The vast majority of neurons in the human brain are produced during the last trimester of gestation and during the first postnatal year. Neurogenesis during normal development occurs in two distinct phases. During the initial progressive phase, stem cells and progenitor cells undergo mitotic cell divisions to produce postmitotic neurons, which increase in number to peak levels in specific brain regions at a characteristic age. During the subsequent regressive phase, 30% to 50% of these newly generated neurons are eliminated through apoptosis, a genetically controlled process of cell degeneration. Research in my laboratory is designed to investigate factors controlling the progressive and regressive phases of neurogenesis. Currently, we are using a number of animal models to investigate naturally occurring growth factors (e.g. insulin-like growth factor-I) and essential dietary nutrients (e.g. n-3 fatty acids) for their abilities to alter either the rate of mitotic cell divisions or the rate of neuronal degeneration in the developing brain.
The role of insulin-like growth factor-I in the control of neurogenesis and synaptogenesis
Insulin-like growth factor-I (IGF-I) is a naturally occurring peptide, related to insulin, that has been shown to play a role in the development of the central nervous system. In genetically engineered mice with increased levels of IGF-I in the brain, there is a significant increase in the number of neurons as well as an increase in the number of axons and synapses formed by these neurons. This research investigates the role of IGF-I in controlling neurogenesis and axon outgrowth during embryonic and early postnatal development in one such line of mice, designated nestin/IGF-I transgenics. Increases in brain weight and volume in these mice are detectable before birth. These mice are being studied to test the hypothesis that IGF-I stimulates neurogenesis by amplifying the proliferation of neuronal precursors and directing neuronal differentiation during embryogenesis. Studies of the cerebral cortex and hippocampus of nestin/IGF-I transgenic mice are being conducted to: 1) determine developmental changes in the numerical density and total number of neuroepithelial progenitor cells, which give rise to neurons of the cerebral cortex and hippocampus; 2) measure the length of the mitotic cycle, and the lengths of the individual phases, in these progenitor cells to detect accelerated cell division; and 3) identify genes that are regulated by IGF-I in the brain, which act to directly or indirectly control neurogenesis in these regions. This research contributes necessary information on the mechanisms by which IGF-I controls neuron number in the normal brain, and on the therapeutic potential of IGF-I for the treatment of several neurodegenerative diseases and developmental disorders of the brain.
The functional role of dietary n-3 polyunsaturated fatty acids in the control of neurogenesis
Docosahexaenoic acid (DHA) is an n-3 polyunsaturated fatty acid that is important in central nervous system function during development and in several disease states. The n-3 polyunsaturated fatty acids are essential dietary nutrients and deficiency results in impaired learning and memory, abnormal brain growth and alterations in the metabolism of key neurotransmitters. Recently, we have shown that n-3 fatty acid deficiency during gestation results in severe growth retardation of the fetal brain. This research will use an animal model of n-3 fatty acid dietary deficiency to elucidate the role of DHA in controlling neuron genesis in the developing brain. The research will investigate the effects of DHA deficiency on the ability of neuronal precursor cells to undergo normal cell divisions in the embryonic brain. In addition, we will investigate the effects of DHA dietary deficiency on neuronal cell survival during the early postnatal period. This research will contribute necessary knowledge on the importance of an adequate dietary source of n-3 fatty acids for normal brain development and function, broadly relevant to neurological disease states associated with altered n-3 fatty acid metabolism.
Hodge RD, D’Ercole AJ, O’Kusky JR. Increased expression of insulin-like growth factor-I (IGF-I) during embryonic development produces neocortical overgrowth with differentially greater effects on specific cytoarchitectonic areas and cortical layers. Dev Brain Res, 154:227-237, 2005.
Hodge RD, D’Ercole AJ, O’Kusky JR. Insulin-like growth factor-I accelerates the cell cycle by decreasing G 1 phase length and increases cell cycle reentry in the embryonic cerebral cortex. J Neurosci, 24(45):10201-10210, 2004.
Popken G, Hodge RD, Ye P, Zhang AJ, Ng W, O’Kusky JR, D’Ercole AJ. In vivo effects of insulin-like growth factor-I (IGF-I) on prenatal and early postnatal development of the central nervous system. Eur J Neurosci, 19:2056-2068, 2004.
O'Kusky JR, Ye P, D'Ercole AJ. Increased expression of insulin-like growth factor-I (IGF-I) augments the progressive phase of synaptogenesis without preventing synapse elimination in the hypoglossal nucleus. J Comp Neurol, 464:382-391, 2003.
D'Ercole AJ, Ye P, O'Kusky JR. Mutant mouse models of insulin-like growth factor actions in the central nervous system. Neuropeptides, 36: 209-220, 2002.
O'Kusky JR, Ye P, D'Ercole AJ. Insulin-like growth factor-I promotes neurogenesis and synaptogenesis in the hippocampal dentate gyrus during postnatal development. J Neurosci, 20(22): 8435-8442, 2000.
MRC Research Scholar Award – 1986-1991