V3 interneurons in the spinal cord are a group of excitatory commissural interneurons that play an important role in producing balanced and stable gaits in animals. We discovered that Sim1-expressing V3 interneurons arise from the ventral-most progenitor domain in the developing neural tube and migrate in a dorso-lateral trajectory to settle into three distinct subpopulations. The most ventral subpopulation projects axons in both an rostral and caudal direction, while the intermediate and dorsal subpopulations are mostly rostrally-projecting. The role of Sim1 as a transcription factor was shown to play a role both in the proper migration and axon projection of V3 interneurons.

It has long been acknowledged that inhibitory interneurons play a crucial role in regulating the input-output functions of principal cells in the hippocampus. The investigations we conducted focus on one specific population of interneurons, expressing the protein parvalbumin. The thesis describes three different studies, aimed to characterize anatomical and functional aspects of parvalbumin positive interneurons in the mouse hippocampal formation. The first study examines long-range projections of these neurons from CA1 and subiculum to distant regions of the brain, finding potential targets mainly in septal, thalamic and hypothalamic areas. The second study investigates the role of parvalbumin-positive interneurons of the dentate gyrus in spatial memory. Behavioural experiments with radial arm and Morris water maze have been carried out to understand how these GABAergic interneurons regulate information flow during reference and working memory. Finally, a third study describes basic anatomical features of parvalbuminpositive dendritic spines in the dentate gyrus. Their characteristics have been widely studied in principal neurons but little is known about spines in interneurons. Here I show a peculiar distribution of spines on apical dendrites of these cells, with a predominant localization within the inner third of the molecular layer. All studies utilized a combination of transgenic Cre-expressing mice and Creactivatable AAVs. For the first and third study AAV-based neuronal labeling was applied to visualize neurons, including their projections and their spines, respectively, through expression of fluorescent proteins. For the second study instead two genetic tools have been used in order to disrupt the neurotransmission from parvalbuminpositive interneurons and examine the effects on behavioral task performance.

The majority of corticospinal projections in primates and all corticospinal projections in other mammals exert their influence by integrating into spinal interneuronal circuits. Interneurons therefore represent an evolutionarily conserved target through which the corticospinal tract achieves motor and sensory control. Here I describe the postnatal maturation of the corticospinal tract. I show work aimed at fractionating cortical projections by combining recently developed retrograde viral tracing strategies with genetic access to distinct spinal interneuron populations. Using a 3-D reconstruction pipeline, I discuss the cortical origins of the corticospinal pathway in mice. I then demonstrate the differential distribution of corticospinal inputs to three interneuron populations with divergent functional roles. These studies suggest that primary motor cortex contacts functionally diverse spinal interneurons whilst premotor and somatosensory cortical regions are more restricted in their postsynaptic targeting.

While the extrinsic factors regulating neurogenesis in the developing forebrain have been widely studied, the mechanisms downstream of the various signaling pathways are relatively ill-defined. In particular, we focused on proteins that have been implicated in cognitive dysfunction. Here, we ask what role two cell intrinsic factors play in the development of two different neurogenic compartments in the forebrain. In the first part of the thesis, the transcription factor FoxP2, which is mutated in individuals who have specific language deficits, was identified to regulate neurogenesis in the developing cortex, in part by regulating the transition from the radial precursors to the transit amplifying intermediate progenitors. Moreover, we found that ectopic expression of the human homologue of the protein promotes neurogenesis in the murine cortex, thereby acting as a gain-of-function isoform. In the second part of the thesis, the histone acetyltransferase CREB-binding protein (CBP) was identified as regulating the generation of neurons from medial ganglionic eminence precursors, similar to its role in the developing cortex. But CBP also plays a more substantial role in the expression of late interneuron markers, suggesting that it is continuously required for the various stages of neurogenesis at least in the ventral neurogenic niche. Finally, similar to cortical precursors, the function of CBP in the ventral forebrain precursors is also dependent on histone acetylation. Together, these studies shed light on some of the key intrinsic players that regulate the differentiation of neural precursors in the embryonic murine forebrain, and they also suggest potential mechanisms for the pathogenesis of various cognitive dysfunctions.

While the extrinsic factors regulating neurogenesis in the developing forebrain have been widely studied, the mechanisms downstream of the various signaling pathways are relatively ill-defined. In particular, we focused on proteins that have been implicated in cognitive dysfunction. Here, we ask what role two cell intrinsic factors play in the development of two different neurogenic compartments in the forebrain. In the first part of the thesis, the transcription factor FoxP2, which is mutated in individuals who have specific language deficits, was identified to regulate neurogenesis in the developing cortex, in part by regulating the transition from the radial precursors to the transit amplifying intermediate progenitors. Moreover, we found that ectopic expression of the human homologue of the protein promotes neurogenesis in the murine cortex, thereby acting as a gain-of-function isoform. In the second part of the thesis, the histone acetyltransferase CREB-binding protein (CBP) was identified as regulating the generation of neurons from medial ganglionic eminence precursors, similar to its role in the developing cortex. But CBP also plays a more substantial role in the expression of late interneuron markers, suggesting that it is continuously required for the various stages of neurogenesis at least in the ventral neurogenic niche. Finally, similar to cortical precursors, the function of CBP in the ventral forebrain precursors is also dependent on histone acetylation. Together, these studies shed light on some of the key intrinsic players that regulate the differentiation of neural precursors in the embryonic murine forebrain, and they also suggest potential mechanisms for the pathogenesis of various cognitive dysfunctions.

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Dissertation (Ph.D.)--University of Toledo, 2005. / Typescript. "A dissertation [submitted] as partial fulfillment of the requirements of the Doctor of Philosophy degree in Engineering." Bibliography: leaves 128-141.

archives@tulane.edu / 1 / Xin Fu

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