1985 — 1987 |
Olney, John W |
K05Activity Code Description: For the support of a research scientist qualified to pursue independent research which would extend the research program of the sponsoring institution, or to direct an essential part of this research program. |
Cns Ultrastructure Disease, Drugs, and Development
For several years the applicant has been studying the neurotoxic properties of the putative excitatory transmitters, glutamate and asparate and certain structural analogs -- the so-called excitotoxic amino acids. Recently he observed that other excitatory agents found naturally in brain such as folic acid and acetylcholine, mimic neurotoxic properties of the powerful excitotoxic glutamate analog, kainic acid. The applicant proposes to study mechanisms by which endogenous neuroexcitants destroy central neurons and to explore possible roles of excitatory mechanisms in human neuropathological conditions such as epilepsy-related brain damage, lithium neurotoxicity, tardive dyskinesia and neuronal degeneration associated with aging. A combined ultrastructural, immunohistochemical, neurochemical, neuropharmacological, behavioral and chemical lesioning approach will be employed.
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1 |
1985 |
Olney, John W |
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. |
Lithium Neurotoxicity
Lithium (Li) is used widely in the treatment of certain mental disorders and both cholinergic agonists and cholinesterase inhibitors are being used and/or proposed for treatment of the same mental conditions. In addition, these cholinergic agents are employed in various other fields of medicine and patients receiving Li and/or cholinomimetic agents may also be exposed to anticholinesterase insecticides environmentally. Relevant to the above, the applicants recently observed that subcutaneous (sc) administration of a single dose of the cholinergic agonist, pilocarpine or the cholinesterase inhibitor, physostigmine to adult rats treated 24 hr previously with a single sc injection of lithium chloride results in a dramatic acute neurotoxis syndrome consisting of sustained seizure activity plus fulminant degeneration of neurons in numerous brain regions. This neurotoxic syndrome does not occur from administration of these cholinergic agents without Li pretreatment of from Li by itself. Administering atropine in the interval between Li and pilocarpine prevents the neurotoxic syndrome. The applicants propose a series of experiments aimed at clarifying the mechanism(s) underlying this neurotoxic syndrome and at evaluating, in experimental animals, the nature and degree of risk that combined exposure of humans to Li and cholinomimetic agents may entail. We will employ a combination of neurochemical quantitative microhistochemical, ultrastructural, autoradiographic, immunocytochemical, electrophysiological, neuropharmacological and selective lesioning methods.
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1 |
1987 — 1991 |
Olney, John W |
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. |
Pcp, Sigma Opiates, and Glutamergic Transmission
The excitatory amino acids (EAA), glutamate (Glu) and aspartate, are major excitatory transmitters in the CNS and also have potent neurotoxic (excitotoxic activity which is mediated through EAA synaptic receptors. Several EAA receptor subtypes have been identified, the N-methyl aspartate (NMA) receptor being the best characterized and comprising the majority of EAA receptors in brain. It was recently found that drugs in the PCP/sigma opiate category powerfully and selectively block both the excitatory and toxic effects of NMA on central neurons. Also, it has been shown that NMA and PCP receptors have nearly an identical distribution pattern throughout rat forebrain. The ability of PCP to powerfully inhibit EAA transmission raises the important question whether this might be the mechanism underlying PCP psychotomimetic effects and, if so, whether impaired EAA transmitter function might underlie schizophrenia and/or other psychotic processes. Recent evidence also implicates NMA receptors in long term potentiation, a phenomenon putatively mediating memory formation, which suggests an EAA-linked mechanism by which PCP might interfere with memory. Currently there is considerable interest in the possibility that NMA antagonists might be useful neuroprotective agents in the clinical management of neurodegenerative conditions such as cerebral ischemia (at the potential risk of inducing psychotomimetic effects or memory impairment). We are requesting support for a series of in vitro studies that will generate information relevant to the above. In the chick embryo retina we will study the mechanism(s) by which PCP/sigma opiate compounds block NMA neurotoxicity and will compare PCP/sigma opiate compounds with other EAA antagonists for efficacy in preventing ischemic neuronal degeneration. In cultured chick spinal neurons we will apply voltage and patch clamp techniques to explore the mechanism(s) by which PCP/sigma opiate compounds antagonize the excitatory action of NMA. In rat hippocampal slices we will study the ability of PCP/sigma opiate compounds to block long term potentiation.
