Cell Type Specification In Developing CNS: Functional Analysis Of Sox14
Funder
National Health and Medical Research Council
Funding Amount
$468,055.00
Summary
The central nervous system (CNS) is the most complex organ in the body. The vast majority of nerve cells in the CNS are classified as 'interneurons'. These cells relay sensory information and motor commands within the CNS. Abnormal functioning of interneurons is likely to be the underlying cause of some, if not many, human nervous system diseases. However, very little is known of the precise anatomy and function of interneurons, which genes control their development, and how these functions are ....The central nervous system (CNS) is the most complex organ in the body. The vast majority of nerve cells in the CNS are classified as 'interneurons'. These cells relay sensory information and motor commands within the CNS. Abnormal functioning of interneurons is likely to be the underlying cause of some, if not many, human nervous system diseases. However, very little is known of the precise anatomy and function of interneurons, which genes control their development, and how these functions are maintained in the adult. This has been largely due to a lack of efficient and reliable methods to identify and study interneurons. We have previously discovered that a gene termed Sox14 is active in distinct interneuron groups in the embryonic brain and spinal cord. Sox14 is a member of the Sox gene family, many of which act as genetic switches to control cell and tissue development. We found that Sox14 has been extremely well conserved throughout evolution and is active in similar interneuron groups in a number of animal species. These studies led us to hypothesise that Sox14 controls a critical molecular step in the generation of certain interneurons that may be involved in reflexes, locomotion or motor coordination. In this project, we will investigate both the role of Sox14 in interneuron development and the functions of interneurons in which this gene is active. We will do so by combining modern molecular and genetic techniques with physiological approaches. This project will reveal critical molecular steps in CNS development and determine the functions of a specific group of interneurons. To this end, we will generate mouse strains in which a specific group of interneurons are genetically marked and can be manipulated during development. We envisage that these mice with 'modified brain circuits' will become unique resources for future investigations of selected interneuron types and their functions.Read moreRead less
We are able to identify and discriminate objects in the world because of exquisitely detailed and rapid processing of sensory information by neurons in the cortex of the brain. In this project we will examine these operations in neurons in the cortex that receive input from the large face whiskers of the rat. These whiskers are used for fine-grain discrimination and for gauging distance. They are deflected by being actively moved, under muscle control, over objects (active touch) or by being pas ....We are able to identify and discriminate objects in the world because of exquisitely detailed and rapid processing of sensory information by neurons in the cortex of the brain. In this project we will examine these operations in neurons in the cortex that receive input from the large face whiskers of the rat. These whiskers are used for fine-grain discrimination and for gauging distance. They are deflected by being actively moved, under muscle control, over objects (active touch) or by being passively deflected by objects. Deflection results in inputs to the brain that are processed to form the neural basis for very finely detailed perceptual behaviour. In rats, with impoverished visual and auditory senses, the whiskers are the major sensory system for interacting with the world, and are used in navigating the environment and in finding and distinguishing foods. Thus they contribute strongly to the remarkable success of this species. This elegant sensory system has a number of advantages that make it a very good model for the study of brain mechanisms responsible for active fine-grain sensory function. We plan to take advantage of the unique features of this system to define the information processing that occurs in the cortex in this elegantly complex system. This will address an issue relevant to all sensory systems - namely the neural basis of complex fine grain perceptual behaviour. Understanding the mechanisms underlying active tactile perception also has relevance to clinical conditions involving deficits in active touch e.g., in diabetic polyneuropathy (which eventually affects ~50% of diabetics), in leprosy (in which an early sign is damage to active touch). Knowledge of the core brain processes in active touch gained in this study could eventually underpin the ameliorative technologies for such deficits.Read moreRead less
Generation Of Complex Responses In Retinal Ganglion Cells
Funder
National Health and Medical Research Council
Funding Amount
$490,500.00
Summary
The retinal ganglion cells, whose axons form the optic nerve, comprise numerous distinct types, which respond to visual stimuli in either a simple or complex manner. The project will investigate how the complex responses of the direction-selective ganglion cells (DSGCs) and the local-edge-detector ganglion cells (LEDs) are generated. It appears that the retinal neurons providing inhibitory input to DSGCs and LEDs use different neurotransmitters, and the project will investigate how this shapes t ....The retinal ganglion cells, whose axons form the optic nerve, comprise numerous distinct types, which respond to visual stimuli in either a simple or complex manner. The project will investigate how the complex responses of the direction-selective ganglion cells (DSGCs) and the local-edge-detector ganglion cells (LEDs) are generated. It appears that the retinal neurons providing inhibitory input to DSGCs and LEDs use different neurotransmitters, and the project will investigate how this shapes the response properties of the ganglion cells. This will be done both by recording the visually evoked responses of the ganglion cells in an isolated preparation of the retina and by using two-photon laser-scanning microscopy to functionally image the neuronal interactions between the neurons that inhibit the DSGCs.Read moreRead less
Through the research supported by this Australia Fellowship, Prof Goulding will recruit and establish an internationally recognized team of researchers to study how nerve cells in the spinal cord function and contribute to the sensorimotor networks that control movement, posture, balance and protective reflexes. Sensory pathways in the spinal cord are important for protecting individuals from tissue damage and noxious insults and they also play an important role in regulating locomotion and move ....Through the research supported by this Australia Fellowship, Prof Goulding will recruit and establish an internationally recognized team of researchers to study how nerve cells in the spinal cord function and contribute to the sensorimotor networks that control movement, posture, balance and protective reflexes. Sensory pathways in the spinal cord are important for protecting individuals from tissue damage and noxious insults and they also play an important role in regulating locomotion and movement. They provide sensory feedback to the motor system to modulate it or activate particular reflexes. A multidisciplinary approach will be taken to dissect these circuits, using cutting edge mouse molecular genetics that allows specialized cell types to be studied and manipulated.Read moreRead less
Investigating Action Potential Initiation And Propagation In Neurons Using Voltage-sensitive Dyes
Funder
National Health and Medical Research Council
Funding Amount
$317,076.00
Summary
Nerve impulses, or action potentials, are the fundamental electrical signals used by the nervous system for communication. Critical to an understanding of neuronal function is the knowledge of where these events are initiated and how they propagate. Furthermore, this knowledge is required for understanding what goes wrong under conditions where there is a disturbance in neuronal communication, as occurs in many neurological disorders such as multiple sclerosis and epilepsy.
