Yasushi Nakagawa - US grants

[unreadable] DESCRIPTION (provided by applicant): The long-term goal of this project is to understand the molecular mechanisms for the formation of sensory maps in the cerebral cortex. Our current focus is to test the hypothesis that reciprocal interactions between the thalamocortical projections and the neocortex are responsible for the formation of area-specific and topographic sensory maps in the neocortex. In Specific aim 1, we will characterize the spatiotemporal relationship between the thalamocortical projections and the formation of anatomically and molecularly distinct areas, which is a critical first step to test the above hypothesis. In Specific aim 2, by using conditional gene targeting, we will analyze the roles of thalamocortical projections in establishing area-specific features o the neocortex. SIGNIFICANCE:Studies of the interactions between the thalamocortical axons and the differentiating neocortex have been limited because of the lack of reproducible experimental systems to specifically manipulate either of the components. We will use conditional molecular genetic techniques of the mouse to explore these interactions. This study will provide insight into the pathophysiology of developmental disorders that may involve the thalamocortical system. In addition, a better understanding of the roles of sensory inputs in the development and plasticity of brain circuitry will improve therapeutic interventions to manipulate activity to encourage compensatory changes in both children and adults with brain damage. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Human neuropsychology and monkey ablation studies show that the prefrontal cortex (PFC) is involved in affect, social behavior as well as executive functions such as working memory and decision-making. Dysfunction of the PFC is associated with neuropsychiatric disorders including schizophrenia, autism and depression. Given the developmental origin of many of these disorders, it is crucial to understand the mechanisms of generation, specification and differentiation of PFC neurons during normal development. Despite the recent advances in the studies of neocortical development, how much of the findings on other parts of the neocortex is applicable to the PFC has remained unknown. Region-specific developmental programs of the neocortex have been studied extensively in recent years. These include intrinsic patterning mechanisms that confer positional identity to neural progenitor cells, as well as the extrinsic influences by thalamic afferents. A majority of research in this field, especially the studies on the extrinsic roles of the thalamus in regional development of the neocortex, has focused on primary sensory areas, while little attention has been paid to the PFC. In order to elucidate the developmental mechanisms of the PFC with molecular genetic approaches, we have identified genes whose expression patterns delineate early postnatal PFC areas. We then analyzed the expression of these genes in mutant mice that lack thalamus-PFC connections, and found a profound change that predicts an altered retinoid signaling in the PFC. Based on these preliminary data, we propose to study the roles of the thalamus and retinoid signaling in PFC development. Abnormal development of the thalamic nuclei that project axons to the PFC as well as abnormal retinoid signaling in the PFC are both implicated in the pathogenesis of developmental brain disorders. However, molecular and cellular basis of such correlations have remained largely elusive. Our proposed research will be a first step to a better understanding of these important questions.

? DESCRIPTION (provided by applicant): The mammalian thalamus is uniquely positioned to regulate diverse functions of the cerebral cortex including sensation, motor control, learning and memory and emotion. These functions critically depend on the proper development of dozens of thalamic nuclei, each of which exhibits characteristic patterns of afferent and efferent connections to and from different areas and layers of the cerebral cortex. Understanding how thalamic neurons are generated from neural stem cells and assembled to form specific nuclei during early development is needed to determine the underlying principles of thalamic organization. Despite recent advances in the study of developmental mechanisms responsible for laminar cytoarchitecture such as that of the neocortex, little is known about the formation of nuclear organization that is representative of many brain structures. Clonal lineage analysis has shown that in the neocortex, cohorts of neurons generated from individual neural stem cells form a radial column that spans the entire cortical wall and acts as a functional unit. In contrast we do not know whether thalamic nuclei are each composed of progeny derived from distinct neural stem cell populations, or if there is a spatial or temporal organization that determines the fate of neural stem cell progeny, which is not aligned with the anatomical borders of individual nuclei. The goal of the proposed research is to combine the expertise of two investigators to explore this important question. The Song laboratory has long been a leader in investigating the cellular and molecular mechanisms underlying hippocampal adult neurogenesis and has extensively used genetic lineage tracing at the clonal level to determine the patterns of proliferation and differentiation of adult stem cells. The Nakagawa laboratory characterized the molecular diversity of progenitor cell domains of the embryonic thalamus and has made significant contributions to understanding the mechanisms of patterning and neurogenesis in the developing thalamus. Based on preliminary data using a genetically-based single cell lineage tracing technique that employs the MADM (mosaic analysis of double marker) method, we hypothesize that individual neural stem cells in the thalamus produce postmitotic neurons that are distributed in radial columns that span several thalamic nuclei and that the repertoire of the thalamic nuclei that are generated from individual stem cells is determined by the initial position of the originating cell. Completion of the proposed experiments will be a critical first step towar understanding fundamental mechanisms governing the development and organization of nuclear structures in the brain. This knowledge will have important implications for future investigations of the functional and structural consequences of dysregulation within thalamic progenitor domains in early neural development.

The mammalian neocortex is the center of higher sensory, motor and cognitive functions, and is composed of dozens of functionally and anatomically distinct areas. Each neocortical area contains a unique set of neuronal types distributed across six layers. Construction of this complex cellular organization begins with area-specific regulation of neurogenesis during embryonic development. Because of their area- specific pattern of projections, the thalamocortical axons (TCAs) are ideally positioned to influence the fundamental ground plan of the neocortex by regulating neural progenitor cells. In addition, recent studies have discovered that microglia, resident immune cells in the brain, modulate many aspects of cortical development including neurogenesis. However, how TCAs and microglia each regulate neurogenesis in the neocortex is poorly understood. In this grant proposal, we plan to fill these knowledge gaps by 1) developing genetic approaches to molecularly dissect the role of TCAs on neuron-committed neural progenitor cells in the future primary sensory cortex and 2) testing the novel hypothesis that TCAs promote the maturation of microglia via a TCA-derived neuropeptide and its receptor that is specifically expressed in immune cells in developing cortex. Because development of microglia is heavily influenced by maternal environment, our research will shed light on how intrinsic genetic programs and extrinsic environmental factors may converge on common mechanisms that control fundamental organization of the cortical architecture. This will lead to a better understanding of the pathogenesis of many neurological and psychiatric disorders that stem from aberrant regulation of embryonic neurogenesis.