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1 |
1988 — 1992 |
Olney, John W |
K05Activity Code Description: For the support of a research scientist qualified to pursue independent research which would extend the research program of the sponsoring institution, or to direct an essential part of this research program. |
Cns Ultrastructure: Disease, Drugs &Development
This is a request for renewal of a Research Scientist Award to allow the applicant to continue studying the role(s) of excitatory transmitters in neuropsychiatric disorders. The applicant has shown that the excitatory amino acids (EAA), glutamate (Glu) and aspartate, which are major excitatory transmitters in the CNS, have potent neurotoxic (excitotoxic) activity which is mediated by EAA synaptic receptors. Several EAA receptor subtypes have been identified and, very recently, new classes of EAA antagonists were discovered (e.g., agents in the phencyclidine/sigma opiate family) which penetrate blood brain barriers. Recent evidence suggests that endogenous EAA may be responsible for neuronal degeneration in conditions such as anoxia/ischemia, hypoglycemia and epilepsy. A major aim of the proposed research is to clarify the mechanism(s) of, and develop appraoches for preventing, EAA-mediated neuronal dgeneration in both the adult and developing CNS. In addition to exploring the role of EAA in hypoxic/ischemic and epilepsy-related brain damage, the applicant will study the relationship between EAA and phencyclidine (PCP) receptors and explore the potential role of EAA receptors in schizophrenia or other psychotic processes and in the physiology and pathology of memory and learning. His studies will also focus on the other major excitatory transmitter system in mammallian brain--the cholinergic system. He will continue to study the role of excitatory transmitters (both glutamergic and cholinergic) in cognition and the cognitive deficits in Alzheimers Disease and will continue to explore mechanisms by which lithium enhances the epileptogenicity and the neurotoxic potential of cholinergic agonists such as pilocarpine. A number of animal models, both in vitro and in vivo, will be employed, as will various methods spanning several disciplines, including light and electronmicroscopic neuropathology, immunohistochemistry, receptor autoradiography, electrophysiology, neuropsychology, neurotoxicology, neuropharmacology and neurochemistry.
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1 |
1988 — 1990 |
Olney, John W |
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. |
Perinatal Brain Damage--Mechanisms and Prevention
We propose to investigate, in experimental animals, the possibility that the excitatory amino acids (EAA), glutamate (Glu) and aspartate, may be responsible for a type of brain damage (anoxic/ischemic) that occurs perinatally in the human and constitutes a major cause of neuropsychiatric developmental disability. These compounds are major excitatory transmitters in the CNS and also have potent neurotoxic (excitotoxic) activity which is mediated by EAA synaptic receptors. Several EAA receptor subtypes have been identified and, very recently, new classes of EAA antagonists were discovered which penetrate blood brain barriers. Several lines of evidence suggest that endogenous EAA may cause or that EAA antagonists can prevent brain damage associated with anoxia/ischemia. Such evidence derives from both in vitro and in vivo research. However, the in vivo evidence has a tenuous character because of inadequacies inherent in the animal models of anoxia/ischemia used. Moreover, it was generated in adult animal models that may not be entirely relevant to mechanisms operative in earlier life. The research proposed herein is aimed at clarifying the mechanism(s) of, and developing approaches for preventing, anoxic/ischemic neuronal degeneration in the developing CNS. The proposed research will be conducted with two models, one in vitro and one in vivo, which we have developed for the specific purpose of investigating the role of excitotoxic mechanisms in perinatal anoxic/ischemic neuronal degeneration. A major goal of the research is to test drugs that we find effective in preventing Glu-induced and ischemic neuronal degeneration in vitro for their ability to prevent hypoxic/ischemic brain damage in vivo in the 10 day old infant rat. We also will study the vulnerability of rat brain to hypoxic/ischemic damage in earlier post or prenatal stages of development, will evaluate whether this new rat model of perinatal brain damage is suitable for studying neurobehavioral consequences of such damage, and will investigate the ontogeny of EAA and related transmitter systems that may be important determinants of vulnerability to hypoxic/ischemic brain damage.
