Wnt Signaling In Dopaminergic Neuronal Connectivity
Funder
National Health and Medical Research Council
Funding Amount
$387,489.00
Summary
During development, the brain establishes intricate and precise connections. In several brain pathways, little is known about the processes regulating this connectivity. Furthermore, it is likely that the same processes will be required to repair the injured- diseased brain. This project builds on our preliminary data, that Wnt proteins are important regulators of developing dopamine pathways, and has implications for dopamine disorders including Parkinson’s disease and addiction.
Influences Of Oestrogen On Neurodegeneration And Behaviours
Funder
National Health and Medical Research Council
Funding Amount
$620,352.00
Summary
More women develop Alzheimer's disease whereas more men develop Parkinson's disease. This study will try to understand whether sex hormones play a part in the devlopment of these diseases. This study will also try to answer how the female sex hormone, oestrogen, influences behaviour and or development of mental health problems such as depression and obsessive-compulsive disorder.
Wnt Signaling In Dopaminergic Neuronal Connectivity
Funder
National Health and Medical Research Council
Funding Amount
$564,721.00
Summary
A major obstacle in repairing the injured or diseased brain is inducing axons (nerve cell processes) to make the appropriate connections. This is especially true following cell replacement therapy (CRT) in Parkinson's disease (PD). We will examine the processes inducing axons in the dopamine pathways to grow. We hypothesize that Wnt signaling plays and important role and that therapeutic introduction of Wnt is required to repair the dopamine pathways following CRT in PD.
Chemical Neurobiology Of Ventral Mesencephalon: Mechanisms Underlying Neuronal Death In Parkinsonism.
Funder
National Health and Medical Research Council
Funding Amount
$286,830.00
Summary
Parkinson's disease (PD) is a neurodegenerative disease which has profound effects on the Australian community. It affects about 1% of individuals aged more than 50 years and approximately 50,000 Australians. Brain cells die over many years and eventually the loss is so bad from the parts of the brain that coordinate motor control that uncontrollable motor movements occur. The cause of the condition is unknown and although drugs can control the motor disorders for some 5 years, eventually increa ....Parkinson's disease (PD) is a neurodegenerative disease which has profound effects on the Australian community. It affects about 1% of individuals aged more than 50 years and approximately 50,000 Australians. Brain cells die over many years and eventually the loss is so bad from the parts of the brain that coordinate motor control that uncontrollable motor movements occur. The cause of the condition is unknown and although drugs can control the motor disorders for some 5 years, eventually increasing disability occurs and finally complete dependency. The condition has profound effects on the families of the sufferers and the Australian health care system. Clearly, it is most important to understand how brain cells die in this debilitating neurological condition because once this death mechanism is understood then strategies can be devised to protect at risk brain cells so that new drugs can be developed to prevent the onset and progression of the disease. Since post-mortem studies on human brain suggest that cells in Parkinson's disease die by a process of programmed cell death (i.e. an unknown stimulus gives the cells a message to die by an exact mechanism involving gene activation), we shall examine the involvement of this unique form of brain cell death and attempt to determine what factors initiate the process. By establishing experimental models where rat brain cells are cultured, we plan to test how multiple factors could start the death cascade and how possible treatments may be preventitive. These assessments will be performed by measuring cellular biochemistry and electrical activity. We also hope to examine how at risk brain cells can be rescued and stimulated to grow to re-establish normal brain circuits. Overall, the programme aims to understand the disease process such that new directions for its management will be revealed.Read moreRead less
Regulation Of Regeneration Of Dopaminergic Neurones In The Substantia Nigra
Funder
National Health and Medical Research Council
Funding Amount
$115,880.00
Summary
Parkinson's Disease (PD) results from the progressive loss of brain cells in the part of the brain called substantia nigra. These brain cells contain a chemical called Dopamine (DA). The symptoms of Parkinson's disease arise when about 80% these DA neurones are lost suggesting that some form of compensation must occur up to this point. In previous studies we have demonstrated that one mechanism for this compensation is through sprouting or branching of the remaining neurones. We have preliminary ....Parkinson's Disease (PD) results from the progressive loss of brain cells in the part of the brain called substantia nigra. These brain cells contain a chemical called Dopamine (DA). The symptoms of Parkinson's disease arise when about 80% these DA neurones are lost suggesting that some form of compensation must occur up to this point. In previous studies we have demonstrated that one mechanism for this compensation is through sprouting or branching of the remaining neurones. We have preliminary evidence about the way this is sprouting and regeneration is controlled. The aim of this grant is to explore in detail the mechanisms whereby sprouting is induced and regulated. The significance of this study is that it may provide insights into the way in which regulation of regeneration of the nervous system is controlled. It has specific applications to therapies for Parkinson's disease.Read moreRead less
By the time a patient first presents with symptoms of Parkinson's disease at the clinic, a large proportion (60-70%) of the cells in a specific part of the brain have been destroyed. This degeneration progresses until, within a few years, most of the cells have died. This project investigates the mechanisms involved in the continued death of cells and a possible new therapy that interrupts the progression. If the aims of this proposal are met, the drug could rapidly go to clinical trial.
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
Relationship Between Nigral Injury, Dopamine Handling And Dyskinesia In Parkinsonism
Funder
National Health and Medical Research Council
Funding Amount
$65,685.00
Summary
Parkinson's Disease is a disabling condition that results from loss of nerve cells (neurones) in the part of the brain known as the substantia nigra (SN). These neurones make dopamine. Symptoms become apparent when 80% of these neurones are gone, suggesting that compensation can occur in the brain. Dopamine can be replaced with the drug L-dopa. Unfortunately this benefit is not sustained and is frequently marred by the production of unpleasant writhing wriggling movements called dyskinesia. Thes ....Parkinson's Disease is a disabling condition that results from loss of nerve cells (neurones) in the part of the brain known as the substantia nigra (SN). These neurones make dopamine. Symptoms become apparent when 80% of these neurones are gone, suggesting that compensation can occur in the brain. Dopamine can be replaced with the drug L-dopa. Unfortunately this benefit is not sustained and is frequently marred by the production of unpleasant writhing wriggling movements called dyskinesia. These movements can also complicate the treatment for schizophrenia and other neurological conditions. The way the brain compensates for loss of SN neurones and why dyskinesia occur is unknown. However we present a hypothesis that the mechanisms for compensation also produce the dyskinesia. We have shown that an injury to the SN results in a compensatory response of vigorous sprouting of the surviving dopamine neurones. This sprouting may also explain why dyskinesias occur. The aim of this study is to establish whether the degree of compensatory response corresponds with the severity of dyskinesia and how this compensatory response can be modified or regulated.Read moreRead less
I am a practicing neurologist with a clinical interest in movement disorders and dementia with an international reputation in neurosciences in the fields of neural stem cells, transgenic animal models of movement disorders and epilepsy. In line with my cl