Cellular Plasticity in the Brain: discovering molecular mechanisms controlling the production of neurons during brain development, function, ageing and disease. The program aims to understand the mechanisms regulating Brain Plasticity - this recently discovered property of the brain to respond to environmental stimuli, both physiological and pathological, by producing new functional neurons. Specifically, the program will discover how the brain's stem cells are stimulated to produce new neurons. ....Cellular Plasticity in the Brain: discovering molecular mechanisms controlling the production of neurons during brain development, function, ageing and disease. The program aims to understand the mechanisms regulating Brain Plasticity - this recently discovered property of the brain to respond to environmental stimuli, both physiological and pathological, by producing new functional neurons. Specifically, the program will discover how the brain's stem cells are stimulated to produce new neurons. This understanding will significantly expand our knowledge of how the brain develops, and how functions, like memory, are modulated by neuronal replacement. Discoveries will underpin the development of, in association with Australia's biotechnology sector, a new generation of therapeutics, which treat neurological diseases, like Stroke, by stimulating the production of functional neurons.Read moreRead less
The Rane And Spain Routes In The Brain: Functional Studies And Remediation In Dyslexia Subtypes.
Funder
National Health and Medical Research Council
Funding Amount
$374,426.00
Summary
According to a recent DEST report a disturbingly high number of Australian school children are failing to meet a minimum acceptable standard in literacy . Failure to reach these standards is associated with poorer outcomes in mental health and socioeconomic status, greater representation among the prison population and with failure to achieve to true ability. Further, failure to correct these problems may well result in transmission of the problems associated with failed literacy into the next g ....According to a recent DEST report a disturbingly high number of Australian school children are failing to meet a minimum acceptable standard in literacy . Failure to reach these standards is associated with poorer outcomes in mental health and socioeconomic status, greater representation among the prison population and with failure to achieve to true ability. Further, failure to correct these problems may well result in transmission of the problems associated with failed literacy into the next generation. Despite the obvious immense social and personal ramifications and cost, literacy instruction for adults continues to lack a theoretical and research based approach . It is plain that improving population literacy would have significant benefits and it is also plain that early detection, intervention and remediation is desirable. This project brings to bear on these important aims current expertise in the nature of reading, how children learn to read and why some have so much difficulty in doing so, and techniques for determining the neural substrates of the mechanisms involved in reading and learning to read. We will subdivide child readers on the basis of their ability to read words using the letter to sound route or dictionary look-up route. We will use magnetic resonance imaging and spectroscopy to examine which parts of the brain are disrupted and-or disconnected when ability to read in either of these two routes is poor. We will then remediate these poor readers using targetted remediation therapy and re-image them to see whether remediation has altered the way the brain reads.Read moreRead less
The Role Of Netrin-DCC In The Development Of The Corpus Callosum
Funder
National Health and Medical Research Council
Funding Amount
$512,065.00
Summary
During embryonic development neurons send out axons that connect to other target neurons within the brain. The proper connectivity of these axons is vital to brain function. The largest axon tract in the brain is called the corpus callosum and connects neurons in the left and right cerebral hemispheres. When the corpus callosum does not form, significant cognitive, motor and sensory deficits occur in patients. This condition, known as agenesis of the corpus callosum (ACC), is associated with ove ....During embryonic development neurons send out axons that connect to other target neurons within the brain. The proper connectivity of these axons is vital to brain function. The largest axon tract in the brain is called the corpus callosum and connects neurons in the left and right cerebral hemispheres. When the corpus callosum does not form, significant cognitive, motor and sensory deficits occur in patients. This condition, known as agenesis of the corpus callosum (ACC), is associated with over 50 different human congenital syndromes. Thus understanding how the genes and molecules involved in the formation of the corpus callosum function in normal development can provide the basis for our understanding of what goes wrong in ACC. In this proposal we will investigate the role of the axon guidance molecule Netrin1, and its receptor DCC, in development of the corpus callosum in both a mouse model and in humans with malformations of the corpus callosum. Although Netrin1-DCC signalling has traditionally been associated with mechanisms of axon guidance, we hypothesize that these molecules may play a different role, specifically in cellular adhesion and ultimately in the fusion of the two cerebral hemispheres, in a manner that allows the corpus callosum to form. A second role for Netrin1-DCC signalling may be in the guidance of these axons once the midline has fused correctly and we investigate this in Aim 2 of the proposal. Finally, we are collaborating with a paediatric neurologist at UCSF, who has identified several mutations in the DCC gene in patients with ACC. In Aim 3 we test whether these mutations disrupt the function of DCC in callosal axon pathfinding. Understanding how these genes function during development of the brain and how their function may be altered in ACC is crucial to providing a proper diagnosis and prognosis for these patients. Ultimately, understanding more about how these genes function could also lead to prevention of these disorders.Read moreRead less
