Clinical And Biological Markers Of Disease Presentation And Progression In Early Frontotemporal Dementia
Funder
National Health and Medical Research Council
Funding Amount
$507,636.00
Summary
Frontotemporal dementia accounts for 12-20% of all dementia cases and is as common as Alzheimer's disease in the < 65 year olds. Our understanding of this disease remains limited. This project aims to better characterise the range and progression of deficits in early frontotemporal dementia using tests of brain function and magnetic resonance imaging. This will assist in better diagnosis of these patients and, ultimately, may be used to monitor the outcomes of therapeutic interventions.
The Extinction Of Conditioned Fear And Its Implications For Cue Exposure Therapy
Funder
National Health and Medical Research Council
Funding Amount
$322,430.00
Summary
This project studies extinction of Pavlovian conditioned fear reactions in rats. Extinction of these reactions is an animal model for exposure therapy used in the treatment of anxiety disorders in people. In exposure therapy, the patient, aided by the clinician, confronts trauma-related cues in the absence of any overt danger. The intention of this therapy is to reduce the ability of the trauma-related cues to provoke the fear reactions that are undermining the patient's quality of life. In Pavl ....This project studies extinction of Pavlovian conditioned fear reactions in rats. Extinction of these reactions is an animal model for exposure therapy used in the treatment of anxiety disorders in people. In exposure therapy, the patient, aided by the clinician, confronts trauma-related cues in the absence of any overt danger. The intention of this therapy is to reduce the ability of the trauma-related cues to provoke the fear reactions that are undermining the patient's quality of life. In Pavlovian conditioning, subjects (typically rats) are exposed to a signaling relation between an initially neutral stimulus (e.g., a noise) and a feared outcome (e.g., foot shock). When later repeatedly exposed to the initially neutral but now feared stimulus (the noise) in the absence of the feared outcome, the fear reactions it acquired progressively decline until eventually it fails to elicit any such reactions. The fear reactions are said to have been extinguished. There has been significant progress in understanding the psychological processes and neural mechanisms underlying the acquisition of fear reactions, but much less is known about the processes and mechanisms underlying the extinction of these reactions. The project has two general objectives. The first is to determine the conditions of extinction training that promote long-term loss of fear reactions. The second objective is to determine how the brain controls this extinction of learned fear. Achieving these aims will be significant for two reasons. First, it will contribute to understanding the mechanisms by which animals (including people) learn to adjust their behaviour to bring it into line with the current relations that exist between events in the world. Second, it will provide important information about how such adjustment is facilitated or impaired across extinction training and, thereby, contribute towards understanding both the successes and failures of cue exposure therapy for fear-related disorders.Read moreRead less
Iron is essential for brain health. Too little iron can cause problems with memory, concentration and attention and can result in below average intellectual performance or even stroke in children. Too much iron can also be harmful. In the iron overload disease haemochromatosis, iron deposition throughout the body can lead to organ damage in the liver and other tissues. Concentrations of iron in the brain can equal those in liver. Yet surprisingly little is known about the effects of iron on the ....Iron is essential for brain health. Too little iron can cause problems with memory, concentration and attention and can result in below average intellectual performance or even stroke in children. Too much iron can also be harmful. In the iron overload disease haemochromatosis, iron deposition throughout the body can lead to organ damage in the liver and other tissues. Concentrations of iron in the brain can equal those in liver. Yet surprisingly little is known about the effects of iron on the adult human brain. Although the adult brain has traditionally been considered to be protected from the effects of high body iron by the blood-brain barrier, modern techniques show brain iron loading in patients with iron overload disorders or with various brain diseases such as Alzheimer's disease and Parkinson's disease. Several recent studies, including our own, have found associations between mutations in genes important in iron metabolism and brain diseases such as Alzheimer's disease. As many as 30% of Australians have abnormal iron levels (too high or too low) that are often undiagnosed and untreated. There is growing reason to believe these men and women are more likely to have memory problems as well as being at increased risk of brain diseases such as Alzheimer's disease. There is an urgent need for a large-scale study of the short-term and long-term effects of iron levels and related genetic factors on brain health and function. Residents of the Western Australian town of Busselton have participated in a set of health surveys since 1966. We have studied the iron status and related genetic factors in over 3,000 Busselton people. We now propose to perform tests of memory, attention, concentration and related brain activities on the older members of this community group. This will allow us to discover the effects of relevant gene factors, and short- and long-term iron status on memory and other brain functions and on Alzheimer's disease and related disorders.Read moreRead less
IRAP inhibitors are currently being developed as a new class of drugs for treating dementia and other forms of memory deficits. However, there are still gaps in our knowledge about how these drugs act to improve memory. The experiments outlined in this proposal will provide important insights into the drug action in different mouse models of memory deficit.
