1985 — 1993 |
Sachs, Benjamin D [⬀] |
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. |
Analysis of Masculine Behavior @ University of Connecticut Storrs
This project is an examination of the mechanical and neuroendocrine causes and effects of sexual potency in animals. This basic research on laboratory rats and other rodent species will promote our comparative understanding of the mechanisms underlying sexual reflexes in males, thereby also facilitating the use of appropriate animal models for the study of the organic origin of human erectile dysfunction and its treatment by pharmacological or surgical means. Sexual reflexes will be studied within and outside the context of copulation in three groups of studies. In one series of experiments, behavioral observations and electromyographic (EMG) recordings of long-term castrated male rats will be used (a) to examine the rate of androgen-induced restoration of activity in the two mechanical systems--i.e., the penile vasculature and the striated penile muscles-- that are normally coordinated in generating penile responses, and (b) to examine indirectly the relative roles of neural cytosol and membrane hormone receptors in the early stages of response restoration by androgen. A second group of studies uses behavioral observation, videorecording, and EMG recording to analyze the coordination of the vascular and striated penile muscle effector systems with each other and with the skeletal movements characteristic of mating in rats. In the third set of studies the mechanical and neuroendocrine effects of penile actions in copula will be compared in laboratory mice, hamsters, and meadow voles. These species were selected because they differ in important aspects of their mating behavior and female reproductive physiology from each other and from previously studied rats. Investigative techniques in this group of studies include surgical and endocrine manipulation of the penile response potential of the males, and scanning electron microscopy of the penile glands to record the changes resulting from castration and androgen replacement.
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0.985 |
2007 |
Sachs, Benjamin D [⬀] |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Exploring the Role of Phosphodiesterase 4a in Axonal Regeneration @ University of California San Diego
[unreadable] DESCRIPTION (provided by applicant): The failure of the Central Nervous System (CNS) axons to regenerate has been attributed primarily to the presence of inhibitory components within CNS environment that bind receptors on axons to stimulate inhibitory signaling cascades. Given that elevation of cyclic AMP (cAMP), a ubiquitous intracellular second messenger, enhances nerve regeneration and overcomes the inhibition of neurite outgrowth, molecules that regulate cAMP in neurons are prime candidates for molecular intervention in the context of nervous system repair. Indeed, rolipram, an inhibitor of type four phosphodiesterases (PDE4s), the enzymes responsible for cAMP degradation, has been shown to overcome the inhibition of neurite outgrowth (28). However, rolipram is a general inhibitor of all PDE4s (PDE4A-D) and causes many side effects in patients that preclude its use in the clinic. To treat patients effectively, a more specific inhibitor with fewer side effects is required. To date, the specific PDE4 isoforms that are targets for rolipram in the disinhibition of neurite outgrowth remain to be determined. Our major hypothesis is that phosphodiesterase 4A (PDE4A) plays a major role in the regulation of cAMP after nerve injury and is an attractive target for therapeutic intervention in neurodegenerative diseases, such as spinal cord injury. Our preliminary data indicate that: 1. Expression of the p75 neurotrophin receptor (p75NTR), a receptor implicated in the inhibition of neurite outgrowth and nerve regeneration, leads to decreased cAMP levels in neurons. 2. Inhibition of PDE4s with rolipram rescues the p75NTR induced decrease in cAMP. 3. PDE4A5 forms a complex with p75NTR and targets cAMP degradation to the membrane. 4. The extreme C-terminus of PDE4A5 directly interacts with the intracellular domain of p75NTR. In the research proposed in this fellowship application, we will determine the role of PDE4A in regulating the inhibition of neurite outgrowth (Specific Aim 1). We will examine the role of PDE4A in the regulation of both cAMP and Rho signaling, two intersecting pathways known to play major roles in the inhibition of neurite outgrowth (Specific Aim 2). We will extend these studies by examining the role of PDE4A in axonal regeneration in vivo (Specific Aim 3). There are an estimated 250,000 individuals with permanent disabilities resulting from spinal cord injuries living in the United States with 11,000 new injuries reported every year. At present, there are no effective pharmacologic agents that promote complete functional recovery after injury. The identification of novel, specific drug targets, such as PDE4A, could greatly enhance our ability to overcome the inhibition of axonal regeneration that proves so costly for victims of spinal cord injury. [unreadable] [unreadable]
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0.976 |
2010 — 2013 |
Sachs, Benjamin D [⬀] |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
The Effects of 5-Ht Deficiency On Responses to Stress and Antidepressant Drugs
DESCRIPTION (provided by applicant): Major depression is the leading cause of disability among Americans between the ages of 15 and 44 and is one of the top ten causes of morbidity and mortality worldwide. Current treatments are well tolerated but can lead to less than 50% remission rates among patients. Due to the fact that most antidepressant drugs act by increasing extracellular levels of serotonin (5-HT), it has been hypothesized that decreased levels of 5-HT might underlie major depressive illness. However, this theory has been difficult to test in a preclinical setting due to a lack of hyposerotonergic mouse models. The tryptophan hydroxylase 2 R439H knock-in mouse (Tph2KI) provides a novel system in which the consequences of chronic 5-HT deficiency can be examined. This mouse exhibits an 80% reduction in brain 5-HT as the result of a mutation in Tph2, the enzyme responsible for brain 5-HT synthesis. In addition, these mice recapitulate several physiological features often associated with depression, including inhibited prolactin secretion and hypothermic responses to serotonergic activation, and decreased levels of the 5-HT metabolite, 5-HIAA. Because of these physiologic parallels to the human condition, Tph2KI mice represent a highly relevant, naturalistic rodent model for studying the impact of low levels of 5-HT on cell biological processes and behaviors related to depression and antidepressant action. Work from the past decade has demonstrated that elevation of 5-HT promotes neurogenesis and has revealed a requirement for neurogenesis in several antidepressant-like effects in mice. Elevation of 5-HT using antidepressant drugs can also prevent the inhibition of neurogenesis and the depressive-like behaviors induced by exposure of rodents to chronic stress. However, whether decreased levels of 5-HT lead to impaired neurogenesis, altered antidepressant-like responses, or increased vulnerability to stress has not been determined. The proposed research will test the hypothesis that chronic 5-HT deficiency will lead to inhibition of baseline adult hippocampal neurogenesis, diminished responses to antidepressant drugs, and decreased resilience to chronic stress. This hypothesis will be evaluated through the performance of three specific aims: 1) To examine the effects of hyposerotonergia on baseline hippocampal neurogenesis. 2) To determine the neurogenic and behavioral responses of 5-HT deficient mice to antidepressants. 3) To study the neurogenic and behavioral consequences of chronic stress in Tph2KI mice. These experiments will provide some of the first experimental evidence regarding the impact of chronic hyposerotonergia on adult neurogenesis, antidepressant responses, and vulnerability to stress. The data obtained from the proposed study will address several prominent depression theories, including the Serotonin Deficiency, the Neurogenesis Deficiency, and the Diathesis-Stress Hypotheses of depression and may shed light on the pathophysiology underlying depressive-like states.
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0.97 |