β
1R CRHR1CRHR2MR GR MedialprefrontalcortexCA1CA3Lat.septumBnSTPVNCeAMABLALCNTSDR DG
We cnfine the discssin t CRH and vas-pressin, athgh ther peptides as edi-ate the effects f stress (rexin, ghrein anddynrphin) r cnteract the stress respnsender specific cntexts (xytcin and ner-peptide Y); additina peptides ay regatestress-reated anxiety and dysphria (frexape, gaanin and sbstance P)
26
.The cannica stress-activated ner-peptides incde the CRH faiy and vaspressin, which were first discvered inthe hypthaas
24,25
. CRH is reeasedin respnse t stress fr axn terinas inthe hypthaaic edian einence and actsn receptrs in the pititary
24
. Hwever, it isnw knwn t as be expressed in nernappatins in the aygdaa
24,26
, the hipp-caps
27
and the cs ceres
28
. Actingcay, the peptide exerts nerdatry effects n target nerns within secndsafter its reease
9,29,30
, thrgh tw G prtein-cped receptrs, CRHR1 and CRHR2.CRH receptr ccpancy infences ner-na firing patterns
9,29,30
, gene expressin
11,26
and behavir
11,26,31–33
, in a CRH dse- andcntext-dependent anner. Fr exape,reease f CRH in the centra nces f the aygdaa dring acte stress enhancesery cnsidatin
34,35
, and CRHreeased by dest stress fr hippcapainternerns
11,56
pries ng-ter ptentia-tin
36
and iprves ery
37
. By cntrast,hippcapa reease f arge ants f CRH in respnse t severe stress
38,39
can eadt hyperexcitabiity and seizres
9,40
and trapid ss f dendritic spines in CA3pyraida ces
39
. CRH ight ascntribte t the strctra changes inhippcapa pyraida ces that are pr- vked by chrnic stress in bth adt anddeveping brains
4,12,38
. other ebersf the CRH nerpeptide faiy, incdingthe rcrtins (uCN1, 2 and 3), can bindt CRH receptrs and act in distinct spatiadains. Ths, uCN1-expressing nernsin the nn-preganginic Edinger–Westphances in the brainste ight cntribte tstress adaptatin
41
.In the hypthaas, vaspressin inter-acts with CRH, prting adrencrtic-trpic hrne (ACTH) reease fr thepititary in respnse t stress
42
. In the brainas a whe, vaspressin acts n a wide array f nerns
25,43
(TABLe 1)
: in the aygdaa,the excitatry actins f vaspressin, per-haps reeased fr dendrites
25
, ight cn-tribte t the behavira stress respnse.Vaspressin ight as date etinaery and anxiety
26
.The ‘activating’ actins f stress-indcedCRH reease are ediated priariy thrghbinding t CRHR1
(reFs 11,28,33,39)
, andthe panpy f effects described abve takepace in a tie frae f secnds t intes.In additin, stdies in knckt ice sg-gest that CRHR2 binding cd exert effectsat nger tiescaes and ight fnctin tsht dwn the stress respnse
31,32
. The yin–yang fnctins f the tw CRH receptrsdescribed abve are rearkaby siiar tthe res f the tw crticsterid receptrsin ediating the eary and ate effects f stress-indced crticsterid reease nnerns, as described bew.
Steroids.
Crticsterids are secreted ina psatie and circadian fashin; stresstriggers the reease f a arge brst f cr-ticsterids that is speripsed n theserhyths
44
. Crticsterids’ access t thebrain is regated by p-gycprteins
45
(hwever, see
reF. 46
), bt the circadianpattern and the stress-indced srge f crticsterid eves are aintained in thebrain (as was recenty denstrated frthe hippcaps
47
), awing peripheraand centra aspects f the stress respnset be integrated. A brain ces, incdinggia, are in principe expsed t crtic-sterid hrnes — this cntrasts withthe spatiay restricted pathways thrghwhich naines and peptides exert theiractins.
Nevertheess, the sites in the brainwhere crticsterids are effectiveare restricted by the distribtin f crticsterid receptrs.In the aaian brain, crticsteridhrnes priariy act thrgh inera-crticid and gccrticid receptrs(mRs and GRs, respectivey). mRs have ahigh affinity fr crticsterids, s they aresty ccpied even when circating cr-ticsterid eves are w
2
. GRs have tenfdwer affinity; cnseqenty, these recep-trs are ny partiay ccpied nder basacnditins and bece re ccpied ascrticsterid eves increase — fr exape,after stress. The tw receptr types are dif-ferentiay distribted in brain
2
. mRs arehighy expressed in nerns f the hipp-capa fratin and the atera septand deratey expressed in sbncei f theaygdaa, the hypthaaic paraventric-ar nces (PVN) and the cs ceres
(FIG. 2)
. These regins define a circit thatis invved in the cgnitive, etina andnerendcrine prcessing f stressfevents
5
. The distribtin f mRs ths ver-aps with the distribtin f CRHR1
(reF. 48)
.GRs are biqitsy expressed in the brain,bt they are enriched in the hippcaps,the atera sept and the PVN.on binding f the hrne, crtic-sterid receptrs transcate t the nces,where they act as regatrs f gene tran-scriptin
49
. Therefre, sterid effects nnerna fnctin say reqire at eastan hr t devep and ast hrs t days.In the hippcaps, mR activatin is aprereqisite fr aintaining the nginginfratin fw
6
, whereas activatin f
Figue 2 |
‘Ht pt’ f pt f ky t mdat.
The
β
1-adenoceptos fo noadena-line (
b
1rs), CrH ecepto 1 (CrHr1), CrHr2 and the minealocoticoid and glucocoticoid eceptos(Mrs and Grs, espectively) cluste in ‘hot spots’ in the bain. These hot spots include the pefontalcotex, specific amygdala nuclei, the hippocampus (CA1, CA3 and the dentate gyus (DG)), the pa-aventicula nucleus of the hypothalamus (PVN), the dosal aphe nuclei (Dr) and the locus coeuleus(LC). In these aeas, eceptos fo at least two classes of mediatos ae highly expessed. The hot spotsae stategic hubs that connect netwoks involved in divese aspects of the bain’s stess esponse,including leaning and memoy, decision making and homonal, autonomic and emotional esponses.BLA, basolateal amygdala; BnST, bed nucleus of the stia teminalis; CeA, cental amygdala; CrH,coticotopin-eleasing homone; lat. septum, lateal septum; MA, medial amygdala; NTS, nucleustactus solitaii. Data fom
reFs 48,74–78
.
PersPectives
NATuRE REVIEWS
|
NeuroscieNce
VolumE 10
|
juNE 2009
|
461
focus
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