2005 — 2006 |
Mooney, Sandra M |
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.) |
Ethanol, Neurotrophins, and Thalamocortical Matching @ Upstate Medical University
DESCRIPTION (provided by applicant): Early exposure to ethanol profoundly affects development of the nervous system. Indeed, fetal alcohol exposure has been described as the primary cause of mental retardation. During development, neurons are overproduced and a subset are eliminated during a period of naturally occurring neuronal death (NQND). NOND is the mechanism used to match projection and target populations within a system Exposure to ethanol interferes with numerical matching in the trigeminal-somatosensory (tri-ss) system. There are 33% fewer neurons in the principal sensory nucleus of the trigeminal nerve and somatosensory cortex (2nd and 4th order neurons) in ethanol-treated rats. In contrast, the number of neurons; n the thalamic ventrobasal nucleus (VB) (3rd order neurons) is not altered by ethanol. Neuronal survival results from the ability of young neurons to successfully compete for neurotrophin(s) (e.g., nerve growth factor; that are available in limited supply. Expression and activity of these factors is compromised by ethanol. The proposed project will test the hypothesis that ethanol-induced disruption of neurotrophin systems underlies the changes in the tri-ss organization. Two complementary studies will be performed. (1) In vivo experiments will examine the effect of ethanol on neurotrophin ligand and receptor expression in both the somatosensory cortex and the VB. The possibility that ethanol targets an autrocine/paracrine -regulation will be explored with a combined immunohistochemical-in situ hybridization approach. (2) In vitro studies will examine the effects of ethanol on expression and activation of neurotrophin receptors, and activation of signaling pathways. Studies will use organotypic slice cultures that maintain the thalamocortical afferents that can retrogradely transport neurotrophins from cortex to thalamus. These studies will (1) assess mechanisms by which ethanol disrupts tri-ss development, (2) provide valuable data on neurotrophin function, and (3) be a base for future mechanistic studies of the role of neurotrophins in development.
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0.934 |
2009 — 2013 |
Mooney, Sandra M |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Animal Core @ Upstate Medical University
A primary goal of the DEARC is to determine the consequences of exposure to ethanol during development on brain structure and function. Development is defined as encompassing the gestational period through adolescence, inclusive. All projects described in this application will use rodents (Sprague- Dawley rats and mice) as a model;thus, the ANIMAL CORE is a critical component for the DEARC. The ANIMAL CORE has multiple roles within the Center. It provides a rodent breeding program, standardized modes of ethanol administration (and administration of other drugs), standardized maintenance of pregnant, pre-weanling, and adolescent rodents, standardized determination of blood and brain ethanol concentrations (BECs and BrECs, respectively), collaboration in the design of experimental paradigms, and maintenance of a database containing maternal/litter data. As all animal research will be performed in Binghamton (Binghamton University) and Syracuse (Upstate Medical University), there are two components to the ANIMAL CORE. Each subdivision will be supervised by a member with more than a dozen years of experience with animal models, many of those years performing alcohol research. The subdivisions offer complementary, non-overlapping models of ethanol exposure. Having a coordinated ANIMAL CORE increases the efficient use of animals and standardizes the generation of animals. This is critical for the generation of compatible models that are the basis for the proposed anatomical, biochemical, molecular biological, and behavioral studies. To this end, the ANIMAL CORE will purchase, house, and breed animals. In addition, BECs and BrECs will be determined and databases following the subjects (cradle-to-grave) will be maintained by the ANIMAL CORE.
