RADIAL DIVERGENCE HYPOTHESIS: CLONAL ANALYSIS OF FUNCTIONAL DEVELOPMENT OF THE CEREBRAL CORTEX IN HIGHER MAMMALS

UNDERSTANDING THE DEVELOPMENTAL MECHANISMS THAT UNDERLIE THE INCREASE IN SIZE AND FUNCTIONAL COMPLEXITY OF THE HUMAN CEREBRAL CORTEX IS A FUNDAMENTAL CHALLENGE OF BASIC RESEARCH, THE IMPACT OF WHICH EXTENDS FROM BIOLOGY TO ANTHROPOLOGY. OUR CURRENT UNDERSTANDING OF THE EMERGENCE OF THE ANATOMICAL AND FUNCTIONAL NEURONAL ENSEMBLES DURING DEVELOPMENT IS ESSENTIALLY BASED ON DATA FROM RODENTS COMBINED WITH THE DOGMATIC RADIAL UNIT HYPOTHESIS. WHEREAS THIS HYPOTHESIS EXPLAINS MANY ASPECTS OF CORTICAL DEVELOPMENT IN RODENTS WITH A SMALL AND SMOOTH CORTEX, IT IS INSUFFICIENT TO EXPLAIN THE DEVELOPMENT AND FOLDING OF THE MUCH LARGER AND COMPLEX CEREBRAL CORTEX OF HIGHER MAMMALS, LIKE CARNIVORES AND PRIMATES INCLUDING HUMAN. WE HAVE PROPOSED THE RADIAL DIVERGENCE HYPOTHESIS, WHERE INDIVIDUAL PROGENITOR CELLS GIVE RISE TO SIBLING NEURONS THAT DISPERSE TANGENTIALLY TO FORM MULTIPLE ANATOMICAL AND FUNCTIONAL COLUMNS IN THE CORTEX, AND ITS FOLDING. THE CORTICLONES PROJECT WILL TEST THIS NOVEL AND GROUNDBREAKING HYPOTHESIS BY GENERATION A TRANSGENIC FERRET (WITH A FOLDED CORTEX) AND APPLYING A SPECTRUM OF INTERDISCIPLINARY AND COMPLEMENTARY APPROACHES. AFTER LABELING CLONES OF INDIVIDUAL CORTICAL NEURONS, WE WILL ANALYZE THEIR TOPOGRAPHY ACROSS FOLDS, FISSURES AND CORTICAL AREAS. THEN WE WILL FUNCTIONALLY ANALYZE THE DIFFERENT NEURONS IN EACH CLONE BY OPTICAL IMAGING OF INTRINSIC SIGNALS, MAPPING THEIR RESPONSE PROPERTIES OVER THE CORTICAL SURFACE. THIS ORIGINAL AND INTERDISCIPLINARY COMBINATION OF APPROACHES IS THE GREAT ASSET OF THIS PROJECT, AS IT WILL ALLOW US TO FINALLY PROOF OR REFUTE A DOGMA ABOUT THE BASIC MECHANISM OF CORTICAL DEVELOPMENT AND FUNCTIONAL SPECIFICATION. THE SUCCESSFUL EXECUTION OF THIS PROJECT WILL ENABLE US TO BETTER UNDERSTAND THE DEVELOPMENTAL MECHANISMS THAT PROMOTE THE MAXIMIZATION OF COGNITIVE FUNCTION IN HIGHER MAMMALS.