A DENDRITIC SUBSTRATE FOR THE CHOLINERGIC CONTROL OF NEOCORTICAL OUTPUT
Funder
National Health and Medical Research Council
Funding Amount
$898,340.00
Summary
The forebrain cholinergic system controls neocortical activity and cognitive function. This project will investigate the mechanisms by which the cholinergic system controls neocortical circuit activity in rodent models using advanced optical and electrical recording methods. The results will provide a foundation for the understanding of how dysfunction of the cholinergic system results in cognitive decline in humans, and identify new targets for improved treatment of human cognitive impairment.
A Potential Analgesic Target In A Novel Clinically-relevant Neuropathic Pain Pathway.
Funder
National Health and Medical Research Council
Funding Amount
$685,811.00
Summary
Persistent pain arising from tissue damage, to nerves, muscles or joints for example, is devastating for patients and a huge social and economic burden. This work will investigate one of the pathways that goes awry after sensory nerves are damaged. These experiments will also test whether a drug being developed to treat Alzheimer's disease is effective at blocking the persistent nerve hypersensitivity that sometimes develops after injury.
The Role Of Presynaptic Inhibition In Neuropathic Pain
Funder
National Health and Medical Research Council
Funding Amount
$466,045.00
Summary
Inhibitory nerve cells in the spinal cord are thought to play an important role in governing the interaction between painful and non-painful stimuli. Defects in this process underlie allodynia, an important symptom of neuropathic pain. We will use recent advances in genetic techniques (optogenetics) to manipulate and study how inhibitory nerve cells separate touch and pain signalling in the spinal cord of normal and neuropathic animals.
Debilitating anxiety disorders, such as post-traumatic stress disorder or panic disorder, affect 14% of adult Australians and current therapy is often ineffective. The amygdala is a brain region that is key to learning fear responses but also in reducing our fear responses. This project will determine whether the brain’s own endogenous opioids can modify the activity of the amygdala in order to provide new leads for novel pharmacotherapies with enhanced efficacy.
Chronic pain is a debilitating syndrome caused by damage to tissue and the nervous system, arising from trauma and disease. It is poorly served by current drugs. To identify novel more effective therapies we propose to examine the mechanisms underlying this syndrome. We have identified a novel protein which is involved in synaptic plasticity. We will examine its role the development of chronic pain at the cellular level and how it might be exploited for the treatment of chronic pain.
Development Of Pthaladyn-based Dynamin I-selective Inhibitors For Treatment Of Epilepsy
Funder
National Health and Medical Research Council
Funding Amount
$564,310.00
Summary
About 1% of the World�s population suffers from epilepsy; 30% fail to respond to anti-epileptic drugs (AED). Current AED development pathways have changed little in the past 20 years with the majority of current AEDs dampening the release of crucial chemical signals 24/7. Our new drugs, which inhibit a protein called dynamin, are only recruited at the onset of a seizure. Our approach will significantly enhance the day to day lives of those afflicted by epilepsy.
Mechanisms And Consequences Of Cholinergic Signaling In Neocortical Pyramidal Neurons
Funder
National Health and Medical Research Council
Funding Amount
$258,000.00
Summary
Dementia, including Alzheimer s Disease, represents the second highest non-fatal disease burden in Australia. Modern theories suggest that cognitive deficits associated with disorders such as Alzheimer s Disease result in part from impairment of the action of the neurotransmitter acetylcholine. Despite the obvious importance of acetylcholine in brain function, there is currently a lack of basic knowledge regarding how this chemical works at the cellular level. We have recently discovered that ac ....Dementia, including Alzheimer s Disease, represents the second highest non-fatal disease burden in Australia. Modern theories suggest that cognitive deficits associated with disorders such as Alzheimer s Disease result in part from impairment of the action of the neurotransmitter acetylcholine. Despite the obvious importance of acetylcholine in brain function, there is currently a lack of basic knowledge regarding how this chemical works at the cellular level. We have recently discovered that acetylcholine produces opposing phasic and tonic actions on the excitability of brain cells in the cortex. The data collected in this study will reveal the receptor type, intracellular signalling pathways, and ionic mechanisms through which acetylcholine influences information processing in the brain. Together, these results will provide a framework for understanding the biological basis by which acetylcholine influences cognitive function. This new knowledge will in turn increase our understanding of why dysfunction of this important neurotransmitter system leads to the functional deficits observed in Alzheimer s Disease and other forms of dementia, and will hopefully suggest new targets for therapeutic intervention.Read moreRead less
Role Of Dynamin In Modes Of Synaptic Vesicle Endocytosis
Funder
National Health and Medical Research Council
Funding Amount
$905,985.00
Summary
Neurons communicate by neurotransmitter release from synaptic vesicles stored in nerve endings. There is a finite vesicle number, so they are recycled (endocytosis) by dynamin. Our aim is to reveal the molecular mechanisms underlying endocytosis to better understand diseases of the synapse like epilepsy. We propose that two forms of the dynamin gene mediate two forms of endocytosis, one of which is activated only under conditions of high neuronal firing, such as occurs during a seizure.
