the suprachiasmatic nucleus (scn) a mammalian pacemaker

The Suprachiasmatic Nucleus (SCN)

A Mammalian Pacemaker

Joshua Gooley

MCB 186: Circadian BiologyOctober 19, 2005

The SCN is located in the anterior hypothalamus

Krieg, 1932

Moore, 1991

Location of the SCN in Human

The SCN receives direct retinal input

Hendrickson et al., 1972Moore and Lenn, 1972

SCN Lesion

SCN lesions eliminate corticosteroid rhythm

Moore, 1972

SCN-XShamBody Temperature

SCN-XShamLocomotor Activity

SCN lesions disrupt circadian rhythms

Stephan and Zucker, 1972; Kittrell, 1988

Drinking Rhythm

0 12 24 0 12 24

Enucleated SCN-X

SCN lesions block circadian rhythm of sleep

Ibuka et al., 1977

Solid line: Sham

Dashed line: SCN-X

DG

Nissl

0900 2100

The SCN is shows diurnal rhythm of glucose utilization

Lights on: 0600-1800

Schwartz and Gainer, 1977

Circadian rhythm of electrical activity persists in the SCN isolated in vivo – the “SCN island experiment”

Inouye and Kawamura, 1979

Circadian rhythms measured in hypothalamic slices

Martha Gillette

Multiunit electrical activity Vasopressin Release

The Tau hamster displays a short circadian period

Ralph and Menaker

Normal Heterozygous Homozygous mutant

Circadian period is genetically encoded in the SCN

Ralph et al., 1990

Welsh et al., 1995

Individual SCN neurons show circadian rhythm of electrical activity and display different periods

Dunlap, 1999

Light- and circadian-regulated expression of clock genes in the SCN

Antle and Silver, 2005

The SCN determines the circadian phase of behavior

de la Iglesia, 2000

Circadian rhythm of Per1In four SCN neurons

Wild Type: Per1 circadianrhythm is robust in individualSCN neurons

Per1-luciferase rhythm in individual SCN neurons

Double Cry knockout: Per1 rhythm is lost inindividual SCN neurons

Individual SCN neurons show circadian expression of Per1 in hypothalamic slices

Yamaguchi et al., 2003

Many genes are under circadian regulation in the SCN with broadly distributed circadian phases

Panda et al., 2002

The SCN is heterogeneously organized

Gooley and Saper, 2004 Karatsoreos et al., 2004

Antle and Silver, 2005

The SCN is functionally subdivided

VIP signaling is required for circadian expression of behavioral rhythms

Harmar et al., 2004

Inputs to the Suprachiasmatic Nucleus

Gooley and Saper, 2004

Morin et al., 2004; Leander et al., 1998

The intergeniculate leaflet and median raphe nucleus project to the suprachiasmatic nucleus

IGL (retros from SCN) MRN (5-HT) MRN (retros from SCN)

Cassone et al., 1996

Circadian entrainment by exogenous melatonin

Melatonin binding in SCN

Weaver, 1991

Efferent projections of the Suprachiasmatic Nucleus

Gooley and Saper, 2004

Circadian outflow pathways from the SCN

Saper et al., 2005

Polymer-encapsulatedSCN graft

Diffusible factors can regulate behavioral rhythms

Silver et al., 1996

EGF receptor signaling can regulate behavior

Kramer et al., 2001

Prokineticin 2 inhibits behavioral activity

Cheng et al., 2002

saline PK2

…but it is not the only circadian clock

BehaviorPhysiology

The SCN is a light entrainable circadian clock…