We are interested in how developmental mediators of neuroplasticity play a role in mediating neuroplasticity in the adult brain. Inability of the brain to "adapt", possibly due to aberrant neuroplasticity, may contribute to or exacerbate psychiatric and neurologic disorders such as addiction, depression, post-traumatic stress disorder, or Alzheimer's Disease. One mediator that we focus on is adult neurogenesis.
The laboratory's primary focus is on the neuroplasticity that may underlie or accompany psychiatric disorders. For example, long-term exposure to drugs of abuse, such as morphine, heroin, cocaine, and ethanol, can result in cognitive deficits. We have previously shown that neurogenesis is inhhibited by chronic exposure to opiates (Eisch et al, 2000). Does the inhibition of adult neurogenesis contribute to the cognitive deficits seen after chronic drug exposure? We have our own self-administration chambers that allow us to ask how a clinically relevant model of addiction, operant i.v. self-administration, alters both neurogenesis and behavior. We are also independently manipulating neurogenesis to see how this influences key aspects of addiction.
We are also interested in the the relationship between mood disorders and adult neurogenesis. Past and future work explores the effects of prescription drugs on adult neurogenesis. For example, we know chronic antidepressant administration increases adult hippocampal neurogenesis. Could alterations in adult hippocampal neurogenesis play a role in depression and in the response to antidepressants? How does periadolescent administration of methylphenidate, a drug commonly used in children to treat ADHD, affect adult hippocampal neurogenesis? Do new neurons regulate the behavioral response of an animal to a stressful situation?
Other examples of our interest in adult neurogenesis and pyschiatry is our exploration of the birth of new neurons in a mouse model of Alzheimer's Disease, the role that growth factors play in development of a depressive-like phenotype, the potential involvement of adult-generated neurons in a mouse model of severe social stress, and the impact of irradiation (both X-ray and cosmic) or voluntary exercise on adult neurogenesis.
Since our ultimate goal is to understand not only if and how new neurons are involved in psychiatric disorders but also "what makes stem cells in the brain tick?", our current and future studies rely on a variety of in vivo and in vitro approaches. These including immunohisto- and cytochemistry along with confocal and two-photon microscopy; transgenic and viral-mediated manipulation of stem and progenitor cells; transgenic, chemical, and irradiation-induced ablation of newly born cells; stereotaxic labeling and lesioning of discrete cells and brain regions; behavioral and metabolic assessment (addiction, depression, anxiety, satiety, etc); and fundamental in vitro approaches like fluorescent activated cell sorting followed by the neurosphere assay. a topic below, visit our Images & Movies page, or please contact me.
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Ongoing Research Topics:
Adult Neurogenesis Overview
Regulation of Adult Neurogenesis
Characterization of Adult Neurogenesis
Growth Factors in Depression and Neurogenesis
Adult Neurogenesis - An Overview
One aspect of hippocampal plasticity that has recently received considerable attention is the ability of this region to produce new neurons. Once controversial, it is now well-established that the hippocampus is one of several regions of the adult mammalian brain that continues to produce new neurons throughout adult life, and it is postulated that this neurogenesis is related to neural plasticity. This theory is especially compelling given the documented link between hippocampal neuroplasticity and learning and memory. Indeed, it is tempting to speculate that the thousands of new neurons born every day in the adult mammalian hippocampus contribute to a variety of hippocampal-related functions (Eisch, 2002).
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Regulation of Adult Neurogenesis
Factors known to regulate neurogenesis in the adult mammalian brain span a seemingly disparate range of environmental, pharmacological, and physiological stimuli. Exercise increases the number of new neurons, while stress and age decrease the number of newly born cells. We have already identified opiate as a factor that decreases the number of new neurons in the adult rat brain (Eisch et al, 2000). Opiates share many characteristics with other drugs of abuse, such as cocaine, amphetamine, THC, and ethanol; all of these drugs have addictive potential, and many studies suggest that long-term use of many of these drugs results in deficits in learning and memory as well as in decreases in neurogenesis.