The advantage of being magnocellular: the role of the dorsal visual stream in object identification. The primary benefit of this project is to basic science and tertiary teaching globally. Visual processing and how it activates attention and operates to guide actions and cognitive behaviour is fundamental to our understanding of life and brain evolution. In particular this new knowledge will further understanding of many cognitive symptoms associated with neurodevelopmental disorders and in the ....The advantage of being magnocellular: the role of the dorsal visual stream in object identification. The primary benefit of this project is to basic science and tertiary teaching globally. Visual processing and how it activates attention and operates to guide actions and cognitive behaviour is fundamental to our understanding of life and brain evolution. In particular this new knowledge will further understanding of many cognitive symptoms associated with neurodevelopmental disorders and in the future should lead to design of better educational technologies for such children. Similarly understanding of temporal sequencing of vision has commercial implications for design of bionic eyes and robotic vision processing.Read moreRead less
Mechanisms of fear learning and extinction in the mammalian brain. The brain is a remarkable machine that coordinates all aspects of our daily lives including the storage and retrieval of memories. Given that many age-related degenerative disorders are associated with marked changes in learning and memory it also has implications for Australia's National Research Priority 2 "Ageing well and ageing productively". This research aims to discover the basic mechanisms that underlie memory storage an ....Mechanisms of fear learning and extinction in the mammalian brain. The brain is a remarkable machine that coordinates all aspects of our daily lives including the storage and retrieval of memories. Given that many age-related degenerative disorders are associated with marked changes in learning and memory it also has implications for Australia's National Research Priority 2 "Ageing well and ageing productively". This research aims to discover the basic mechanisms that underlie memory storage and how these are modulated in an emotional context. It will also shed light on states such as anxiety, depression and post-traumatic stress, enhancing our ability to identify new therapeutic targets for such disorders.Read moreRead less
Blood-brain Barrier And White Matter Damage In The Immature Rat Brain Following Systemic Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$353,173.00
Summary
Clinical obstetric and paediatric studies have identified an association between intrauterine infection occurring around two thirds of the way through pregnancy, premature birth and a specific form of damage to the brain of the newborn. This damage mainly affects white matter tracts. These tracts are aggregations of nerve fibres that make the connections between different parts of the brain and may result in cerebral palsy or other neurological disorders. The association between maternal infecti ....Clinical obstetric and paediatric studies have identified an association between intrauterine infection occurring around two thirds of the way through pregnancy, premature birth and a specific form of damage to the brain of the newborn. This damage mainly affects white matter tracts. These tracts are aggregations of nerve fibres that make the connections between different parts of the brain and may result in cerebral palsy or other neurological disorders. The association between maternal infection and brain damage, one form of which is cerebral palsy, is well established from clinical epidemiological studies, but the biological mechanism of this link is unknown. The CIs' group has recently shown that the condition can be reproduced in neonatal rats at a stage of brain development in the rat that is equivalent to the critical time in human brain development when infection may be associated with brain damage. The CIs' group has shown that an induced inflammatory state similar to a bacterial infection, results in damage to blood vessels in the white matter and is associated with changes in white matter, as occurs in affected babies. The purpose of this study is to understand the nature of the damage to white matter blood vessels and the mechanisms by which materials in blood, which in the normal brain do not pass from the blood to the brain across the blood-brain barrier, are able to do so via the inflammation damaged blood vessels. The study also aims to show whether it is components of the blood entering the brain via the damaged blood vessels that are responsible for the damage to white matter in the immature brain. The outcome should lead to development of ways to improve clinical care of women who acquire infections during pregnancy.Read moreRead less
Targeting Central Inflammation To Combat Obesity And Obesity-related Cognitive Dysfunction
Funder
National Health and Medical Research Council
Funding Amount
$470,144.00
Summary
The current obesity epidemic means many of us will suffer from overweight or obesity for at least some of our lives. My findings show obesity can cause inflammation throughout the brain including in regions related to learning and memory. Here I hypothesize that obesity induces long-term changes in the brain’s immune cells, that this can explain why we see susceptibility to cognitive decline in obese individuals, and that we can reverse these negative effects by targeting these immune cells.
