Cellular Repair of Complex Cortical Circuitry

Abstract

The mammalian neocortex is a highly complex structure that consists of a large number of distinct cell types and connections unparalleled throughout the rest of the mammalian central nervous system (CNS). The neocortex is responsible for high-level functions including sensorimotor integration, associative behavior, and cognition. Although many studies demonstrate that embryonic tissue or precursor cells transplanted into the embryonic or neonatal cortex can integrate and connect with a wide variety of targets, such connectivity in most studies using adult recipients has been quite limited (1, 2). In contrast, relatively recent advances in transplantation paradigms from our laboratory and other laboratories have made apparent the possibility of successful reconstruction of complex cortical circuitry in the adult mammalian brain by transplantation or by manipulation of endogenous precursors in situ. These advances include the ability to isolate increasingly specific populations of immature neurons and precursors from donor animals, and the establishment of a highly selective model of targeted degeneration in the neocortex (3-10, Leavitt, unpublished observations). Such advances now allow both the transplantation of more defined and specific populations of immature neocortical neuroblasts and precursors, and also make it possible to study the cellular, anatomic, and functional efficacy of both transplantation and manipulation of endogenous precursors in situ (9, 11) in increasingly refined models of neocortical degeneration. The neocortex has become a model system for studying circuitry formation, regional specification, cell specification, and cell autonomous versus environmental influences on neuronal development and function in the CNS. Although neocortical transplantation paradigms have proven very useful for elucidating how complex circuits and CNS cytoarchitecture evolve in the mammalian brain, more recent work using cell transplantation has made apparent the possibility of cell replacement and complex circuit repair in the neocortex. Our most recent results (9, 11) suggest that neuronal replacement therapies for neurodegenerative disease and other CNS injury may even some day be possible via molecular manipulation of endogenous neural precursors in situ, without transplantation. Although only fanciful just several years ago, it now appears that studies of cellular repopulation and circuitry reconstruction in the neocortex may provide a foundation toward developing cellular therapies for degenerative or acquired disease in neocortex and other regions of the CNS.