The neocortex, the largest and most complex brain structure, is unique to mammals. It is responsible for sensory perception and cognition, as well as control of our motor systems. In its tangential dimension, the neocortex is organized into subdivisions referred to as "areas" that are distinguished from one another by major differences in their cytoarchitecture and chemoarchitecture, thalamocortical axon (TCA) input and layer 5 and 6 output connections, and patterns of gene expression. These attributes form a specific combination of properties unique for each area, and together with unique combinations of gene expression, determine the functional specializations that characterize and distinguish areas in the adult. The first transcription factor shown to potentially influence arealization was only identified a decade ago. Although of inarguable importance, the mechanisms controlling arealization of the neocortex remain sketchy and controversial, and are largely limited to generalized axial changes in the size and position of primary areas. Here we propose a series of aims to address specific hypotheses on the requirements of certain regulatory genes to specify the identities and properties of cortical areas in the progenitors that generate them. These studies will break new ground, generate novel insights, and revise and correct misconceptions. The studies include determining the specific mechanisms and transcription factors that are required to specify the primary visual area, V1, redundancy in their function, and limits in their action across the cortical hemisphere. We will also address for the first time the genetic mechanisms involved in the specification of higher order areas and test specific hypotheses on these mechanisms. We will reassess roles for Pax6 is arealization, and use its function as a model for studying the effects of specification of area field size on the representation of the sensory periphery within a cortical area, and the importance of graded expression of transcription factors on their function in establishing sensory maps and representations. Finally, we will investigate the influence of cortex-intrinsic genetic changes to area patterning on the principal sensory thalamic nuclei that relay sensory input to cortex, and define mechanisms of reverse plasticity that serve to systems-match thalamic nuclei to their target areas, and to re-pattern them through a retrograde interaction with their target area. These studies will be carried out using conditional loss- and gain-of-function genetics in mice, using numerous mouse lines that we have made for this proposal, and will make use of new gene markers developed for higher order areas. Further, the considerable amount of preliminary findings that we present support our hypotheses, and indicate that our findings will lead to the development of new concepts, in some cases challenging and replacing dogma, that will have implications for neocortical development and plasticity.

Public Health Relevance

The neocortex, the largest and most complex component of the mammalian brain, is the center for sensory processing and perception, motor control, and cognitive functions. The neocortex is organized into anatomically and functionally specialized areas, with four modality-specific primary areas, visual, somatosensory, auditory and motor, each anchoring an extensive, hierarchically organized array of higher order areas, and reciprocally connected with principal nuclei in dorsal thalamus that feed sensory information from the periphery to the cortex. This proposal addresses the genetic mechanisms that specify area patterning of the neocortex and the influence of this patterning on subsequent thalamic differentiation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS031558-18
Application #
8323271
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Riddle, Robert D
Project Start
1993-12-15
Project End
2016-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
18
Fiscal Year
2012
Total Cost
$605,394
Indirect Cost
$287,602
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Stocker, Adam M; O'Leary, Dennis D M (2016) Emx1 Is Required for Neocortical Area Patterning. PLoS One 11:e0149900
Kawaguchi, Daichi; Sahara, Setsuko; Zembrzycki, Andreas et al. (2016) Generation and analysis of an improved Foxg1-IRES-Cre driver mouse line. Dev Biol 412:139-47
Perez-Garcia, Carlos G; O'Leary, Dennis D M (2016) Formation of the Cortical Subventricular Zone Requires MDGA1-Mediated Aggregation of Basal Progenitors. Cell Rep 14:560-71
Zembrzycki, Andreas; Perez-Garcia, Carlos G; Wang, Chia-Fang et al. (2015) Postmitotic regulation of sensory area patterning in the mammalian neocortex by Lhx2. Proc Natl Acad Sci U S A 112:6736-41
Perez-Garcia, Carlos G (2015) ErbB4 in Laminated Brain Structures: A Neurodevelopmental Approach to Schizophrenia. Front Cell Neurosci 9:472
Pao, Gerald M; Zhu, Quan; Perez-Garcia, Carlos G et al. (2014) Role of BRCA1 in brain development. Proc Natl Acad Sci U S A 111:E1240-8
Hatori, Megumi; Gill, Shubhroz; Mure, Ludovic S et al. (2014) Lhx1 maintains synchrony among circadian oscillator neurons of the SCN. Elife 3:e03357
Del Barrio, Marta Garcia; Bourane, Steeve; Grossmann, Katja et al. (2013) A transcription factor code defines nine sensory interneuron subtypes in the mechanosensory area of the spinal cord. PLoS One 8:e77928
Kang, Ji-Yong; Kawaguchi, Daichi; Coin, Irene et al. (2013) In vivo expression of a light-activatable potassium channel using unnatural amino acids. Neuron 80:358-70
Chou, Shen-Ju; O'Leary, Dennis D M (2013) Role for Lhx2 in corticogenesis through regulation of progenitor differentiation. Mol Cell Neurosci 56:1-9

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