1985 — 1988 |
Mckenna, Kevin E |
R23Activity Code Description: Undocumented code - click on the grant title for more information. S07Activity Code Description: To strengthen, balance, and stabilize Public Health Service supported biomedical and behavioral research programs at qualifying institutions through flexible funds, awarded on a formula basis, that permit grantee institutions to respond quickly and effectively to emerging needs and opportunities, to enhance creativity and innovation, to support pilot studies, and to improve research resources, both physical and human. |
Spinal Organization of Sexual Function @ Northwestern University |
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1985 — 1987 |
Mckenna, Kevin E |
R23Activity Code Description: Undocumented code - click on the grant title for more information. |
The Spinal Organization of Sexual Function @ Northwestern University
The proposed study represents the beginning of a long-term project to investigate the role of the spinal cord and peripheral innervation of pelvic organs in sexual function. A particular goal of this project is to compare the anatomical and physiological organization of sexual function in males and females. This aspect of the study is motivated by reports that sexual behavior and physiology of males and females show both similarities and differences. The human relevance of this research concerns the understanding of normal sexual function and of the devastating deficits in sexual dysfunction suffered after lesions of the spinal cord, peripheral nerves or as a consequence of systemic diseases such as diabetes. The specific aims of the study are to examine in rats of both sexes the anatomy and physiology of the spinal cord as it relates to sexual function. The anatomical studies are motivated by the fact that the peripheral course of pelvic nerves and the spinal organization of somatic and autonomic afferents and efferents are not well understood. These results will form a crucial basis for the understanding of the coordination of the somatic, sympathetic and parasympathetic systems in sexual physiology. These studies will include tract-tracing experiments using fluorescent dyes, horseradish peroxidase and lectins to analyze somatic and autonomic afferents and efferents innervating sexual organs. Other anatomical studies are motivated by the necessity to analyze the anatomy of transmitter-specific pathways in the spinal cord. Transmitters to be analyzed include monamines, and neuropeptides which may all play an important role in the spinal control of sexual reflexes. These studies will use immunohistochemical and histochemical techniques to localize these putative neurotransmitters in the spinal cord. The physiological studies will examine in anesthetized, spinalized rats of both sexes the spinal reflexes elicited by electrical stimulation of afferents (both somatic and autonomic) innervating sexual organs. Reflexes will be recorded from efferents (both somatic and autonomic) contained in peripheral nerves. These studies are motivated by the fact that these reflexes, under the control and coordination of supra-spinal centers, probably represent an integral part of normal sexual functioning.
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1989 — 1991 |
Mckenna, Kevin E |
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. |
Spinal Organization of Function @ Northwestern University
This proposal is a focused and rigorous test of a single hypothesis concerning male sexual function. Preliminary experiments with a novel preparation developed in this laboratory demonstrated that intraurethral stimuli elicited a fully developed ejaculatory-like response (the coitus reflex) in male rats. These findings have prompted a unifying hypothesis which proposes that ejaculation is induced by mechanical and chemical stimulation of the urethra by seminal fluids. The present proposal represents a definitive test of this theory using a multidisciplinary approach. The sensory responses elicited by seminal fluids and chemically inert fluids will be compared in quantitative electrophysiological experiments. The threshold (urethral pressure and flow) for evoking the coitus reflex will be measured to determine if seminal fluids are more stimulatory than chemically inert fluids, a strong indication of chemosensory mechanisms. Multi- and single-unit studies will examine the afferent response to these intraurethral stimuli. The presence of serotonergic paracrine cells have been demonstrated in the urethra sensory processes. This suggestion will be tested by immunohistochemical mapping studies, specific neurotoxic lesions with functional assessment, and pharmacological studies using specific serotonergic agonists and antagonists. Peptidergic afferents have been localized in the urogenital system and physiological studies suggest a role for peptidergic mechanisms in mediating some pelvic functions. The role of peptidergic afferents in the coitus reflux will be examined by immunohistochemical mapping, specific neurotoxic lesions with functional testing, release studies and pharmacological studies using tackykinin agonists.
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1992 — 1997 |
Mckenna, Kevin E |
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. |
Innervation and Neurotransmitters in Prostate Biology @ Northwestern University
Most research on benign prostatic hypertrophy (BPH) has focused on hormonal control because it has been well established that development, growth and maintenance of the prostate involve hormonal mechanisms. However, it is now clear that other factors in addition to androgens are involved in the development of BPH. Recently, we have determined that neural innervation of the prostate is required for normal prostatic structure and function. The present study will focus on the mechanisms of the trophic control of the prostate by autonomic innervation and its interaction with aging. The following hypotheses will be tested with the overall goal of determining if changes in autonomic innervation play a role in BPH: 1.Neural innervation is critical for prostatic growth and maintenance: We demonstrated that the prostate atrophies following total denervation. In this set of experiments, we will examine the effects of selective denervations to determine if the trophic role of autonomic innervation is mediated by sympathetic or parasympathetic fibers, the intrinsic serotonergic paraneurons or a combination of these neural factors. The morphological and functional effects of selective denervations will be studied by quantitative anatomical and biochemical methods. Age related changes in the trophic control by innervation will be studied by similar experiments in old rats. 2.The trophic effects of innervation are mediated by autonomic neurotransmitters: We will directly test whether the trophic effects are mediated by neurotransmitters by neurotransmitter following specific denervation will attenuate the denervation-induced atrophy. Second, we will determine if chronic administration of specific neurotransmitter antagonists can mimic the effects of denervation. The effect of neurotransmitters during aging will be studied. In the third set of experiments, we will apply known concentrations of neurotransmitter agonists to cultured rat prostatic cells and measure the resulting mitogenic, morphological and biochemical changes. 3.The trophic effects of innervation are regional: Significant regional effects should be observed in our denervation studies because of the regional pattern of BPH presentation and the fact that the ductal system is an important determinant of cellular growth. Therefore our denervation, autonomic antagonist and neurotransmitter stimulation studies will focus on regional effects in the three lobes of the prostate and on prostatic cells along the ductal system. Immunohistochemical studies will be performed to map the density of autonomic innervation throughout the prostate. The changes of the innervation with age will be documented.
