1996 — 1999 |
Elsworth, John D |
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. |
Graft Function
The fragmentary understanding of the biological sequelae of neural transplantation is reflected in the variable success of attempts to reverse parkinsonism in human and non-human primates using intrastriatal fetal tissue grafts. This project will investigate the basis of functional recovery employing neurochemical and morphological measures and relating them to behavioral recovery following grafting in a primate model of parkinson's disease. This knowledge will facilitate refinement of the transplantation technique. The model used in these studies is allograft of fetal ventral mesencephalon transplanted into the caudate nucleus of the MPTP-treated parkinsonian monkey. The proposed experiments will address the controversy that the improvement in parkinsonism observed following transplantation of fetal ventral mesencephalon is due to the presence of the graft and that the graft- induced recovery is dependent on the presence of dopamine derived from the graft. These issues will be examined in a study that involves immunological rejection of the grafted tissue, once the improvement has occurred. If the recovery is found to be significantly dependent on the presence of the graft, we will investigate the dopamine-dependence of the improvement by destruction of the dopamine neurons in the graft. Other studies will investigate a) whether athe extent of improvement is dependent on the degree of dopaminergic restoration of the caudate nucleus, and how much reinnervation is necessary, b) whether the dopaminergic reinnervation changes with time and if this change is paralleled by alterations in parkinsonism, and c) whether the dopaminergic reinnervation can be enhanced by the presence of co-grafts of fetal striatum or adult peripheral nerve-derived Schwann cells, and if so, if it corresponds to decreased parkinsonian behavior. These experiments will utilize quantitative dopamine transporter autoradiography, dopamine concentrations, homovanillic acid to dopamine ratios and tyrosine hydroxylase immunohistochemistry. Further experiments will determine whether the grafted dopamine neurons establish normal synaptic connections with GABAergic and cholinergic neurons in the host caudate nucleus. This will be addressed using correlated light and electron microscopy of double-immunostained sections from a defined region of the caudate nucleus in close proximity to the grafts. These studies will provide further insight into the basis of transplant- induced behavioral recovery from parkinsonism. The outcome of these investigations will have an important impact in tailoring research and future treatments of neurodegenerative disorders.
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2001 — 2003 |
Elsworth, John D |
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.) |
Selective Prenatal Dopamine Damage in Non Human Primates
Several brains disorders with onset before adulthood are thought to involve irregularities in the development of midbrain dopamine neurons. These include some dystonias, LeschNyhan disease, schizophrenia, and developmental hypoxicischemic injury. As relatively little is known about the ontogeny of primate dopamine neurons, the goal of this proposal is to advance understanding of the early development of these neurons, and the effects and compensations that occur in response to their selective damage. Initial studies will use normal African green monkey fetuses which will span in age from the time just after differentiation of dopamine neurons to the time just before birth. The assays performed will provide data regarding possible critical times in development in which damage to dopamine systems might have longlasting deleterious effects, including periods of natural cell death (apoptosis) in dopamine neurons and synaptogenesis of dopamine neurons with postsynaptic targets. Subsequently, the neurochemically specific protoxin, M11rP, will be given to pregnant monkeys at these times. Fetuses that are exposed to MPTP during a peak of programmed cell death may mimic situation where exaggerated or abnormal natural cell death occurs in dopamine neurons. Other fetuses will be exposed to the effects of MPTP over a substantial proportion of the gestation period, incorporating an extended period of synaptogenesis, which may mimic situations where there are fewer than normal dopamine neurons, or where there are deficits in outgrowth or synapse formation. In humans such developmental abnormalities may occur as a result of genetics, drug abuse, environmental toxins, physical trauma, anoxia or infection. Postmortem measurements in monkey fetuses will include biochemical assays of dopamine neuron number, integrity and function, and will be made just prior to birth. Subsequently we plan to examine the brains of neonates which have been exposed to MPTP in utero, when have reached 6 months of age. In the latter group, behavioral observations and a challenge with Ldopa, will also be carried out to indicate whether the infants show deficits that compromise their survival, and identify potential abnormalities for more detailed behavioral and psychological studies which would need to follow later. We are hopeful that these studies will provide insight into both the normal development of primate dopamine neurons, and their response to injury at critical times in ontogeny. Thus, the proposed work may lead ultimately to an animal model for one or more pediatric brain disorders.
