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Investigation Of The Molecular Mechanisms Underlying Alpha Synuclein Function At The Presynapse
Funder
National Health and Medical Research Council
Funding Amount
$419,180.00
Summary
Parkinson’s Disease (PD) is a common brain disease affecting 7 million people worldwide. It is caused by the death of brain cells. ?-synuclein is a protein in that brain that is likely to contribute to the cell death in PD, but the normal role of the protein remains unknown. This study will investigate the function of ?-synuclein in maintaining normal healthy brain activity. In addition, this work will help us understand how normal brain processes are affected in diseases such as PD.
The Neuronal PIKfyve Complex Regulates Neurotransmission And Neurodegeneration
Funder
National Health and Medical Research Council
Funding Amount
$372,965.00
Summary
Neuronal communication is essential for the functioning of our bodies and mind. We have identified a novel pathway for the regulation of this process involving a little studied lipid, PI3,5P2. This lipid also appears to be important for neuronal survival. We will investigate the regulation and function of this lipid in neurons. The outcomes of this proposal will be an important step closer to understanding the processes underlying neuronal communication and neurodegeneration.
The neocortex is the region of the brain that underlies all cognitive functions. Mental disorders, such as schizophrenia, occur when the communication between nerve cells in the neocortex breaks down. We propose to make electrical measurements from the thin processes of neurons that receive input from widely separated neocortical areas to understand how areas of the neocortex are functionally interlinked, with the ultimate aim to identify how these processes are disturbed in mental disorders.
Impact Of Somatic Versus Dendritic Inhibition On Neuronal Output
Funder
National Health and Medical Research Council
Funding Amount
$1,047,686.00
Summary
The brain is made up of literally billions of neurons connected in complex networks. These neurons come in two primary flavors - excitatory and inhibitory - which work in balance. Too much excitation and the brain becomes epileptic, too much inhibitory and we go into a coma. This proposal focuses on the role of specific inhibitory cell types in regulating brain function, and has relevant to a range of neurological disorders from epilepsy, to schizophrenia to depression.
Persistent Firing In Cortical Interneurons: Mechanisms And Potential Anticonvulsant Role
Funder
National Health and Medical Research Council
Funding Amount
$520,552.00
Summary
The normal brain treads a fine line between too much electrical activity (epilepsy) and too little (sedation). We have discovered a class of brain cell that seems to behave like a sentinel, monitoring brain activity for signs of epilepsy. If a seizure occurs, this cell switches on an electrical brake that dampens excess activity. In this project we will study how this brake works and whether it really can inhibit seizures. Our research may lead to better treatments for epilepsy.
The Role Of Central And Peripheral Synaptic Activity In The Developmental Death Of Motoneurons.
Funder
National Health and Medical Research Council
Funding Amount
$463,145.00
Summary
Information processing in the nervous system relies on the effective communication between neurons and their target cells which make up our neuronal circuitry. At the centre of all this is the synapse, the specialized contact between a neuron and its target cell, be it another neuron in the brain or a target organ such as skeletal muscle. Our primary goal is to determine how the formation of synaptic connections during development regulates neuronal survival. In this proposal we have focussed on ....Information processing in the nervous system relies on the effective communication between neurons and their target cells which make up our neuronal circuitry. At the centre of all this is the synapse, the specialized contact between a neuron and its target cell, be it another neuron in the brain or a target organ such as skeletal muscle. Our primary goal is to determine how the formation of synaptic connections during development regulates neuronal survival. In this proposal we have focussed on the neuromotor system as it is a well characterised part of the nervous system. During development, 50% of motoneurons die at a time when they are making contact with skeletal muscle, and when contacts onto motoneurons by other neurons are being established. We believe that the formation of effective synaptic contacts onto motoneurons, as well as connections by motoneurons onto muscle are the key regulators of motoneuron survival. We are in a position to be able to address what regulates motoneuron death; as we have a number of mice which lack key molecules needed for the formation of specialisations that allow neuronal contacts to be made between motor neurons and their muscle, and with other neurons within the spinal cord. By examining the function of motoneurons, counting them and screening for molecular changes in these mice, we will be able to dissect out the mechanism of how a motoneurons' fate is determined during developmental motoneuron death. This research could help in developing strategies aimed at improving neuronal connections to improve neuronal viability. Our research will have important implications for our understanding about the basis of adult neuro-degenerative diseases, such as motor neuron disease and Alzheimer's, which are in part characterised by a molecular breakdown in neuronal connections that ultimately result in neuronal death.Read moreRead less
Neural Circuits For Odour-processing In The Rodent Piriform Cortex 'in Vivo'
Funder
National Health and Medical Research Council
Funding Amount
$488,817.00
Summary
We are studying the brain circuits that enable mammals to recognise odours. We will apply puffs of odorants to the nose of an anaesthetised mouse while measuring electrical signals in the odour-processing region of its cerebral cortex. Our work will answer fundamental questions about how the brain interprets sensory inputs in order to build a coherent picture of the world. This is basic research that will, in the longer term, shed light on the disturbances that occur during mental illness.
Excitability And Hyperexcitability Of Neural Circuits In The Rodent Piriform Cortex
Funder
National Health and Medical Research Council
Funding Amount
$371,807.00
Summary
We are studying the properties of neurons (nerve cells) and brain circuits that enable mammals to recognise and remember odours. Our experiments will focus on neurons in the odour-processing region of the cerebral cortex of mice. This work will answer fundamental questions about how the brain interprets sensory inputs in order to build a coherent picture of the external world. Our findings will also provide a deeper understanding of the causes of epilepsy, leading to improved treatments.
Absence epilepsy is the commonest form of idiopathic generalized epilepsy. It can lead to hundreds of seizures per day, and mainly affects children between the ages of four and eight. Its cause is in most cases unknown. In this study we will use a rat model of absence epilepsy to investigate the cellular basis of this disease. Preliminary work indicates that a particular protein - HCN1 - is reduced in the cortex of rats with absence epilepsy. This protein codes for a pore in the membrane of nerv ....Absence epilepsy is the commonest form of idiopathic generalized epilepsy. It can lead to hundreds of seizures per day, and mainly affects children between the ages of four and eight. Its cause is in most cases unknown. In this study we will use a rat model of absence epilepsy to investigate the cellular basis of this disease. Preliminary work indicates that a particular protein - HCN1 - is reduced in the cortex of rats with absence epilepsy. This protein codes for a pore in the membrane of nerve cells, which acts like a switch. We have preliminary evidence that in rats with absence epilepsy this switch does not work properly. We wish to investigate how this influences the activity of nerve cells in rats with absence epilepsy. Furthermore, as absence epilepsy is an inherited disease, we wish to track down the genetic basis of this disease. This will give us clues as to the cause of the disease in this rat model. This research will shed light on the potentially important role of the HCN1 protein in absence epilepsy, which may represent an potentially new therapeutic target for the development of drugs for the treatment of absence epilepsy.Read moreRead less
Sulfonadyn-based Dynamin I-specific Inhibitors And Epilepsy
Funder
National Health and Medical Research Council
Funding Amount
$835,291.00
Summary
Epilepsy affects 1% of people, yet 30% do not respond to anti-epileptic drugs (AEDs). Traditional drug discovery fails to improve this situation. Our team discovered dynamin as a new target for better AED design and our lead sulphonadyns reduces seizures in animals. We will design better sulfonadyns that can ultimately be used for clinical trials by designing the drugs away from its actions outside of neurons. If successful, this will accelerate new AED development with less side-effects.