PACAP-deficient mice exhibit light parameter-dependent abnormalities on nonvisual photoreception and early activity...

Area of Science:

• Neuroscience
• Chronobiology
• Ophthalmology

Background:

• Melanopsin mediates nonvisual light responses, including circadian clock entrainment, masking, and pupillary light reflex (PLR).
• Pituitary adenylate cyclase-activating polypeptide (PACAP) is coexpressed with melanopsin in retinal ganglion cells and is implicated in these responses, but its exact role is unclear.

Purpose of the Study:

• To elucidate the functional role of PACAP in nonvisual light responses mediated by melanopsin.
• To investigate the effects of PACAP deficiency on circadian entrainment, masking, and PLR.

Main Methods:

• Generation and analysis of PACAP-deficient mice.
• Assessment of circadian entrainment to light-dark cycles.
• Evaluation of masking responses to light and darkness.
• Measurement of pupillary light reflex.
• Histological examination of retinal morphology and melanopsin expression.

Main Results:

• PACAP-deficient mice exhibited severe, time-dependent deficits in circadian entrainment.
• Masking responses were blunted in PACAP-deficient mice, but restored by PACAP-38 infusion.
• Pupillary light reflex remained normal in PACAP-deficient mice.
• PACAP deficiency led to an early onset of activity before the dark period without altering the endogenous circadian phase.
• Retinal morphology and melanopsin cell innervation were unaffected.

Conclusions:

• PACAP is essential for normal circadian entrainment and masking, conveying parametric light information (intensity and duration).
• The findings reconcile previous inconsistent reports on PACAP's role in photic entrainment.
• PACAP plays a critical role in regulating daily behavioral patterns, particularly around the light-to-dark transition.
• PACAP's function in PLR is distinct from its role in entrainment and masking.