Properties Of Dendritic Spines And Their Role In Synaptic Plasticity
Funder
National Health and Medical Research Council
Funding Amount
$336,767.00
Summary
Connections between nerve cells in the brain often occur onto enlarged protrusions called dendritic spines. This proposal will investigate the properties of dendritic spines, and relate differences in spine properties to synaptic plasticity. This information can be used to better understand and treat neurological disorders associated with spine malfunction, as occur in some forms of mental retardation, and may help with understanding the memory loss that occurs during ageing and dementia.
Investigating Cortical Plasticity And Connectivity In People With Chronic Low Back Pain And Controls Using Combined TMS_EEG
Funder
National Health and Medical Research Council
Funding Amount
$318,768.00
Summary
Little is known about the factors that predispose the development of chronic low back pain or what changes underpin effective treatment. Brain changes, thought to reflect adaptive processes are associated with chronic pain, but the extent of their contribution to CLBP is unknown. By measuring the adaptability of brain changes in people with CLBP I will determine if they differ from healthy controls in a way that predisposes them to develop chronic pain and is related to treatment response.
How Does Fampridine Affect Upper Limb Function In Multiple Sclerosis?
Funder
National Health and Medical Research Council
Funding Amount
$113,237.00
Summary
Multiple sclerosis (MS) is a common and disabling neurological disease affecting thousands of young Australians. In 2011 Fampridine received TGA approval for walking impairment in MS, but its mechanism of action is unknown and its effects on domains other than lower limb function remain untested. Our study will test whether Fampridine improves upper limb impairment in MS patients and will use electrophysiological measures of central nervous system conduction to uncover its mechanism of action.
Intraocular Transplantation And Regeneration Of Retinofugal Pathways In Rodents
Funder
National Health and Medical Research Council
Funding Amount
$370,937.00
Summary
In the adult human brain and spinal cord there is little or no intrinsic capacity for replacement of lost or dying neurons, and there is minimal spontaneous repair of nerve fibre pathways. Thus traumatic injuries, stroke, or loss of neurons due to chronic degenerative disease result in functional impairments that are usually severe and long-lasting. The personal, social and economic costs associated with these neurological problems are enormous. New ways must be found of protecting and-or replen ....In the adult human brain and spinal cord there is little or no intrinsic capacity for replacement of lost or dying neurons, and there is minimal spontaneous repair of nerve fibre pathways. Thus traumatic injuries, stroke, or loss of neurons due to chronic degenerative disease result in functional impairments that are usually severe and long-lasting. The personal, social and economic costs associated with these neurological problems are enormous. New ways must be found of protecting and-or replenishing nerve cells in damaged CNS gray matter, and new methods are also required to help reconstruct fibre tracts after injury. Using the visual system as an experimental model, the aims of the proposed work are to develop novel transplantation and surgical strategies to: (i) Incorporate new cells into retinae that have been selectively depleted of endogenous neurons (ii) Promote the effective regeneration of large numbers of adult retinal axons through prosthetic peripheral nerve bridging grafts and into host CNS distal to the injury. The results obtained from the first series of studies will not only be of direct relevance to the future treatment of human retinal degenerative disorders, but will also increase our overall understanding of how best to ensure the differentiation and stable integration of different types of transplanted cells within the compromised host CNS. The second series of experiments should lead to an entirely new approach to nerve pathway reconstruction, relevant to both brain and spinal cord injuries. The ultimate aim of this experimental work is to improve the management and treatment of human CNS injury and disease, leading to better functional recovery and rehabilitation.Read moreRead less