e., intrinsic determinism)? Or does information carried by afferents to those neurons instruct them about their ultimate function (i.e., extrinsic determinism)? In the late 1980s, these questions were formalized into Rakic’s protomap model (Rakic, 1988) and O’Leary’s protocortex model (O’Leary, 1989). Both models recognized roles for genetic and epigenetic mechanisms, including important interactions with thalamocortical afferents. They differed substantially, though, in scope and emphasis, with the former arguing for primacy of intrinsic information and the latter emphasizing extrinsic information in the ultimate determination

buy Target Selective Inhibitor Library of areal fate (O’Leary et al., 1994). With the identification in the 1990s of transcription factors involved Dolutegravir nmr in telencephalic development, such as Emx2 and

Pax6 (e.g., Bishop et al., 2000), these hypotheses could be tested with state-of-the-art molecular approaches and genetic manipulations. As a consequence, over the past 20 years, considerable progress has been made in understanding the mechanisms that lead to the patterning of the neocortex, though the story is far from complete. Little debate remains at present regarding whether or not intrinsic and extrinsic mechanisms interact so that functional specialization and areal differentiation can occur. The nascent neocortex has been demonstrated to possess robust intrinsic information for regionalization; normal-appearing molecular patterning is evident even in mice genetically altered to lack thalamocortical afferents (Myashita-Lin et al., 1999), for example. Several groups of investigators using animal models have worked to delineate the basic mechanisms underlying this early regionalization of the nascent neocortex (e.g., O’Leary et al., 2007). Based on these studies, a complex hierarchy of transcription factor expression that controls cortical patterning those has been described. Patterning centers along the anterior and posterior midline, such as the anterior neural

ridge (which becomes the commissural plate) and the cortical hem (located posteriorly), set up gradients of transcription factor expression important for the establishment of patterning. Gradients of transcription factor expression are also established in the neuroepithelium along anterior-posterior and mediolateral axes. Thus, these genetically determined factors comprise the molecular framework for an early and coarse regionalization. Such intrinsic mechanisms provide the template for the establishment of appropriate thalamocortical and other afferent inputs, as well as other aspects of architectural and connectional features. These features are influenced by the afferents themselves or by information regarding the status of the periphery carried by those afferents (e.g., O’Leary et al., 1994 and Sur and Rubenstein, 2005).