Brain Angiotensin: Generation, Localisation And Physiological Function
Funder
National Health and Medical Research Council
Funding Amount
$209,250.00
Summary
The renin angiotensin system is one of the major homonal systems of the body that regulate the cardiovascular system and bodily salt and water balance. Drugs that inhibit the function of this system by reducing the blood level of the hormone angiotensin II or blocking the receptors at which it acts are in the forefront of treatment of high blood pressure and heart failure. It has been proposed that a separate brain renin angiotensin system exists that is not influenced by angiotensin II in the b ....The renin angiotensin system is one of the major homonal systems of the body that regulate the cardiovascular system and bodily salt and water balance. Drugs that inhibit the function of this system by reducing the blood level of the hormone angiotensin II or blocking the receptors at which it acts are in the forefront of treatment of high blood pressure and heart failure. It has been proposed that a separate brain renin angiotensin system exists that is not influenced by angiotensin II in the blood stream because of the blood-brain barrier. Strains of mice in which the genes that code for two components of this system - angiotensin converting enzyme (the enzyme responsible for generating angiotensin II) and angiotensinogen (the protein which gives rise to angiotensin II) provide excellent tools to elucidate this system in the brain. By studying these mice we will be able to determine whether angiotensin converting enzyme is necessary in the brain for foreming angiotensin II, and we will be able to determine the sites in the brain where authentic angiotensin peptides exist. We will also determine whether angiotensin II transmits information between neurons in the brain that play a role in control of the cardiovascular system and body fluid balance.Read moreRead less
Reinstating Emotion Perception After Brain Damage: An Experimental Approach
Funder
National Health and Medical Research Council
Funding Amount
$338,421.00
Summary
Many people with traumatic brain injury (TBI) cannot recognise emotions in others. This disrupts social behaviour leading to isolation and unemployment. In this project we determine whether: (1) selectively attending to a person's expression improves empathy and emotion recognition; (2) whether mimicking an expression improves recognition of the emotion and; (3) whether poor recognition of emotional tone of voice (prosody) and audiovisual displays is improved by focusing on voice or face alone.
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.
Dynamic Aspects Of Inhibitory Synaptic Transmission And Modulation By Neuroactive Drugs
Funder
National Health and Medical Research Council
Funding Amount
$370,500.00
Summary
Information moving through the brain is typically encoded as brief bursts of signals. These signals travel along the microscopic wiring that connect the brain's nerve cells into complex circuits. Information is encoded in the frequency of the signals within a burst, and the duration of each burst. This frequency-coded information is processed at the contact points between nerve cells (synapses). Almost all neuroactive drugs target synapses, where they alter information processing. Most of the in ....Information moving through the brain is typically encoded as brief bursts of signals. These signals travel along the microscopic wiring that connect the brain's nerve cells into complex circuits. Information is encoded in the frequency of the signals within a burst, and the duration of each burst. This frequency-coded information is processed at the contact points between nerve cells (synapses). Almost all neuroactive drugs target synapses, where they alter information processing. Most of the information about how neuroactive drugs work has been acquired from experiments performed under steady-state conditions. Typically, drugs are applied at a constant concentration and a synapse is stimulated at an unrealistically low frequency. The data obtained under these conditions are very useful, but tell only part of the story. For example, during an extended burst of signals, some neuroactive drugs may be displaced from their synaptic binding sites, reducing their effectiveness. In contrast, other drugs can only bind when synapses are active, and their effectiveness will increase during a burst of signals. For optimal drug design and delivery, it is important to understand how drugs work during bursts of activity. To date, the highly dynamic, non-equilibrium conditions encountered at central synapses have not been extensively studied. The central goal of this research proposal is to investigate the dynamic properties of synapses, and the drugs that modulate them. The results will provide insights into information processing in the brain, and will have significant implications for the development and targeting of clinically relevant neuropharmacological compounds.Read moreRead less
The Role Of Neuropeptides In The Acute And Long-term Effects Of MDMA, Methamphetamine And GHB
Funder
National Health and Medical Research Council
Funding Amount
$472,321.00
Summary
The widespread use of 'party drugs' (ecstasy, methamphetmaine and GHB) is a major health issue in Australia. We propose a novel hypothesis that key acute and long-term effects of these drugs may involve an action on the neuropeptide oxytocin. A number of experiments are planned to test this hypothesis. The findings from this project will be used to better understand and to explore novel treatments for people who suffer problems as a result of using these drugs.
