New Methods And Applications Of Vestibular Electrophysiology In Humans.
Funder
National Health and Medical Research Council
Funding Amount
$165,509.00
Summary
This project consists of a series of experiments and investigations using new methods to test the vestibular apparatus (balance organs). These receptors lie deep within the skull in the inner ear and disease of them can cause dizziness (vertigo) and unsteadiness. Due to their location, investigation of the function of these receptors has been difficult. With NH and MRC support, I have developed two new methods of vestibular assessment. These are now being applied both here and overseas. Perhaps ....This project consists of a series of experiments and investigations using new methods to test the vestibular apparatus (balance organs). These receptors lie deep within the skull in the inner ear and disease of them can cause dizziness (vertigo) and unsteadiness. Due to their location, investigation of the function of these receptors has been difficult. With NH and MRC support, I have developed two new methods of vestibular assessment. These are now being applied both here and overseas. Perhaps the clearest example of how these new techniques have improved current diagnostic methods is the Tullio phenomenon, in which patients feel dizzy in response to loud sounds. My colleagues and I have shown that these patients always have a characteristic abnormality to click activation of the inner ear, one of the tests that I developed. It is likely to have a very important role in distiguishing between patients with Xray abnormalities predisposing to this condition and those who actually have the full-blown syndrome, so that the correct treatment is offered. This proposal seeks to build on the previous successful one. In it, I propose further new methods of investigating the vestibular apparatus, which avoid some of the preconditions necessary for the present tests and would allow more widespread application of them. Furthermore, additional specific disease states which are characterised by unsteadiness (ataxia) will be assessed with these new methods to determine whether abnormal vestibular reflexes are partly responsible for the loss of balance. In one of the conditions to be investigated, gentamicin-induced vestibular impairment, there is the possibility in the future of applying these techniques to detect changes early, at a time when they are potentially reversible.Read moreRead less
Relaxin-3 Systems In Brain: Neurophysiology And Behaviour
Funder
National Health and Medical Research Council
Funding Amount
$287,321.00
Summary
The project aim is to better understand the function of a newly-discovered signalling molecule in the mammalian brain, know as relaxin-3. Recent research suggests that this chemical is vital for normal animal behaviour, such as arousal, stress, and learning and memory processes. This project will thoroughly characterise how this chemical modulates activity of brain regions that subserve behaviour in rats. This should reveal clinical implications of relaxin-3 in human behavioural disorders.
Synaptic Transmission In The Mammalian Central Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$460,500.00
Summary
In order to properly understand the complex functions of the brain and the abnormalities underlying neurological disorders, we must understand how individual neurons communicate with each other. Communication occurs at specialized contacts, or synapses. An individual neuron may receive tens of thousands of synaptic contacts from hundreds or thousands of other neurons. Despite intensive investigation, the processes which regulate synaptic strength between central neurons are poorly understood. Th ....In order to properly understand the complex functions of the brain and the abnormalities underlying neurological disorders, we must understand how individual neurons communicate with each other. Communication occurs at specialized contacts, or synapses. An individual neuron may receive tens of thousands of synaptic contacts from hundreds or thousands of other neurons. Despite intensive investigation, the processes which regulate synaptic strength between central neurons are poorly understood. The overall aim of this proposal is to understand the basic mechanisms underlying synaptic transmission at excitatory and inhibitory synaptic connections in the mammalian brain. We will investigate specific synaptic connections in the central pathways of the auditory system, because our previous studies have demonstrated a number of key technical advantages in studying these synapses. We will use electrophysiological recording from synaptic terminals and neurons in isolated living slices of the brainstem of mice. We will use imaging techniques and electron-microscopy to examine the structural details of synaptic connections, as structure is thought to play a major role in determining the strength of synaptic transmission. We will also study the structural and functional properties of auditory synaptic connections in congenitally deaf animals. Our recent study comparing normal and congenitally deaf mice has already revealed significant differences. Our results will provide important insights in the regulation of synaptic strength in the central nervous system, and into the regulation of synaptic transmission at central synapses which have developed under conditions of abnormal sensory activation.Read moreRead less
IDENTIFICATION OF BRAIN NEURONS INVOLVED IN THE CARDIOVASCULAR RESPONSE TO FEAR AND FLIGHT
Funder
National Health and Medical Research Council
Funding Amount
$400,247.00
Summary
The circulatory system of the body acts in concert with the respiratory system to distribute oxygenated blood to the brain and other organs and tissues of the body. Control of blood pressure and heart rate is achieved largely through the actions of the central nervous system on effector organs and tissues such as the heart and blood vessels. This control is exerted through the actions of nerves in the body which affect the rate and force of contraction of the heart and the diameter of blood vess ....The circulatory system of the body acts in concert with the respiratory system to distribute oxygenated blood to the brain and other organs and tissues of the body. Control of blood pressure and heart rate is achieved largely through the actions of the central nervous system on effector organs and tissues such as the heart and blood vessels. This control is exerted through the actions of nerves in the body which affect the rate and force of contraction of the heart and the diameter of blood vessels which restrict the flow of blood to the tissues. These nerves, in turn, are under the control of brain cells or neurons which are located in the brainstem. Blood pressure-controlling neurons, acting upon information they receive from pressure sensors in the major blood vessels in the chest cavity, can alter their activity so that blood pressure is maintained within normal limits. Our laboratory has been examining the properties of these blood pressure-controlling neurons by recording their minute electrical discharges and by studying other brain regions which are able to influence them. In this study, we will use newly-developed procedures which will allow us to identify the precise locations of these neurons in the brain, to study which neurotransmitters (chemicals released by neurons which are used to communicate with other neurons) they use, as well as to identify other regions of the brain they connect with and influence. The major significance of this work will be that new brain circuits which transmit information about the status of the cardiovascular system to other areas of the brain will be identified. Our understanding of, and the development of new treatments for, cardiovascular diseases such as high blood pressure and heart failure are critically dependent on advancing our understanding of the nervous system.Read moreRead less
