Neurosteroid Modulation Of GABA-inhibition In Vivo: Central Auditory Pathway Models
Funder
National Health and Medical Research Council
Funding Amount
$331,650.00
Summary
All neurons at higher levels of the central nervous system signal in response to the outcome of various excitatory and inhibitory inputs (synapses) from other neurons. Most of the fast-acting inhibition is mediated by chloride ion influx through a channel which is gated by the neurotransmitter GABA. Termed the GABAa-receptor, this channel is known to be modulated by a wide range of pharmacological agents (e.g. valium; ethanol, many anaesthetics) which may enhance or suppress its efficacy. There ....All neurons at higher levels of the central nervous system signal in response to the outcome of various excitatory and inhibitory inputs (synapses) from other neurons. Most of the fast-acting inhibition is mediated by chloride ion influx through a channel which is gated by the neurotransmitter GABA. Termed the GABAa-receptor, this channel is known to be modulated by a wide range of pharmacological agents (e.g. valium; ethanol, many anaesthetics) which may enhance or suppress its efficacy. There are also good reasons for concluding that there is a capacity for modulation by endogenous substances. Brain synthesized steroids (neurosteroids) are known to have a potent enhancement effect upon the efficacy of GABAa-receptors, and have been implicated in a number of clinical situations, including menstrual cycle related depression. Work of others has shown that rapid synthesis of neurosteroids acts to increase inhibition in response to anxiety-inducing stimuli. Our recent work has shown that neurosteroids mediate an induced increase in inhibition in the auditory midbrain area. A surprising aspect of that study was that neurosteroids also appear to mediate ongoing levels of inhibition. This now allows us to use the many inhibitory interactions in the auditory pathway as potential models for studying the role of neurosteroid modulation of GABA inhibition in normal brain function. This is important because a number of medical treaments have the side effect of changing the synthesis of neurosteroids. We will also use an auditory system model of neurotrauma to examine the role of neurosteroids in increasing inhibition (to counter a potentially lethal increase in excitability). The work will involve electophysiological functional measurements and the development of highly sensitivity analytical protocols using an electrospray mass spectrometer for direct measurement of neurosteroids in submicrogram samples of brain tissue.Read moreRead less
A decade ago the adult brain was thought of as a structurally-fixed organ. Against this are well-documented cases of slow recovery after massive injuries or stroke. Simple models of brain injury using the tactile, visual and auditory systems of animals as models have now revealed multiple stages of recovery (plasticity). Some of these are inbuilt into the wiring of the neural systems such that functional plasticity can result without the need for any structural or cellular changes. A second grou ....A decade ago the adult brain was thought of as a structurally-fixed organ. Against this are well-documented cases of slow recovery after massive injuries or stroke. Simple models of brain injury using the tactile, visual and auditory systems of animals as models have now revealed multiple stages of recovery (plasticity). Some of these are inbuilt into the wiring of the neural systems such that functional plasticity can result without the need for any structural or cellular changes. A second group of plastic phenomena depend upon minute changes in the connections between neurons and these are invoked in the first few days following an injury (synaptic plasticity; changes in the pattern and strength of the connections between neurons). Aside from being model systems, there are also parallels of this plasticity with clinical situations such as losses in hearing and sight, and of the adaptations made by the brain in response to prosthetics (e.g. bionic ear) and resorative surgery but the degree of relevance for these situations is unclear. An intriguing aspect of the experiments on auditory and visual systems is that neurons with inputs from both ears, or both eyes, undergo the plastic changes when the relevant sense organ on only one side is damaged but the other is intact. In fact, on the basis of the limited available evidence, it appears that the changes are independent of there being a normal input from the other side. This is difficult to explain in terms of the modern understanding neuronal plasticity at a cellular level. It is thus proposed to study both auditory and visual models of this brain plasticity with stimuli which are systematically varied to extract the extent of bilateral interaction in the induced plasticity. This will enable prediction of how these plasticity mechanisms will be involved in adaptations made to prosthetics and surgical corrections.Read moreRead less
Thalamic And Basal Forebrain Contributions To Auditory Cortical Reorganization Produced By Partial Hearing Loss
Funder
National Health and Medical Research Council
Funding Amount
$364,768.00
Summary
When part of the cochlea is damaged in adult animals, leading to a partial hearing loss, the auditory area of the cerebral cortex reorganizes itself, so that the area deprived of input by the peripheral lesion is not silent, but is occupied by expanded representations of adjacent frequencies. This reorganization has been observed in a number of species, including non-human primates, and it seems likely that it also occurs in humans with cochlear damage and hearing loss of this sort. If it does, ....When part of the cochlea is damaged in adult animals, leading to a partial hearing loss, the auditory area of the cerebral cortex reorganizes itself, so that the area deprived of input by the peripheral lesion is not silent, but is occupied by expanded representations of adjacent frequencies. This reorganization has been observed in a number of species, including non-human primates, and it seems likely that it also occurs in humans with cochlear damage and hearing loss of this sort. If it does, it would have important consequences for the way in which input from a hearing aid or cochlear prosthesis (bionic ear) is processed in the brain. This Project is designed to clarify the nature of the systems in the brain