1992 — 1996 |
Doncarlos, Lydia L |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Ontogeny of Estrogen Target Neurons in the Forebrain @ Loyola University Chicago
Estrogen is known to play a fundamental role in sculpting the developing nervous system. The ultimate goal of this research will be to understand the profound impact of estrogen on the developing mammalian brain. Perinatal estrogen exposure, derived from estrogenic metabolites of circulating testosterone, permanently masculinizes the morphology, connectivity, and chemistry of many regions of the central nervous system. Many behaviors and physiological functions also permanently acquire a male-typical pattern in response to perinatal estrogen. The most dramatic effects of estrogen in development occur in neural circuits that, in the adult, contain estrogen target cells and participate in reproductive behavior and physiology. Abnormal hormone secretion or neurotransmission during early development may affect estrogen-induced differentiation of the brain, possibly disrupting neural control of reproduction or other brain functions. Estrogen binds to estrogen-specific receptors that act as transcription factors, importantly altering protein synthesis. The hypothesis that is central to the proposed studies is that estrogen receptor-containing neurons in the developing brain receive and transduce the estrogenic signal and so are crucial to estrogen-induced differentiation. The experiments performed will determine when estrogen receptor-containing neurons are born, when they begin to express functional estrogen receptor, whether they are subject to selective cell death in the presence or absence of estrogen, and whether selected synaptic and hormonal signals interact to affect the survival of estrogen target neurons. The analyses will initially concentrate on the development of estrogen target cells in the rat preoptic area. This reproductively relevant brain region has documented. hormone-dependent differences in morphology and receptor distribution. Histochemical techniques to detect estrogen receptors, birthdate markers, cell death markers, developing neural connections, and other markers of neuronal differentiation will be employed to identify selected subsets of estrogen receptor-expressing cells from early embryonic stages through adulthood.
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0.958 |
2001 — 2005 |
Doncarlos, Lydia L |
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. |
Androgen Receptor Expression in Developing Rat Forebrain @ Loyola University Chicago
The overall goal of this research is to elucidate the mechanisms underlying the impact of testosterone on the developing mammalian nervous system. Testosterone sculpts the developing nervous system, insuring that the sexual phenotype of the brain matches that of the gonads. In rodents, testosterone exposure during the perinatal period permanently masculinizes not only the morphology, connectivity, and chemistry of the central nervous system but also behavioral and neuroendocrine functions. The prominent role of both estrogenic metabolites of testosterone and estrogen receptors in the process of forebrain masculinization is undisputed. Compelling accumulated data, however, have led us to hypothesize that androgen receptors are an integral component of the organizational effects of testosterone on the nervous system, and that spatial and temporal shifts in androgen receptor expression and regulation contribute to specific actions of androgens in modulation of brain development. An integrated molecular and anatomical approach will be used to examine the development and hormonal regulation of androgen receptor expression in seven functionally relevant regions of the rat brain. These studies will form the basis for behavioral experiments that will test whether androgen receptor activation during development modifies the development of sexually differentiated behaviors. Four specific hypotheses will be tested: I. The anatomical substrate for testosterone action via androgen receptors exists prenatally in the forebrain; II. Prenatal testosterone masculinizes androgen receptor mRNA and protein levels during later development; III. Hormonal regulation of androgen receptor expression is specific to the developmental stage; IV. Androgen exposure masculinizes behaviors via androgen receptor dependent mechanisms. Rats will be treated with specific steroid receptor ligands or antagonists, and androgen receptor mRNA and protein expression will be assessed using in situ hybridization, immunocytochemistry and western blots, or behaviors will be analyzed using standard measures of adult behavioral responses to hormones. These studies will determine when androgen receptor mRNA and protein expression begins, the cellular phenotype of androgen receptor protein expressing cells through development, whether pre or postnatal androgen modifies subsequent androgen receptor expression, and when adult patterns of androgen receptor regulation arise, and finally, whether alterations in androgen receptor expression and regulation affect sensitivity to subsequent hormone exposure and play a role in maturation of adult sexual behaviors. The studies proposed will provide data essential to dissecting the complex mechanisms underlying the process of sexual differentiation of the brain, and contribute to an understanding of developmental stage-specific responses to hormones. Further, these studies will shed light on the etiology of neurologic and mental disorders that are more prevalent in men vs. women.
