Research objectives and content The post-doctoral research proposal aims lo determine the functional organisation of the sensory photic pathway involved in mediating circadian entrainment in mammals. The ralionale for this study is based upon I) accumulating evidence that the neural substrate controlling photic circadian responses is distinct from the visual channels subserving image formation and visual perception. and 2) the lack of knowledge concerning the specific opsins and associated neuronal chain (photoreceptors. intraretinal neurons ganglion cells) providing photic information to central circadian pacemakers The concept of an independent pathway devoted to photic regulation is of fundamental and clinical interest and is relevant to health related issues of chronobiological disorders and temporal pharmaceutical treatments in humans. The specific objectives of the study will focus on defining the neuroanatomical components of entrainment pathway and an analysis of the spatial and spectral response properties. The research strategy will rely on the use of animals with selective genetic Iesions within the retina and altered photoreceptor populations. These include mice with hereditary retinal disorders in which the retinal photoreceptors have either partially of fully degenerated. This photoreceptor degeneration Ieads to the loss of visual function although circadian responses to light remain unattenuated. A second model includes transgenic mice in which rod and/or cone photoreceptors have been eliminated by attaching the attenuated diptheria toxin gene (DTA) to the human rhodopsin promoter (or to cis elements for cone expression). These models will be particularly helpful for isolating those components of the retina required for circadian responses to light. In addition part of my study will deal with photic detection properties of the human circadian system. The main questions we address are (1) What intraretinal neurons and ganglion cells compose the circadian pathway and are these distinct from other visual channels? (2) How are the functional characteristics of the photic pathway modified or retained in blind mammals with genetically altered photoreceptor populations? (3) Is circadian photoreception mediated by known or novel opsin(s) ? What are the functional and spectral response characteristics of the photic pathway? Training content (objective benefit and expected impact) The project will focus on neurophysiological and neuroanatomical studies of the mammalian circadian system. The host institution is ideal to complete successfully the proposed research since Dr Cooper is an expert in the field and his laboratory is well equiped to carry out the experiments. In addition the laboratory lNSERM U371 has an excellent environment and international reputation and is composed of an international team of researchers specialised in brain and v ision research. I am also interested by the opportunities of participating in the BIOMED2 programme coordinated by Dr Cooper since I will have lhe possibility to benefIt from numerous exchanges with other labs and from the different techniques available throughout the research network. I alreldy have acquired good experience in neurobiological techniques such as electrophysiology, intracellular staining and pharmacology. This project will allow me to complement my experienee in the field by consolidating my present experience and by gaining expertise in new techniques (neuroanatomical viral tracing, early gene expression, image analysis, photobiology, pholoreceptor anatomy and function. In particular. it will allow me to carry out future independent research and transmit my knowledge upon return to Sardegna (ltaly) Links with industry / industrial relevance (22) In the framework of an upcoming BIOMED2 project (#pL962327) Phillips acts as industrial consultant and participates in the annual meetings of the research consortium. This participation is aimed at fostering the transfer of fundamental results to industrial applications. Dr Cooper's research team in tum acts as scientific consultant to Phillips Lighting and attends meetings on 'Non-Visual Effects of Light' organised by the company. Part of lhe present postdoctoral research project aimed at defining the circadian neural network and its response properties is directly related to the objectives of these research/industrial exchanges.