frmth activity f ca inhibitry intrnrns (fr xam-p, GABA (γ-aminbtyric aci)-rgic baskt cs anchanir cs
(FIG. 1d)
), which prvi atra inhibitin.
REVIEWS
 412
|
juNe 2009
|
VoluMe 10
www.na.m/w/n
 
REVIEWS
© 2009 Macmillan Publishers Limited. All rights reserved
of 00

Leave a Comment

You must be to leave a comment.
Submit
Characters: ...
You must be to leave a comment.
Submit
Characters: ...