1990 — 1993 |
Henderson, Leslie P |
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. |
Regulation of Acetylcholine Receptor Function
Synaptic transmission at the vertebrate skeletal neuromuscular junction is mediated by functionally distinct classes of nicotinic acetylcholine (ACh) receptors. The expression of these different types of ACh receptors is regulated by a complex interplay between the developmental age of the animal and the state of innervation of the muscle. An extensive number of studies has made it clear that innervation plays a major role in regulating the expression of ACh receptors in developing and adult animals. Although the regulation of ACh receptor expression by nerve-induced activity is indisputable, it is equally clear that other humoral and "intracellular factors affect ACh receptor expression as well. However, the physiololical consequences of these factors on ACh receptor function have not been addressed. The objective of this proposal will be to examine two preparations in which functional changes in ACh receptors are induced by factors independent of the state of innervation of the muscle fiber. First, it has been shown in a number of electrically excitable cells that steroid hormones induce changes in the expression of neurotransmitter receptors. In hormone-sensitive muscles of the frog, exposure to androgenic steroids significantly increases the time course of synaptic current decay, suggesting that steroids induce the expression of functionally distinct synaptic ACh receptors. This hypothesis will be directly tested by single channel recording and analysis. It will be established by Northern blot analysis whether steroid effects on channel function are mediated by changes in the levels of transcripts encoding the different subunits of the ACh receptor. The functional consequences of changes in message levels will be confirmed by expressing mRNA from steroid-treated fibers in Xenopus oocytes. Second, single channel analysis indicates that ACh receptors in dystrophic mouse muscle have significantly different properties than receptors in control muscle and that these differences are not dependent on the state of innervation of the fiber. Experiments will be made to determine whether a defective association between specific cytoskeletal elements and the ACh receptor protein causes functional changes in channel properties or if the dystrophic phenotype leads to altered expression of ACh receptor genes. Combined physiological/molecular biological studies on muscle ACh receptors have laid the groundwork for elucidating the structural bases of neuronal ion channels and have clearly demonstrated the relevance of experiments on muscle ACh receptors to the broader field of neurobiology. By using this approach, the experiments presented here will increase our understanding of the regulation of ion channels in excitable membranes. More specifically, these studies will elucidate cellular mechanisms associated with pathological conditions induced by steroid abuse and by genetic dystrophies
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0.958 |
1994 — 1999 |
Clark, Ann [⬀] Henderson, Leslie |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
The Influence of Gonadal Steroids On the Development of Gaba-Mediated Synaptic Transmission
During development, gonadal steroids (androgens and estrogens) confer permanent sex-specific differences (sexual dimorphism) onto the organization and function of the brain. This sexual dimorphism in the brain, in turn, leads to production of behavior that is different in male and female animals. The estrogens and androgens act during a very specific and limited period in early development to induce these permanent sex-specific differences in brain structure and in behavior. The best studied brain structure which is both sexually dimorphic and is known to be critical in mediating sex-specific behavior is the hypothalamus. We know that much of the information transfer in neurons in the hypothalamus depends upon the presence of a class of proteins called GABA (gamma-aminobutyric acid) receptors. The goal of this work is to determine if androgens and estrogens act during this critical period in early development to alter the types of GABA receptors that are expressed in the hypothalamus and to determine if steroid-dependent changes in GABA receptor expression lead to changes in sex-specific behaviors in adult animals. The results from this study may help us to understand how development in the brain is regulated to produce sex-specific behaviors.
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1 |
1996 — 2011 |
Henderson, Leslie P |
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. |
Steroid Regulation of Ion Channels |
0.958 |
1999 — 2000 |
Henderson, Leslie P |
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. |
Endocrine Disruptors in the Developing Nervous System
In recent years, both the evidence and the concern have been steadily growing that synthetic compounds, including pesticides, herbicides, and industrial solvents, have deleterious effects on the development of a wide range of species by disrupting endocrine sensitive processes. Numerous studies indicate that these putative endocrine disrupting compounds (EDCs) induce abnormalities in peripheral reproductive organs and in reproductive behaviors (Gray et al, 1992; Cooper and Kavlock, 1997; Reiter et al, 1998). Gonadal steroids are known to have significant and widespread effects on the development of the nervous system (Dohler, 1991), and deficits in neural systems are inferred from studies demonstrating EDC-dependent abnormalities in reproductive behaviors (Gray et al, 1985; Andersen et al, 1997). In spite of these studies, little data is available documenting potential effects of EDCs on cellular processes underlying neuronal differentiation. Moreover, although data clearly suggest that developing organisms are more sensitive to endocrine disruption than adult animals, little information is available delineating critical periods for EDC effects. The goal of the present study is to determine both critical periods and dose-response relationships for putative EDCs in inducing adverse effects on the early embryonic development of vertebrate spinal neurons from the amphibian, Xenopus laevis. Xenopus embryos provide a highly tractable system in which early events underlying formation of the nervous system and establishment of synaptic connections can be screened rapidly in a large number of animals, and in which developmental changes for identified neurons in vivo, as well as these same cells dissociated and maintained in vitro, have been amply documented (Brehm and Henderson, 1988; Spizter, 1994). Using a multidisciplinary approach that includes morphometric analysis, fluorescence microscopy, whole cell patch clamp recording, and ultrafast perfusion techniques, we will determine if exposure to putative estrogenic and anti-androgenic EDCs leads to selective defects in the differentiation of identified populations of spinal cord neurons during early embryonic development.
