Standardisation Of Prepulse Inhibition Of The Startle Reflex For Pharmacological And Interspecies Comparisons
Funder
National Health and Medical Research Council
Funding Amount
$252,761.00
Summary
People and other animals startle when they here a sudden loud sound. How much one startles depends in part on how loud the sound is. The relationship between the loudness of the sound and the size of the startle resembles a ski slope. Each individual has a ski slope that differs from others; the beginning of the ski slope (threshold) occurs at a different loudness, the slope is a different steepness, and the height of the ski slope where the plateau occurs is different. There are genetic differe ....People and other animals startle when they here a sudden loud sound. How much one startles depends in part on how loud the sound is. The relationship between the loudness of the sound and the size of the startle resembles a ski slope. Each individual has a ski slope that differs from others; the beginning of the ski slope (threshold) occurs at a different loudness, the slope is a different steepness, and the height of the ski slope where the plateau occurs is different. There are genetic differences in ski slopes as well. The size of the startle reflex can also be reduced by preceding the startling sound with a quiet stimulus a few tens of milliseconds before the startling stimulus. This is known as prepulse inhibition of the startle reflex or PPI for short. There is much interest in PPI, because it differs in people with certain mental illnesses, such as schizophrenia or post-traumatic stress disorder, and certain neurological illnesses, such as Huntington's chorea. It is also affected by drugs, including stimulants, stress hormones, and cannabis. In almost all the hundreds of experiments on PPI the effect of the prepulse on the response to a startling stimulus is measured at only one startling stimulus loudness. This loudness can be at very different parts of the ski slope for different people or other animals: it may be in the steep slope for one person, well into the plateau for another, or even at the bottom of the ski slope below the threshold in others. The effect of PPI is very different depending on what part of the ski slope the loudness represents. A lack of consistent effects in the literature on PPI by drugs and genetics is explained by this difference. Experiments are planned that will investigate the effect of drugs that are similar to those that treat schizophrenia, stress hormones and cannabis on the effect of prepulses on the whole ski slope. This procedure will provide the consistency in results so far absent.Read moreRead less
Structure-function Studies Of Ion Permeation And Selectivity In Recombinant Glycine Receptor Channels
Funder
National Health and Medical Research Council
Funding Amount
$331,300.00
Summary
Ligand-gated ion channels (LGICs) are members of a superfamily of receptor channels, with very significant structural and functional similarities, which play a major role in fast synaptic neurotransmission within the brain and spinal cord, and underlying the complex behaviour of the nervous system, but when dysfunctional can result in major neurological problems. Glycine is one of the two most important inhibitory neurotransmitters in the central nervous system. Impaired glycine-mediated neurotr ....Ligand-gated ion channels (LGICs) are members of a superfamily of receptor channels, with very significant structural and functional similarities, which play a major role in fast synaptic neurotransmission within the brain and spinal cord, and underlying the complex behaviour of the nervous system, but when dysfunctional can result in major neurological problems. Glycine is one of the two most important inhibitory neurotransmitters in the central nervous system. Impaired glycine-mediated neurotransmission underlies a range of inherited neurological diseases and already, it has been shown that the human disorder, familial Startle disease (hyperekplexia) occurs because of point mutations that have impaired the permeation and activation of the glycine receptor (GlyR). Similarly, certain epilepsies are now known to be caused by mutations in, or close to, the channel region in the excitatory acetylcholine receptors (AChRs), which affect channel activation and ion permeation. However, because of their very significant structural and functional similarities, information obtained in one member of the LGIC family of receptors has strong potential application to the other members and the GlyR with its simpler structure has certain advantages for investigation. The first aim of this project is to investigate how the molecular biological structure of these ion channels controls permeation, how it affects how different ions are selectively allowed to move through it and how it affects channel activation. A second related aim is to learn more about the process of desensitization of GlyR receptors, whereby a sustained presence of a high concentration of agonist can cause a reduction in receptor response. A third aim is to specifically investigate the mechanisms underlying the mode of molecular disruption resulting from two new Startle disease mutations, which, in addition to their own inherent clinical value, can also give general information about receptor function.Read moreRead less
Mechanism Of Signal Transduction And Receptor Activation In Ligand Gated Ion Channel Receptors
Funder
National Health and Medical Research Council
Funding Amount
$551,560.00
Summary