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1989 — 1992 |
Olney, John W |
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. |
Phencyclidine Toxicity: Neuropsychiatric Implications
Phencyclidine (PCP), pharmacologically classified as a dissociative anesthetic, is best known as a widely abuse drug with potent psychotomimeti properties. Evidence that PCP binds with high affinity and spccifici(y to a unique class of membrane receptor in the mammalian CNS has given rise to speculation that the CNS contains a yet-to-be-identified PCP-like peptidergic neuromodulator and that dysfunction of this neuromodulatory system might underly psychotic disorders such as schizophrenia. It was recently shown that PCP receptors are physically co-localized with N-methyl-Daspartate (NMDA) receptors (a subtype of glutamate receptor) and that PCP powerfully antagonizes NMDA receptor-mediated excitatory and neurotoxic (excitotoxic) phenomena. MK-801 is a PCP-like compound which displays even greater potency than PCP in binding to the PCP receptor and in antagonizing the excitatory and toxic actions of NMDA. We and others hav shown that MK-801 and PCP can protect CNS neurons against hypoxic/ischemic or epilepsy-related brain damage (both of which are considered NMDA receptor-mediated processes). However, very recently we discovered that, quite separately from their neuroprotective properties, PCP and MK. 801 reproducibly induce pathomorphological changes in certain CNS neuronal populations when administered sub-cutaneously in subanesthetic doses. These findings raise new questions regarding the safety of these agents for use in the clinical management of neurodegenerative diseases, and suggest thec possibility that the neuronal populations selectively vulnerable to the neurotoxic actions of PCP might be the same populations through which the psychotoxic (psychotomimetic) actions of PCP are mediated, in which case further study of these neurons and the mechanisms underlying their peculiar vulnerability to PCP toxicity might eventually yield clues relevant to the pathophysiology of schizophrenia. Our findings also raise new questions concerning the nature and degree of risk associated with the use of PCP as a "recreational" drug. The aims of this proposal are to better characterize this newly discovered PCP neurotoxic syndrome and further investigate the underlying mechanism(s).
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1990 — 2001 |
Olney, John W |
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. |
Neuroprotection Against Retinal Ischemia
We propose to investigate the hypothesis that ischemia-induced degeneration of neurons in the retina, a clinical condition frequently leading to blindness, is mediated by the endogenous excitatory amino acids (EAA), glutamate and aspartate. These compounds are major excitatory transmitters in the retina and also have potent neurotoxic (excitotoxic) activity which is mediated by EAA synaptic receptors. Several EAA receptor subtypes have been identified and, recently, new classes of potent EAA antagonists have been discovered. Several lines of evidence suggest that endogenous EAA may cause or that EAA antagonists can prevent neuronal damage associated with anoxia/ischemia. However, evidence for in vivo protection against anoxic/ischemic brain damage is rather tenuous because of inadequacies inherent in the animal models available for such studies. The retina lends itself to both in vitro and in vivo studies of ischemic neuronal degeneration. We have developed an oxygen/glucose deprivation model for studying ischemic neuronal degeneration in the isolated (ex vivo) chick embryo retina and propose to screen various EAA antagonists (anti-excitotoxins) for their ability to prevent such degeneration in this model. We have developed a model for reproducibly inducing a similar pattern of acute neuronal degeneration in the in vivo adult rat retina by using a rose bengal dye/photothrombosis approach to occlude the retinal vasculature. We are now developing a model of delayed neuronal degeneration in the in vivo adult rat retina using an intraocular hypertension approach. We propose to continue developing the latter model, to utilize both rodent models to study mechanisms of ischemic retinal degeneration, and to systematically evaluate anti-excitotoxic drugs found effective in protecting the isolated chick retina against ischemic degeneration for their ability to protect against acute and delayed ischemic damage in the in vivo rat retina.
