Mechanisms Of Testosterone Action On The Male Pelvic Autonomic Nervous System: The Role Of Estrogens
Funder
National Health and Medical Research Council
Funding Amount
$417,750.00
Summary
The aim of this project is to understand how the circulating hormone, testosterone, affects the autonomic nervous system in adult males. We are particularly interested in the effects this hormone has on the nerve supply of the urogenital organs, ie. the lower urinary tract and reproductive organs. We have already found that many different parts of this pelvic autonomic nervous system are androgen-sensitive, and if the levels of hormones drop significantly, then many properties of the neurons cha ....The aim of this project is to understand how the circulating hormone, testosterone, affects the autonomic nervous system in adult males. We are particularly interested in the effects this hormone has on the nerve supply of the urogenital organs, ie. the lower urinary tract and reproductive organs. We have already found that many different parts of this pelvic autonomic nervous system are androgen-sensitive, and if the levels of hormones drop significantly, then many properties of the neurons change. This is likely to impact negatively on reflexes like penile erection, prostate secretion and propulsion of seminal fluid. Our recent experiments suggest that many of these actions may be caused by testosterone acting in a way that does not involve the typical activation of its receptor molecule (the androgen receptor) and we think it is very likely that it is first converted by some pelvic autonomic neurons into estradiol. We have recently shown that estradiol has potent actions on signalling cascades in these neurons, and that many of the neurons make estrogen receptors. It is also possible that testosterone causes the release of growth factors from the organs, and these growth factors cause changes in their nerve supply. We will investigate both of these possibilities. The outcomes of this study will be relevant for understanding how pelvic autonomic reflexes are affected by endocrine disorders, ageing and various drugs that act on the endocrine system. Our results may also be useful for designing drugs that act on the endocrine system but with less side-effects on the nervous system.Read moreRead less
Heartbeats are considered to arise through specialised pacemaker cells establishing rhythmically generated (i.e. pacemaker) action potentials, which then trigger propagating action potentials in heart muscle causing contraction and pumping of blood. This research proposal aims to challenge the physical model that is used to describe this pacemaker process and resultant heart conduction. Our reasons for doing this derive from our discovery of an alternative pacemaker-conduction mechanism, which w ....Heartbeats are considered to arise through specialised pacemaker cells establishing rhythmically generated (i.e. pacemaker) action potentials, which then trigger propagating action potentials in heart muscle causing contraction and pumping of blood. This research proposal aims to challenge the physical model that is used to describe this pacemaker process and resultant heart conduction. Our reasons for doing this derive from our discovery of an alternative pacemaker-conduction mechanism, which we have shown to operate in various smooth muscles. This mechanism, termed store-based pacemaking, is entirely different to the currently held cardiac model but could readily achieve the same outcome. We will investigate the hypothesis that this pacemaker mechanism is also fundamental to heart pacemaking and conduction. Positive support for our hypothesis, as indicated by our pilot findings, may severely challenge the present model for cardiac pacemaking. Such an outcome will have major ramifications on present interpretation of cardiac function in health and disease and will be particularly important to interpretation of disorders associated with cardiac arrhythmias and heart conduction.Read moreRead less
Mechanosensitive Afferent Nerves And Gastrointestinal Motility
Funder
National Health and Medical Research Council
Funding Amount
$384,693.00
Summary
This project aims to identify the different types of sensory nerves from the gut which cause sensations such as fullness, nausea or pain. These sensory nerves also activate important reflexes that coordinate different regions of the gut to ensure that food is properly digested and propelled. Many studies have examined these sensory nerves and how they can be activated by stretching the gut wall, but very basic questions remain to be answered. We do not know how many different types of sensory ne ....This project aims to identify the different types of sensory nerves from the gut which cause sensations such as fullness, nausea or pain. These sensory nerves also activate important reflexes that coordinate different regions of the gut to ensure that food is properly digested and propelled. Many studies have examined these sensory nerves and how they can be activated by stretching the gut wall, but very basic questions remain to be answered. We do not know how many different types of sensory nerves there are and whether they all respond to stretch in the same way. We cannot identify their