1994 — 1995 |
Eisch, Amelia J |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Processes Underlying Methamphetamine-Induced Toxicity @ University of California Irvine |
0.939 |
2004 — 2008 |
Eisch, Amelia J |
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. |
Regulation of Adult Neurogenesis by Opiates @ University of Texas SW Med Ctr/Dallas
DESCRIPTION (provided by applicant): Drug dependence is linked to decreased volume of limbic-related structures and to altered hippocampal morphology. Clinically, drug dependence is associated with limbic- and hippocampal-related symptoms, such as alterations in affect and emotion, and deficits in learning and memory. Clarification of the time course, extent, and cause of the changes in hippocampal structure and function will likely improve our understanding and treatment of addiction. One aspect of hippocampal plasticity potentially important for addiction research is the ability of the hippocampus to make new neurons throughout adulthood. Evidence suggests that the new hippocampal neurons are functionally integrated into hippocampal circuitry, and are involved in aspects of learning and memory. While much has been learned about what increases and decreases the number of new cells in the hippocampus, little progress has been made in identifying the cellular mechanisms underlying the regulation of adult hippocampus neurogenesis. This proposal is designed to explore how opiates regulate adult neurogenesis, and to explore the potential consequences of opiate-induced alterations in adult neurogenesis. There are three aspects to this proposal: a) We have shown that chronic, but not acute, opiate exposure inhibits the birth of new neurons in the adult hippocampus (Eisch et al., 2000). We will characterize the opiate-induced inhibition of adult neurogenesis by examining the time course of inhibition and alterations in the cell cycle. We also present data that a subset of newly born cells in the adult hippocampus express mu-opioid receptors. We will explore if mu-opioid receptor expression fluctuates across the cell cycle. b) We present data that certain cytokines and growth factors are decreased in the hippocampus after chronic morphine. To understand how morphine-induced changes in these factors alter adult neurogenesis, we will determine the time course of these changes relative to morphine exposure and explore if newly born hippocampal cells express receptors for these cytokines and growth factors. c) We present data that the morphine-induced decrease in adult hippocampal neurogenesis correlates with decreased hippocampal function. We will fully explore the deficit in hippocampal functioning caused by chronic morphine, particularly in relation to morphine-induced changes in adult neurogenesis and hippocampal levels of certain cytokines and growth factors. Examination of opiate-induced alterations of adult neurogenesis holds significant potential for testing the hypothesis that new neurons are important for learning and memory. In addition, comprehension of how opiates act to inhibit new neurons in the adult hippocampus will likely shed light on the basic mechanisms regulating neural stem cells. Importantly, such studies will improve our understanding of the complex mechanisms by which opiates affect brain function.
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0.931 |
2007 — 2017 |
Eisch, Amelia J |
K02Activity Code Description: Undocumented code - click on the grant title for more information. |
New Horizons in Adult Neurogenesis @ Ut Southwestern Medical Center
DESCRIPTION (provided by applicant): This is a renewal application for a NIDA Independent Scientist Award (K02). The candidate, Amelia J. Eisch, Ph.D., is a tenured Associate Professor in the Department of Psychiatry at UT Southwestern Medical Center. Dr. Eisch is a pioneer in understanding the reciprocal relationship between certain forms of hippocampal plasticity such as adult hippocampal neurogenesis and behaviors relevant to addiction. The first award period of this K02 provided Dr. Eisch with the protected time she needed to accomplish her past goals, which included renewing her NIDA R01 grant on opiates and neurogenesis, securing additional federal funding, advancing her work from correlative to more mechanistic and causative studies, and being promoted to Associate Professor and receiving tenure. This K02 renewal is requested in order to continue this protected time and to allow Dr. Eisch to utilize the momentum she has established in understanding the proposed reciprocal role between new neurons in the adult brain and addiction. The receipt of a K02 renewal award would allow her continued protection from administrative burdens, and thus allow Dr. Eisch to advance: (1) research on the relationship between adult-generated neurons and behaviors relevant to addiction; (2) dissection of the cellular, molecular, and genetic control of adult-generated hippocampal neurons; (3) newly developed collaborations on translational profiling, ultrastructural analysis, and circuit-level impact of new neurons; (4) application of new techniques for these collaborations (BAC-TRAP, optogenetics, EM, electrophysiology); (5) data collection for grant applications: the 10-year renewal of her existing R01 on opiates and neurogenesis, a new NIDA R01 relevant to the molecular control of hippocampal neurogenesis, and a new NIDA R01 relevant to behavioral and circuit-level impact of adult-generated neurons. By providing this protected time, Dr. Eisch can work closely with her collaborators and rapidly advance her new ideas, thus benefitting the fields of addiction research and stem cell biology and neuroscience as a whole. The stability and protected time offered by this K02 award would ultimately support at least two new projects exploring the intriguing relationship between adult-generated hippocampal neurons and behaviors relevant to addiction. As these studies hold great potential to improve our understanding of the complex mechanisms by which drugs of abuse affect brain function, they therefore may open new avenues for treatment of addiction and relapse to drug seeking. As these studies also will also shed much-needed light on how adult-generated neurons influence complex behavior - such as drug/context association, extinction from drug-seeking, and behavioral response to stress - they will be important to future efforts to harness neural stem cells for repair of the injured, even addicted, brain and to our understanding of what new neurons can/will do in the adult brain.
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0.987 |
2008 — 2012 |
Eisch, Amelia J |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Basic Science Training Program in Drug Abuse @ Ut Southwestern Medical Center
DESCRIPTION (provided by applicant): The objective of the Basic Science Training Program in Drug Abuse (DA) at UT Southwestern is the training of predoctoral, postdoctoral, and short-term research fellows in a broad range of biological research methods relevant to drug abuse and addiction. The DA Training Program fills a critical need by increasing the number of high-quality basic science researchers in the field of drug abuse, and conversely exposing clinical researchers to basic research in addiction. There are numerous strengths of this historically successful Training Program. The DA Training Faculty Members have exemplary research and funding records in addiction neurobiology and related biomedical fields of study. The breadth and depth of our potential trainees is also highly notable, as is the explosive interest specifically in neuroscience research at UT Southwestern, an institution traditionally known for world-class molecular and cellular biology. UT Southwestern itself provides an outstanding environment in which to conduct basic, interdisciplinary, and frequently cutting-edge biomedical research. For example, our Training Program provides a platform on which researchers in diverse academic divisions (Psychiatry, Neuroscience, Molecular Biology, Internal Medicine, Development Biology, Pharmacology, Neurology) can work closely together to integrate their findings to achieve a more holistic and clinically relevant understanding of the addicted phenotype. UT Southwestern also offers a preexisting integration of basic science research with nationally recognized clinical programs in addiction research and treatment, thus providing the unique opportunity for preclinical investigators to couple their work directly to clinical trials. A final strength is the demonstrated commitment of our Core DA Training Faculty to encouraging researchers outside the addiction field as well as the next generation of researchers to turn their considerable talents toward the advancement of our knowledge of the addicted brain, thus forging novel avenues for treatment of drug abuse. UT Southwestern has the resources and capabilities to build significantly on the already notable 15-year history of this DA Training Program. Renewal of this Program will play an essential role in ensuring continued exceptional predoctoral, postdoctoral, and short-term research training in addiction neurobiology at our institution. For this competitive renewal, we began with our previous cohesive program of training, and updated it significantly to address foremost the evolving needs of Trainees, but also those of the mentors and program administrators, as described in this application. Throughout these updates, we have been cognizant to maintain the key aspects of the DA Training Program that have thus far been so successful in training fellows in drug abuse research: exceptionally high-quality mentors, cutting-edge research, translational opportunities, and a supportive atmosphere. As such, we expect the DA Training Program will continue to serve as a seed grant that results in increased recruitment of fellows to our laboratories;this opens the door for fellows to apply for individual grants from federal and private sources, which will in turn further enrich our Training Program. Most importantly, the continued success of the DA Training Program will serve to further enhance the profile of addiction research at UT Southwestern, thus drawing even more of the best and brightest scientific minds to the study of addiction.