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1 |
1993 |
Olney, John W |
K05Activity Code Description: For the support of a research scientist qualified to pursue independent research which would extend the research program of the sponsoring institution, or to direct an essential part of this research program. |
Excitatory Transmitters and Neurophsychiatric Disorders
The applicant's broad objectives are to continue conducting a program of neuroscience research aimed at clarifying mechanisms underlying neuropsychiatric disorders and developing methods for preventing such disorders. His research focus is on excitatory transmitters and related agents that are known to have both neuroexcitatory and neurotoxic properties, the latter stemming from the former and, therefore, being called "excitotoxicity". The applicant's prior research has focused on the role of excitotoxic mechanisms in neuropathological processes; in the coming five years, it will focus both on classical excitotoxicity and on new forms of excitatory transmitter neurotoxicity which the applicant and colleagues have recently discovered. In addition, we will continue to probe the unknown with an aim toward discovering additional neurotoxic mechanisms that may be relevant to human neuropsychiatric disorders. The applicant's research directly addresses neuropathological processes potentially implicated in commonly occurring neuropsychiatric disorders, including schizophrenic and related psychotic processes, Alzheimer's disease, Parkinson's disease, Huntington's disease, perinatal asphyxia and related developmental neuropathological syndromes, stroke and epilepsy-related neuropathology; it also focuses directly on drugs of abuse and mechanisms by which such drugs can cause both neurodegenerative changes in the brain of experimental animals and psychotic reactions in humans. In addition, we are studying the role of excitatory transmitters in cognitive and memory functions and dysfunction. As a new emphasis in the coming 5 years, the applicant will exploit a promising technology which is just becoming available as a result of recent successes in cloning excitatory transmitter receptors, i.e., we will use antibody and nucleotide probes to map and localize various genetically defined excitatory transmitter receptor subunits and study their potential involvement in specific neuropathological processes. To achieve our broad research goals, we will employ a variety of approaches spanning several disciplines, including electron microscopic immunocytochemistry, in situ hybridization histochemistry and receptor autoradiography, neurochemistry, neuropharmacology, neurotoxicology, electrophysiology and behavioral physiology.
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1 |
1994 — 1997 |
Olney, John W |
K05Activity Code Description: For the support of a research scientist qualified to pursue independent research which would extend the research program of the sponsoring institution, or to direct an essential part of this research program. |
Excitatory Transmitters and Neuropsychiatric Disorders |
1 |
1994 — 1998 |
Olney, John W |
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. |
Pcp Induced Permanent Brain Damage
This is an application for renewal of a grant that was previously entitled "PCP, sigma opiates and glutamatergic transmission". During the past grant cycle, the applicant discovered that when adult rats or mice are treated subcutaneously with phencyclidine (PCP), or related PCP receptor ligands (PRL), all of which are non-competitive antagonists of NMDA glutamate receptors, it causes acute pathomorphological changes in pyramidal neurons in the posterior cingulate and retrosplenial cerebral cortices. These changes are reversible over a 24 hour period following a low dose of PRL, but cerebrocortical neurons are killed at higher doses. In recent studies, we have gained significant insight into the mechanisms that mediate the reversible neurotoxic reaction, but the cell killing actions of PRL have not been studies. The focus of the present application is on the irreversible neuron-necrotizing action of PRL. Aim #1 is devoted to the fundamental task of developing accurate and more complete characterization of the neuron-necrotizing action of PRL and identifying variables that are critical for its expression. Within this aim, we will study: a) The acutely evolving neuron-necrotizing process by light and electron microscopy; b) The distribution of neurons affected by the process; c) The relationship between the cell killing effect and concomitant induction of heat shock protein in affected neurons; d) Age dependency of the neuron-necrotizing process; e) Sex differences in susceptibility; f) Ability of competitive NMDA receptor antagonists to mimic the neuron-necrotizing action of PRL. In Aim #2, we will study ways of preventing PRL from killing cerebrocortical neurons; in essence, the strategy will be to determine whether methods already developed for preventing the reversible neurotoxic action of PRL also prevent the cell killing activity. In Aim #3, we will study the opposite, i.e., we will study ways of maximizing the cell killing activity, so that PrL can serve as tools for selectively deleting cingulate/retrosplenial neurons from the brain and thereby providing a means of studying the functional roles of these neurons. In Aim #4, we will follow-up our preliminary finding that high dose PRL treatment causes a profound chronic impairment in memory. Animals treated with a high dose of PRL will be studied behaviorally for disturbances in learning/memory or other behavioral parameters such as nociception and emotional reactivity. Since PRL are agents that are abused by pregnant women with unknown consequences for their fetuses, abused by adolescents and young adults with psychotic consequences, used in human anesthesia (ketamine) with transient psychotic side effects and are being developed by the pharmaceutical industry as drugs for protecting neurons against ischemic injury, it is important to have a detailed and accurate understanding of the neurotoxic potential of these agents. All of the proposed research will be conducted in mice. Methods employed will include light and electron microscopic histopathology, immunocytochemistry, selective brain lesioning and behavioral analysis.