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0.936 |
2010 — 2014 |
Mooney, Sandra M |
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. |
Effects of Developmental Ethanol Exposure On Brain Development @ University of Maryland Baltimore
DESCRIPTION (provided by applicant): The effects of ethanol on a fetus are extensive, devastating, and often permanent. Depending upon the population, ethanol affects as many as 2% of all live births. The most profound effects are on the nervous system. Gestational ethanol exposure causes structural changes in many regions of the brain. The permanent effects of ethanol include (a) a reduction in the number of neurons in the mature brain, (b) aberrant connections formed by surviving neurons, and (c) depression of brain metabolism. Ultimately, these changes manifest as mental retardation and/or alterations in behavior. One region of the brain that appears refractory to ethanol is the ventrobasal nucleus of the thalamus (VB). Not only does exposure to ethanol not affect the final number of neurons, metabolism in this region is also unaltered. The VB is unique in that it includes a period of in situ proliferation in the early postnatal period. A concurrent event is the arrival of corticothalamic afferents, thus, the postnatal neurogenesis in the VB may be important for matching neuronal number in the VB with that in somatosensory cortex. The goal of the present study is to understand the apparent protection this region has against the deleterious effects of prenatal exposure to ethanol. We will test the hypotheses (1) that postnatal neurogenesis in the ventrobasal nucleus of the thalamus (VB) is part of a matching between of connections between the VB and the somatosensory cortex that relies on neurotrophins, and (2) that the apparent refractoriness of the VB results from ethanol-induced changes in postnatal neuronogenesis and neuronal survival, and that neurotrophins play a role in these developmental phenomena. The proposed project consists of two complementary studies. (1) The role of neurotrophins in postnatal proliferation of cells in the VB, and the effect of prenatal exposure to ethanol on the neurotrophin system will be determined. These experiments will utilize the powerful organotypic slice method in which at least a portion of the normal brain connectivity is maintained while allowing manipulation of growth factor concentration. (2) The mechanism of action of the neurotrophins in the developing trigeminal-somatosensory system will be determined. Initial experiments examine the localization of neurotrophin mRNA within the trigeminal-somatosensory system. Subsequent experiments will manipulate neurotrophins and determine (a) the effect of ethanol on the cycling population and (b) the roles of the two distinct mechanisms by which neurotrophins act, long-distance (anterograde/retrograde) communication or local (autocrine/paracrine) processing. In summary, the effect of prenatal exposure to ethanol on the postnatal development of the VB provides (1) an ideal tool to appreciate CNS development, (2) insight into mechanisms underlying neurotrophin-mediated cell proliferation, and (3) further understanding of the neurotoxic effects of ethanol and the etiology of fetal alcohol spectrum disorder (FASD).
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0.972 |
2010 — 2014 |
Middleton, Frank A. [⬀] Mooney, Sandra M |
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. |
Experimental Fetal Alcohol Syndrome @ Upstate Medical University
DESCRIPTION (provided by applicant): Fetal alcohol spectrum disorder is common (affects ~2% of all live births) and is a major cause of mental dysfunction. Of the many negative effects that ethanol has on the developing nervous system, the most severe is neuronal death. It is severe because this loss is permanent; with the exception of a couple of sites, post-mitotic neurons in the CNS are not replaced by newly generated ones. Indeed, after the generation of neurons is complete, the nervous system has to decide if and whether damaged neurons can be repaired. If not, they must be eliminated. A key molecule in this decision process is the oncoprotein p53. p53 is critical for maintaining neuronal integrity and resiliency. We will test the hypothesis that developmental exposure to ethanol alters neuronal survival and DNA repair through p53-dependent activities. In the developing nervous system, neuronal death is a natural and critical process. This death appears to be apoptotic and to involve p53. Our preliminary data and the work of others on developing cerebral cortex show that exposure to ethanol during the period of naturally occurring neuronal death causes a dramatic and transient increase in both active caspase 3 expression and terminal uridylated nick-end labeling (TUNEL). On the other hand, our novel data also show that this pattern does not coincide with the ultimate loss of cortical neurons either in time or space. The implication is that ethanol causes DNA fragmentation, but this degradation may not be obligatory for apoptosis. Instead, it may reveal DNA repair mechanisms. p53 is a key player in DNA repair. Three complementary aims will be addressed using p53 deficient mice and cells. (1) Vulnerability of cortical neurons to ethanol will be addressed in long- and short-term in vivo studies. Long-term studies will determine the ethanol-induced loss of neurons in cortical layers occurring in the deficient mice. Complementary studies will examine short-term changes in the expression of presumed death markers (active caspase3 immunoexpression and TUNEL) in cortical layers and the timing of the neuronal loss. (2) The acute genomic responses of p53 deficient mice and cultured neural stem cells to ethanol will be determined. We will identify changes in the expression of transcripts involved in apoptosis and DNA repair. In addition, we will determine the epigenetic effects of ethanol on the silencing of genes through hyper-methylation. (3) Securin is a protein that is regulated by p53 and is pivotal for DNA repair. Preliminary microarray and immunocytochemical data show that it is profoundly affected by ethanol. Thus, we will examine the effects of ethanol on cells deficient of securin in vitro and in vivo after transplantation into layers that are apparently susceptible and refractory to ethanol. These studies will explore two dovetailed responses that developing neurons have to ethanol: DNA repair, and failing that, apoptotic death. We will address critical questions. For example, what defines the susceptibility of a young neuron to ethanol? Can neurons be manipulated to reduce their ethanol vulnerability? Thus, the studies explore two new targets of ethanol, p53 and securin, that are critical for the neuronal survival and integrity. PUBLIC HEALTH RELEVANCE: Fetal alcohol spectrum disorder affects an estimated 2% of all live births in the United States. One common target of alcohol toxicity is differentiating cells, particularly those that are newly integrating into the complex environment of the developing brain. The present study will explore two complementary mechanisms by which alcohol-induced defects result (a) from ethanol-induced neuronal death and (b) from ethanol-altered DNA repair.