The Role Of Reelin-signalling On Cortical Neuron Migration
Funder
National Health and Medical Research Council
Funding Amount
$716,196.00
Summary
Disorders that occur during brain development can lead to abnormal behaviours traits such as anxiety and altered social interactions, plus abnormalities in neuronal function and information processing. The region of the brain responsible for originating the motor, sensory and cognitive functions of a human is the cortex. This brain region is comprised of two major types of neurons that are arranged in a highly organized manner. One captivating aspect of the brain is that during early stages of d ....Disorders that occur during brain development can lead to abnormal behaviours traits such as anxiety and altered social interactions, plus abnormalities in neuronal function and information processing. The region of the brain responsible for originating the motor, sensory and cognitive functions of a human is the cortex. This brain region is comprised of two major types of neurons that are arranged in a highly organized manner. One captivating aspect of the brain is that during early stages of development neurons are generated in one part of the brain and migrate great distances to a final destination. It is therefore necessary during development to have a well-orchestrated, controlled series of events that lead to the correct positioning and association of neurons. The precise functions of many gene products involved in this process are not known. One major advancement in the development of the cortex is the discovery of the protein Reelin which is found in the outermost region of the developing cortex. Mutations in Reelin, in humans, have been implicated in the causation of schizophrenia and mood disorders. These disease states are the result of altered migration of neurons in the cortex. The research proposed in this application is designed to understand the precise process of how two types of neurons migrate and assemble in the cortex. Technology today allows us to visualize, in culture, neurons as they migrate in real-time. This is referred to real time-lapse imaging and allows the researcher the ability to examine how external factors, affect migration of cortical neurons. We will determine how Reelin is involved in this process and our research will elucidate the fundamental process of cortical brain development.Read moreRead less
The role of the Supplementary Motor Area in time processing. The neural bases of timing mechanisms (0.1-100s range) are the subject of much debate. We hypothesise that the Supplementary Motor Area (SMA), a major cortical structure involving important dopaminergic pathways, subtends duration encoding, in the way depicted by the 'accumulator model'. Using transcranial magnetic stimulation (TMS) over the SMA, we will test healthy subjects in motor and perceptual timing tasks, compared to Parkinson' ....The role of the Supplementary Motor Area in time processing. The neural bases of timing mechanisms (0.1-100s range) are the subject of much debate. We hypothesise that the Supplementary Motor Area (SMA), a major cortical structure involving important dopaminergic pathways, subtends duration encoding, in the way depicted by the 'accumulator model'. Using transcranial magnetic stimulation (TMS) over the SMA, we will test healthy subjects in motor and perceptual timing tasks, compared to Parkinson's disease patients whose timing performance is impaired due to dopaminergic dysfunction. We expect TMS inhibitory effects to induce predictable performance trends, providing support for the accumulator model and the key role of the SMA in timing.Read moreRead less