Development Of Executive Functions In Children With Frontal Lobe Lesions
Funder
National Health and Medical Research Council
Funding Amount
$160,379.00
Summary
Executive functions (EF), refer to the ability to problem solve, think flexibly and in abstract terms and pay attention. EFs are essential for managing daily life activities. The frontal lobes of the brain are believed be important in coordinating EFs. In childhood, frontal areas are developing rapidly and damage may affect ongoing development due to impairments in a child's capacity to function normally within their environment, interfering with adaptive functions such as new learning and reaso ....Executive functions (EF), refer to the ability to problem solve, think flexibly and in abstract terms and pay attention. EFs are essential for managing daily life activities. The frontal lobes of the brain are believed be important in coordinating EFs. In childhood, frontal areas are developing rapidly and damage may affect ongoing development due to impairments in a child's capacity to function normally within their environment, interfering with adaptive functions such as new learning and reasoning. Executive dysfunction in children manifests as disorganisation, impulsivity, inattention and inappropriate behaviour. Such problems are often masked in early chilhood, due to highly structured environments and support of parents and care-givers in day-to-day activities. However, as children mature, expectations of indepence increase and executive deficits become more apparent (ie. child 'grows into' these problems). Appropriate treatment and management is dependent on (i) improvement in early identification of patients at risk for such sequelae; (ii) establishing long-term consequences of executive deficits to ongoing development. This research aims to advance our understanding of EFs and their development through childhood, both in healthy children and children with cerebral lesions to regions believed to subsume EFs(ie the frontal lobes). While anecdotal case data is available, to our knowledge, no other study has attempted to do this using a longitudinal group design. Specific predictions include; (i) Children with frontal lobe damage will perform more poorly on EF measures, in comparison to children with damage to other cerebral areas and healthy children; (ii) Children with frontal lobe damage will show increasing deficits on EF tasks over time, reflecting an inability to acquire executive skills in the expected time frame, when compared with children with localised damage to cerebral areas excluding the frontal lobes, and healthy children.Read moreRead less
Characterisation Of Substance P Antagonists As A Novel Therapeutic Intervention For Use In Traumatic Brain Injury
Funder
National Health and Medical Research Council
Funding Amount
$241,650.00
Summary
Traumatic brain injury (TBI) is responsible for more deaths in Australians under 45 years of age than any other cause. The economic and social cost of head injury to the community is enormous with billions of dollars spent each year on the management and rehabilitation of trauma patients. Despite the enormity of this public health problem, no effective treatment currently exists. A number of studies have demonstrated that much of the morbidity following TBI is associated with the development of ....Traumatic brain injury (TBI) is responsible for more deaths in Australians under 45 years of age than any other cause. The economic and social cost of head injury to the community is enormous with billions of dollars spent each year on the management and rehabilitation of trauma patients. Despite the enormity of this public health problem, no effective treatment currently exists. A number of studies have demonstrated that much of the morbidity following TBI is associated with the development of a secondary injury process that occurs between hours to days after the insult. This delayed progression of injury suggests that appropriate pharmacologic intervention can prevent, or at least attenuate, this secondary injury process with a resultant improvement in outcome. Over the past 15 years, a number of groups, including ours, have been investigating the secondary mechanisms associated with the development of functional deficits after TBI. Our previous studies have demonstrated that decline in brain free magnesium is associated with functional deficits after experimental brain injury, and that magnesium administration after injury can improve outcome. Magnesium is now on clinical trial as a pharmacologic intervention. Recent studies have suggested that magnesium decline facilitates neurogenic inflammation, which has been associated with oedema formation, oxidative damage and cell death. Although a number of neuropeptides have been implicated in this process, it is thought that substance P release is closely associated with these pathophysiological processes. Therefore, inhibiting neuropeptide release, or inhibiting substance P binding, may offer a novel therapeutic approach for the attenuation of oedema and development of neurologic deficits after TBI. This proposal will use a combined biochemical, pharmacologic and behavioural approach to characterise the role of neuropeptides in brain trauma, and attempt to develop a novel therapy for use in clinical trauma.Read moreRead less
The Role Of SPARC In Regeneration And Neurogenesis In The Central Nervous System.
Funder
National Health and Medical Research Council
Funding Amount
$324,870.00
Summary
Stroke is a leading cause of disability in the elderly. Although the brain has built-in mechanisms for repairing itself, these processes are slow and incomplete. We are investigating how these natural repair mechanisms work and how to stimulate them to improve recovery. Our initial results suggest that a protein called SPARC, which is involved in wound healing outside the nervous system, may be able to recruit new nerve cells and blood vessels to damaged brain tissue.
Molecular Definition Of Neural Pathways In The Embryo And Adult Mouse
Funder
National Health and Medical Research Council
Funding Amount
$401,000.00
Summary
It is our objective to gain insight into the role of the Stem Cell leukaemia (SCL) gene in the central nervous system (CNS). SCL is known to play a crucial role in blood cell development and if aberrantly expressed can lead to T-cell leukemia. Although we do know that SCL is expressed in the brain, its role in the CNS has not been addressed so far and it is of great interest to us to study its potential function in neural development. We have designed a series of experiment in mice to elucidate ....It is our objective to gain insight into the role of the Stem Cell leukaemia (SCL) gene in the central nervous system (CNS). SCL is known to play a crucial role in blood cell development and if aberrantly expressed can lead to T-cell leukemia. Although we do know that SCL is expressed in the brain, its role in the CNS has not been addressed so far and it is of great interest to us to study its potential function in neural development. We have designed a series of experiment in mice to elucidate the expression pattern of SCL in the CNS, to identify the phenotype of neural cells that express SCL in different regions of the mouse brain, and to ablate the SCL gene at different time points during life (during embryonic development, just after birth and during adulthood). These experiments will be performed in conditional transgenic mice that have unique and precisely defined genetic alteration and are generated by us specifically for our research on the SCL-gene. This genetic approach is used to define the neuroanatomical and molecular bases of SCL-function in the brain.Read moreRead less