2002 — 2004 |
Puche, Adam C |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Cell Migration and Differentiation in the Olfactory Bulb @ University of Maryland Baltimore
DESCRIPTION (provided by applicant): Neural stem cells in the subventricular zone (SVZ) are involved in the continual generation of new cells throughout development and in adult. The major target of these newly formed cells is the olfactory bulb. These SVZ progenitors migrate from the SVZ along the rostral migratory stream and into the olfactory bulb. In the olfactory bulb these cells migrate radially to different layers and differentiate into primarily interneurons, although glia are also thought to be generated. The cues directing the differentiation of these cells, and many of the mechanisms involved in their radial migration in the olfactory bulb, are unclear. This goal of this research is to investigate the migration and differentiation of SVZ progenitors in the olfactory bulb. Aim 1 will determine what cell phenotypes are derived from SVZ progenitor migration at different developmental stages, and whether the fate of these cells can be perturbed by environmental cues using organotypic slice culture. Aim 2 investigates the mechanisms used by SVZ progenitors to migrate along the rostral migratory stream and into the olfactory bulb. These experiments focus upon the relationship between migrating neurons and different putative migratory scaffolds present in postnatal and adult, and the role that matrix metalloproteinases may have in facilitating the migration of these cells. Understand the mechanisms of SVZ progenitor migration through the olfactory bulb and cues governing phenotype selection have important implications for the use of these cells as clinical therapy.
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0.908 |
2020 — 2021 |
Puche, Adam C |
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. |
Basal Forebrain Modulation of Olfactory Bulb Function @ University of Maryland Baltimore
PROJECT SUMMARY Sensory systems, including olfaction, are heavily dependent on signals from higher brain regions that regulate behavioral states of alertness and attention. A major center for these modulatory inputs is the basal forebrain. The basal forebrain (BF) sends axonal projections throughout the brain and has been implicated in dynamic modulation of cortical as well as sensory circuits during behavior. BF is classically thought of as a center for cholinergic projections throughout the brain, whose chief functional role is to mediate attentional modulation of information processing. However, the recent advent of novel tools for probing neural circuits in vivo has enabled a deeper and more nuanced understanding of basal forebrain organization and role in cognition. BF projections to neocortex are in fact neurochemically diverse and precisely organized with respect to projection target. Further, different BF subpopulations are linked to distinct aspects of behavior and are implicated in diverse cognitive functions including reward signaling, behavioral responding to sensory cues and task learning. Despite these advances, however, we still know little about BF impact on the initial processing of sensory inputs on their way to cortex. The olfactory bulb (OB) is advantageous for investigating basal forebrain function, as it is the only primary (pre-cortical) sensory processing area receiving BF inputs and because olfaction is a primary modality driving behavior in rodents. BF sends massive projections to the OB, with terminations in all OB layers. Many of these projections are cholinergic. However, as for neocortex, BF projections to OB are neurochemically diverse with substantial numbers of GABAergic neurons. The importance of this diversity has only recently begun to be appreciated for cortex, but almost entirely unexamined with respect to OB circuitry. A recent study showed that GABAergic basal forebrain projections to the olfactory bulb target distinct neuronal subpopulations and can, independent of cholinergic projections, modulate OB circuits to affect odor perception. However, our understanding of the respective roles played by BF cholinergic and GABAergic in modulating OB circuits and odor perception remains rudimentary. Fundamental unanswered questions include whether cholinergic and GABAergic basal forebrain projections target distinct components of olfactory bulb circuits, whether they have complementary or opposing effects on odor representations at the level of olfactory bulb output, what are the activity patterns of cholinergic and GABAergic basal forebrain neurons during behavior, and what role these projections play in odor perception or odor-guided behaviors? The overall goal of this proposal is to investigate how the basal forebrain neuromodulatory inputs affect olfactory bulb function in a multi-disciplinary study spanning investigation at the level of single neurons through to animal behavior utilizing advances in electrophysiology, opto-/pharmacogenetics, and high resolution activity imaging and microendcosopy in behaving animals.
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0.908 |
2021 |
Merchenthaler, Istvan Jozsef Prokai, Laszlo (co-PI) [⬀] Puche, Adam C |
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. |
Brain-Selective Estrogen Therapy For Menopausal Hot Flushes in An Advanced Translational Animal Model @ University of Maryland Baltimore
ABSTRACT Menopause is an inevitable stage in normal human aging, affecting the quality of life of millions of women all over the world. Menopausal symptoms including hot flushes, sleep disorders, depression/anxiety, decline in cognitive function (Alzheimer?s disease is more prevalent in women and linked to estrogen), cardiovascular disease, genitourinary conditions, and osteoporosis. These symptoms have been shown to be causally linked to a sharp decline in circulating sex steroid concentrations after menopause. While men have similar decline in sex hormones, andropause symptoms are usually infrequent and mild. Consequently, menopausal symptoms are of considerably more pressing medical concern in elderly women than andropause in elderly men. Thus, this proposal focuses on women?s health and improved therapies for menopause. The most immediate and patient reported ?unbearable? symptom of the menopause are hot flushes, which cause not only physical discomfort but also negatively impact mood, behavior and general quality of life. Among current treatments of hot flushes, only estrogen therapy (ET) and hormone therapy (HT, estrogens and progestins) have satisfactory efficacy. Although ET/HT prevents hot flushes, they have unwanted side effects in the periphery, including the stimulation of the uterus and breast leading to a significantly increased cancer risk in these organs. Although there have been extensive efforts to develop safer estrogens, the lack of animal model(s) that naturally recapitulate the symptoms and pathophysiology of human menopause has had a tremendous negative impact on the success of this effort. Only humans and our close mammalian cousins exhibit menopausal hot flush symptoms in normal aging or with ovariectomy. However, the most commonly utilized model for thermoregulation is rodent, which is limited for translational drug discovery with human menopause as rodents do not normally flush and do not sweat. We developed an old-world advanced translational animal model which undergoes a menopausal process that is hormonally identical to that of human women. We show that ovariectomy induces hot flushes that are exacerbated by niacin and nearly eliminated by estrogen therapy. This also involved development of novel use of non-invasive thermal imaging to detect these events, alleviating the need for older train-and-restrain models used in this species for hot flush research in the past. Using this model, we propose to test a novel estrogen prodrug therapy using 10?,17?-dihydroxyestra-1,4-dien-3-one (DHED). DHED has ideal properties for a translational therapy for hot flushes. In the prodrug form it is highly shelf-stable at room temperature, can be taken orally, has no peripheral bioactive properties in the prodrug form and it is selectively converted to estrogen only in the brain, resulting in no peripheral side effects on uterus/breast. We propose a comprehensive testing of the pharmacological effectiveness of DHED to treat hot flushes in our advanced translational model as a key step to human clinical trials.
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0.908 |