Investigating The Role Of The UPF3B Gene And Nonsense Mediated RNA Decay (NMD) Process In Mental Retardation.
Funder
National Health and Medical Research Council
Funding Amount
$572,710.00
Summary
Intellectual disability is a frequent and important medical problem. Genetic and environmental factors contribute about equally to the aetiology of intellectual disability. Estimated 1-3% of population suffer from a form of intellectual disability. Among the genetic factors contributing to intellectual disability are genes, and their mutations, on one of the human chromosomes, chromosome X. We have been studying human X-chromosome genes for many years and discovered in excess of 20 novel genes c ....Intellectual disability is a frequent and important medical problem. Genetic and environmental factors contribute about equally to the aetiology of intellectual disability. Estimated 1-3% of population suffer from a form of intellectual disability. Among the genetic factors contributing to intellectual disability are genes, and their mutations, on one of the human chromosomes, chromosome X. We have been studying human X-chromosome genes for many years and discovered in excess of 20 novel genes causing various forms of intellectual disability. Surprisingly the number of genes, in which mutations cause various forms of intellectual disability is unexpectedly high. Just on the human X-chromosome we expect in excess of 200 such genes, which is nearly 30% of the gene content of this chromosome. We propose to study a novel gene, UPF3B, we recently identified to be mutated in a form of intellectual disability. The normal function of this gene and its protein is known to a certain extent. The UPF3B protein plays a role of a guardian of other genes in human (and also other species) cells. The role of the UPF3B protein is to prevent erroneous genetic information to be used for the building of proteins with potentially toxic effects to the organism. In our patients this process clearly malfunctions as a consequence of the damaged UPF3B gene. We propose to shed some more light in to the molecular intricacies of this process with the aim to better understand the mechanics of the process. Families, which participate in our studies and have this gene involved will benefit from the availability of direct test. Multiple other families around the world are also likely to benefit, now or in the future.Read moreRead less
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
How are memories stored in the brain? We know much about the brain regions involved in memory storage but we know little or nothing about how individual memories are represented and stored within those brain areas. The purpose of this project is to label and manipulate the specific subsets of brain cells that store individual memories. We will label memory-bearing cells in multiple brain regions and then ask how the connections between those cells encode learned information in the brain.
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 Contributions Of Different Sources Of Calcium To The Induction Of Long Term Potentiation
Funder
National Health and Medical Research Council
Funding Amount
$267,750.00
Summary
When we make memories, we alter the strength of synaptic connections between nerve cells.These changes are particularly marked in the hippopcampus ; a region of the brain involved in the formation of memories. The strength of a synaptic connection is altered if it activates a neurone sufficiently to cause a rise in the level of calcium ions. Calcium can be derived from several sources within the neurone. This project aims to assess the relative importance of these different sources of calcium in ....When we make memories, we alter the strength of synaptic connections between nerve cells.These changes are particularly marked in the hippopcampus ; a region of the brain involved in the formation of memories. The strength of a synaptic connection is altered if it activates a neurone sufficiently to cause a rise in the level of calcium ions. Calcium can be derived from several sources within the neurone. This project aims to assess the relative importance of these different sources of calcium in inducing increases in synaptic strength.Read moreRead less
Brain Plasticity Following Changes In Sensory Input
Funder
National Health and Medical Research Council
Funding Amount
$312,576.00
Summary
The research proposed here will investigate the mechanisms our brains use to adapt to changes in sensory input, as occurs following blindness, deafness, nerve damage or loss of a limb. The information gathered will help develop treatments for diseases associated with sensory loss, as well as those associated with deficits in our ability to learn and remember, such as Alzheimer's disease.
Disorders of fear and anxiety impose significant burdens on individual sufferers, their families, and communities. This project studies the brain mechanisms of fear and anxiety, with special focus on the role of the prefrontal cortex. It tests the novel hypothesis that prefrontal cortex is part of a neural pathway critical for regulating fear learning and ensuring that fear learning is adaptively guided by past experience. In the absence of this pathway, fear learning is maladaptive and excessiv ....Disorders of fear and anxiety impose significant burdens on individual sufferers, their families, and communities. This project studies the brain mechanisms of fear and anxiety, with special focus on the role of the prefrontal cortex. It tests the novel hypothesis that prefrontal cortex is part of a neural pathway critical for regulating fear learning and ensuring that fear learning is adaptively guided by past experience. In the absence of this pathway, fear learning is maladaptive and excessive relative to the danger posed by a situation.Read moreRead less
Insulin-regulated Aminopeptidase, Glucose And Memory
Funder
National Health and Medical Research Council
Funding Amount
$555,693.00
Summary
We have previously shown that inhibitors of IRAP improve performance in memory tasks in normal and memory impaired animals and are currently developing new treatments for memory loss using IRAP as a target. In this study, we will investigate the physiological roles of IRAP and its association with intracellular proteins. The knowledge obtained will provide insights of how the brain process memory and confirm the suitability of IRAP inhibitors as drugs for treating memory deficits.
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.