2004 |
Mandyam, Chitra D |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Opiate Regulation of Adult Mouse Sgz Proliferation @ University of Texas SW Med Ctr/Dallas
[unreadable] DESCRIPTION (provided by applicant): [unreadable] Morphine is used for its therapeutic effects and abused for its euphoric effects. Use and abuse of this opiate can result in hippocampal deficits, which may impede treatment. New hippocampal neurons in the hippocampal subgranular zone (SGZ) are generated throughout adulthood and are suggested to play a role not only in hippocampal circuitry but also in hippocampal-dependent learning and memory. Evidence suggests that chronic morphine inhibits cell proliferation and adult neurogenesis in the rat SGZ, and this decrease may contribute to decreased hippocampal function in the addicted brain. The mechanism behind opiate-induced inhibition of adult neurogeneis is poorly understood. The aim of this proposal is to determine whether chronic morphine alters adult mouse hippocampal neurogenesis, and to examine how morphine impacts the cell cycle kinetics of mouse SGZ proliferating cells and other endogenous components that promote or maintain neurogenesis. Completion of these studies would enhance our understanding of morphine actions in the hippocampus, and would facilitate the use of transgenic mouse models to study the mechanisms underlying opiate-induced decrease in adult neurogenesis. Three specific aims are proposed. Aim 1: Demonstrate the utility of exogenous and endogenous cell cycle phase markers to analyze the approximate cell cycle phase and kinetics of the proliferating cells of the adult naive mouse SGZ. Aim 2: Evaluate the impact of chronic morphine on cell cycle phase and mature cell fate of the proliferating cells in adult mouse SGZ. Aim 3: Determine chronic morphine's action on factors that promote and maintain hippocampal neurogenesis. Immunohistochemistry, confocal microscopy, immunoblotting and in situ hybridizations are some of the techniques that will be utilized to study the above aims. Comprehension of the mechanisms underlying chronic morphine-mediated decrease in hippocampal neurogenesis will benefit addiction research, and may also shed light on general mechanisms of stem cell regulation. [unreadable] [unreadable] [unreadable] [unreadable]
|
0.904 |
2007 — 2012 |
Mandyam, Chitra D |
K01Activity Code Description: For support of a scientist, committed to research, in need of both advanced research training and additional experience. |
Regulation of Adult Neurogenesis by Methamphetamine @ Scripps Research Institute
DESCRIPTION (provided by applicant): My immediate goal is to establish myself as an independent researcher in the fields of neuroscience and cell biology, and obtain training in methods such as drug self-administration and animal behavior. For my long- term goals, I see myself as a faculty member in an academic environment with an established independent laboratory focusing on neuroscience and pursuing my interests in drug abuse and adult neurogenesis. Abuse of the psychostimulant methamphetamine has reached epidemic proportions and poses significant medical and social problems in the United States. Methamphetamine abuse in humans severely damages the prefrontal cortex and hippocampus, reducing cortical and hippocampal volume and producing memory deficits. Interestingly, adult precursor cell genesis has been demonstrated in the proliferative regions of the mammalian brain, namely, the medial prefrontal cortex (mPFC) and the hippocampal subgranular zone (SGZ). The newly born precursors mature into neurons or glia and are implicated in maintaining adult brain structure and function. While the devastating effects of methamphetamine on the structure and function of the RFC and hippocampus are becoming very clear, very little information exists on the affects of methamphetamine on adult gliogenesis and neurogenesis. The objective of this proposal is to investigate the mechanisms underlying methamphetamine self-administration-induced decrease in cell proliferation, gliogenesis and neurogenesis in the adult rat mPFC and hippocampus and to explore a possible relationship between methamphetmine-induced alterations in cortical and hippocampal structure and function. Importantly, we will use a clinically relevant self-administration paradigm of methamphetamine exposure to implement our specific aims. First, we will determine the harmful effects of methamphetamine escalation on cell proliferation and cell death over an escalation time course. Second, we will explore a possible mechanism for chronic methamphetamine-induced decrease in adult cortical and hippocampal gliogenesis and neurogenesis. Third, we will uncover the relationship between chronic methamphetamine- induced alteration in cell genesis and behavior. Taken together, our findings will improve our understanding of the complex mechanisms by which chronic exposure to psychostimulants affect adult brain function and may help generate better therapies to treat methamphetamine addiction.