Therapeutic Implications Of A Molecular Link Between Survivin And Telomerase Reverse Transcriptase
Funder
National Health and Medical Research Council
Funding Amount
$547,970.00
Summary
A unifying feature of all types of cancer cells is that they are immortal. Our investigations will build upon our recent results that showed the gene survivin is involved in cancer cell immortalisation. We will characterise a molecular link between survivin and the enzyme telomerase, which is central to cancer cell immortality. Furthermore, we will demonstrate the therapeutic potential of turning off both survivin and telomerase as a novel approach to halting the growth of cancer cells.
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
The amygdala is an area of the brain that is involved in assigning emotional content to sensory information. Disorders of the amygdala lead to a variety of anxiety-related mental disorders such as panic attacks and post-traumatic stress. This grant will study how the NMDA receptor, which plays a central role in memory formation, works in the amygdala. We will determine the functional role of this receptor in the amygdala and how it may be modified by experience.
Molecular Memory: How DNA Methylation Contributes To Spatial Memory
Funder
National Health and Medical Research Council
Funding Amount
$482,842.00
Summary
The brain stores memories that can last a lifetime and our memory is core to mental health, but we still do not know how memories are stored. Here we explore a radical new theory that memory storage involves chemical modification of the DNA molecule - DNA-methylation. We will examine how memory changes patterns of DNA-methylation, and how modifying DNA-methylation can change memory. Our work will examine the biochemical basis of memory, and will inspire new strategies to treat memory disorders.
The research described in this Project Grant application should help to us understand how our brains make memories. Our brains contain billions of interconnected nerve cells forming unimaginable numbers of possible networks. Previous research indicates that repetitive activation of individual networks can lead to changes in the strength of connections between nerve cells. These changes in connection strength are thought to underlie learning and memory. The experiments described in this proposal ....The research described in this Project Grant application should help to us understand how our brains make memories. Our brains contain billions of interconnected nerve cells forming unimaginable numbers of possible networks. Previous research indicates that repetitive activation of individual networks can lead to changes in the strength of connections between nerve cells. These changes in connection strength are thought to underlie learning and memory. The experiments described in this proposal will address the mechanisms underlying changes in the strength of connections between nerve cells. As most of the inputs nerve cells receive from other nerve cells are made onto their dendrites (small branching processes that extend from the cell body), the main objective is to investigate the interactions at the dendritic level responsible for changes in connection strength. The results of this work will raise our understanding of how memories are formed, which will be essential if we are to understand the cellular processes disrupted during memory dysfunction in neurological disorders such as dementia.Read moreRead less
Investigation Of The Mechanisms Involved In Consolidation Of Memory By Beta 3 Adrenoceptoragonists.
Funder
National Health and Medical Research Council
Funding Amount
$241,018.00
Summary
The inability to form new memories is a major and increasingly prevalent health problem for an aging population. In addition to aging, the inability to form new memories is associated with serious medical conditions including Alzheimer's Disease and diabetes. Common to these conditions is the inability to consolidate memories. Memories are intact for a short while (30 minutes) after the event to be remembered, but memory does not pass on into permanent storage. We have been able to achieve memor ....The inability to form new memories is a major and increasingly prevalent health problem for an aging population. In addition to aging, the inability to form new memories is associated with serious medical conditions including Alzheimer's Disease and diabetes. Common to these conditions is the inability to consolidate memories. Memories are intact for a short while (30 minutes) after the event to be remembered, but memory does not pass on into permanent storage. We have been able to achieve memory consolidation in a particular learning task, which is not normally remembered, by injection of drugs acting on novel receptors (beta 3 adrenoceptors) in the brain of day old chicks. These drugs mimic the action of noradrenaline at beta-3 adrenoceptors. There are a number of ways in which memory consolidation can be enhanced, and we will compare the effects of beta-3 drugs with other potential drugs acting at other types of noradrenaline receptors. One of the actions of beta-3 agonists is related to the uptake of glucose into cells in the brain. We will investigate whether the mechanism of beta-3 enhancement of memory involves the uptake of glucose in brain tissue and studies in cultures of individual cell types will show us which cells are involved. Although this work is done using young chicks, there is no reason to suppose that the basic memory mechanisms at the level of the nerve cell should be different in birds or mammals. There are distinct advantages to using chicks in this research as they can form a long lasting memory for an experience lasting only 10 seconds, and they will discriminate between different colours as part of their learning. This research is aimed at understanding the processes involved in and influencing memory formation. If we are going to develop drugs to alleviate the cognitive problems of old age and more serious cognitive diseases, we need to understand more about the basic mechanisms of memory formation in the normal animal.Read moreRead less