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0.934 |
2011 — 2013 |
Mooney, Sandra M |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Pilot 3 - Developmental Exposure Alcohol Research Center @ State University of Ny,Binghamton
Social behavior is affected by prenatal exposure to ethanol. The oxytocin system in the amygdala is thought to play a major role in social behavior. We will test the hypothesis that acute exposure during gastrulation (gestational day (G) 7) or during the time of generation of amygdala neurons (G14) will result in a significant deficit in social behavior. Animals will be given ethanol on G7 or G14. Offspring will undergo social behavior testing then the brains will be collected for analysis of the effect of ethanol on the amygdala. These studies will provide valuable data on the etiology of the social behavior deficits associated with prenatal exposure to ethanol and will begin to examine the mechanism(s) underlying such deficits.
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0.936 |
2014 — 2018 |
Mooney, Sandra M |
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. |
Experimental Factors in Fetal Alcohol Spectrum Disorder @ University of Maryland Baltimore
DESCRIPTION (provided by applicant): The effects of ethanol on a fetus are extensive, devastating, and often permanent. Depending upon the population, ethanol affects as many as 2-5% of all live births. The most profound effects of ethanol are on the nervous system. Gestational ethanol exposure causes behavioral changes such as hyperactivity, attention deficit hyperactivity disorder (ADHD), learning and memory deficits, alterations in social behavior, and mental retardation. Such behavioral changes can also be seen in animals exposed to ethanol in the prenatal period, thus they provide good models for examining the underpinnings of the changes. One system that is particularly important for both social behavior and ADHD is the somatosensory system. Blocking sensory information within this system is sufficient to negatively affect social behavior. Ethanol causes alterations in the structure and function of this area. We will test the hypothesis that exposure to ethanol during development that causes structural alterations in somatosensory cortex will negatively affect behavior (including social behavior) and alter the neurochemistry of this region. Further, we will test the hypothesis that supplementation with docosahexaenoic acid, an omega-3 fatty acid, in the postnatal period will reverse ethanol-induced deficits in behavior, neurochemistry, and brain structure.
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0.972 |
2017 — 2021 |
Mooney, Sandra M |
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. |
Model of Fetal Alcohol Spectrum Disorder @ Univ of North Carolina Chapel Hill
Fetal Alcohol Spectrum Disorder (FASD) is an umbrella term used to describe the range of outcomes that result from prenatal exposure to alcohol (ethanol). Behavioral effects may include hyperactivity, attention deficit, impaired sensory processing, and learning and memory problems. People with FASD may also have difficulties using information flexibly which likely underlies deficits in cognition. Such problems are thought to be seated in frontal cortices, including prefrontal cortex. Devising new strategies for amelioration of these problems has great clinical relevance. While deficits in learning and memory have been extensively demonstrated in rodent models of FASD, we will examine cognitive flexibility. We propose an innovative experimental design in which rats exposed to a moderate dose of ethanol prenatally are given choline AND behavioral training during adolescence. Either alone can improve learning and memory in normal animals, as well as in models of FASD. We have chosen the attentional set shifting and reversal learning task because it captures deficits reported in clinical observation of individuals with FASD and also because it can be used repeatedly in the same rats without observable diminution of responding or changes in task strategy. We propose a multidisciplinary set of experiments that will assess behavior, brain function and structure, as well as expression of neurometabolites. These experiments will determine whether modulating plasticity during frontal cortex development can improve both memory and problem solving in the same animals and how the effects manifest in brain connectivity and structure.