|
1 |
2012 — 2021 |
Mandyam, Chitra D |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Medial Prefrontal Cortical Gliogenesis and Alcohol Dependence @ Scripps Research Institute
DESCRIPTION (provided by applicant): Alcohol use disorders, generally known as alcoholism, have taken emotional and financial tolls on American society, cutting across ages, races, ethnicities, and genders, with over 17 million Americans meeting the diagnostic criteria for alcohol abuse or dependence. Clinical data demonstrate alterations in brain structure and function in chronic alcoholics, injuries that may promote the individual s decline to meeting diagnostic criteria for alcohol dependence. Alcohol dependence is characterized by cycles of repeated high alcohol intake and negative emotional consequences of withdrawal that contribute to excessive drinking and susceptibility to relapse. There is a high likelihood that alcohol-dependent individuals will relapse to drinking even after long periods of abstinence, making treatment options challenging. One promising approach for the treatment of relapse to drinking is the identification of mechanisms that contribute to alcohol-induced reductions in brain mass and neurodegeneration. Recent evidence demonstrates that alcohol-induced neurodegeneration is affected by the decreased production of neural and glial progenitors in the adult brain. In the proposed studies, our research will specifically focus on alcohol s effects on the birth and survival of progenitors (glial stem cells and gliogenesis) in the medial prefrontal cortex (mPFC), a brain region implicated in the acute reinforcing effects of alcohol and relapse to alcohol-seeking behavior. Preliminary evidence from our laboratory demonstrated that excessive drinking in a rodent model of alcohol vapor-induced dependence decreased the proliferation and survival of adult-generated mPFC progenitors. Such regulation was not observed in nondependent alcohol self-administering rats, suggesting that the mPFC gliogenic niche is more vulnerable to dysregulation of the homeostatic system during dependence. These results raise a number of fundamental questions about the neuroplastic changes that contribute to alcohol dependence and the neuroplastic mechanisms that underlie the relapse stage of alcoholism. Therefore, this proposal will identify whether reduced gliogenesis in the mPFC could be a vulnerability factor for alcohol dependence and relapse. Animal models of excessive drinking during vapor-induced alcohol dependence and nondependent drinking will be used to (1) determine the cellular mechanisms underlying reduced mPFC plasticity during alcohol dependence (Specific Aim 1), (2) determine impairments in memory and cognitive function dependent on the mPFC during alcohol dependence (Specific Aim 2), and (3) demonstrate a causal relationship between newly born glial progenitors and relapse to alcohol seeking (Specific Aim 3). Immunohistochemical, biochemical, neuroanatomical, and behavioral measures will be used to determine the functional relationships between neocortical gliogenesis and alcohol dependence. The proposed aims will reveal new vulnerability markers for alcohol dependence and impart significant information about targets for medication development.