The Role Of Down Syndrome Candidate Region 1 (DSCR1) In Neurotransmitter Release, Vesicle Recycling And Down Syndrome.
Funder
National Health and Medical Research Council
Funding Amount
$352,318.00
Summary
Individuals with Down syndrome (DS) have three copies of human chromosome 21 (HSA21), rather than the normal two. The symptoms observed in DS individuals are therefore due to the overexpression of HSA21 genes. Since all individuals with DS develop symptoms in the brain similar to those see in Alzheimer's disease (AD), there may be a common mechanism that can be traced to the extra gene dosage from HSA21. We are interested in one of these genes, Down syndrome candidate region 1 (Dscr1), which is ....Individuals with Down syndrome (DS) have three copies of human chromosome 21 (HSA21), rather than the normal two. The symptoms observed in DS individuals are therefore due to the overexpression of HSA21 genes. Since all individuals with DS develop symptoms in the brain similar to those see in Alzheimer's disease (AD), there may be a common mechanism that can be traced to the extra gene dosage from HSA21. We are interested in one of these genes, Down syndrome candidate region 1 (Dscr1), which is overexpressed in both DS and AD brains. We hypothesise that Dscr1 has a role in regulating exocytosis, a process in which chemical messengers are released from cells. Exocytosis is highly specialised in the brain where neurotransmitters are released from neuronal synapses in a process known as synaptic transmission. Reduced synaptic transmission is one of the earliest hallmark of DS and AD occurring long before the classical neurological traits of DS and AD such as plaque formation and dementia. We propose that alterations in Dscr1 expression are responsible for the reduced neuronal exocytosis observed in the early stages of DS and AD. We have generated mice in which Dscr1 expression is altered, as occurs in DS and AD brains, and our preliminary studies indicate that exocytosis is reduced in these mice. We now wish to find the intracellular changes responsible for regulating exocytosis when Dscr1 expression is altered. We also aim to compare this to exocytosis in classical DS mouse models which have an extra chromosome 21 and in similar DS mouse models which have normal levels of Dscr1. This project will uncover the currently unknown functions of Dscr1 in exocytosis in an animal model, allow us to gauge whether Dscr1 is solely responsible for altering exocytosis in DS amongst other HSA21 genes, enable us to better understand the mechanisms initiating DS and AD and possibly lead to new targets of early intervention in these diseases.Read moreRead less
Therapeutic Potential Of Glycine Receptors In Pain Sensory Pathways
Funder
National Health and Medical Research Council
Funding Amount
$292,223.00
Summary
Inflammation caused by infection or injury leads to a heightened sensation of pain and can convert non-painful stimuli (e.g., touch) into painful stimuli. This effect is mediated by the production of prostaglandins both in peripheral tissues and in the spinal cord. Prostaglandins have recently been shown to decrease the magnitude of the inhibitory neurotransmission that normally occurs onto pain sensing neurons in the spinal cord. This has the effect of raising the excitability of these neurons, ....Inflammation caused by infection or injury leads to a heightened sensation of pain and can convert non-painful stimuli (e.g., touch) into painful stimuli. This effect is mediated by the production of prostaglandins both in peripheral tissues and in the spinal cord. Prostaglandins have recently been shown to decrease the magnitude of the inhibitory neurotransmission that normally occurs onto pain sensing neurons in the spinal cord. This has the effect of raising the excitability of these neurons, thereby making it easier for weak pain stimuli to be relayed to the brain. Inhibitory neurotransmission onto pain sensing neurons is largely mediated by the alpha3 glycine receptor subunit that is not found anywhere else in the body. Very little is known about the physiological and pharmacological properties of these receptors. We hypothesise that drugs that increase the activation of alpha3 glycine receptors may provide a novel treatment for pain. This project will firstly identify new drugs that can increase the activation of these receptors. It will then test whether these drugs are likely to work in vivo. The project will also establish why these receptors are found only on pain neurons. Together, this information will establish whether alpha3 glycine receptors represent a promising new therapeutic target for inflammatory pain, and will place us in an excellent position to begin the next step of identifying novel therapeutic lead compounds.Read moreRead less