In mammals, the suprachiasmatic nuclei (SCN) constitute the main circadian clock, receiving input from the retina which allows synchronization of endogenous biological rhythms with the daily light/dark cycle. Over the year, the SCN encodes photoperiodic variations through duration of melatonin secretion, with abundant nocturnal levels in winter and lower levels in summer. Thus, light information is critical to regulate seasonal reproduction in many species and is part of the central photoperiodic integration. Since intrinsically photosensitive retinal ganglion cells (ipRGCs) are vital for circadian photoentrainment and other nonvisual functions, we studied the contribution of ipRGCs in photoperiod integration in C3H retinal degeneration 1 (rd1) mice. We assessed locomotor activity and melatonin secretion in mice exposed to short or long photoperiods. Our results showed that rd1 mice are still responsive to photoperiod variations in term of locomotor activity, melatonin secretion, and regulation of the reproductive axis. In addition, retinas of animals exposed to short photoperiod exhibit higher melanopsin labeling intensity compared with the long photoperiod condition, suggesting seasonal-dependent changes within this photoreceptive system. These results show that ipRGCs in rd1 mice can still measure photoperiod and suggest a key role of melanopsin cells in photoperiod integration and the regulation of seasonal physiology.

The eye is formed by tissues and cavities that contain liquids whose compositions are highly regulated to ensure their optical properties and their immune and metabolic functions. The integrity of the ocular barriers, composed of different elements that work in a coordinated fashion, is essential to maintain the ocular homeostasis. Specialized junctions between the cells of different tissues have specific features which guarantee sealing properties and selectively control the passage of drugs from the circulation or the outside into the tissues and within the different ocular compartments. Tissues structure also constitute selective obstacles and pathways for various molecules. Specific transporters control the passage of water, ions, and macromolecules, whilst efflux pumps reject and eliminate toxins, metabolites, or drugs. Ocular barriers, thus, limit the bioavailability of gene therapy products in ocular tissues and cells depending on the route chosen for their administration. On the other hand, ocular barriers allow a real local treatment, with limited systemic side-effects. Understanding the different barriers that limit the accessibility of different types of gene therapy products to the different target cells is a prerequisite for the development of efficient gene delivery systems. This review summarizes actual knowledge on the different ocular barriers that limit the penetration and distribution of gene therapy products using different routes of administration, and it provides a general overview of various methods used to bypass the ocular barriers.