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0.958 |
2000 — 2003 |
Henderson, Leslie P |
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. |
Gaba a Receptor Modulators in the Developing Rat Forebra
DESCRIPTION: (Adapted from the applicant's Description) Anabolic androgenic steroids (AAS) are synthetic derivatives of testosterone that in recent years have become significant drugs of abuse among preteen and teenage children. AAS are known to elicit detrimental effects on neuroendocrine function, as well as increase psychiatric symptoms, including anxiety, paranoia, hostility, and aggression in adults. However, little is known as to the mechanism of action of these compounds in the central nervous system, and even less is known about how these compounds may act in the developing brain. Neural transmission mediated by GABAA receptor is the primary molecular target for a wide range of both therapeutic and abused drugs, including neurosteroids, benzodiazepines, and ethanol. The investigators have shown recently that AAS induce rapid, reversible, and region-specific modulation of GABAergic currents in the forebrain of prepubertal rats, and thus can be added to the list of substances that act as allosteric modulators of this channel. Both the ontogeny of GABAA receptor subunit gene expression and developmental changes in receptor pharmacology have been well described in the hippocampus and cerebellum during the first two weeks of postnatal development. In contrast, there is a dearth of information delineating developmental changes in receptor pharmacology for other forebrain regions or in the hypothalamus, and few studies have assessed changes in GABAA receptor expression associated with puberty. In particular, no experiments have been performed to determine if sensitivity to AAS is significantly different during the progression from puberty to adulthood. In this application, the investigators will use molecular biological and electrophysiological approaches to determine if, concomitant with puberty, there are significant changes in GABAA receptor subunit expression, as well as the ability of AAS to modulate GABAergic synaptic currents. In addition, the investigators will use electrophysiological and behavioral approaches to determine if chronic AAS exposure in peripubertal versus adult rats induces significant changes in the ability of benzodiazepines or neurosteroids, as well as the AAS, to modulate GABAA receptor currents and to elicit anxiolytic or sedative effects. Together, these studies will demonstrate if puberty is associated with significant changes in the acute or chronic actions of AAS at the GABAA receptor, and thus provide important new information to indicate if adolescents are at increased risk for abuse of AAS or other psychoactive drugs.
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0.958 |
2007 — 2008 |
Henderson, Leslie P |
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. |
Interactions of Anabolic Steroids and Stress Hormones in the Forebrain
[unreadable] DESCRIPTION (provided by applicant): In the past several decades, the therapeutic use of anabolic androgenic steroids (AAS) has been overshadowed by illicit self-administration of these drugs, not only by elite athletes, but also by a growing number of ordinary citizens, most disturbingly junior high- and high school-age kids. As in adults, AAS use in adolescents is associated with a range of behavioral effects, including increased anxiety and altered responses to stress. In addition AAS users, and in particular adolescent AAS users, are more likely to engage in other risk-taking behaviors, including consumption of other illicit and or /addictive drugs, including alcohol. Neural transmission mediated by y-aminobutyric acid type A (GABAA) receptors in the forebrain plays a crucial role in the expression of anxiety, and activity of this neurotransmitter system is altered by both the AAS and alcohol. Within the forebrain, regions of the extended amygdala, including the central amygdaloid nucleus (CeA) and the bed nucleus of the stria terminalis (BNST) provide a crucial nexus for mediating the interactions of both the gonadal and stress hormones on GABAA receptor-mediated transmission and in the generation of stress-induced behavior and anxiety. Of particular interest to us is to explore a potential parallel between AAS actions and the known effects of alcohol on corticotropin releasing hormone (CRH) and its interactions with the GABAergic system in the amygdala. CRH is a critical mediator of the stress response and has been implicated as playing a prominent role in drug-seeking and dependence, especially for alcohol. Moreover, effects of alcohol in the CeA can be attributed, at least in part, to a CRH-mediated enhancement of GABAergic transmission. A key question is, do the AAS also alter the CRH/GABAA receptor system in the amygdala in a manner that may contribute both to the generation of anxiety behaviors and the increased use of other illicit drugs in adolescent AAS users? The goal of this proposal will be to determine if chronic exposure to a "cocktail" of three commonly abused AAS alters the expression of CRH or its receptors in the CeA and the BNST of the adolescent female mice; to determine if this steroid regime alters the ability of CRH to modulate GABAergic transmission within these forebrain regions; and to determine if this regime alters the acoustic startle response, a behavioral assay for anxiety that reflects a CRH-sensitive and GABAA receptor-mediated behavior. Data demonstrating that the AAS influence GABAergic transmission and CRH modulation in the extended amygdala will be important for delineating not only the neural basis for how the AAS produce behavioral effects, but also in setting the groundwork for future experiments to determine if the actions of AAS on this system provide an underlying mechanism that predisposes adolescent AAS users to have an altered sensitivity to, and therefore a higher likelihood to use, other drugs of abuse. [unreadable] [unreadable] [unreadable]
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0.958 |