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0.958 |
2004 — 2006 |
Doncarlos, Lydia L |
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.) |
Exploratory Studies of Androgen Receptors in Axons @ Loyola University Chicago
DESCRIPTION (provided by applicant): Androgens exert powerful effects on the function of the central and peripheral nervous system, modifying the morphology, function, survival and recovery of neurons in many regions. Androgens have been thought to exert their effects exclusively through the androgen receptor, traditionally considered to be a ligand dependent nuclear transcription factor. However, considerable evidence for non-transcriptional effects of gonadal steroid hormones has been in the literature since the late 70's and has accumulated exponentially in recent years, yet the receptors or alternative mechanisms remain largely unknown. This laboratory recently discovered that androgen receptors are present not only in neuronal nuclei, but in axons and dendrites in the mammalian cerebral cortex. This discovery points to the intriguing possibility that androgen receptors have a novel, extranuclear mode of action in the mammalian cortex. The exploratory studies described in this application will provide information essential to generating hypotheses about this potential extranuclear route of androgen action. A straightforward set of experiments will use combinations of histochemical methods along with light microscopic, electron microscopic and confocal microscopic analysis to: 1) Identify the subcellular distribution of androgen receptor immunoreactivity in axons and terminals; 2) Identify the source of androgen receptor immunoreactive axons in the cerebral cortex; and 3) Determine whether the expression of androgen receptors in axons is sexually differentiated and hormonally regulated. Sex differences in a broad range of mental and neurological disorders suggest that androgens are in some cases protective and in others deleterious. Thus, understanding the mechanisms of action of androgens may provide an essential key to understanding and exploiting the cellular and global impact of endogenous and exogenous androgenic ligands on the healthy and diseased nervous system in both men and women.
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0.958 |
2010 — 2014 |
Doncarlos, Lydia L Sisk, Cheryl L. (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. |
Mechanisms Underlying Sexually Differentiated Brain Remodeling During Adolescence @ Loyola University Chicago
DESCRIPTION (provided by applicant): Adolescence has only recently been recognized as a protracted period of extensive brain remodeling. This critical period of development is associated with the emergence of sex differences in susceptibility to and manifestation of several mental illnesses, including eating, mood, and conduct disorders, and schizophrenia. Thus, the etiology of these illnesses is likely to be impacted by how pubertal hormones influence the remodeling of sexually differentiated behavioral circuits during adolescence. The longstanding view has been that sexual differentiation of the brain occurs during late embryonic or early postnatal brain development, and that these sex differences are passively maintained throughout adolescence and into adulthood. Recent findings from the PIs' laboratories overturn this view by providing evidence in rats for active maintenance of sexual dimorphisms during puberty via active and hormonally modulated cell addition in sexually differentiated cell groups during puberty. This finding represents a fundamental shift in the understanding of how and when sexual dimorphisms in the brain are established and maintained in the mammalian brain. This newly discovered developmental process may be an active mechanism for either maintaining structural and functional sexual dimorphisms in the face of remodeling of the adolescent brain or for creating new sex differences that emerge during adolescent development. Using timed injections of bromo-deoxyuridine (BrdU) coupled with immunohistochemistry for markers of neurons and glial cells, as well as functional assays, the mechanisms underlying this addition of new cells to the adolescent brain will be determined. The questions to be addressed are: 1) Do gonadal hormones modulate the pubertal addition of cells to the adolescent brain in cell groups that are either male-biased or female-biased by increasing cell proliferation, survival, or both? 2) Is addition of new cells a pubertal or a life-long mechanism for maintenance of structural sexual dimorphisms? 3) What are the fates and functional outcomes of cells that are added to the adolescent brain during puberty? These studies will generate new knowledge and potentially new therapeutic targets to explain and appropriately treat sex-biased mental illnesses that are associated with puberty and adolescence.
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0.958 |