Role Of The Hypothalamus, Oxidative Stress And Angiotensin In Chronic Stress
Funder
National Health and Medical Research Council
Funding Amount
$535,333.00
Summary
Stress can trigger life threatening cardiovascular events and its impact is much greater when blood pressure is raised. We seek to determine which chemical type of brain neuron and which region is responsible for amplifying the responses to repeated stress in an animal model that closely resembles the human form of the disease. We will focus specifically on the hypothalamus which controls the sympathetic nervous system.
Investigations Of Neural Pathways For Heat Loss And Heat Gain In Thermoregulation And Fever
Funder
National Health and Medical Research Council
Funding Amount
$349,486.00
Summary
This project aims to map the nerve pathways in the brain that participate in the regulation of body temperature in the laboratory rat. The area of the brain that will be studied is the hypothalamic region. We will determine how this region influences the constriction of blood vessels in the skin to reduce heat loss when an animal is exposed to a cool environment, or when it exhibits a fever in response to a bacterial infection. As well, we will compare the nervous pathway that controls the gener ....This project aims to map the nerve pathways in the brain that participate in the regulation of body temperature in the laboratory rat. The area of the brain that will be studied is the hypothalamic region. We will determine how this region influences the constriction of blood vessels in the skin to reduce heat loss when an animal is exposed to a cool environment, or when it exhibits a fever in response to a bacterial infection. As well, we will compare the nervous pathway that controls the generation of heat from fat tissue in response to cold or fever with those controlling blood flow to the skin. These nervous pathways may be critical for maintaining correct body temperature during general anaesthesia, infections or in the aged subjected to temperature extremes. Thus, they are of importance in the health and well-being of much of the population.Read moreRead less
Forebrain Neuroadaptations To Chronic Morphine Treatment
Funder
National Health and Medical Research Council
Funding Amount
$435,956.00
Summary
Drug addiction is caused by long term changes in brain areas that normally produce the drives that sustain normal behaviours such as eating, drinking and sex. Addictive drugs effectively hijack these brain areas so that behaviours relating to drug taking become associated with feeling good. In some individuals, over time the pattern of drug taking becomes compulsive and no longer can be controlled. This transition is now known to be due to drugs causing physical changes to certain groups of nerv ....Drug addiction is caused by long term changes in brain areas that normally produce the drives that sustain normal behaviours such as eating, drinking and sex. Addictive drugs effectively hijack these brain areas so that behaviours relating to drug taking become associated with feeling good. In some individuals, over time the pattern of drug taking becomes compulsive and no longer can be controlled. This transition is now known to be due to drugs causing physical changes to certain groups of nerve cells in the brain. The affected nerve cells are responsible for causing new behaviours that appear once addiction is established. Addiction is not exclusive to humans. Animals will self-inject the same addictive drugs that humans use, and show many other kinds of addictive behaviours that parallel aspects of human addiction. Studying the effects of addictive drugs on rats and other animals has been very important in working out where and how drugs work. We now have a very good idea of which parts of the brain are affected by drugs, and it turns out that most addictive drugs act in the same places. We also now know for all of the major drugs, exactly which parts of nerve cells they affect. However, this turns out to be only the first step as the nerve cells that directly respond to drugs can affect other whole networks of nerve cells. This study is going to look at how morphine, a drug that is related to heroin, affects nerve cells in a part of the brain that helps cause addiction. It is going to work out which of the many pathways in this brain region are affected by morphine treatments that cause addiction in rats. It will then see what is happening to single nerve cells in the affected pathways. If we can understand more about these processes it may become possible to come up with new ways to treat addiction. We will also understand much more about the production of powerful emotional and behavioural drives so many of us find hard to control.Read moreRead less
Role Of SOCS 3 In Regulating Oligodendroglial Phenotype In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$419,187.00
Summary