Therefore, one of the avenues of research in the Eisch Laboratory is exploration of the regulation of adult neurogenesis by drugs of abuse. We have made significant progress in characterizing the inhibition of adult neurogenesis by opiates and stimulants. We ar,e also extremely interested in HOW these factors alter adult neurogenesis. Do they kill progenitors, or just stop them from entering S phase? (For a basic introduction to the cell cycle, click here, here and here.) Do they act directly on progenitor cells, or via alterations in blood flow, growth factors, cytokines, etc? How permanent are the alterations in adult neurogenesis? And, importantly, what funtional impact does altered neurogenesis have on the adult brain? Recent research suggests that addiction itself is a form of learning, though it might be one that utilizes non-hippocampal brain structures.
Addiction is one of the most straightforward psychiatric disorders to model in laboratory animals. However, there are several other psychiatric disorders that we are interested in studying in regards to adult neuorgenesis. Depression has been correllated to decreases in hippocampal volume and to alterations in learning and memory, the hallmarks of neuroplasticity. Though not as straightforward as addiction, depression can also be modeled in animals.
Another avenue of research in the Eisch Laboratory is exploring the role of adult hippocampal neurogenesis in depression and regulation of adult neurogenesis by antidepressants. Chronic antidepressant administration increases adult hippocampal neurogenesis (Malberg et al, 2000). The amount of time necessary to observe clinical effects of antidepressants correlates with the time needed to observe an increase in neurogenesis. Recent research, though still controversial, suggests that the increase in neurogenesis is necessary for the antidepressant effects of the drugs. One of the most common findings in post-mortem evaluation of patients suffering from depression is a decrease in hippocampal volume. Could alterations in adult hippocampal neurogenesis play a role in depression and in the response to antidepressants? What is the mechanism by which antidepressants increase adult neurogenesis? Do the progenitor cells have the necessary receptors to respond to antidepressants, or is it an alteration in the hippocampal environment that is responsible for the increased neurogenesis? Are the learning and memory deficits associated with depression linked to decreased neurogenesis?
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Characterizing Newly Born Cells via Immunohistochemical, Transgenic, and Molecular Approaches
In addition to studies exploring the potential link between psychiatric disorders and adult neurogenesis, we are extremely interested in answering basic questions about the newly born cells in the adult mammalian hippocampus. Cell in the hippocampal subgranular zone, or SGZ, are born in clusters. We have an active research team using exogenous, as well as endogenous, cell cycle markers to characterize these clusters. Do all cells in a cluster move through the cell cycle together? Do they all have the same fate? Do they all express the same cell surface receptors and use the same second messenger signalling pathways?
To ask these questions, we take several approaches. First, we do multiple immunostaining of clusters, analyze them on a confocal microscope and analyze them with a 3D reconstruction program. These tools allow us to ask important, but basic questions about the essential characteristics of the clusters of progenitor cells in the mammalian hippocampus. See our Images & Movies page for examples, and visit the Confocal page for more information.
Another approach we use is transgenic mouse technology. In collaboration with the DiLeone Laboratory at Yale University, we have made a transgenic mouse that is designed to inducibly label or cut out genes in the progenitor cells. In collaboration with Bob Beech and the Picciotto Laboratory at Yale University, we characterized another line of mice which inducibly over-express a certain gene in the progenitor cells. Finally, in collaboration with Masahiro Yamaguchi, currently in Dr. Kensaku Moir's Laboratory at the University of Tokyo, we are studying the effects of drugs of abuse and antidepressants on mice that express a fluorescent protein in their progenitor cells.
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Involvement of the Ventral Midbrain in a Depressive-like Phenotype
We are also intrigued by the role of growth factors in psychiatric disorders such as depression. We have data suggesting that the growth factor BDNF appears to be "depressive" in the ventral midbrain. This is in contrast to the "antidepressive" role that BDNF appears to play in other brain regions, such as the hippocampus. We are very interested whether BDNF in the ventral midbrain plays a role in learning, as is also suggested by our data. These studies were generously supported by the National Alliance for Research on Schizophrenia and Depression.
Involvement of Growth Factors in Regulation of Neurogenesis
We have also recently identified a number of growth factors and cytokines that are altered in specific brain regions after chronic exposure to drugs of abuse. Given the role that many growth factors play in regulating the proliferation and differentiation of newly born cells, we are very interested in persuing the role that these growth factors may play in regulating the alterations in adult hippocampal neurogenesis seen after chronic exposure to both drugs of abuse and antidepressants.
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