Very little is known about mechanisms whereby depression harms the heart. This is especially disturbing as recent evidence indicates that while antidepressants alleviate a depressed persons negative mood, they do not eliminate danger to the heart. We will use an animal model to determine: How depression affects the electrical stability of the heart; The identity of the brain mechanisms that are involved; and which drugs can be used to protect the heart fro the harmful effects of depression.
What Central Mechanisms Increase Cardiac Sympathetic Nerve Activity In Heart Failure?
Funder
National Health and Medical Research Council
Funding Amount
$401,389.00
Summary
Heart failure is a disabling and deadly syndrome that has reached epidemic proportions in western populations. In heart failure, the activity of the sympathetic nerves to the heart is dramatically increased, leading to development of arrhythmias and sudden death. Using our unique model of heart failure, in which we directly record cardiac sympathetic nerve activity, we aim to determine the mechanisms in the brain that cause this large, detrimental increase in nerve activity.
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
Distribution, Pharmacology, Molecular Identity And Roles Of Purine Receptors In Enteric Neurons
Funder
National Health and Medical Research Council
Funding Amount
$395,250.00
Summary
Digestive function needs to be adapted to the great variety of foods that we eat, and to our variable dietary habits. Adaptation is controlled through an extensive nervous system in the wall of the gastrointestinal tract, the enteric nervous system, and through digestive system hormones. The enteric nervous system detects the volume and key chemical components in the gastrointestinal lumen and, through an integrating nerve circuitry, causes changes in the patterns of movement, fluid secretion an ....Digestive function needs to be adapted to the great variety of foods that we eat, and to our variable dietary habits. Adaptation is controlled through an extensive nervous system in the wall of the gastrointestinal tract, the enteric nervous system, and through digestive system hormones. The enteric nervous system detects the volume and key chemical components in the gastrointestinal lumen and, through an integrating nerve circuitry, causes changes in the patterns of movement, fluid secretion and local blood flow. Digestive system diseases, for example irritable bowel syndrome, can involve disordered function of the enteric nervous system, and there is considerable research and development focus to identify drug targets in the enteric nervous system that can be used in therapy. Amongst potential targets are receptors for purines that are located on enteric neurons and are one of the important classes of receptor that is involved in communication between the neurons. These studies aim to identify the purine receptors, their roles in controlling digestive function and their potential as therapeutic targets in the treatment of digestive disease.Read moreRead less
Changes In Pelvic Autonomic Neurons After Spinal Nerve Injury
Funder
National Health and Medical Research Council
Funding Amount
$176,734.00
Summary
This project is about the effects of spinal injury on autonomic neurons that control the bladder, lower bowel and reproductive organs. One of the consequences of some types of spinal injury is that there are no signals being sent from the spinal cord to the nerve cells outside the cord, and this leads to poor bladder control, impotence, etc. We are mimicking this problem experimentally by damaging the spinal nerves that carry these signals. We have found that after this type of damage the pelvic ....This project is about the effects of spinal injury on autonomic neurons that control the bladder, lower bowel and reproductive organs. One of the consequences of some types of spinal injury is that there are no signals being sent from the spinal cord to the nerve cells outside the cord, and this leads to poor bladder control, impotence, etc. We are mimicking this problem experimentally by damaging the spinal nerves that carry these signals. We have found that after this type of damage the pelvic autonomic neurons make many new connections between each other, and the types of new connections depend on which spinal nerves have been injured. This leads to the question: are these new connections good or bad? ie are they helpful in trying to get organ control back to normal or will they stop the correct connections from the spinal cord from being made in the future? This project addresses these questions by using sophisticated techniques for staining and visualising individual nerve fibres growing out from the spinal cord. We will track how well these fibres grow back and connect with the pelvic autonomic neurons. In particular, we will see whether they make correct connections, and if these connections are influenced by the new fibres that have grown between the autonomic neurons in the interim period. We will also do physiological tests to see if the new connections have the correct function. The ultimate aim of these studies is not only to understand more about regeneration, but to see what determines whether the correct connections have been made - and ideally, to give us insight into how we can make regeneration work more quickly and accurately. We believe that this work is an important adjunct to other studies on spinal injury, which mostly focuses on regaining voluntary motor control (e.g. walking); however loss of bladder, bowel and reproductive function is another important quality of life issue for spinal injury patients.Read moreRead less
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
The sphincter of Oddi is a valve-like structure, which regulates the flow of bile and pancreatic juice into the gut. The sphincter of Oddi is under complex control involving nerves and hormones. We know that abnormal sphincter of Oddi function (sphincter of Oddi dysfunction) is associated with a number of human diseases including acute pancreatitis. We are able to recognise abnormal sphincter activity, but we do not know what causes it. One possible reason may be that the nerves going to the sph ....The sphincter of Oddi is a valve-like structure, which regulates the flow of bile and pancreatic juice into the gut. The sphincter of Oddi is under complex control involving nerves and hormones. We know that abnormal sphincter of Oddi function (sphincter of Oddi dysfunction) is associated with a number of human diseases including acute pancreatitis. We are able to recognise abnormal sphincter activity, but we do not know what causes it. One possible reason may be that the nerves going to the sphincter along the bile duct (which carries bile from the liver and gallbladder) may be damaged due to the passage of gallstones or during surgery on the bile ducts or gallbladder. We know that the main bile duct is able to sense pressure changes within and communicate this information (via nerves) to the sphincter which inturn alters its activity to relieve the pressure. Where these nerves are located and the chemical messages they use, are unknown. The aim of this project is to gain some of this information. This knowledge may allow us to design different surgical procedures or develop drugs to prevent or manage the abnormal sphincter of Oddi.Read moreRead less