|
1 |
2013 — 2017 |
Mandyam, Chitra D |
P60Activity Code Description: To support a multipurpose unit designed to bring together into a common focus divergent but related facilities within a given community. It may be based in a university or may involve other locally available resources, such as hospitals, computer facilities, regional centers, and primate colonies. It may include specialized centers, program projects and projects as integral components. Regardless of the facilities available to a program, it usually includes the following objectives: to foster biomedical research and development at both the fundamental and clinical levels; to initiate and expand community education, screening, and counseling programs; and to educate medical and allied health professionals concerning the problems of diagnosis and treatment of a specific disease. |
Cellular Physiology @ Scripps Research Institute
Neural stem cells persist in the adult hippocampal subgranular zone (SGZ) and generate dentate gyrus (DG) granule cell neurons (GCNs) - a process known as adult hippocampal neurogenesis. Alcohol use disorders, commonly called alcoholism is a chronic, relapsing disorder, characterized by withdrawal syndromes of negative emotional symptoms that putatively promote relapse via pathological neuroadaptations in the hippocampus. Of notable interest is the discovery of ethanol (TSRI-ARC model of excessive drinking during chronic ethanol induced dependence (CEID))-induced inhibition of neurogenesis in the DG, and withdrawal from ethanol (CEID and binge alcohol)-induced 'aberrant' neurogenesis in the DG of the hippocampus. These studies suggest that the inhibitory effect of CEID on the regenerative capacity of the adult hippocampus can be considered as a precursor for alcohol-induced neurodegeneration, and that alcohol withdrawal-induced aberrant neurogenesis in the DG may be due to central nervous system hyperexcitability that is associated with alcohol withdrawal symptomatology resulting from termination of CEID. However, cellular mechanisms regulating alcohol withdrawal-induced aberrant neurogenesis in the DG have not been identified. Particularly interesting is the accumulating evidence from Component 02 (Zorrila) and others using the TSRI-ARC CEID model that altered corticotropin-releasing factor (CRF) signaling in the basolateral complex of the amygdala (BLA) and concurrent hyperglutamatergic activity (perhaps manifested as 'kindling-like' activity) in the BLA are evident in withdrawn dependent rats. Therefore we hypothesize that specific neuroadaptations in the CRF system in the BLA following ethanol withdrawal could produce a hyperglutamatergic state in the hippocampus that may regulate aberrant neurogenesis in the DG, and the resulting pathological plasticity could be facilitating the recruitment of new GCNs into emotional memory circuits and therefore contributing to the pathology underlying alcohol dependence via our specific hypotheses that inhibiting this process will alleviate dependence by preventing aberrant DG neurogenesis and withdrawal-associated behaviors. Integration within TSRI-ARC: Our component will use retroviral vectors produced by viral vector core (Contet) and will draw dependence models from animal models core (Koob & George). The proposed studies will require close communication and collaboration with other center components, most notably, Components 01(Roberto) and 03 (Zorrilla).
|
1 |
2013 — 2017 |
Mandyam, Chitra D |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Methamphetamine and Adult Hippocampal Neurogenesis @ Scripps Research Institute
DESCRIPTION (provided by applicant): The overall goal of this proposal is to determine the importance of adult hippocampal neurogenesis to the recovery process following extended access methamphetamine intake. Research into understanding the neurobiological basis of addiction and relapse has significantly progressed, but to date few treatments are known to reverse the drug-induced neuroplasticity changes that convey vulnerability to relapse. Understanding the neuroplastic changes that underlie the relapse stage of addiction can help generate better treatment options for addiction. One potential mechanism to accelerate brain repair during withdrawal is stimulating the generation of neurons from adult neural stem cells - a process known as adult hippocampal neurogenesis. Neural stem cells persist in the adult hippocampal subgranular zone (SGZ). Adult hippocampal neurogenesis is involved in some aspects of methamphetamine addiction, as reinforcing doses of methamphetamine reduce proliferation, differentiation and neurogenesis of neural stem cells in the SGZ. However, the effects of withdrawal from methamphetamine on these stages of hippocampal neurogenesis are unknown. Furthermore, it is unclear if the process of adult neurogenesis can be stimulated during withdrawal; the types of neurons that can be replaced during withdrawal and their ability to integrate into preexisting circuitry. In the proposed studies, innovative genetic, electrophysiological and immunohistochemical techniques and behavioral models will be used to specifically label, stimulate or inhibit adult-generated neurons in the setting of extended access methamphetamine intake. Using these approaches, we will test our central hypothesis that hippocampal neurogenesis contributes to repair after withdrawal from extended access methamphetamine via neuronal replacement; thus, inhibiting this process will impair recovery and stimulating this process will augment recovery and reduce or prevent relapse. Studies in Aim 1 will characterize the long-term survival and integration of adult-generated neurons after methamphetamine self-administration. Experiments in Aim 2 will determine if adult neurogenesis is critical to the prevention of relapse. In Aim 3, we will determine whether adult neurogenesis during withdrawal contributes to functional recovery and prevents relapse.
|
1 |