The response of nerve cells, known as oligodendrocytes, to an inflammatory insult dictates the severity of demyelinating diseases such as multiple sclerosis (MS). We have previously discovered that a key protein in this response is the cytokine leukaemia inhibitory factor (LIF) which, by activating the LIF receptor expressed on these cells, limits their death and reduces the clinical impact on animal models of MS. However, the therapeutic benefit of LIF is incomplete and we do not completely und ....The response of nerve cells, known as oligodendrocytes, to an inflammatory insult dictates the severity of demyelinating diseases such as multiple sclerosis (MS). We have previously discovered that a key protein in this response is the cytokine leukaemia inhibitory factor (LIF) which, by activating the LIF receptor expressed on these cells, limits their death and reduces the clinical impact on animal models of MS. However, the therapeutic benefit of LIF is incomplete and we do not completely understand the mechanisms by which LIF exerts these effects. To maximise the treatment potential of LIF we need to understand how LIF receptor signaling is modulated in the nervous system. An important protein known to regulate the activity of LIF and of other cytokines in other organs of the body is the suppressor of cytokine signaling 3 (SOCS 3) molecule. We have recently shown that the expression of SOCS 3 is increased in an animal model of MS, indicating that it is likely to modulate the activity of LIF in this context. We plan to investigate the nature of this regulation. SOCS 3 might limit the efficacy of LIF but it could also limit the deleterious effect of unbridled LIF receptor signaling. To distinguish between these possibilities, we plan to study the impact of demyelinating disease in animals in which SOCS 3 is either deleted or overexpressed in oligodendrocytes. In this way, we should be able to learn how to optimise the therapeutic potential of LIF in MS and related nervous system diseases.Read moreRead less
Brain Pathways For Neurally-mediated Fever: From Vagal Afferent To Sympathetic Output To Brown Adipose Tissue Via Brain
Funder
National Health and Medical Research Council
Funding Amount
$405,223.00
Summary
Fever is one of the immune defence reactions to the invasion of microorganisms such as bacteria and viruses. Fever reflects increased heat production and decreased heat loss. Systems regulating heat production and heat loss are under brain control. To trigger fever, the immune system must alert the brain to the presence of infection. The general view of how the alerting system triggers fever is that it develops in sequential steps. Macrophages ingest microorganisms, and then regulatory proteins ....Fever is one of the immune defence reactions to the invasion of microorganisms such as bacteria and viruses. Fever reflects increased heat production and decreased heat loss. Systems regulating heat production and heat loss are under brain control. To trigger fever, the immune system must alert the brain to the presence of infection. The general view of how the alerting system triggers fever is that it develops in sequential steps. Macrophages ingest microorganisms, and then regulatory proteins (cytokines) are released. The cytokines enter the blood stream and are transported to the brain. Recently, the existence of another signalling pathway has been demonstrated. The pathway is via a special peripheral sensory nerve, the abdominal vagal sensory nerve. However, special neural pathways in the brain have not yet been clarified, even though several neural relay stations have been proposed. To elucidate neural pathways transmitting information of infection to the brain, both input and output of the pathway need to be specified. Specific outputs other than body temperature have not been determined, so far. I have recently developed a new reflex model, in which I focus on sympathetic nerves supplying the specialised fat tissue as an output as well as the vagus sensory nerve as an input. The fat tissue, brown adipose tissue (BAT), generates heat. When the vagus sensory nerve is stimulated electrically, BAT sympathetic nerve is activated. We were very exited when we discovered the potency of the combination in our rat model. We are now ready to elucidate brain pathways for neurally-mediated fever, using our new reflex model. Signalling to the brain via the nervous system is faster than via the blood stream, and thus must be very important for the earliest phase of fever. Understanding the neural pathways by which the brain perceives peripheral infection and triggers fever may promote beneficial aspects of the acute-phase immune reaction.Read moreRead less
Investigation Of A Novel Sympathetic Vasomotor Pathway
Funder
National Health and Medical Research Council
Funding Amount
$354,586.00
Summary
