The mammalian basal telencephalic limbic system is comprised of a number of structures that are involved in the regulation of complex emotional and motivational behaviors. The two most prominent of these are the nucleus accumbens, which functions in the regulation of positive reward stimuli, and the amygdala, which regulates specific aspects of emotional memory and conditioned responses to aversive stimuli. The work proposed here is designed toward understanding the embryonic spatial and temporal origin of neuronal cell diversity in these structures (Specific Aims 1 & 2) and the mechanisms by which a unique subset of these cells migrate to their final destinations (Specific Aim 3). Considering that the amygdala-nucleus accumbens pathway is a major target of drugs of abuse, understanding the mechanisms that govern normal development of these structures may provide insight into the etiology of such disorders in which these regions are affected. Given the economic and societal cost of substance addiction, determination of the biological programs that regulate development of these key brain regions is a crucial and largely unmet challenge. Furthermore, these proposed studies will provide a framework for ensuing work aimed at understanding how drugs of abuse may affect normal development of the nucleus accumbens and the amygdala, as well as be invaluable in guiding the rational generation of genetic mouse models of addictive behavior.
The specific aims of this proposal are:
Specific Aim 1 : Using ultrasound guided in utero transplantation to fate map progenitor cells from four distinct embryonic telencephalic progenitor zones (the medial, lateral, caudal ganglionic eminences and the cortico- striatal border), we will test the hypothesis that each of these regions contributes a unique cohort of neuronal subtypes to the mature nucleus accumbens and amygdala and at different times during development.
Specific Aim 2 : Using molecular fate mapping techniques, we will test the hypothesis that the cortico-striatal border is a source of two separate populations of progenitor cells that will give rise to distinct subsets of inhibitory neurons, and excitatory neurons, in the mature nucleus accumbens and amygdala.
Specific Aim 3 : Using a combination of in vitro and in vivo approaches, we will test the hypothesis that the two distinct populations of progenitor cells derived from the cortico-striatal border migrate to the developing nucleus accumbens and amygdala via differential chain and radial modes of migration. ? ? ?
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