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1995 — 2004 |
Olney, John W |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Excitatory Transmitters, Memory, Aging and Dementia
The title of this Program Projects Application "Excitatory Transmitters, Memory, Aging and Dementia" accurately identifies the several closely related themes that the proposed research addresses. The principal excitatory neurotransmitters in the mammalian CNS are glutamate (Glu) and acetylcholine (ACh). Both of these transmitters act at multiple receptor subtypes; either hyperstimulation or blockade of either Glu or ACh receptors is associated with neuropathological changes in animal brain and/or memory/cognitive disturbances in animals and humans. Within the framework of two cores and seven separate projects, the Principal Investigator, 11 Co-investigators and 7 Consultant/Collaborators will study mechanisms by which excitatory transmitters, either in early adulthood or old age, can contribute to normal memory/cognitive functions or to memory/cognitive impairment, neuronal degeneration and cell death. A major emphasis of the research will be on identifying mechanisms of neuronal degeneration that might help explain the pathophysiology of Alzheimer's disease. One project pertains to human subjects and will involve the measurement of excitotoxic amino acids (Glu, aspartate, glycine, cysteine) in cerebrospinal fluid and blood of clinically characterized AD patients in different stages of the illness. The remainder of the proposed research comprises either in vivo or in vitro animal experiments. A wide range of neurochemical, neuropharmacological, neurophysiological, neurobehavioral, neurohistological and molecular biological or immunobiological methods will be employed, including the use of nucleotide and immunological probes for studying subtypes of excitatory amino acid and muscarinic cholinergic receptors which have recently been cloned.
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1996 — 2000 |
Olney, John W |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Excitatory Neurodegenerative Mechanisms-I
excitatory aminoacid; glutamate receptor; neural degeneration; cellular pathology; neurotoxins; neuroprotectants; age difference; cysteine; muscarinic receptor; pregnancy; aging; cerebral cortex; Alzheimer's disease; acetylcholine; hormone regulation /control mechanism; histopathology; neuropharmacology; phencyclidine; progesterone; NMDA receptors; gender difference; dizocilpine; cingulate gyrus; laboratory rat; chick embryo;
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1999 — 2001 |
Olney, John W |
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. |
Acute Brain Injury, Mechanisms and Protection
Acute brain injury conditions such as ischemia and head trauma are thought to be triggered by an excitotoxic process involving excessive activation of glutamate receptors. In the infant rat brain, evidence implicating the NMDA subtype of glutamate receptor is particularly strong. It has also been reported, but is less well established, that mechanisms associated with programmed cell death may play a role. The applicant has undertaken a systematic investigation of the role of excitotoxicity and programmed cell death in acute brain injury conditions. Initially, the applicant performed an ultrastructural analysis of physiological cell death (PCD) that occurs naturally in the developing CNS, and compared this process with three conditions that are generally considered examples of excitotoxicity, namely acute neuro- degeneration induced in the infant rat brain by hypoxia/ischemia, head trauma or by systemic administration of glutamate. This analysis revealed that PCD is characterized by ultrastructural changes that have a distinctive appearance and occur in a distinctive sequence, and that the three examples of excitotoxicity appeared identical to one another but were very different from the PCD process. In addition, the three examples of excitotoxicity can be prevented by drugs that block NMDA glutamate receptors. This evaluation pertains only to the acute neurodegenerative process that occurs within a 6 hr period following hypoxia/ischemia or head trauma, and in the case of head trauma the excitotoxic damage was observed only at the site of impact. The applicant recently examined the brains of infant rats at later intervals following head trauma, and found striking evidence for a delayed neurodegenerative reaction that evolves over a 6 to 24 hr period at a distance from the impact site and has all of the distinctive ultrastructural characteristics of a PCD process. Although treatment with an NMDA antagonist protected against the acute excitotoxic lesion at the impact site, this mode of treatment appeared to increase the severity of the distant, delayed PCD lesion. The aims of the present application are to study the mechanisms responsible for and methods that can protect against the delayed trauma-induced PCD-like lesion, and to determine whether ischemic neurodegeneration in the infant rat brain also has a delayed PCD-like component. The long term goals are to clarify the underlying mechanisms and develop improved methods of treating human pediatric acute brain injury conditions.
