2005 — 2021 |
Medina, Alexandre Esteves |
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. R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Alcohol in Neocortex Development and Plasticity @ Virginia Commonwealth University
[unreadable] DESCRIPTION (provided by applicant): Fetal alcohol syndrome (FAS) is a major cause of learning and sensory deficits in people. There is growing evidence that abnormalities of neocortical function and plasticity underlie these deficits. Animals exposed to alcohol during the third trimester equivalent of human gestation and examined following a prolonged alcohol- free period were characterized by disruption of neocortical function and plasticity. However, the mechanisms by which prenatal alcohol exposure disrupts neocortical development and plasticity remain elusive. Neural plasticity in the neocortex is especially interesting in the context of the learning deficits that characterize FAS since it shares basic mechanisms with learning and memory, including a requirement for activation of the N- methyl-D-aspartate (NMDAR) receptor and the transcription factor cAMP/calcium-dependent response element binding protein (CREB), which regulates expression of genes required for cortical plasticity. Chronic alcohol exposure has important effects on NMDA receptor function, CREB activation and intracortical inhibition, all of which are crucial for cortical function and plasticity. The central hypothesis of this proposal is that these effects result in abnormal transmission of synaptic signals to the nucleus, disrupting activation of transcription factors that regulate expression of plasticity genes. The primary goal of this proposal is to rescue cortical plasticity in an animal model of FAS. The proposed studies will use molecular-genetic and pharmacological approaches to enhance transmission of synaptic signals to the nucleus of cortical neurons. The second major goal is to prevent developmental problems in the neocortex. The proposed studies will restore cortical plasticity and inhibition to normal level during and after the period when the animal is exposed to alcohol. Collectively, these studies should provide a new and exciting opportunity to elucidate how early alcohol exposure impairs cortical function and plasticity. The results of these studies may one day contribute to devise therapeutic interventions that will prevent or alleviate morbidity in FAS. [unreadable] [unreadable]
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0.972 |
2014 — 2018 |
Medina, Alexandre Esteves |
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. |
Improving Neuronal Plasticity in a Mouse Model of Fasd @ University of Maryland Baltimore
SUMMARY There is growing evidence that poor neuronal plasticity underlies many of the neurological deficits seen in Fetal Alcohol Spectrum Disorders (FASD). Neuronal plasticity involves making and breaking connections, which in turn are related to potentiation and depression of neuronal responses. These processes are evident in the plasticity of ocular dominance in primary visual cortex. This paradigm is based on functional and morphological cortical changes that occur after a monocular deprivation (MD) by eyelid suture is performed during a critical period of development. Accordingly, in normal animals few days of MD lead to a depression of responses of neurons driven by the deprived (closed) eye, and a potentiation of responses in neurons driven by the experienced (open) eye. Using a ferret model, we demonstrated in the past that early alcohol exposure leads to a permanent impairment in ocular dominance plasticity (ODP). Subsequently, ODP has been used by different groups to study neuronal plasticity in models of Fragile X, Neonatal-Hypoxia ischemia and Angelmann Syndrome. Our studies in ferrets used a combination of optical imaging of intrinsic signals and single unit recordings (in vivo extracellular electrophysiology). Here we will use a combination of in vivo and in vitro electrophysiology techniques to tease out the mechanisms of early alcohol exposure (EAE) on neuronal plasticity. Specifically we will test the following hypothesis: A) EAE disrupts potentiation BUT NOT depression of responses in cortical layer IV, possibly by affecting glutamatergic neurotransmission. B) EAE disrupts BOTH potentiation and depression of responses in cortical layer II/III possibly by a combined effect on glutamatergic and endocannabinoid neurotransmission. And finally C) That phosphodiesterase type 1 inhibition by vinpocetine and caffeine will restore both potentiation and depression components of neuronal plasticity in alcohol exposed mice. Testing caffeine would be of particular relevance because this drug is routinely used as a therapeutic intervention in premature babies, which could facilitate its translation to FASD subjects.
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0.972 |
2018 |
Medina, Alexandre Esteves |
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. |
Amplifier Replacement For Slice Electrophysiology Studies @ University of Maryland Baltimore
Project Summary The supplemental activities will not change the project summary of the parent award.
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0.972 |
2021 |
Medina, Alexandre Esteves |
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.) |
A New Model of Gestational Cannabis Exposure @ University of Maryland Baltimore
Summary The use of cannabis during pregnancy have dramatically increased during the last ten years. While the effects of cannabis and its components on brain development are poorly known, recent studies have observed frequent mental health problems in the offspring of mothers that used marijuana during gestation. During the third trimester of human gestation the brain undergoes a ?growth spurt? that is characterized by an intensive process of synaptogenesis. This stage is followed by a period of refinement by activity-dependent neuronal plasticity where synapses reaching ?correct targets? are strengthened whereas synapses reaching ?incorrect targets? are pruned. The exposure to drugs and certain medications during this period have the potential to alter these processes, resulting in multiple neurobehavioral problems. It has been demonstrated in humans and animal models that developmental THC exposure reduces the expression of CB1r. In layer 2/3 of the visual cortex endocannabinoid neurotransmission is essential for the expression of iLTD and for the developmental transition between high to low GABA release probability characteristic of mature inhibitory cells in this region. Proper levels of inhibition are essential for the ocular dominance plasticity and the establishment of neuronal circuits responsible for neuronal orientation tuning and formation of orientation selectivity columns. Based on this scientific premise we hypothesize that THC exposure during the third trimester equivalent of human gestation leads to persistent reduction in endocannabinoid transmission, resulting in an impairment in iLTD and preventing maturation of inhibition. As a consequence, both ocular dominance plasticity and orientation selectivity would be impaired. Here we will use a combination of in vivo and ex vivo electrophysiology and optical imaging of intrinsic signals to test this hypothesis. The accomplishment of these experiments would result in the development of a novel model of prenatal exposure to cannabis that could be used to investigate mechanisms of action of gestational marijuana and potential interventions.
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0.972 |