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0.931 |
2008 — 2009 |
Eisch, Amelia J |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Cdk5 and Adult Hippocampal Neurogenesis @ University of Texas SW Med Ctr/Dallas
[unreadable] DESCRIPTION (provided by applicant): Identification of novel intracellular and microenvironmental signals that influence adult neurogenesis is a major research priority. Here we provide evidence for a novel role of cyclin dependent kinase 5 (Cdk5) in adult neurogenesis. This is striking since, unlike other cyclins, Cdk5 and its cofactors p35 and p39 are enriched in post-mitotic neurons. Based on our preliminary data, we hypothesize that Cdk5 activity in the adult hippocampus regulates proliferation and maturation of adult neural precursors. To test this hypothesis, we propose three aims to be accomplished in two years. Aim 1: Define protein expression of Cdk5 and required cofactors in subgranular zone (SGZ) precursors as they mature. We have validated the use of a novel Cdk5 antibody for protein analysis, including immunohistochemistry. Guided by our preliminary data, we will define when Cdk5 protein and its required cofactors, p35 and p39, are expressed in maturing SGZ cells. Aim 2: Determine the impact of Cdk5 ablation from precursors and their progeny on neurogenesis. New pilot data with our nestin-CreERT2 mouse suggest that inducible loss of Cdk5 from SGZ precursors and their progeny is detrimental to discrete stages of adult neurogenesis. We will determine how transgenic-mediated, precursor-specific ablation of Cdk5 impacts the a) number, b) phenotype, and c) morphology of these cells as they mature into dentate gyrus neurons. We hypothesize that loss of Cdk5 from precursors and their progeny will negatively impact their differentiation but have no effect on proliferation. Aim 3: Explore the impact of Cdk5 ablation from dentate gyrus neurons on SGZ neurogenesis. We show new data that loss of Cdk5 in mature dentate gyrus neurons has profound negative effects on SGZ precursors and immature neurons. We will test the hypothesis that Cdk5 in mature neurons in the hippocampus is critical for maintaining the SGZ neurogenic niche. We will use viral-induced ablation of Cdk5 to quantify the impact of Cdk5 ablation from mature dentate gyrus neurons on the a) number and b) morphology of SGZ precursors and immature neurons. These studies will provide fundamental insight into the potential cell autonomous effects of Cdk5 on adult neural stem cell development (Aims 1, 2), and the cell non-autonomous effects of Cdk5 in mature neurons on adult hippocampal neurogenesis via alteration of the neurogenic microenvironment (Aim 3). These studies will shed much-needed light on the physiological and pathological functions of Cdk5, and potentially indicate a highly novel role for Cdk5 in regulation of adult hippocampal structure and function. Contrary to a long-held belief that the brain cannot regenerate, the adult brain is now known to give rise to new neurons throughout life. Understanding the cues that influence these adult-generated neurons is critical, as it may hold the key to understanding brain functions, like learning and memory, and may allow us to harness these new neurons for repair of the injured or addicted brain. Here we propose to explore the impact of a novel regulator, cyclin dependent kinase 5, on the birth of new neurons in the adult brain. [unreadable] [unreadable] [unreadable]
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0.931 |
2009 — 2013 |
Eisch, Amelia J |
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. |
Opiates and Adult Neurogenesis @ Ut Southwestern Medical Center
DESCRIPTION (provided by applicant): Drug dependence is linked to decreased volume of limbic-related structures, altered hippocampal morphology, and limbic- and hippocampal-related symptoms, such as deficits in learning and memory. Conversely, the hippocampus is involved in drug reward and relapse to drug seeking. Clarification of the time course, extent, and cause of drug-induced hippocampal neuroadaptations and identification of how hippocampal neuroadaptations impact addictive behaviors will greatly improve our understanding and treatment of addiction. A notable aspect of the hippocampus is its ability to generate new neurons throughout life. Adult-generated neurons are functionally integrated into hippocampal circuitry, and appear to be involved in hippocampal- dependent learning. Drugs of abuse, including morphine, decrease neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate gyrus. This raises the possibility that opiate-induced alteration in neurogenesis leads to cognitive deficits, continued drug taking or relapse, or otherwise impedes recovery. We will test this possibility using state-of-the-art techniques to overcome obstacles in SGZ precursor analysis and thus advance our understanding of the relationship between opiate and hippocampal neurogenesis. Aim 1. Determine how morphine self-administration and withdrawal alter discrete stages of adult hippocampal neurogenesis. Chronic, but not acute, opiates decrease the birth of new cells and generation of neurons in adult hippocampus. Using morphine self-administration, here we will take the next essential step in understanding this action: delineate the precise effects of opiates and withdrawal on all cellular stages, from proliferation of stem and precursor cells, to