specialised endings in the wall of the gut. While these sensory nerves definitely respond to stretch, they are also known to respond to contractions of the gut wall. Despite this, we do not understand how the normal movements of the gut wall activate them, nor why some movements can lead to pain. Most of the experiments will be carried out on small pieces of tissue taken from humanely killed guinea pigs and studied, under highly controlled conditions, in organ baths. The remainder of the study will be on specimens of human gut tissue obtained at surgery. This project will use new techniques to record sensory nerves during both stretch and contraction of the gut wall to understand what activates them. In addition, their endings will be labelled with dye to reveal their different shapes. Using computerised imaging techniques we will identify whether they respond to particular patterns of movement in the gut wall. Lastly we will record from these sensory neurones in live specimens of human colon to see whether the same types of sensory nerves are present in humans as in the small animals. This study will provide the first comprehensive account of sensory nerves to the gut wall that respond to distension, including those that activate pain pathways. This is a pre-requisite for designing new drugs that will target these nerve cells with minimal side effects.Read moreRead less
Cardiovascular Responses To Stress And Arousal: Hypothalamic And Brainstem Mechanisms
Funder
National Health and Medical Research Council
Funding Amount
$566,468.00
Summary
Stressful episodes in everyday life cause increases in blood pressure, mainly via activation of nerves that constrict blood vessels and increase heart rate. This in turn increases the risk of heart attacks, strokes, or other cardiovascular diseases. This project aims to identify the brain mechanisms that cause these stress-evoked effects. This knowledge may lead to much more effective ways of minimising stress-evoked responses, and thus reduce the risk of cardiovascular disorders.
Determination Of Sympathetic Preganglionic Neuronal Phenotype
Funder
National Health and Medical Research Council
Funding Amount
$241,527.00
Summary
The nervous system is the single most complex part of our body. Its function depends on millions of connections between neurons, all of which must form correctly during development. Furthermore, each neuron must select a neurotransmitter with which to talk to its target neuron. A neurotransmitter is a chemical released from a neuron, which passes a signal to a target cell. Some neurotransmitters cause excitation of the target cell, others inhibition. Each neurotransmitter signals to the target c ....The nervous system is the single most complex part of our body. Its function depends on millions of connections between neurons, all of which must form correctly during development. Furthermore, each neuron must select a neurotransmitter with which to talk to its target neuron. A neurotransmitter is a chemical released from a neuron, which passes a signal to a target cell. Some neurotransmitters cause excitation of the target cell, others inhibition. Each neurotransmitter signals to the target cell via receptor molecule, matched to the neurotransmitter. Thus, a neuron is faced not only with making choices about what connections to make within the developing brain, but also it must select from a range of potential neurotransmitters and receptor molecules. We are interested in how neurons select the appropriate neurotransmitter. There are a number of ways that a neuron might be guided to the correct choice. It is possible that it could receive from the target cell a signal that guides the choice of neurotransmitter. We wish to examine this hypothesis to see if it is applicable to the autonomic nervous system, that part of the nervous system that controls functions like changes in blood pressure and heart rate. Our laboratory is expert in identifying the chemistry of autonomic neurons. We will use this knowledge to see what happens when we deliberately perturb the normal connections of autonomic neurons. Do they persist in expressing the neurotransmitters they would have done prior to the perturbation? Alternatively, do they adapt to the change of target via a signal received from the new target cell and express the appropriate phenotype? The results of these experiments will give insights into how the brain develops. The results will be important for both our basic understanding of biology and as a basis for the development of techniques for reversing neuronal damage.Read moreRead less
Convergent Regulation Of Sympathetic Neuronal Excitability By Peptide Hormones And Transmitters
Funder
National Health and Medical Research Council
Funding Amount
$498,465.00
Summary
This project will examine how hormones involved in regulating blood pressure interact with the nerves that control blood flow to the gut. We will combine electrical recordings of the activity of single nerve cells with an innovative new method of optically tracking the movements of single molecules, including hormons and neuronal messengers, that send signals to the nerve cells. Our results will reveal how blood pressure is normally maintained at healthy levels, even if we are ill.