Blood pressure is regulated by sympathetic nerves to the heart and blood vessels, and it is believed that overactive sympathetic nerves contribute to many cases of hypertension. Overactive sympathetic nerves also contribute to, and worsen the disease process, in heart failure as well as other cardiovascular diseases. The regulation of sympathetic nerves is thus central to the understanding and treatment of cardiovascular disorders. The present proposal is specifically relevant to the hypertensio ....Blood pressure is regulated by sympathetic nerves to the heart and blood vessels, and it is believed that overactive sympathetic nerves contribute to many cases of hypertension. Overactive sympathetic nerves also contribute to, and worsen the disease process, in heart failure as well as other cardiovascular diseases. The regulation of sympathetic nerves is thus central to the understanding and treatment of cardiovascular disorders. The present proposal is specifically relevant to the hypertension which accompanies airway obstruction during sleep (obstructive sleep apnoea - OSA). We plan to study a novel class of sympathetic nerves ('accessory' sympathetic nerves), which are likely to be centrally involved in the hypertension of OSA, and probably also other conditions where sympathetic nerve activity is pathologically raised. 'Accessory' sympathetic nerves can cause a long-lasting amplification of the activity in the 'regular' sympathetic nerve pathway, enhancing its actions on the heart and blood vessels. The brain pathways that drive 'accessory' sympathetic nerves are essentially unknown. We seek to find out those pathways, study how they amplify the activity in the 'regular' pathway and explore their significance in an animal model of OSA. The outcomes of this study will be first, essential basic knowledge of a novel, but probably important, mechanism whereby the brain controls the cardiovascular system in health and disease. Second, the relevance of that mechanism to a specific type of neurogenic hypertension will have been defined.Read moreRead less
THE AUTONOMIC, SOMATIC AND CENTRAL NEURAL RESPONSES TO DEEP AND SUPERFICIAL PAIN IN HUMAN SUBJECTS
Funder
National Health and Medical Research Council
Funding Amount
$375,750.00
Summary
Pain is a subjective experience, the intensity of which can be readily influenced by personal experience. Despite this, pain originating from a particular part of the body will usually be described by all individuals as having similar character. For example, pain arising from the skin is commonly described as being sharp or burning and is usually easy to localise, whereas pain arising from muscle is commonly dull, throbbing and diffuse. In addition to producing sensory changes, pain also evokes ....Pain is a subjective experience, the intensity of which can be readily influenced by personal experience. Despite this, pain originating from a particular part of the body will usually be described by all individuals as having similar character. For example, pain arising from the skin is commonly described as being sharp or burning and is usually easy to localise, whereas pain arising from muscle is commonly dull, throbbing and diffuse. In addition to producing sensory changes, pain also evokes changes in blood pressure, heart rate and motor activity (often in an attempt to remove the source of the pain). The proposed research aims to characterise the cardiovascular and motor patterns associated with pain originating in skin and in muscle and to examine the brain regions that produce these changes. More specifically, microelectrodes will be used to investigate changes in peripheral nerve activity during transient painful skin and muscle events in awake human subjects. In a separate investigation functional magnetic resonance imaging will be used to determine brain sites that are activated by skin or muscle pain.Read moreRead less
Mechanisms Behind The Activation Of Cardiac And Renal Sympathetic Nerve Activity In Heart Failure
Funder
National Health and Medical Research Council
Funding Amount
$452,670.00
Summary
Heart failure is associated with an increase in messages from the brain that control how fast the heart beats but the factors involved remain poorly understood. This project will enable a better understanding ot the mechanisms controlling this increase in the activity of the nerves. This understanding will provide a new avenue for therapy and for the development of new treatments.
Nerve pathways exist that carry information from the highest parts of the brain to the peripheral hearing organ, the inner ear. These descending control pathways have the potential to affect the hearing process in a number of ways; protecting from loud sounds, improving the detection of signals in noisy backgrounds, selecting stimuli of interest and regulating a variety of aspects of inner ear function. Abnormal function of these pathways can affect hearing sensitivity and may be important in ph ....Nerve pathways exist that carry information from the highest parts of the brain to the peripheral hearing organ, the inner ear. These descending control pathways have the potential to affect the hearing process in a number of ways; protecting from loud sounds, improving the detection of signals in noisy backgrounds, selecting stimuli of interest and regulating a variety of aspects of inner ear function. Abnormal function of these pathways can affect hearing sensitivity and may be important in phenomena such as tinnitus and other disorders of hearing. This project will investigate the subtle effects that selective activation of these pathways has on inner ear function and will attempt to unravel the different influences that subcomponents of the pathways have on the different aspects of hearing.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