maturation of young neurons, and eventual survival to maturity. Aim 2. Assess how altered adult hippocampal neurogenesis relates to drug seeking. Guided by Aim 1 and our preliminary data on the importance of new neurons to drug seeking after withdrawal, we will explore how voluntary running and hippocampal-dependent learning are altered by opiate exposure, and how running and learning influence drug-seeking and opiate-induced alterations in hippocampal neurogenesis. Aim 3. Evaluate the involvement of adult-generated hippocampal neurons in drug/context association. It is unknown if adult-generated neurons are influenced by or important in the drug/context association critical for reinstatement to self-administration or conditioned place preference (CPP). Using our novel transgenic mouse models to inducibly and selectively reduce hippocampal neurogenesis, we will examine the hypothesis that adult-generated neurons are activated by drug/context associations during a critical maturation window. These studies may indicate therapeutic approaches for treating opiate addiction or preventing opiate relapse. These studies will also improve our understanding of the complex mechanisms by which opiates affect brain function hippocampal function, and will provide insight into the role of the hippocampus and adult neurogenesis in addictive processes, a critical issue for addiction research in particular and biomedical science in general. Drug addiction is a devastating disorder marked by compulsive drug use, high propensity to relapse to drug taking, and cognitive deficits. Drugs of abuse, including heroin, lead to a decrease in the number of new neurons in the hippocampus, a brain region important for learning and memory. We will explore the potentially reciprocal relationship between opiate addiction and adult hippocampal neurogenesis, thus providing much- needed insight into the structure and function of the addicted brain as well as the function of new neurons in the adult brain.
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0.901 |
2013 — 2015 |
Eisch, Amelia J |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Basic Science Training Program in Drug Abuse Research @ Ut Southwestern Medical Center
DESCRIPTION (provided by applicant): The objective of the Basic Science Training Program in Drug Abuse Research (DAR) at UT Southwestern is the training of predoctoral and postdoctoral research fellows in a broad range of biological research methods relevant to substance abuse and addictive disorders. The DAR fills a critical need by fueling the number of high-quality basic science researchers in the field of drug abuse. There are numerous strengths of the DAR. The DAR Faculty Members are exemplary in their research, funding, and mentoring records relevant to addiction biology. Our past trainee record is excellent, and our potential trainee pool has notable breadth and depth. There has been an explosive interest specifically in neuroscience research at UT Southwestern, an institution traditionally known for world-class molecular and cellular biology, making this an ideal place to recruit trainees from diverse disciplines into addiction research. As for atmosphere, UT Southwestern is an outstanding place in which to conduct basic, interdisciplinary, and frequently cutting-edge biomedical research, and UT Southwestern has the resources and capabilities to build significantly on the 20-year history of the DAR. UT Southwestern also offers a preexisting integration of basic science research with nationally recognized clinical programs in addiction and access to imaging facilities and tissue repository, thus providing truly translational research opportunities. A fina strength is the demonstrated commitment of our DAR Faculty to encouraging faculty members outside the addiction field to turn their considerable talent towards the advancement of our knowledge of the addicted brain, thus forging novel avenues for the treatment and prevention of drug abuse. The DAR is extremely collaborative, as its Faculty Members in diverse academic divisions (Psychiatry, Neuroscience, Neurology & Neurotherapeutics, Developmental Biology, Cell Biology, Internal Medicine) work closely to integrate their findings and thus achieve a more holistic and clinically relevant understanding of the addicted phenotype. For this competitive renewal, we updated the Program in response to Trainee and Board Member feedback. For example, in response to the large number of qualified applicants we turn away each year, we request funds to support 6 predoctoral and 5 postdoctoral Trainees for 2-3 years. In response to our Trainee desire for more integrated and relevant experiences, we have introduced novel ways for Trainees to interact with and learn from each other, DAR Faculty, and the broader addiction research community in Dallas, and we have provided numerous Trainee career-development programs. However, we have kept the key aspects of the DAR that have been so successful: exceptionally high-quality mentors, cutting-edge research, translational opportunities, and an atmosphere conducive to performing the best research possible. Renewal of the DAR is critical to ensuring continued exceptional pre- and postdoctoral research training in addiction neurobiology at our institution, which will help NIDA with its mission of bringing the power of science to bear on substance abuse and addictive disorders.
