Circadian Photoreception in Circadian Photoreception in MammalsMammals

Joshua GooleyJoshua GooleyMCB 186: Circadian BiologyMCB 186: Circadian Biology

October 26, 2005October 26, 2005

The retinohypothalamic tract

Laminar Organization of the Retina

Rods and Cones are not required for light entrainment

Freedman et al., 1999

Light entrainment and the pupillary light reflex are mediated by a short wavelength-sensitive, vitamin A1-

based photopigment

Hattar et al., 2003 Lucas et al., 2001

Phase Shifting Pupillary light reflex

rdta/cl

Cryptochromes are expressed in the inner retina

Miyamoto and Sancar, 1998

Melanopsin is expressed in retinal ganglion cells

RGCs that project to the SCN contain melanopsin

Gooley et al., 2001 Hannibal et al., 2002

SCN injection

Opn4 mRNA

Retro label

PACAP mRNA

OPN4 immuno

Gene-targeted tracing in OPN4-tauLacZ mice reveals an intense projection to the SCN

Hattar et al., 2002

Science paper –inject and record

Recording SCN-projecting rat ganglion cellsretrolabel ‡ record ‡ dye-fill

Control

Retinal ganglion cells that project to the SCN are intrinsically photosensitive

Berson et al., 2002

melanopsin Lucifer yellow merged

Intrinsically photosensitive RGCs contain melanopsin

Some intrinsically photosensitive RGCs show a rapid and transient response to light

David Berson

Spectral

λmax = 484 nm

Spectral tuning implicates a vitamin-A1 based pigmentipRGCs are most sensitive to short-wavelength light

Berson et al., 2002

IGLIGL

Melanopsin cells project to the IGL and olivary pretectal nucleus (involved in the pupillary light reflex)

Hattar et al., 2002

Gooley et al., 2003

OPN4 cells send collateralized projections to the SCN and olivary pretectal nucleus

Tracer injection in SCN Tracer injection in OPT

Retros from SCN Retros from OPT OPN4 mRNA

Gooley et al., 2003

A broad role for OPN4 in non-visual photoreception

Gooley et al., 2003

Melanopsin is necessary for intrinsic photosensitivity

Hattar et al., 2003

Panda - OPN4 knockout

(Panda et al., 2002)

Melanopsin knockoutPhase shifting weakened but not abolished

wildtype

knockout

Phase shifting is attenuated, but not absent in OPN4 knockout mice

Panda et al., 2002

Pupillary light reflex is attenuated, but not absent in OPN4 knockout mice

Lucas et al., 2003

radial schematic

OPN4 cells likely receive input from the classical visual photoreceptors

Light entrainment abolished in mice without rods, cones, and melanopsin

Panda et al., 2003

Pupillary light reflex abolished in mice without rods, cones, and melanopsin

Hattar et al., 2003

Negative masking and light-induced suppression of NAT absent in mice without rods, cones, and melanopsin

Panda et al., 2003

Masking absent NAT suppression absent

Mammalian photoreceptorsclassical ganglion-cell

sluggishbrisk

melanopsin (?)rhodopsin, cone opsin

huge receptive fieldsmall receptive field

insensitivesensitive

independent of RPEdependent on RPE

spikingnon-spiking

depolarizinghyperpolarizing

output to brainoutput to retina

inner retinaouter retina

Mammalian Photoreceptors

The vertebrate phototransduction cascade

The invertebrate phototransduction cascade

Melyan et al., 2005

Human melanopsin confers photosensitivity to light-insensitive neuro-2a cells

GFP OPN4

Light-evoked current

Panda et al., 2005

OPN4 may function as a bireactive opsin

Xenopus oocytes

Qui et al., 2005

HEK293 cells that co-express OPN4 and TRPC3 channels are photosensitive

OPN4 retinal ganglion cells in primate

Dacey et al., 2005

Dacey distribution

~3000 cells (0.3% of all GCs)

Dacey et al., 2005

Distribution of primate OPN4-containing ganglion cells