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0.972 |
2019 |
Mooney, Sandra M |
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. |
Does Pae Increase Susceptibility to Adrd in Later Life? @ Univ of North Carolina Chapel Hill
ABSTRACT Alzheimer?s disease and related dementias (ADRD) are progressive and irreversible neurodegenerative disorders that affect 10% of Americans over the age of 65. Genetic and environmental factors, including excessive alcohol consumption, modify ADRD risk. In the US, 10.2% of pregnant women report alcohol consumption and 3.2% report binge drinking. The consequence of this prenatal alcohol exposure (PAE) is Fetal Alcohol Spectrum Disorder (FASD), that encompasses a range of outcomes featuring neurodegeneration and persistent behavioral deficits affecting cognition, learning and memory, and sensory processing. Those with FASD have striking impairments in cognitive flexibility, and the current award investigates the cholinergic systems responsible for these cognitive deficits. ADRD and FASD affect the same cognitive domains, brain subregions, and feature cholinergic impairments; mechanistically, both pathologies are driven, in part, by neuroinflammation. Our recent transcriptome analyses in two independent models of PAE identified significant neuronal upregulation of AD-related genes (PSEN1, PSEN2, APP, BACE1, and APOE) and this persisted into adolescence. These findings suggest that PAE, as with adult alcohol abuse, may increase ADRD risk in later life. Surprisingly, no one has ever tested whether PAE increases ADRD risk; a single self-study suggests those with FASD have premature dementia. In this supplement request, we will test the novel hypothesis that PAE is a prenatal ?primer? that accelerates the progression and/or severity of AD-related pathologies and behavioral impairments. We test this hypothesis using two novel resources. In the first, we test whether PAE accelerates ADRD progression using an established AD model, the 3xTg-AD mice, which were engineered to express human PSEN1, MAPT, and APP and display early-onset AD. In the second, we test whether PAE increases risk for AD in our unique cohort of aged, wild-type C57BL/6J mice (born March-June 2018). Subaim 4A evaluates whether PAE increases the deposition of amyloidosis and tau tangles (cortex, hippocampus) in aged B6J and 3xTg-AD mice. Subaim 4B tests if PAE causes a decline in behavioral performance in aged B6J that worsens with age, and whether PAE and ADRD interact in 3xTg-AD mice to accelerate that behavioral decline. 3xTg-AD are tested at ages with intermediate pathology (3mo-9mo) to avoid a potential ceiling effect of PAE- AD interaction. Aged wild-type mice are tested at ages 3mo & 10mo (done), and 17mo and 24mo (this supplement). This hypothesis represents a novel risk factor for ADRD, and reflects their mechanistic, behavioral, and pathological similarities. This pilot study provides core preliminary data in support of a larger, mechanistic-driven R01 that will continue to investigate the role of alcohol in the etiology of AD. Using biomarkers and models from the AD field allows integration with that body of work. Understanding the long- term pathologies that can result from PAE will be critical to supporting people with FASDs and to guide research into interventions that improve their quality of life and behavioral performance.
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0.919 |
2019 |
Mooney, Sandra M |
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. |
Nutrient Combination to Mitigate Fetal Alcohol Spectrum Disorder @ Univ of North Carolina Chapel Hill
Abstract Fetal Alcohol Spectrum Disorder (FASD) is an umbrella term used to describe the range of outcomes that result from prenatal exposure to alcohol (ethanol). Behavioral effects may include hyperactivity, attention deficit, impaired sensory processing, and learning and memory problems. People with FASDs may also have difficulties using information flexibly, and this could contribute to deficits in cognition. Such problems are thought to be seated in frontal cortices, including prefrontal cortex, but also require hippocampal input. Devising new strategies for amelioration of these problems has great clinical relevance. Given that deficits in learning and memory have been extensively demonstrated in rodent models of FASD, we examine cognitive flexibility (the ability to ?switch mental gears?) in young adults. We propose to continue using our innovative experimental design in which rats exposed to a moderate dose of ethanol prenatally are given choline ± working (short term) memory training during adolescence. The combination of choline + training improves the alcohol-induced deficit in cognitive flexibility but not to the point that performance is equivalent to control animals. In this proposal, we plan to use a mixture of nutrients (that includes choline) that has been shown to provide substrate for dendritic spines in animals and to improve cognitive performance in developing and aging humans. We will assess behavior and brain synaptic protein expression to determine whether our intervention can improve both memory and problem solving and how the effects manifest in the brain in the same animals.
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0.919 |