that contribute to this form of cortical plasticity, using an animal model. One aim is to determine whether the plasticity is intrinsic to the cortex or occurs in the pathways over which information is conveyed to the cortex. This will be assessed by determining whether such plasticity is also found in the auditory thalamus, the final subcortical auditory nucleus from which information is sent to the cortex. The second aim is to determine whether the occurrence of plasticity is controlled by modulatory influences from the basal part of the forebrain. Neurons in this area project to many parts of the cortex, and evidence from other sensory systems suggests that these projections exert a permissive function, allowing the cortex to reorganize when input is altered. This aim will be pursued by determining whether cortical reorganization occurs after hearing loss when this basal forebrain system is inactivated. The significance of these studies is that they will elucidate the way in which the brain reorganizes itself when it is confronted with altered input. This information is important for our understanding of normal auditory information processing mechanisms and of the way in which input from prosthetic devices is processed in the hearing-impaired.Read moreRead less
Cellular Mechanisms Underlying The Sense Of Balance
Funder
National Health and Medical Research Council
Funding Amount
$192,960.00
Summary
Dizziness, vertigo, and imbalance are major reasons for visits to the doctor, particularly by the elderly. For example, balance related falls account for an astonishing 50% of accidental deaths in people over 65. Inner ear disturbances account for 85% of these cases. Illness, infections, disease, head trauma or simply the natural aging process cause these disturbances and it is thought that they result in abnormal signals being sent from the inner ear to the brain. In spite of the health costs a ....Dizziness, vertigo, and imbalance are major reasons for visits to the doctor, particularly by the elderly. For example, balance related falls account for an astonishing 50% of accidental deaths in people over 65. Inner ear disturbances account for 85% of these cases. Illness, infections, disease, head trauma or simply the natural aging process cause these disturbances and it is thought that they result in abnormal signals being sent from the inner ear to the brain. In spite of the health costs associated with disorders of balance, very little is known about how signals are generated in our vestibular organs, let alone what abnormal changes may occur. Our attempts to understand balance in humans have been hampered by the lack of suitable experimental models. This proposal takes advantage of a newly developed mouse preparation to study key problems that could not be realistically addressed in whole animal or dissociated cells. We will investigate three critical components of balance organs. These components are: 1) hair cells that detect motion; 2) nerve endings that send information from hair cells to the brain; and 3) nerve endings that bring information from the brain. The aim of this proposal is to understand how these components interact with each other to provide us with a sense of balance. This knowledge will be the first of its kind and contribute significantly to our understanding of human vestibular function and pathology.Read moreRead less
Lesions of the primary visual area (V1) are sufficient to cause blindness, even though there are many other brain areas normally involved in vision. However, when V1 is lesioned very early in life people show some recovery, and may be able to see well enough to perform everyday activities. In order to understand what happens in the brain that allows this preservation of vision, we will study changes in the pathways linking the eyes to the brain, following lesions at different ages.
I am a neuroscientist interested in injury to the nervous system with emphasis on promoting functional recovery and clinical translation. Injury models are neurotrauma, the long-term effects of maternal drug administration on offspring and diabetic retino
Over thirty different areas, comprising nearly half the primate cerebral cortex, are involved in processing visual information. From the anatomical viewpoint, each of these areas should be capable of receiving visual information independently, through parallel anatomical channels involving the brainstem. Yet, it has been observed that lesion of one particular area (the primary visual area, V1) results in loss of vision. This raises several questions. What type of visual information is carried by ....Over thirty different areas, comprising nearly half the primate cerebral cortex, are involved in processing visual information. From the anatomical viewpoint, each of these areas should be capable of receiving visual information independently, through parallel anatomical channels involving the brainstem. Yet, it has been observed that lesion of one particular area (the primary visual area, V1) results in loss of vision. This raises several questions. What type of visual information is carried by the parallel pathways to the other visual areas? Why aren t these other areas capable of sustaining vision without V1? Do V1 lesions trigger changes in the adult brain, which affect the other visual areas? As a step towards answering these questions, we will study the neural pathways that convey visual information directly to the middle temporal area (MT). MT is one of the best-characterised visual areas, and the anatomy of its neural inputs is well known, facilitating the interpretation of the results. We will investigate the type of visual information being sent to MT after lesions of V1, as well as the changes in the electrical responses of MT cells which result from this type of condition. This is a basic science study, the primary benefit of which will be advancement of knowledge on the mechanisms that underlie visual processing in normal and pathological situations. However, this type of work may also lay the groundwork for developments in areas of applied research. These may include medicine (e.g. the design of better rehabilitation strategies for people with brain damage), robotics- artificial intelligence (e.g. the development of more robust artificial systems capable of vision), and cognitive sciences (e.g. a better understanding of factors that limit human responses to visual stimuli).Read moreRead less