Mental illnesses like schizophrenia, autism and depression are common, destabilize families, and incur years of lost work productivity making them the most costly illnesses throughout the world. While some excellent treatment for depression and schizophrenia are available many patients are treatment resistant necessitating novel treatment approaches and no treatment widely accepted to be efficacious for Autism exists. For over thirty years treatment attempts to inject cultured nerve cells into brain areas that are affected by disease have produced disappointing results. The recent possibility of using stem cells for cell-based therapy is intriguing because while stem hold the potential to become neurons and other cells (multipotency). However, the cellular and molecular signals directing stem cells to become neurons remain elusive. One reason for limited success of transplantation therapy is that neurogenesis in the adult brain is restricted to two discrete regions. Other brain structures are thought to be non-permissive to the birth of new neurons. Amongst the two permissive structures is the hippocampus, which is affected by depression, anxiety, schizophrenia, autism and Alzheimer's disease. Several of these diseases were reported to be associated with disturbances in adult hippocampal neurogenesis. Experimental disruption of adult hippocampal neurogenesis leads to deficits in both learning and behavioral responses to antidepressant/antianxiety treatment in rodents. Therefore, hippocampal neurogenesis in the adult brain may be involved in disease states. The cellular and molecular events that permit neurogenesis in the adult brain remain unknown. Using a novel genetic technology we recently discovered that stem cells produce not only neurons, as currently accepted, but also more stem cells, depending on the experiences of the animal and on the location of the stem cell. We also developed a series of environmental manipulations that can drive stem cells to replicate themselves, to become neurons. The goal of the current proposal is to employ our genetic and behavioral systems to uncover the structural and molecular logic that makes neurogenesis and stem cell proliferation permissive in the adult brain. In a series of transplantation, gene expression analyses, and circuit-mapping experiments we intend to explore the mechanisms by which social environment can direct transplanted stem cells to proliferate and to become neurons. The experiments will help us determine how experience changes the stem cell environment and the stem cells themselves to regulate the production of new cells in the adult brain. I will also explore if this type of response to environmental changes helps the brain adapt to adversity by increasing the number of stem cells that can produce more neurons when life experiences become more favorable. Our results will lay the foundation for exploring how existing stem cells can be instructed to multiply and produce more neurons in the adult brain to improve brain function and possibly combat disease. This knowledge may also hold clues to overcoming resistance to neurogenesis in non-permissive brain structures.
The promise of cell-based therapy in the adult brain has not born fruit, but is actively pursued for brain disorders. Here the investigators propose to utilize their technical advances to identify changes in local brain microenvironments and in the stem cells, themselves, that instruct stem cells to proliferate or to make neurons and to examine if these changes can be co-opted for cell-based therapy in the brain. Finally, investigators will explore what role this "experience-directed" stem cell fate plasticity plays in adaptation to stress.
|Sproul, Andrew A; Jacob, Samson; Pre, Deborah et al. (2014) Characterization and molecular profiling of PSEN1 familial Alzheimer's disease iPSC-derived neural progenitors. PLoS One 9:e84547|
|Kirshenbaum, Greer S; Lieberman, Sophie R; Briner, Tamara J et al. (2014) Adolescent but not adult-born neurons are critical for susceptibility to chronic social defeat. Front Behav Neurosci 8:289|
|Samuels, Benjamin A; Leonardo, E David; Dranovsky, Alex et al. (2014) Global state measures of the dentate gyrus gene expression system predict antidepressant-sensitive behaviors. PLoS One 9:e85136|
|Dranovsky, Alex; Needleman, Joshua P; Sylvester, Jessica et al. (2014) Progressive paranoid psychosis in a 20-year-old with central congenital hypoventilation syndrome. Pediatrics 134:e900-2|
|Quesseveur, G; David, D J; Gaillard, M C et al. (2013) BDNF overexpression in mouse hippocampal astrocytes promotes local neurogenesis and elicits anxiolytic-like activities. Transl Psychiatry 3:e253|
|Dranovsky, Alex; Leonardo, E David (2012) Is there a role for young hippocampal neurons in adaptation to stress? Behav Brain Res 227:371-5|
|Richardson-Jones, Jesse W; Craige, Caryne P; Nguyen, Thanh H et al. (2011) Serotonin-1A autoreceptors are necessary and sufficient for the normal formation of circuits underlying innate anxiety. J Neurosci 31:6008-18|
|Sahay, Amar; Scobie, Kimberly N; Hill, Alexis S et al. (2011) Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472:466-70|
|Dranovsky, Alex; Picchini, Alyssa M; Moadel, Tiffany et al. (2011) Experience dictates stem cell fate in the adult hippocampus. Neuron 70:908-23|