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2000 — 2010 |
Olney, John W |
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. |
Developmental Brain Damage by Drugs of Abuse
DESCRIPTION: (adapted from applicant's abstract)This is an application for competing renewal of a grant that was funded for five years (1994-1999) and was devoted to an investigation of neurotoxic damage induced in the adult rodent brain by phencyclidine (PCP) and related drugs that block NMDA (N-methyl-D-aspartate) glutamate (Glu) receptors. During the grant period, the applicants developed significant new insight into the mechanism of this adult brain damage syndrome and into the potential relevance of this mechanism to human neuropsychiatric disorders. In the course of this work, it was discovered that the immature brain is not vulnerable to damage by this mechanism, but that NMDA antagonists, including PCP and ketamine (both of which are drugs of abuse), can induce an extensive pattern of permanent damage in the developing rat brain by an entirely different mechanism. As a tool for studying this mechanism we have primarily used MK801, a powerful NMDA antagonist that binds with high affinity to the PCP recognition site in the NMDA receptor ion channel. Our interpretation of the mechanism, based primarily on MK801 studies, is that immature neurons during a specific stage in development (the synaptogenesis stage, also known as the brain 'growth spurt' stage) are intrinsically dependent on NMDA receptor stimulation for survival, and they are programmed to commit suicide (die by apoptosis) if deprived of this receptor input for several consecutive hours during this critical period. The objectives of this renewal application are to further characterize the ability of several drugs of abuse to trigger apoptotic neurodegeneration in the developing mammalian brain, and evaluate the potential relevance of this neurodegenerative phenomenon to human neurodevelopmental disorders.
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2002 — 2011 |
Olney, John W |
R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Acute Brain Injury, Mechanisms and Consequences
This is an application for competing renewal of an RO1 grant which was funded for 3 years (11/1/98 - 10/31/01) to support studies aimed at clarfying the role(s) of excitotoxic and/or apoptotic cell death mechanisms in developmental (perinatal) brain injury associated with head trauma and hypoxia/ischemia. In addition to addressing these aims during the grant period, the PI has made the unanticipated discovery that during the synaptogenesis period of development transient ethanol intoxication triggers a massive wave of apoptotic neurodegeneration, deleting millions of neurons from many different regions of the developing rat, mouse or guinea pig brain. Our findings document that ethanol triggers apoptosis by a dual mechanism - blockade of NMDA glutamate receptors and excessive activation of GABAA receptors. We propose that our findings can help explain the reduced brain mass and lifelong neurobehavioral disturbances associated with the human fetal alcohol syndrome (FAS). Significance of this discovery is broadened by accompanying evidence that ethanol's neurotoxic properties are shared by numerous other agents that either block NMDA glutamate receptors or activate GABA^ receptors, and many of these agents are drugs of abuse and/or are used regularly in obstetric and pediatric medicine. An important feature of our findings is that within the synaptogenesis period (first 2 weeks after birth for rats and mice, but third trimester and first several years after birth for humans) different neuronal populations have different temporal patterns for responding to the apoptosis-inducing effects of these drugs. Thus, depending on the timing of exposure, different combinations of neuronal groups will be deleted, which signifies that this is a neurodevelopmental mechanism that can contribute to a wide spectrum of neuropsychiatric disturbances. Consistent with this interpretation is evidence that victims of FAS manifest not only childhood hyperactivity/attention deficit and learning disorders, but have a high incidence of adult onset psychiatric disturbances, including major depressive disorder and psychosis. The aims of this competing renewal proposal are threefold, the first being to continue exploring the role of excitotoxic and apoptotic mechanisms in ischemic neurodegeneration, and the second and third being to more fully characterize molecular, neuropathological and neurobehavioral aspects of the apoptotic neurodegenerative syndrome we have found can be induced in the developing mouse brain by transient exposure to ethanol during synaptogenesis.