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1995 — 1997 |
Mckenna, Kevin E |
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. |
Hypothalamic Control of Sexual Function @ Northwestern University
DESCRIPTION: In spite of great progress in recent years, in the understanding of the neural control of sexual behavior, there is still a large gap in our understanding of how forebrain control is exerted on the spinal systems mediating sexual reflexes. A major issue to be addressed in this proposal is the brainstem pathways and mechanisms that mediate activation of sexual reflexes by the medial preoptic area of the hypothalamus. The Principal Investigator has recently developed a novel experimental approach in which behaviorally meaningful genital reflexes, specifically erectile and ejaculatory responses, can be elicited in anesthetized rats. This model provides a unique means of studying integrated central nervous system control of sexual function. The foundation of these experiments is a method in which the urethral bulb is either mechanically stimulated or infused with saline during constriction of the urethral meatus. Such stimulation elicits what the Principal Investigator calls the urogenital reflex, which consists of penile erection, ejaculation, and clonic contractions of the striated perineal muscles. The reflex lasts for an average of about eighteen seconds and can be produced in urethane-anesthetized, spinalized rats. Recent studies have demonstrated that this reflex is normally tonically inhibited by descending influences from the paragigan to cellular nucleus in the ventromedial medulla. This descending influence apparently utilizes serotonin as a principal neurotransmitter. Destruction of this descending system disinhibits ejaculatory reflexes in copulating rats and neurotoxic destruction of descending serotonin systems disinhibit the reflex in spinalized animals as well. In this proposal, the urethrogenital reflex would be used to identify the brain stem sites that relay activation of genital reflexes in response to stimulation of the medial preoptic region. A coordinated series of an anatomical and physiological experiments would be performed to identify the pathways by which the medial preoptic region exerts control over the lumbosacral spinal cord. Brain stem sites projecting to spinal nuclei controlling male genital reflexes would be identified by the transneuronal tracing technique using pseudorabies virus. This technique has proven valuable for the identification of synaptically connected neuronal circuits. Additional electrical and chemical stimulation studies in anesthetized animals will identify neuronal sites in the preoptic region that activate sexual reflexes. In separate anatomical studies, these active regions will be injected with more conventional anterograde and retrograde tracers fluorogold and neurobiotin as an independent verification of pathways labeled with the pseudorabies method. The pathways involved in sexual reflex function will be thus identified by coordinated electrical and chemical stimulation studies. Combination of the anatomical and physiological techniques is expected to identify locations of neurons and fibers that are functionally related to the control of sexual function in this model system. Preliminary studies have identified the periaqueductal gray of the midbrain as a region activating sexual reflexes in a manner similar to the medial preoptic region. This observation suggests that the periaqueductal gray is a relay for descending activation from the medial preopticregion, a hypothesis that will be tested by a combination of tract tracing and stimulation studies.
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2000 — 2002 |
Mckenna, Kevin E |
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. |
The Role of Oxytocin in Male Sexual Function @ Northwestern University
DESCRIPTION (applicant's abstract): Erectile dysfunction is a common and personally devastating disease. Effective therapies are dependent on knowledge of the fundamental mechanisms underlying normal function. Recently, there has been considerable progress in understanding of the peripheral mechanisms of penile erections. Unfortunately, CNS mechanisms have lagged far behind. The pathways by which the hypothalamus excites the spinal erectile and ejaculatory centers remain undefined. Our laboratories have joined together to make a concerted effort at one important aspect of this CNS control. We have identified a direct hypothalamic pathway from the paraventricular nucleus to lumbosacral spinal cord as a potent facilitator of penile erection and ejaculation. The neurotransmitter for this excitation is the peptide oxytocin. We propose a broad comprehensive plan to examine the mechanism of the role of oxytocin in male sexual function. Electrophysiological studies in anesthetized rats will examine the excitation of erection and ejaculation by PVN stimulation. These will be combined with neuroanatomical staining for oxytocin and pharmacological blockade of oxytocin to verify that the effects of PVN stimulation are mediated by oxytocin. Several spinal sexual reflexes will be tested to see if they are facilitated by PVN stimulation and intrathecal administration of oxytocin. An extensive anatomical study is proposed looking at the relationship between oxytocin fibers in the lumbosacral cord and identified pelvic efferents and intereurons. Interneurons will be identified by transneuronal viral tracing, Fos staining and neurochemical identification. Our preliminary studies demonstrate that oxytocin exerts its facilitatory effects on male sexual function via a spinal nitric oxide pathway. We propose a series of pharmacological studies to examine the mechanisms of the oxytocin-nitric oxide interaction. We further propose that our results of this interdisciplinary program be validated using behavioral and pharmacological testing in unanesthetized animals.
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