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2008 — 2012 |
Elsworth, John 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. |
Susceptibility of Primate Dopamine Neurons to Toxicity During Development
DESCRIPTION (provided by applicant): Both methamphetamine and MPTP are toxic to dopamine neurons in the adult human and adult, non-human primate through mechanisms involving oxidative stress. Recent findings, supported by a R21 NINDS grant, have demonstrated a remarkable resistance to both methamphetamine and MPTP in the infant and late- gestational fetal monkey and raised questions concerning differences in the mechanisms of oxidative stress in developing dopamine neurons. Other studies supported by this exploratory grant have identified a time period that primate dopamine neurons undergo apoptotic natural cell death. During the peak of natural cell death, fetal dopamine neurons were sensitive to the toxic effects of methamphetamine or MPTP. Together these studies identify a vulnerable window in gestation where methamphetamine or MPTP are toxic to the immature dopamine neurons, potentially through developmental changes in the response to oxidative stressors. The proposed studies will pursue these findings by investigating the mechanism(s) of the differential sensitivity to the effects of MPTP and methamphetamine during development and in adult monkeys. We will examine the biochemical response of the midbrain dopamine system to MPTP and methamphetamine at various stages of development, to see whether differences in degree of oxidative stress, uncoupling protein-2 activity, neurotrophic factors, and glutamate innervation of the substantia nigra and/or DNA repair mechanisms explain the observations. This work has relevance to the etiology and treatment of neurological and psychiatric disorders that may be initiated by damage to developing dopamine neurons. Besides being models of oxidative stress, the actual drugs used in the studies also have clinical relevance. MPTP is structurally related to herbicides that have been implicated in Parkinson's disease. Methamphetamine is currently a widely abused drug, yet there have been no previous studies on the toxicity of methamphetamine on developing primate brain dopamine neurons. This research will enhance our biochemical understanding of the changing vulnerability of the developing brain dopamine neurons to oxidative stress, and may identify strategies for protecting dopamine neurons from neurodegeneration. PUBLIC HEALTH RELEVANCE: Our data shows that exposure to oxidative stress at a certain period in primate development induces exaggerated damage to dopamine neurons in the brain. The drugs methamphetamine or MPTP are administered to produce an oxidative stress model in the monkey. The studies have direct relevance to the risk of acquiring Parkinson's disease and to the behavioral consequences of exposure to drugs of abuse during development.
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2010 — 2014 |
Elsworth, John 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. |
Dopamine Modulation of Cortical Spine Synapses and Cognition in Mptp Monkeys
DESCRIPTION (provided by applicant): Parkinson's disease is usually characterized as a movement disorder;however cognitive abilities, such as working memory and executive function, decline at early stages of the disease in most patients. The changes in brain that underlie the cognitive deficits are not well understood. We hypothesize that reduced dopamine transmission in the prefrontal cortex in Parkinson's disease is a harbinger of detrimental morphological changes in pyramidal neurons in the prefrontal cortex whose function is necessary for normal cognition. Our data show that a partial loss of dopamine innervation to the prefrontal cortex in monkeys elicited by systemic low-dose MPTP treatment produces cognitive deficits in prefrontal cortex-dependent tasks. Other preliminary data show that there is a decrease of asymmetric (excitatory) synapses on the spines of dendrites on pyramidal neurons in the dorsolateral prefrontal cortex of MPTP-treated monkeys. Together these findings suggest that the number of spine synapses on dendrites in the prefrontal cortex is dopamine-dependent and may be a morphological substrate of the cognitive deficits induced by sustained reductions in dopamine neurotransmission in this region. Modulation of spine synapses number represents a novel neuroplasticity function for dopamine. That cognitive deficits are persistent in the motor-asymptomatic MPTP-treated monkey suggests that this is a good model for the stage of Parkinson's disease in which there are few if any noticeable motor abnormalities, but significant detectable cognitive deficits. The Specific Aims of this proposal will examine this new direction, by investigating the dopamine dependency and specificity of spine synapse changes in the motor-asymptomatic primate MPTP model, examining GDNF gene transfer and pharmacological strategies for their restoration, using biochemical, electron microscopic and behavioral methods, and taking advantage of the primate facilities at the St Kitts Biomedical Research Foundation. This research will use the best animal model available to examine causes and treatments for cognitive decline in Parkinson's disease, which has received scant research attention, despite its substantial impact on patients and caregivers, and ineffectiveness of available therapy. PUBLIC HEALTH RELEVANCE: Parkinson's disease presently affects 1 to 1.5 million Americans, and this number is expected to increase with aging of the population: it is commonly viewed as movement disorder, but it also affects many facets of cognition even at early stages of the disease. The cognitive changes seen in Parkinson's disease are not well understood and have received relatively scant attention in research, despite the substantial impact they have on the patient and caregivers. The proposed research uses a primate animal model to pursue new leads on biochemical and morphological changes in the brain that may underlie the cognitive deficits, and tests novel gene therapy and pharmacological strategies for ameliorating the dysfunction.