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2007 — 2011 |
Olney, John W |
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. |
Anesthesia-Induced Developmental Neuroapoptosis in Non-Human Primates
DESCRIPTION (provided by applicant): This is a revised competing RO1 application requesting support for studies pertaining to the ability of anesthetic drugs to trigger apoptotic neurodegeneration in the developing monkey brain. In a series of recent studies, the applicants have shown that brief exposure of infant rats or mice to certain classes of drugs, including NMDA glutamate antagonists, GABAA agonists or ethanol, during the developmental period of synaptogenesis, triggers widespread neuroapoptosis in the developing brain. The period of synaptogenesis, also known as the brain growth spurt period, in rats and mice occurs during the first two weeks of postnatal life, but in humans, begins in mid-gestation and extends until approximately 3 years after birth. At the heart of the developmental neuroapoptosis mechanism is the biological fact that neurons in the developing brain are programmed to kill themselves if they fail to make appropriate synaptic connections. Although normally, only a small percentage of neurons commit suicide due to faulty synaptogenesis, our findings from rodent experiments suggest that if neuronal activity is abnormally suppressed for a period of only several hours this disrupts the synaptogenesis process sufficiently to cause large numbers of neurons to commit suicide. These findings are of potential concern in an anesthesia context because most, if not all, general anesthetics have either NMDA antagonist or GABAmimetic properties, and when used in concentrations or doses sufficient to render patients unconscious and insentient to pain, they profoundly suppress neuronal activity. While anesthesia-induced developmental neuroapoptosis (AIDNA) is a readily demonstrable phenomenon in rodent brain, only limited information is available pertaining to susceptibility of other species. In very limited pilot experiments we have observed that fetal monkeys appear to be sensitive to the apoptogenic properties of either ethanol or anesthetic drugs. To further evaluate susceptibility of the developing primate brain to AIDNA injury, we will expose squirrel monkeys to anesthesia during the brain growth spurt period, which in this species occurs primarily prenatally (last two trimesters of gestation). In Aim #1, we will expose monkey fetuses in utero to a triple anesthetic cocktail (isoflurane, nitrous oxide, midazolam) at one of three time points during the brain growth spurt period, and study the brains for evidence of AIDNA. In Aim #2, at the age of peak sensitivity (as determined in Aim #1 experiments), we will expose squirrel monkey fetuses to individual anesthetic agents (isoflurane or propofol), or to double combinations (isoflurane + nitrous oxide, or propofol + nitrous oxide), to help clarify the degree of risk posed by each agent or combination of agents.