Neurotransmission In Functionally Distinct Vasodilator Pathways
Funder
National Health and Medical Research Council
Funding Amount
$809,934.00
Summary
A surprising feature of our body is that there is not enough blood to fully supply all our organs at once. This is why we sometimes faint when we are hot or get cramps when we are exercising. Consequently, the blood vessels change their diameter so that blood can be directed to the organs with greatest demand at any particular time. For example, if the vessel decreases in diameter, less blood flows through it, but if it increases in diameter, more blood flows through it to reach the appropriate ....A surprising feature of our body is that there is not enough blood to fully supply all our organs at once. This is why we sometimes faint when we are hot or get cramps when we are exercising. Consequently, the blood vessels change their diameter so that blood can be directed to the organs with greatest demand at any particular time. For example, if the vessel decreases in diameter, less blood flows through it, but if it increases in diameter, more blood flows through it to reach the appropriate organ. An important function of the nervous system is to control the flow of blood to different organs by changing the diameters of the blood vessels. One set of nerves decreases the diameter of the arteries, and another set of nerves increases the diameter. The nerves do this by releasing special combinations of chemicals when they get a message from the brain to do so. In this project we are especially interested in the nerves which increase blood flow to organs in the head and the pelvis. We will use a wide range of modern methods to find out how these nerves work. In some experiments, we will use sophisticated electrical equipment to measure just how the nerve cells controlling the diameter of the vessels respond to the instructions sent by the brain. In other experiments, we will find out which chemicals the nerves use to make the blood vessels increase in diameter. We also will discover how the various chemicals get released by the nerves at the right times, so that messages from the brain get to the blood vessels as efficiently as possible. One of the special parts of our project is that we will be able to observe directly the connections between the nerve cells and the blood vessels we are studying. Our results will be important for designing new drugs that could help people whose nerves are not working properly, such as in some patients with diabetes or vascular disease.Read moreRead less
Morphological Determinants Of Neurotransmission In Autonomic Ganglia.
Funder
National Health and Medical Research Council
Funding Amount
$450,111.00
Summary
The nervous system consists of billions of nerve cells that are connected together in special ways to process information about the outside world and our internal state and then generate the appropriate responses of our body to this information. To understand the complex working of the brain and its nerves, we have to understand how all these nerves are connected to each other. We are interested in the nerves that control the functions of the internal organs, such as arteries, glands and the gut ....The nervous system consists of billions of nerve cells that are connected together in special ways to process information about the outside world and our internal state and then generate the appropriate responses of our body to this information. To understand the complex working of the brain and its nerves, we have to understand how all these nerves are connected to each other. We are interested in the nerves that control the functions of the internal organs, such as arteries, glands and the gut. The brain controls these functions automatically, so we usually are not directly aware of their activity. The instructions to change the activity of the internal organs are sent from the brain down the spinal cord. The information is then sent from the spinal cord to the organs via a special set of nerves. However, instead of going directly to their targets, these nerves make connections with yet another set of nerves, which then go on to make the final connections with the appropriate target organs. We know a lot about these final nerve cells, including how big they are, how complicated they look, and what kinds of chemicals they use to send messages to the organs that they control. However, we still do not very much about how all these nerves are connected to each other. In this project we will use different types of modern microscopes that use either lasers or electron beams to look directly at the nerves and their connections. We then will use computerised models to construct a detailed map of the pathways taken by the nerves on their way to their target organs. By knowing how the nerves are connected to each other in these pathways, we will be able to understand how the instructions of the brain are modified depending on what other things are going on in the body at the same time. This information will be vital to help us appreciate how the nerves work when we get sick or injured.Read moreRead less
Gastrointestinal Sensory Function In Normal And Diseased States
Funder
National Health and Medical Research Council
Funding Amount
$691,026.00
Summary
Chronic pain and discomfort from the digestive system is a major health care issue world-wide. There is currently no effective treatment for these problems, which often have no apparent organic cause. Lack of treatment is due to a lack of understanding about how sensations are transmitted from the digestive system to the brain. Our research group has unique and powerful techniques that allow us to probe the basic mechanisms of sensory function, and make rapid progress towards finding drugs that ....Chronic pain and discomfort from the digestive system is a major health care issue world-wide. There is currently no effective treatment for these problems, which often have no apparent organic cause. Lack of treatment is due to a lack of understanding about how sensations are transmitted from the digestive system to the brain. Our research group has unique and powerful techniques that allow us to probe the basic mechanisms of sensory function, and make rapid progress towards finding drugs that reduce specific types of sensory signals from the gut. We shall investigate sensory mechanisms in the upper and lower regions of the gut, where symptoms are most prevalent in diseases such as non-cardiac chest pain, functional dyspepsia and irritable bowel syndrome. Six aspects of sensory nerve endings in the gut are to be investigated: 1. The grouping of endings into functional classes (similar to touch or pressure receptors in skin) 2. How endings respond to chemicals and hormones found in the gut 3. How currently available drugs may be useful in reducing sensitivity 4. The mechanisms by which inflammation affects sensitivity 5. How nerve growth factors may trigger changes in sensitivity 6. How pores or channels in nerve endings determine their functionRead moreRead less