Alex Dranovsky - US grants

[unreadable] DESCRIPTION (provided by applicant): This proposal was designed to prepare the candidate for an independent career in neuroscience research. It includes training and research plans. The training plan combines formal mentorship and consultations, didactics, seminars, and meetings, all designed to provide: 1) expertise in the breeding, maintenance, and characterization of inducible transgenic mice; 2) expertise in molecular and genetic approaches for tracing complex neural circuits from defined populations of neurons; 3) a fund of knowledge in neurobiological issues that will enhance the candidate's ability to think creatively about animal models of psychiatric illness as they pertain to the regulation of neural circuits by stress and the environment; 4) exposure to ethical issues in the responsible conduct of science; and 5) experience in effective laboratory management and mentoring trainees. The research plan entails an analysis of the role of adult-born neurons in hippocampal plasticity. Recent evidence implicates adult hippocampal neurogenesis in response to stress and antidepressant treatment. However, little is known about the contribution of adult-born neurons to the cellular composition of the dentate and to hippocampal projection circuits. In this research proposal, the investigator intends to determine the representation of adult-born neurons within the cellular structure of the dentate gyrus and within hippocampal projections over time. The effects of stress and antidepressant treatment on neuronal turnover and associated projections will also be assessed. Inducible transgenic mice will be used to restrict expression of reporter proteins to neuronal progenitor cells in adult animals. A series of viral and transgenic approaches will be used to restrict expression of trans-synaptic markers to neuronal progenitors. The outlined approaches will allow the investigator to assess how adult-born neurons are represented in the dentate gyrus and in hippocampal connections as a function of time and behavioral/pharmacologic manipulations. Completing the proposed research will define how adult-born neurons contribute to hippocampal plasticity. Completing the training and research plans will lead to establishing the candidate as an independent investigator with expertise in using molecular biological techniques to study how genes and experience modulate complex neural circuits. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

? DESCRIPTION (provided by applicant): Virtually all mental and some medical illnesses are exacerbated by stressful experiences, while social enrichment offers protection. Disorders linked to stress exposure like affective and anxiety disorders are some of the most prevalent diseases in the United States and throughout the world. Depression and anxiety often affect young individuals, cause years of lost productivity, and impose a tremendous public health burden. Stress confers vulnerability to genetic risks for major depressive disorder during distinct sensitive developmental periods. Unfortunately, the cellular and molecular mechanisms by which time-restricted environmental exposures produce delayed and sustained effects on mood, affect, anxiety, and other dimensions of mental functioning are poorly understood. In both rodents and humans, stress dramatically suppresses adult hippocampal neurogenesis. Moreover, the lasting effects of stress on adult stem cell function can vary greatly depending on the animal's age at the time of exposure. We recently discovered that in adult mice, chronic stress increases the number of neural stem cells. Young neurons generated by these stem cells are implicated in behavioral and physiological responses to chronic stress. Studies outlined in this proposal aim to identify the cells that are important in governing hippocampal response to stress. We will use a series of genetic approaches for targeting discrete populations of dentate gyrus neurons as they would be by stress during development and then examine how each population of cells contributes to normal hippocampal functioning and circuitry. Completing the proposed studies will help decipher which hippocampal neurons contribute to encoding stress responses.