This project seeks to provide fundamental new information about the means by which neurotransmitter receptors, which mediate fast synaptic neurotransmission, operate. This knowledge is important since the Cys-loop family of ligand gated ion channel receptors are responsible for a wide range of neuronal signalling and the control of both excitatory and inhibitory receptors. The Cys-loop receptors are modulated by both therapeutic drugs (eg. benzodiazepines, barbiturates, antiemetics) and by recre ....This project seeks to provide fundamental new information about the means by which neurotransmitter receptors, which mediate fast synaptic neurotransmission, operate. This knowledge is important since the Cys-loop family of ligand gated ion channel receptors are responsible for a wide range of neuronal signalling and the control of both excitatory and inhibitory receptors. The Cys-loop receptors are modulated by both therapeutic drugs (eg. benzodiazepines, barbiturates, antiemetics) and by recreational drugs (eg. alcohol, nicotine). They are also targets for development of new therapeutic drugs, such as allosteric modulators of nAChR for memory enhancement, or modulating GlyR to relieve spasticity or chronic pain. The project will use a range of molecular advances made by this and other laboratories to clarify how neurotransmitters enable their receptors to activate and signal. This fundamental information is of major medical significance as defective synaptic transmission, caused by mutations in ligand gated ion channel receptors, gives rise to a number of neurological and psychiatric disease states. The ligand gated receptors are also major targets for therapeutic drugs and the information gained in this study may also provide insights into new ways in which drugs could be used to enhance or inhibit synaptic signalling.Read moreRead less
Dynamic Aspects Of Inhibitory Synaptic Transmission And Modulation By Neuroactive Drugs
Funder
National Health and Medical Research Council
Funding Amount
$370,500.00
Summary
Information moving through the brain is typically encoded as brief bursts of signals. These signals travel along the microscopic wiring that connect the brain's nerve cells into complex circuits. Information is encoded in the frequency of the signals within a burst, and the duration of each burst. This frequency-coded information is processed at the contact points between nerve cells (synapses). Almost all neuroactive drugs target synapses, where they alter information processing. Most of the in ....Information moving through the brain is typically encoded as brief bursts of signals. These signals travel along the microscopic wiring that connect the brain's nerve cells into complex circuits. Information is encoded in the frequency of the signals within a burst, and the duration of each burst. This frequency-coded information is processed at the contact points between nerve cells (synapses). Almost all neuroactive drugs target synapses, where they alter information processing. Most of the information about how neuroactive drugs work has been acquired from experiments performed under steady-state conditions. Typically, drugs are applied at a constant concentration and a synapse is stimulated at an unrealistically low frequency. The data obtained under these conditions are very useful, but tell only part of the story. For example, during an extended burst of signals, some neuroactive drugs may be displaced from their synaptic binding sites, reducing their effectiveness. In contrast, other drugs can only bind when synapses are active, and their effectiveness will increase during a burst of signals. For optimal drug design and delivery, it is important to understand how drugs work during bursts of activity. To date, the highly dynamic, non-equilibrium conditions encountered at central synapses have not been extensively studied. The central goal of this research proposal is to investigate the dynamic properties of synapses, and the drugs that modulate them. The results will provide insights into information processing in the brain, and will have significant implications for the development and targeting of clinically relevant neuropharmacological compounds.Read moreRead less
Mechanism Of Signal Transduction And Receptor Activation In Ligand Gated Ion Channel Receptors
Funder
National Health and Medical Research Council
Funding Amount
$456,000.00
Summary
This project seeks to provide fundamental new information about the means by which neurotransmitter receptors, which mediate fast synaptic neurotransmission, operate. It will use a range of molecular advances made by this and other laboratories to clarify how neurotransmitters enable their receptors to activate and signal. This fundamental information is of major medical significance as defective synaptic transmission, caused by mutations in ligand gated ion channel receptors, give rise to a num ....This project seeks to provide fundamental new information about the means by which neurotransmitter receptors, which mediate fast synaptic neurotransmission, operate. It will use a range of molecular advances made by this and other laboratories to clarify how neurotransmitters enable their receptors to activate and signal. This fundamental information is of major medical significance as defective synaptic transmission, caused by mutations in ligand gated ion channel receptors, give rise to a number of neurological and psychiatric disease states. The ligand gated receptors are also major targets for therapeutic drugs and the information gained in this study may also provide insights into new ways in which drugs could be used to enhance or inhibit synaptic signalling.Read moreRead less
Molecular Determinants Of Inhibitory Synaptic Function Studied Using Mutant And Transgenic Mice
Funder
National Health and Medical Research Council
Funding Amount
$496,500.00
Summary