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0.901 |
2015 — 2016 |
Eisch, Amelia J |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Molecular and Chemogenetic Control of Dentate Gyrus Inputs: a Novel Approach to Combat Depression-Like Behavior @ Ut Southwestern Medical Center
? DESCRIPTION (provided by applicant): Major Depressive Disorder is one of the most common psychiatric disorders, affecting millions of people worldwide. Antidepressant drugs are widely used, but 50% of depressed patients receiving these medications will relapse, and 30% are drug resistant. Thus, new targets for antidepressants are needed. Converging evidence indicates an important role for depression-associated changes in hippocampal circuitry. For example, depressed humans and animal models of depression have smaller hippocampi, and decreased activity-dependent genes and processes, like hippocampal dentate gyrus (DG) neurogenesis. Notably, antidepressant drugs and non-pharmacological treatments like electroconvulsive treatment ameliorate these changes. From such work, a new framework for discovery of novel antidepressants has emerged: find treatments that recalibrate depression-linked dysfunctional neural circuits and behavior. Indeed, other approaches to stimulate neural circuits - such as deep brain stimulation (DBS) - can reverse depression-related symptoms and neuropathology, particularly in the hippocampus. Strikingly, in the context of depression, DBS has only been targeted to non-hippocampal brain regions. DBS of the main hippocampal input - the entorhinal cortex (Ent) via the perforant path (PP) - has proven physiologically beneficial in other contexts: it enhances memory in humans and memory and DG neurogenesis in laboratory animals. However, it remains unknown if stimulation of the PP will produce antidepressant-like behaviors. For this exploratory and developmental R21 project, we will test the hypothesis that controlled activation of PP to DG is antidepressive. This hypothesis emerges from our pilot data showing: a) stress and depression are linked to greater PP levels of TRIP8b, a brain-specific auxiliary subunit of HCN channels; b) germline knockout of TRIP8b - which is antidepressive - increases DG neurogenesis; and c) PP disinhibition (de-repression of Ent neuronal excitability via knockdown of TRIP8b) increases DG neurogenesis and is antidepressive. We also provide d) feasibility data that we can chemogenetically-stimulate DG via PP activation. Based on these data, we will: Aim 1: Determine whether molecular-based PP disinhibition promotes antidepressive behavior using viral-mediated KD of TRIP8b in the PP and a battery of depression-linked and cognitive behaviors; and Aim 2: Determine whether chemogenetic stimulation of PP activity drives antidepressive behavior using DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) to mediate neuronal activity and behavior. While the aims proposed here involve considerable risk, they are logical and highly feasible given the large amount of pilot data and the published ability of PP stimulation to improve hippocampal cognitive function. This project is in an early and conceptual stage, and has focused, behavioral outcomes, making it ideal for the R21 mechanism. Even if the hypothesis is incorrect, the experimental design ensures that the collected data will advance our knowledge of brain circuits contributing to affect and cognition.
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0.987 |