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The Sestan laboratory investigates how neuronal identities and synaptic circuits form during development, and how they have changed during the evolution of the mammalian brain. Our studies focus on the frontal cerebral cortex, due to its importance in higher cognitive functions and the remarkable complexity of its neuronal phenotypes, particularly among the pyramidal (projection) neurons. Pyramidal neurons occupy a central position in all cortical circuits, constituting both the sole output from and the largest input system to the cortex. Our lab’s strategy is to identify genetic mechanisms that are important for the specification, development, and evolution of pyramidal neurons, using parallel molecular- and cellular-level studies in multiple species. It is our premise that key events in the evolution and development of frontal cortex circuitry can be revealed by combining 1) molecular analyses of basic, evolutionarily conserved mechanisms, taking advantage of the feasibility of genetic manipulations in mice; and 2) comparative analyses of neurogenetic processes in human, non-human primate, mouse, and other species, to identify species-specific mechanisms and events in the development of neuronal circuitry. Thus, the ongoing research in our laboratory is organized into these two related areas.
Certain traits, such as the organization of the cerebral cortex into distinct layers with unique complements of cell types and synaptic connections, seem to be conserved across mammals, and many of the projects in our lab are aimed at defining the molecular mechanisms that underlie these traits. In doing so, we hope to uncover the evolutionarily conserved, “core” genetic programs that regulate the molecular identities, dendritic arborizations, and axonal projections of cortical pyramidal neurons.
Pyramidal neurons arising from the same neural stem cell acquire distinct laminar positions and layer-specific identities based on the timing of their birth during neurogenesis. A neuron’s laminar identity is intimately linked to its eventual function: pyramidal neurons of the deepest layers (5 and 6) send subcortical axonal projections to the thalamus and brainstem/spinal cord, respectively, while those of the upper layers (2-4) form exclusively intracortical connections. In addition, local differences in this laminar pattern of pyramidal neuron connectivity underlie the separation of the cortex into functionally distinct areas. For example, layer 5 pyramidal neurons throughout the cortex project to subcortical regions. However, layer 5 neurons of the frontal cortex project to motor nuclei in the brain stem and spinal cord, while those in the visual cortex project only to the tectum. The focus of projects in this part of the Sestan lab is how layer- and area-specific genetic programs arise and translate into functional differences among pyramidal neurons.
What is it about our human brain that makes us human? How is it that our closest evolutionary relative, the chimpanzee, shares so much of our DNA and yet lacks the higher cognition and spoken language that distinguish our species? The answer is likely to lie, at least in part, in our frontal cortex, which has expanded in size and complexity in the course of our evolution and is intimately involved in each of our distinguishing cognitive skills. In our second area of research, the Sestan lab seeks to identify species-specific evolutionary changes in neuronal gene expression, molecular identity, and connectivity that may be important for the development and evolution of the human frontal cortex.
The cognitive specializations of the frontal cortex are the result of phylogenetic differences in the functional properties of its neurons and the organization of its synaptic circuitry. There are no simple differences of the cerebral cortex at the gross anatomic level that can account for our unique cognitive abilities. Rather, it is thought that subtle differences in the diverse set of frontal cortical areas provide a neurobiological substrate for specialized cognitive functions such as working memory, attention, planning, speech, language, and social information processing. Thus, comparative studies of gene expression and function in the developing frontal cortex offer insights into the evolution of these higher cognitive abilities. A major focus of our research in this direction is our ongoing whole transcriptome profiling of the developing frontal cortex and other brain structures in human and non-human primates. These studies use high-throughput methods of gene expression measurement to investigate the spatiotemporal dynamics of the transcriptome, across brain regions and developmental time-points, and to thus identify RNA species that are specifically enriched or uniquely expressed in the human developing frontal cortex.
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