Children that have been abused or neglected during early development are at greater risk for developing anxiety and depression later in life and similar observations have also been documented in primates and rodents. The conserved nature of the parent-offspring interaction in infant emotional and cognitive development supports the use of rodents to study the molecular mechanisms that underlie this process. Most of the work to date in rodents has used rats with only a few studies using mice, and no group has used transgenic animals to study this problem. Our work, and work from several other labs, has demonstrated that, in rodents, low levels of postnatal maternal care are associated with a decrease in neurogenesis and neuronal survival that persist into adulthood. The functional significance of this decrease in adult neurogenesis is unclear at this point, but is intriguing given recent data showing a correlation between levels of adult neurogenesis, learning, and vulnerability to stress. Here we propose that some of the behavioral sequelae of maternal care are due to its ability to regulate neurogenesis during development and/or in adulthood. In order to test this hypothesis we have generated transgenic mice that express thymidine kinase in neural stem cells (NSC) and show that exposure of NSC from these mice to Ganciclovir abolishes proliferation of these cells. These mice provide us with a unique tool to assess the behavioral consequences of maternal care on neurogenesis and demonstrate the potential of using transgenic animals to study this problem. This proposal for a Career Award reflects my wish to combine my training as a cell biologist and a clinician to understand the molecular details by which genes and environment interact to affect stress reactivity in a genetically-tractable and a simpler experimnetal system. Our work will be integrated into an NIH funded Development Center that we are currently establishing in collaboration with Dr. Joan Kaufman and ongoing work done at the Child Study Center here at Yale. We believe that such close collaboration between clinicians and basic behavioral-neuroscience provides the kind of translational work that will yield new treatment strategies for affective disorders in the future. ? ? ?
| Wei, Lan; Simen, Arthur; Mane, Shrikant et al. (2012) Early life stress inhibits expression of a novel innate immune pathway in the developing hippocampus. Neuropsychopharmacology 37:567-80 |
| Kaffman, Arie; Krystal, John H; Krystal, John J (2012) New frontiers in animal research of psychiatric illness. Methods Mol Biol 829:3-30 |
| Wei, Lan; Meaney, Michael J; Duman, Ronald S et al. (2011) Affiliative behavior requires juvenile, but not adult neurogenesis. J Neurosci 31:14335-45 |
| Wei, Lan; David, Aisha; Duman, Ron S et al. (2010) Early life stress increases anxiety-like behavior in Balbc mice despite a compensatory increase in levels of postnatal maternal care. Horm Behav 57:396-404 |
| Kaffman, Arie (2009) The silent epidemic of neurodevelopmental injuries. Biol Psychiatry 66:624-6 |
| Kaffman, Arie; Meaney, Michael J (2007) Neurodevelopmental sequelae of postnatal maternal care in rodents: clinical and research implications of molecular insights. J Child Psychol Psychiatry 48:224-44 |