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2016 — 2020 |
Elsworth, John D Roth, Robert Henry (co-PI) [⬀] |
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. |
Biochemical and Synaptic Mechanisms in Prefrontal Cortex and Vulnerability For Cognitive Deficits
? DESCRIPTION (provided by applicant): Cognitive deficits are an intrinsic part of schizophrenia, occurring independently of positive symptoms, and often persisting even when psychotic symptoms of schizophrenia have been successfully treated. Cognitive functioning is moderately to severely impaired in patients with schizophrenia and is typically present even in the prodromal phase of the disorder, in young drug-naïve patients. The deficits are in the domain of executive function largely controlled by the prefrontal cortex (PFC). However, there is only a fragmentary understanding of biochemical dysfunctions in brain that leads to cognitive impairment in schizophrenia. Furthermore, even though atypical antipsychotic drugs can improve certain aspects of cognition, many patients do not achieve remission. Therefore, the development of new therapeutic drugs for cognitive impairment remains imperative. However, the design of new agents for treating cognitive deficits in schizophrenia is hampered by not knowing how the more successful antipsychotic drugs exert their benefit on cognitive function. The goals of the application are to understand the biochemical and synaptic changes in PFC that underlie schizophrenia-like cognitive deficits and identify the beneficial alterations produce by drugs that have demonstrated efficacy in combating these symptoms. These goals will be addressed using non-human primate models that have face, construct and predictive validity for the cognitive deficits of schizophrenia, together with the sex bias that characterizes the risk for schizophrenia. Our hypothesis is that dopamine, brain derived neurotrophic factor (BDNF) and estradiol are important factors that interact in the PFC to modify excitatory spine synapses on dendrites of pyramidal neurons, which in turn critically modulates executive function. This project will use a novel developmental phencyclidine (PCP) model and an adult primate PCP model that have resonance to the dopamine, glutamate and GABA hypotheses of schizophrenia, in addition to being relevant to the theories of developmental origins for the illness. The application has 3 specific aims: 1) Identify to what extent estradiol contributes to resilience of the peri-adolescent monkey PFC to the detrimental biochemical, synaptic and cognitive effects of PCP, 2) Identify the potential of local over-expression of BDNF to initiate recovery of excitatory spine synapses from the impact of PCP on primate PFC, and 3) Identify biochemical, synaptic and cognitive consequences of acute and repeated novel atypical antipsychotic drug administration in PFC of PCP-exposed monkeys. This current project contains refinement of previous theoretical concepts and approaches, and tests the impact of new interventions, utilizing improvements in current methodology. This work is expected to lead to new strategies in treating cognitive deficits in schizophrenia, which is the prime driver of significant disabilities in occupational, social, and economic functioning in patients, and imposes a heavy emotional burden on the family and an economic toll on the healthcare system.
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2016 — 2020 |
Elsworth, John 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. |
Developmental Factors For Reducing Dopamine Loss in Primate Models of Pd & Aging
? DESCRIPTION (provided by applicant): In normal human brain the population of midbrain dopaminergic neurons falls by about 3-5% every decade, while in Parkinson's disease (PD) this decline is much greater. This inexorable loss of dopamine (DA) innervation to forebrain regions has been firmly linked with declines in both motor and cognitive functions. Despite knowing that oxidative stress is a key conspirator in the loss of DA neuron function in PD and aging, there are no treatments to halt the attrition of DA neurons. Part of this problem is due to the inadequacy of animal models. Adult DA neurons are very susceptible to the parkinsonian-like oxidative stress exerted by either MPTP or methamphetamine (METH), but our group has demonstrated that for a restricted period early in life, the primate brain is remarkably resistant to such damage. This provides a new neuroprotection model for DA neurons, possessing built-in resilience to oxidative damage. The existence of this window of protection against MPTP or METH cannot be explained by altered drug levels, or by immaturity of key transporters or enzymes necessary for the toxic effect of the drugs. The goal of this project is to understand the factors and mechanisms shielding young primate DA neurons from oxidative stress and use this knowledge to provide protection to DA neurons at the later vulnerable stages of life. This approach promises to be successful as it relies on reinstating extant anti-oxidant mechanisms, rather than attempting to protect DA neurons using drugs that may manipulate biochemical signaling non-physiologically. We have identified 2 potential juvenile protection factors that are preferentialy expressed in the young primate brain and have strong anti-oxidant properties; uncoupling protein-2 (UCP2) and paraoxonase-2 (PON2). One aim tests the hypothesis that UCP2 plays a major role in mitigating the level of mitochondrial reactive oxygen species and subsequent damage to young DA neurons, and that 5' adenosine monophosphate-activated protein kinase (AMPK) activity regulates UCP2. Another aim examines the protection against induced oxidative stress in adult DA neurons that is achieved by using novel agents to activate UCP2 expression in vivo. Less is known about PON2 than UCP2, and the final aim will test hypotheses about its regulation and its role in protecting young primate DA neurons against oxidative stress damage, and will also examine to what extent up-regulation of PON2 expression in the adult affords protection against in vivo oxidative stress in DA neurons. In addition, we will pursue our data on male-female differences in expression of these juvenile protection factors in primate brain, as this may relate to the lower incidence of PD in female subjects and also provide new ways to induce protection in DA neurons. This proposal will pursue these novel directions using biochemical, histochemical, and pharmacological studies in vervet monkeys. The timing of critical milestones in developing DA neurons display important species differences, so these primate studies have particular translational relevance. This research is expected to stimulate new approaches to prevent the occurrence or progression of DA-dependent age-related disorders.
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