Although our understanding of the hypocretin/orexin system has been greatly advanced by examination of the morphology of these neurons, their development, efferent projections and comparative studies, it is clear that many aspects of the anatomy of this system remain unstudied. For example, although the Hcrt cells are a distinct neurochemical population of cells within the perifornical area and LHA, it is unclear whether these neurons represent a single, homogeneous population or whether distinct subpopulations exist. Further studies of the topography of the efferent projections of these cells as well as additional colocalization studies should be able to address this issue. Given the central role of the Hcrt system in the maintenance of wakefulness, identification of the inputs to these cells is a critical step to advancing our understanding of this system. Although the afferents to these cells have been little studied to date, it is likely that future neuroanatomical studies will involve use of both conventional and viralbased anatomical methodologies that utilize retrograde transsynaptic transport of marker molecules.102-105 Lastly, a major question regards the apparent vulnerability of the Hcrt neurons that results in degeneration and, ultimately, narcolepsy in both humans and in some breeds of dogs (sporadic form). Although speculation and considerable experimentation has focused on potential immunological insults to the Hcrt cells leading to degeneration, one recent paper suggests that the Hcrt cells may be more susceptible to excitotoxins than the admixed MCH population in the LHA.106 Anatomical tools will undoubtedly also be critical to the success of cell transplantation studies that will surely be undertaken in the coming years.
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