The Development Of Glial Cells In The Sympathetic Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$372,025.00
Summary
Nervous system development entails the co-ordinated multiplication of a small number of founder cells to give the millions of cells of the mature nervous system. Each founder generates a many different cell types. Understanding how this is controlled is among the most challenging problems in modern biology. We will show how the development of the two basic cell types (neurons and glia), is controlled in a part of the nervous system that is relatively simple and accessible for manipulation.
Although the heart contracts spontaneously, the rate and force with which it beats may be modified by the autonomic nervous system. That is, the rate and force of heart muscle contraction may be increased or decreased by the activation of two different sets of nerves. This project will determine how the autonomic nervous system modifies the strength of heart muscle contraction. It will involve the measurement of changes in contractile force, electrical activity and calcium levels within cardiac ....Although the heart contracts spontaneously, the rate and force with which it beats may be modified by the autonomic nervous system. That is, the rate and force of heart muscle contraction may be increased or decreased by the activation of two different sets of nerves. This project will determine how the autonomic nervous system modifies the strength of heart muscle contraction. It will involve the measurement of changes in contractile force, electrical activity and calcium levels within cardiac cells during muscle contraction. The effects of excitatory and inhibitory nerve stimulation on these three parameters will be examined. Results of this study will improve our understanding of how the contraction of heart muscle is controlled and provide an insight into the treatment of heart disease.Read moreRead less
Cardiac Sympathetic Nerve Activity: Understanding Normal Control And The Causes Of The Increase In Heart Failure
Funder
National Health and Medical Research Council
Funding Amount
$531,125.00
Summary
Heart failure is a condition in which the heart muscle becomes weak and is unable to pump sufficient blood around the body to provide adequate perfusion of the organs. This results in breathlessness, lethargy, fatigue, mental confusion and eventually death. At present the life expectancy of patients with heart failure is poor, with a 5 year survival of 25% in men and 38% in women. It is the only form of heart disease that is increasing, the reason being that thousands of patients who have surviv ....Heart failure is a condition in which the heart muscle becomes weak and is unable to pump sufficient blood around the body to provide adequate perfusion of the organs. This results in breathlessness, lethargy, fatigue, mental confusion and eventually death. At present the life expectancy of patients with heart failure is poor, with a 5 year survival of 25% in men and 38% in women. It is the only form of heart disease that is increasing, the reason being that thousands of patients who have survived heart attacks or had coronary bypass operations go on to develop heart failure. In heart failure there is a very large increase in the activity of the nerves that stimulate cardiac rate and contractility, the cardiac sympathetic nerves. This increase in activity is detrimental, higher levels of activity predict greater morbidity and a reduced life span. The mechanisms causing the increase in cardiac sympathetic nerve activity are unknown, but greater understanding is essential if new and improved treatments are to be developed for patients with heart failure. Only two groups in the world measure cardiac nerve activity in conscious animals, neither is studying heart failure. We therefore have a unique opportunity to investigate the factors that control the activity of the cardiac nerves in the healthy state and to establish the causes of the increase in activity in heart failure. In particular, we will investigate how reflex control mechanisms, circulating hormones that are increased in heart failure and specific mechanisms in the brain act to control cardiac nerve activity in the normal state and what changes in these mechanisms lead to the preferential increase in cardiac nerve activity in heart failure. These findings will provide a detailed understanding of the mechanisms controlling cardiac nerve activity in the normal healthy state and increased knowledge of the factors that lead to the preferential activation of the cardiac nerves in heart failure.Read moreRead less