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2010 — 2014 |
Olney, John W |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Animal Model Core
The overall objective of the Animal Models Core (AMC) is to use the expertise of current investigators and existing resources at Washington University to improve the lives of those with intellectual and developmental disabilities by promoting the optimal development and assessment of new and existing animal models. Genetic abnormalities and acquired insults account for most intellectual and developmental disabilities. Animal models are a potent tool for obtaining a better understanding of these conditions and developing novel strategies for treating, preventing, and ultimately curing these conditions. Work at Washington University on mouse models of hypoxia ischemia(5), tuberous sclerosis(6) and lysosomal storage diseases(7-9) demonstrates the power of this approach. However, models are available for only a few of the many conditions associated with developmental disability, such as cerebral palsy and autism. Moreover, although causes are known in many instances, the cause of intellectual and developmental disabilities remains unknown for 20-90% of affected individuals.(10) Genomic, proteomic, and metabolomic approaches will help narrow this gap. Simultaneously, standard biochemical approaches will continue to identify novel causes such as cerebral folate deficiency, which was first described in 2002.(11) Nevertheless, the need for animal models will continue to grow. Until now, individual investigators at Washington University developed animal models in their own laboratories. On their own, they found other investigators with the expertise needed to help them develop and assess their models. Informal discussions with these investigators highlighted fruitful collaborations between specific individuals, but also brought to light the fact that many investigators had not taken full advantage of the vast expertise available at the university. Thus, a key goal of the AMC is to bring together several research methodologies into a cohesive functional unit to facilitate the development and assessment of animal models with relevance to intellectual and developmental disabilities. Through these discussions, we identified three specific areas to benefit the research community and have thus divided the AMC into three subcores: [unreadable] Genetics/Early Development Subcore: This Subcore will assist investigators with the generation of new animal models using genetic and reproductive/early development techniques. It will assist the development of strategies based on prenatal therapies, gene and stem cell therapy. In addition, it will promote a better understanding of the role of genetic modification in disease processes in IDD. [unreadable] Behavior Subcore: This Subcore will provide behavioral assessment of new and current animal models of intellectual and developmental disability. [unreadable] Neuropathology Subcore: This Subcore will provide neuropathologlcal assessment of new and current animal models of intellectual and developmental disability.
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2012 — 2014 |
Olney, John W |
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. |
Anesthesia Toxicity in Neonatal Primate Brain
DESCRIPTION (provided by applicant): A decade ago, the applicant and colleagues discovered that drugs that have either NMDA antagonist or GABAA agonist properties, a description that fits alcohol and all general anesthetics, trigger widespread death of nerve cells in the developing animal brain. In order to maximize the translational significance of our anesthesia toxicity studies, we applied for and were awarded a grant (start date Jan 2007) to study this phenomenon in the developing non-human primate (NHP) brain. The present application is a request for renewal of funding for ongoing studies pertaining to the apoptogenic properties of anesthetic drugs in the developing NHP brain. This work is being performed in collaboration with colleagues at Washington University and Oregon Health & Science University and Oregon National Primate Research Center. In the first 4 years of the grant period we have developed a valuable data base documenting susceptibility of the developing fetal and neonatal NHP brain to apoptotic death of brain cells (both neurons and oligodendrocytes) induced by clinically relevant exposure to each of three anesthetic drugs (isoflurane, ketamine, propofol). In this renewal application we are proposing to conduct additional NHP studies to further clarify the potential neurotoxicity of anesthetic drugs for the developing NHP brain and explore ways of modifying anesthesia protocols to enhance their safety for the developing brain. We have already developed a valuable data base, and now want to build upon that base toward the goal of achieving improved safety in the clinical application of anesthetic drugs in pediatric and obstetric medicine. The aims of the proposed research are to determine: 1) If there is a significant positive correlation between duration of anesthesia exposure and the number of neurons and/or oligodendrocytes that undergo apoptotic cell death; 2) How anesthesia without surgery compares in toxic impact with anesthesia with surgery; 3) How long into the post natal period does the brain remain vulnerable to significant neuronal or glial loss following clinically relevant exposure to anesthesia; and 4) Can the apoptotic response to anesthesia be prevented or significantly mitigated by adjunctive administration of neuroprotective drugs. PUBLIC HEALTH RELEVANCE: Researchers from Washington University will collaborate with colleagues from Oregon Health & Science University and the Oregon National Primate Research Center to study the potential neurotoxic effects of anesthetic drugs in the developing non-human primate brain. A major goal of the proposed research is to develop methods for achieving improved safety in the clinical application of anesthetic drugs in pediatric and obstetric medicine.
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