Epilepsy is an important human disease because it causes physical trauma and sudden death in addition to immense social and economic hardship. The genetic basis of a number of epilepsy syndromes has been identified but the precise mechanism whereby mutations produce seizures is unknown. Several mutations in the alpha4 neuronal nicotinic receptor (a4 nAChR) gene have been identified in Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE). This is a rare form of inherited epilepsy character ....Epilepsy is an important human disease because it causes physical trauma and sudden death in addition to immense social and economic hardship. The genetic basis of a number of epilepsy syndromes has been identified but the precise mechanism whereby mutations produce seizures is unknown. Several mutations in the alpha4 neuronal nicotinic receptor (a4 nAChR) gene have been identified in Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE). This is a rare form of inherited epilepsy characterized by the presence of seizures during light sleep. In vitro studies using the human mutated DNA (i.e. DNA containing the genetic defect) have suggested that this mutation results in reduced activity of the receptor. Therefore a mouse in which this gene is destroyed would be relevant in understanding the human disease. We have generated an a4 nAChR knockout (KO) mouse and plan to use the mouse to test the idea that loss of function of the a4 nAChR in vivo is associated with enhanced seizure activity. The KO mice do not have unprovoked seizures but appear to have an increased number of major motor seizures in response to pentylenetetrazole, an agent which is known to cause seizures by blocking the effects of the brain inhibitory molecule GABA. Interestingly, a4 nAChRs are known to control the release of GABA. We therefore propose that our knockout mice have seizures because they tend to under produce GABA. We will also make and analyse a mouse line with the same genetic mutation as patients with ADNFLE. The experiments are aimed at understanding the way that seizures are generated and spread in the brain in these rare forms of epilepsy. The hope is that understanding these mechanisms will help us better understand and therefore treat common forms of epilepsy.Read moreRead less
Neuropathways And Synaptic Adaptations Underlying Drug Addiction In Central Dopamine Systems
Funder
National Health and Medical Research Council
Funding Amount
$184,812.00
Summary
There is a rising trend in addiction to drugs, such as opioids (heroin) and stimulants (methamphetamine and ecstasy). A key feature of this addiction is intensified craving for the drug with repeated use. A major brain component thought to mediate drug-craving is the dopamine (DA) neurotransmitter system, consisting of cells in the midbrain that project nerve terminals to forebrain structures involved in reward-based learning. DA cells undergo long-term depression (LTD) and potentiation (LTP) of ....There is a rising trend in addiction to drugs, such as opioids (heroin) and stimulants (methamphetamine and ecstasy). A key feature of this addiction is intensified craving for the drug with repeated use. A major brain component thought to mediate drug-craving is the dopamine (DA) neurotransmitter system, consisting of cells in the midbrain that project nerve terminals to forebrain structures involved in reward-based learning. DA cells undergo long-term depression (LTD) and potentiation (LTP) of synaptic strength when excitatory inputs to DA cells are stimulated. These findings are important to drug addiction as amphetamine has been shown to block LTD and enhance LTP in brain slices of DA cells. Thus, changes in LTD and LTP by illicit drugs may underlie the conditions necessary for expression of drug-induced behavioural sensitisation, the best-accepted model of drug-craving in human addiction. To date, these studies have all been conducted in brain slices. Therefore, the functional importance of this synaptic plasticity in midbrain DA cells has yet to be shown in terms of changes in DA release in forebrain terminals in the living animal. For the first time we will address this issue by recording DA cell firing activity together with DA release using a newly developed technique that permits DA release to be monitored in the living brain in 'real-time' (100,000 samples-sec). This will allow us to identify the origin (cortical excitatory inputs) and receptor mechanisms that mediate LTP and LTD in DA cells and their effects on DA release. Recording DA cell activity with real-time measurement of DA release will promote a new cutting-edge technology to the Australian Neurosciences. These data will provide 'first of its kind' evidence of the functional anatomy and receptor mechanisms underlying synaptic plasticity in DA neurons associated with repeated drug use and ultimately enhance our basic understanding of the neural mechanisms of human drug addiction.Read moreRead less
Parkinson's Disease is caused by injury to a group of brain cells called the Basal Ganglia. Our current ideas about how this part of the brain works is dominated by a well know theory. This theory requires that the output pathway of the basal ganglia to have a negative or inhibitory influence on its target. However there are numerous reasons why this would be unlikely, including some recent evidence from experiments in our laboratory. The purpose of this study is to undertake an extensive re exa ....Parkinson's Disease is caused by injury to a group of brain cells called the Basal Ganglia. Our current ideas about how this part of the brain works is dominated by a well know theory. This theory requires that the output pathway of the basal ganglia to have a negative or inhibitory influence on its target. However there are numerous reasons why this would be unlikely, including some recent evidence from experiments in our laboratory. The purpose of this study is to undertake an extensive re examination of the output paths of the Basal Ganglia. If our suspicions are correct, it will lead to a review of the whole way in which we think the Basal Ganglia works.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
The key to how the brain works lies in its capacity to modify the strength of its connections. During development, input to the brain from our sensory organs shapes the properties of synaptic contacts and target neurons. This project is aimed at understanding the pathways in the brain related to our sense of hearing, and discovering what is different about these pathways in congenital deafness, where the brain does not receive the appropriate signals during development.