Samer S. Hattar - US grants

DESCRIPTION (provided by applicant): Light entering our eyes does much more than provide us with image-forming visual information. Light also affects non-image-forming (NIF) visual functions such as daily adjustments of the biological clock by light (circadian photoentrainment), direct effects of light on mood and alertness and pupil constriction. These visual functions require the eyes but are preserved in "blind" mammals lacking the classical photoreceptors rods and cones, which were thought to be the only cells capable of detecting light signals. A third type of photoreceptor responsible for detecting light for NIF was discovered in the mammalian retina. This new system expresses a putative photopigment melanopsin and is found, surprisingly, in a subset (-1-2%) of retinal ganglion cells (RGCs). The melanopsin RGCs receive input from rods and/or cones. The melanopsin expressing RGCs project to areas in the brain important for NIF functions such as the suprachiasmatic nucleus and the olivary pretectal nucleus responsible for circadian photoentrainment and pupillary light reflex, respectively. In the absence of melanopsin, the intrinsic photosensitivity of the melanopsin cells is lost and light detection for NIF visual functions is compromised. The rod/cone system partially compensates for the animals' ability to respond to light for the NIF visual functions. In specific aim I, we will determine the individual contribution of rods, cones and melanopsin cells to NIF vision by using pupil constriction, circadian photoentrainment and direct light effects on behavior. In specific aim II, we will identify the laterally and number of non-melanopsin ganglion cells that project to the NIF centers in the brain using an animal engineered to lose all melanopsin RGCs through diphtheria toxin A subunit expression specifically in these cells. In specific aim III, we will address the fundamental question of how rods/cones signal to the NIF visual centers in the brain. Do they signal light information to the brain only through the melanopsin ganglion cells or do they use other ganglion cells that do not express melanopsin? We will use the animals created in aim II and test light responses using the behavioral assays in aim I. These studies will elucidate how the three classes of retinal photoreceptors interact and coordinate light detection for NIF functions and most importantly determine the individual contribution of each photoreceptor to individual NIF functions. I believe that these studies will be instrumental in defining how light signals are conveyed to the brain to influence our mood, alertness and our sleep/wake cycles.

DESCRIPTION (provided by applicant): Light entering our eyes does much more than provide us with image-forming visual information. Light also affects non-image-forming (NIF) visual functions such as daily adjustments of the biological clock by light (circadian photoentrainment), direct effects of light on mood and alertness and pupil constriction. These visual functions require the eyes but are preserved in "blind" mammals lacking the classical photoreceptors rods and cones, which were thought to be the only cells capable of detecting light signals. A third type of photoreceptor responsible for detecting light for NIF was discovered in the mammalian retina. This new system expresses a putative photopigment melanopsin and is found, surprisingly, in a subset (-1-2%) of retinal ganglion cells (RGCs). The melanopsin RGCs receive input from rods and/or cones. The melanopsin expressing RGCs project to areas in the brain important for NIF functions such as the suprachiasmatic nucleus and the olivary pretectal nucleus responsible for circadian photoentrainment and pupillary light reflex, respectively. In the absence of melanopsin, the intrinsic photosensitivity of the melanopsin cells is lost and light detection for NIF visual functions is compromised. The rod/cone system partially compensates for the animals' ability to respond to light for the NIF visual functions. In specific aim I, we will determine the individual contribution of rods, cones and melanopsin cells to NIF vision by using pupil constriction, circadian photoentrainment and direct light effects on behavior. In specific aim II, we will identify the laterally and number of non-melanopsin ganglion cells that project to the NIF centers in the brain using an animal engineered to lose all melanopsin RGCs through diphtheria toxin A subunit expression specifically in these cells. In specific aim III, we will address the fundamental question of how rods/cones signal to the NIF visual centers in the brain. Do they signal light information to the brain only through the melanopsin ganglion cells or do they use other ganglion cells that do not express melanopsin? We will use the animals created in aim II and test light responses using the behavioral assays in aim I. These studies will elucidate how the three classes of retinal photoreceptors interact and coordinate light detection for NIF functions and most importantly determine the individual contribution of each photoreceptor to individual NIF functions. I believe that these studies will be instrumental in defining how light signals are conveyed to the brain to influence our mood, alertness and our sleep/wake cycles.

DESCRIPTION (provided by applicant): Aberrant light conditions experienced during shift-work and transmeridian travel, as well as seasonal changes in day length, cause mood and cognitive deficits. The prevailing view is that these behavioral effects arise from disruptions in sleep and circadian rhythms. However, we have recently shown that aberrant light schedules directly lead to mood and cognitive deficits. The mammalian retina, which contains three major photoreceptors, rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs), is the site of light detection for all light-dependent behaviors. The ipRGCs express the photopigment melanopsin and respond to light both intrinsically via the melanopsin photopigment but also extrinsically through rod/cone circuitry, similar to conventional RGCs. Furthermore, ipRGCs project to a variety of brain regions that include the master circadian pacemaker as well as areas that have been implicated in mood and affect regulation. We have identified ipRGCs as a critical node in the circuit underling the direct effects of disruptive ligh schedule on mood and cognition. In this proposal, our major goals are to identify the retinal circuits and the brain targets that are necessary for aberrant light to cause mood and learning deficits. Specifically, we have several retinal mouse mutants that will allow us to delineate the relative contributions of the intrinsic melanopsin-based phototransduction versus the extrinsic rod/cone input to the disruptive effects of aberrant light on mood and cognition. In addition, we have generated multiple mouse lines where we have either specifically ablated or specifically retained a subset of ipRGCs that project to the master circadian pacemaker and drive circadian photoentrainment. To identify brain regions that are sufficient for the negative effects of aberran light, we will specifically activate ipRGC terminals using optogenetics, to mimic the effects of aberrant light on individual brain regions. The combination of mutant mouse lines with this optogenetic approach will allow us to begin to identify the circuits that mediate how aberrant light schedules lead to mood and learning deficits. The findings obtained from this proposal will provide a basis to design better lighting environments at homes, schools and work environment to improve mood and cognition leading to increased productivity. In addition, the identification of new brain circuits that impinge on mood regulation will provide new neuronal targets for the better use of light for therapeutic purposes.