Communication between nerve cells is the key to effective brain function and when disturbed, pathological states such as epilepsy, schizophrenia, fear and anxiety, spasticity and motor disorders ensue. This project is based on new data which suggests that the site of this communication, called the synapse, is a much more dynamic structure than previously thought. Based on our work to date, where we have demonstrated the recruitment of selected classes of neurotransmitter receptors into synapses, ....Communication between nerve cells is the key to effective brain function and when disturbed, pathological states such as epilepsy, schizophrenia, fear and anxiety, spasticity and motor disorders ensue. This project is based on new data which suggests that the site of this communication, called the synapse, is a much more dynamic structure than previously thought. Based on our work to date, where we have demonstrated the recruitment of selected classes of neurotransmitter receptors into synapses, our aim is to use a range of naturally occuring mice mutants, as well as transgenic mice to modulate the receptor levels and so to examine the role of synaptic function and synaptic dynamics. The outcomes of this project will provide fundamental new knnowledge aimed at understanding how communication in the nervous system works and may suggest ways in which modulation of this information flow could be used to treat disorders of brain function.Read moreRead less
Attentional Effects On Prepulse Inhibition Of The Acoustic Startle Reflex In Patients With Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$278,625.00
Summary
People suffering from schizophrenia exhibit differences from healthy people in the startle reflex, which is a blink of the eyes when a sudden loud sound occurs. Normally, this reflex is reduced in size when a quiet sound occurs a few milliseconds before the startling sound, but this prepulse inhibition of the startle reflex or PPI does not occur to the same degree in people with schizophrenia. The underlying causes of this reduction in PPI in patients with schizophrenia is not known. The most co ....People suffering from schizophrenia exhibit differences from healthy people in the startle reflex, which is a blink of the eyes when a sudden loud sound occurs. Normally, this reflex is reduced in size when a quiet sound occurs a few milliseconds before the startling sound, but this prepulse inhibition of the startle reflex or PPI does not occur to the same degree in people with schizophrenia. The underlying causes of this reduction in PPI in patients with schizophrenia is not known. The most commonly accepted theory is that it reflects a deficit in a basic sensorimotor gating function which could underlie a variety of attentional abnormalities observed in schizophrenia. However, our data indicate that patients exhibit more PPI when they ignore the prepulse stimuli. We wish to test the hypothesis that alterations in PPI in schizophrenic patients are secondary to abnormalities in attention. This is significant because the theory can point to a specific cognitive deficit associated with schizophrenia. We have also found that patients treated with some kinds of antipsychotic medications (the newer atypical antipsychotic medications) do not show reductions in PPI, but patients treated with older types of antipsychotic drug do show reductions in PPI. We intend to investigate the effects of different types of antipsychotics on attentional modulation of PPI. This is significant because it may indicate that patients with a specific kind of cognitive impairment may show improvement with a specific type of medicine. Our data suggests that chronic cannabis use may associated with differences in the startle reflex and in PPI. Understanding how such cannabis use alters PPI may provide insights into why so many people with schizophrenia regularly abuse cannabis.Read moreRead less
Neurodegeneration In The Ageing Brain: How The Pathways Leading To Aggregated Protein Cause Disease
Funder
National Health and Medical Research Council
Funding Amount
$12,322,838.00
Summary
The team consists of eight highly experienced research scientists who are dedicated to solving the question of how the brain degenerates in the elderly when associated with the accumulation of certain proteins: e.g. A_ amyloid (Alzheimer�s disease) and PrP (Creutzfeldt-Jakob disease). Understanding the molecular pathways leading to the degeneration (loss of neuronal synapses) will permit the development of rational diagnostic and therapeutic interventions. Over the past five years the program ha ....The team consists of eight highly experienced research scientists who are dedicated to solving the question of how the brain degenerates in the elderly when associated with the accumulation of certain proteins: e.g. A_ amyloid (Alzheimer�s disease) and PrP (Creutzfeldt-Jakob disease). Understanding the molecular pathways leading to the degeneration (loss of neuronal synapses) will permit the development of rational diagnostic and therapeutic interventions. Over the past five years the program has identified several diagnostic and therapeutic avenues which are now being developed by the Pharmaceutical and Biotechnology industries. Much more research is still required for maximizing the chances of success using these approaches.Read moreRead less
The Prevalence And Trajectory Of Kidney Disease In Urban Aboriginal Children
Funder
National Health and Medical Research Council
Funding Amount
$94,515.00
Summary
The Study of Environment and Aboriginal Resilience on Child Health is a major NHMRC funded project looking at the health and illness of urban Aboriginal children in Australia. By working together with Aboriginal Community Controlled Health Services across urban and large regional centres in NSW the study team hope to better understand the causes of common diseases such as kidney and heart disease, and whether these first begin in childhood.