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
Temporal Processing In The Superior Olivary Complex: Impact Of Deafness And Peripheral Electrical Stimulation Strategies
Funder
National Health and Medical Research Council
Funding Amount
$225,500.00
Summary
The brain can use timing or temporal information to extract the frequency and location of sound. Timing information is coded by the pattern of responses of brain cells that match the period of the sound wave. These responses can be measured as small voltage spikes or action potentials. Integration of these responses from one brain-processing site to another relies on precise (temporally matched) firing among a population of cells that are activated in response to sound. Sound localisation relies ....The brain can use timing or temporal information to extract the frequency and location of sound. Timing information is coded by the pattern of responses of brain cells that match the period of the sound wave. These responses can be measured as small voltage spikes or action potentials. Integration of these responses from one brain-processing site to another relies on precise (temporally matched) firing among a population of cells that are activated in response to sound. Sound localisation relies on this temporal integration from information coming from both ears. Specifically, the integration of this information relies on the balance of incoming inputs from both ears, which maintains an appropriate time window depending on the location of sound in space. Recent evidence suggests that in deafness this process of integration is disrupted which may be possibly due to an inability to regulate the coherent activation of cells. This has implications for cochlear implant users whose ability to process temporal information is compromised by a loss of temporal coding ability resulting from prior deafness. In this project we will measure voltage changes occurring inside cells of the superior olivary complex, which contains a group of structures that integrate input from both ears. We will examine the ability of these cells to process temporal information in normal and deafened conditions. This study will lead not only to an understanding of basic mechanisms for auditory coding but also to improved electrical stimulation strategies for patients with cochlear implants.Read moreRead less
Normal hearing relies on the generation and transmission of electrical signals in the hearing organ, the inner ear. These electrical signals are generated by the action of specialized molecular ion channels in the cellular membranes of the inner ear and this research aims to charcterize these ion channels and detail their role in the hearing process. The results will impact on our understanding of human hearing disorders such as tinnitus, auditory neuropathy and disturbances of loudness sensatio ....Normal hearing relies on the generation and transmission of electrical signals in the hearing organ, the inner ear. These electrical signals are generated by the action of specialized molecular ion channels in the cellular membranes of the inner ear and this research aims to charcterize these ion channels and detail their role in the hearing process. The results will impact on our understanding of human hearing disorders such as tinnitus, auditory neuropathy and disturbances of loudness sensation.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
Extraction Of Key Features Of Natural Speech By Ventral Cochlear Nucleus Neurons
Funder
National Health and Medical Research Council
Funding Amount
$225,330.00
Summary
Little is known about how speech is processed and transformed by the central auditory pathway, and how the critical temporal and spectral features that identify a speech sound segment (a phoneme) are extracted. To date, most studies have approached this issue by using synthetic speech and examined the responses of the peripheral auditory nerve only. The aim of this study is to examine how important features of naturally-spoken speech are encoded by the cochlear nucleus (CN) - the first station i ....Little is known about how speech is processed and transformed by the central auditory pathway, and how the critical temporal and spectral features that identify a speech sound segment (a phoneme) are extracted. To date, most studies have approached this issue by using synthetic speech and examined the responses of the peripheral auditory nerve only. The aim of this study is to examine how important features of naturally-spoken speech are encoded by the cochlear nucleus (CN) - the first station in the auditory pathway located in the brainstem. The CN is a complex of different cell types that have the capacity to transmit, transform, and encode complex acoustic information in different ways. The proposed experiments involve recording the bioelectrical signal from single CN cells in anaesthetised rats while presenting naturally-spoken syllables, both in quiet and in the presence of noise. It is important to examine what happens to the neural responses in the latter condition, because all animals must cope with the problem of extracting important signals from background noise. While noise clearly interferes with the perception of another sound, the auditory system is in fact quite good at extracting signals in the presence of noise. This is well demonstrated by our ability to understand speech in the presence of quite high noise levels. This ability is severely degraded in the hearing impaired. Thus, one of the aims of this study is to examine the mechanisms and limits of the CN's ability to encode speech in a noisy background. A greater understanding of the mechanisms the nervous system uses to extract critical features of speech will not only build on our knowledge of auditory brainstem processes, but may also provide clues to improving processing strategies for cochlear implants.Read moreRead less
Combining input from vision and hearing greatly enhances perception when information from one of these senses is degraded or incomplete, such as when tracking objects in foggy, dark or noisy places. This enhancement is of considerable importance because degraded input is the daily situation faced by many people with hearing or vision impairment. We will study the neural processes underlying our ability to combine vision and hearing to create a more reliable and accurate perception of the world.
Experimental Validation Of A Clinical Indicator Of Utricular Function.
Funder
National Health and Medical Research Council
Funding Amount
$198,689.00
Summary
The vestibular system is responsible for our sense of balance, it is located in the inner ear and is responsible for maintaining posture and helping an organism to make appropriate eye movements when the head moves. Damage to the vestibular system by disease or accident is extremely debilitating for a patient. A chief goal of our research program is to develop simple tests of the vestibular system that can be used in the clinic to diagnose vestibular disorders. Most present clinical tests only t ....The vestibular system is responsible for our sense of balance, it is located in the inner ear and is responsible for maintaining posture and helping an organism to make appropriate eye movements when the head moves. Damage to the vestibular system by disease or accident is extremely debilitating for a patient. A chief goal of our research program is to develop simple tests of the vestibular system that can be used in the clinic to diagnose vestibular disorders. Most present clinical tests only test the part of the vestibular system that responds to angular rotations (the semicircular canals). There are few good tests that can reliably diagnose problems concerned with sensed position (the otoliths). Recent evidence from human studies has shown that by delivering small electrical currents (galvanic stimulation) via electrodes located on the surface of the skin behind the ears, a characteristic pattern of eye movement occurs. Our hypothesis is that the distinctive pattern of eye movement produced is a result of otolith stimulation. The aim of this project is to determine exactly how these small currents produce the eye movements and if these eye movements are in fact mediated by the otoliths. To determine the physiology that underlies these types of responses we are unable to conduct these experiments in humans. Our present program will therefore use both behavioural and physiological experiments on guinea pigs to test our hypotheses about galvanic stimulation and otolith function. The significance of this work lies in that it will lead to a new way of evaluating the function of the gravity sensing part of the human vestibular system which appear to be uniquely important for patients with balance problems.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.