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No description available.

No description available.

The aim of the research described in this thesis is to improve our understanding of how the central nervous system (CNS) integrates feedback information from different sensory modalities to permit skill acquisition, and the subsequent consolidation of that skill, when exposed to a novel visuomotor environment. Indeed, such adaptation must be consolidated and recalled when appropriate such that we do not have to continually relearn skills we once possessed. By manipulating the sensory feedback available from the visual and proprioceptive systems during learning, it is possible to determine those facets of the sensory feedback that are essential for adaptation to occur. The thesis consists of seven chapters. The first and last provide a conceptual basis for, and an overall discussion of, the research. Chapter 2 reviews current visuomotor adaptation research, with particular focus on the manner in which information about novel tasks is stored within the CNS as we adapt, and the sensory information that is necessary to allow this adaptation to occur. Furthermore, this chapter serves to introduce many of the experimental techniques that are used to investigate motor learning in humans. Chapter 3 is a report of an investigation of the issues of interference and consolidation in an isometric target acquisition task. Exposure to a 30° counter-clockwise (CCW) rotation was followed by a period of rest, trials with no rotation, or trials with a 60° clockwise (CW) rotation. Retention of the initial adaptation was assessed 5 hours later. Full interference was manifested in circumstances in which either counter-rotated or non-rotated trials were encountered following the initial learning period. These results are consistent with the view that the observed interference is anterograde in nature, and highlight differences in the mechanisms employed by the CNS when compensating for novel kinematics (e.g. visuomotor rotations) compared with adapting to novel dynamics (e.g. external forces). Chapter 4 is a report of an investigation of the role of visual feedback in adapting to novel visuomotor environments in an isometric target acquisition task. Following trials with no rotation, participants adapted to a 60° CCW visuomotor rotation before returning to the non-rotated condition. Separate groups received either continuous visual feedback (CF) of cursor position during task execution or post-trial visual feedback (PF), both indicating task performance. One CF group were instructed to make any (feedback) modifications necessary during the task to reduce errors and acquire the target, while another CF group were instructed to make uncorrected, ballistic movements. Colour cues permitted the identification of the task environment (nonrotated/ rotated) on every trial. The results indicate that an automatic recalibration of the visuomotor mapping occurs when CF is provided, and suggest that performance improvements with PF may occur via the adoption of a cognitively mediated strategy. Furthermore, execution of feedback motor commands to correct errors did not enhance the adaptation that occurred when CF was provided, indicating that the perception of sensory errors (and not feedback commands that may be applied to reduce those errors) drives feedforward visuomotor adaptation. To investigate whether additional proprioceptive feedback associated with movement altered the adaptation patterns observed in chapter 4, a study similar to that reported in chapter 4 was undertaken, and is reported in chapter 5. In this instance a discrete, goaldirected, movement task replaced the isometric task. Subjects were deprived of vision of their arm, but were provided with PF or CF indicating task performance. The patterns of adaptation noted in the isometric task were also exhibited in this dynamic task, indicating that the timing of the visual feedback of task performance has a profound effect on how performance improvements in a novel visuomotor rotation occur. The experiment reported in Chapter 6 assessed the ability to adapt to two conflicting visuomotor rotations interleaved within the same training period, when each task variant (rotation) could be identified by contextual (colour) cues. While full dual adaptation was not observed, the results suggest that the colour cues may have been utilised to explicitly select distinct motor commands for each task rotation.

The aim of the research described in this thesis is to improve our understanding of how the central nervous system (CNS) integrates feedback information from different sensory modalities to permit skill acquisition, and the subsequent consolidation of that skill, when exposed to a novel visuomotor environment. Indeed, such adaptation must be consolidated and recalled when appropriate such that we do not have to continually relearn skills we once possessed. By manipulating the sensory feedback available from the visual and proprioceptive systems during learning, it is possible to determine those facets of the sensory feedback that are essential for adaptation to occur. The thesis consists of seven chapters. The first and last provide a conceptual basis for, and an overall discussion of, the research. Chapter 2 reviews current visuomotor adaptation research, with particular focus on the manner in which information about novel tasks is stored within the CNS as we adapt, and the sensory information that is necessary to allow this adaptation to occur. Furthermore, this chapter serves to introduce many of the experimental techniques that are used to investigate motor learning in humans. Chapter 3 is a report of an investigation of the issues of interference and consolidation in an isometric target acquisition task. Exposure to a 30° counter-clockwise (CCW) rotation was followed by a period of rest, trials with no rotation, or trials with a 60° clockwise (CW) rotation. Retention of the initial adaptation was assessed 5 hours later. Full interference was manifested in circumstances in which either counter-rotated or non-rotated trials were encountered following the initial learning period. These results are consistent with the view that the observed interference is anterograde in nature, and highlight differences in the mechanisms employed by the CNS when compensating for novel kinematics (e.g. visuomotor rotations) compared with adapting to novel dynamics (e.g. external forces). Chapter 4 is a report of an investigation of the role of visual feedback in adapting to novel visuomotor environments in an isometric target acquisition task. Following trials with no rotation, participants adapted to a 60° CCW visuomotor rotation before returning to the non-rotated condition. Separate groups received either continuous visual feedback (CF) of cursor position during task execution or post-trial visual feedback (PF), both indicating task performance. One CF group were instructed to make any (feedback) modifications necessary during the task to reduce errors and acquire the target, while another CF group were instructed to make uncorrected, ballistic movements. Colour cues permitted the identification of the task environment (nonrotated/ rotated) on every trial. The results indicate that an automatic recalibration of the visuomotor mapping occurs when CF is provided, and suggest that performance improvements with PF may occur via the adoption of a cognitively mediated strategy. Furthermore, execution of feedback motor commands to correct errors did not enhance the adaptation that occurred when CF was provided, indicating that the perception of sensory errors (and not feedback commands that may be applied to reduce those errors) drives feedforward visuomotor adaptation. To investigate whether additional proprioceptive feedback associated with movement altered the adaptation patterns observed in chapter 4, a study similar to that reported in chapter 4 was undertaken, and is reported in chapter 5. In this instance a discrete, goaldirected, movement task replaced the isometric task. Subjects were deprived of vision of their arm, but were provided with PF or CF indicating task performance. The patterns of adaptation noted in the isometric task were also exhibited in this dynamic task, indicating that the timing of the visual feedback of task performance has a profound effect on how performance improvements in a novel visuomotor rotation occur. The experiment reported in Chapter 6 assessed the ability to adapt to two conflicting visuomotor rotations interleaved within the same training period, when each task variant (rotation) could be identified by contextual (colour) cues. While full dual adaptation was not observed, the results suggest that the colour cues may have been utilised to explicitly select distinct motor commands for each task rotation.

Progressive degeneration in the central nervous system (CNS) of Huntington’s disease (HD) patients is a relentless debilitating process, resulting from the inheritance of a single gene mutation. With limited knowledge of the underlying pathological molecular mechanisms, pharmaceutical intervention has to-date not provided any effective clinical treatment strategies to attenuate or compensate the neuronal cell death. Attention has therefore turned to biotherapeutic molecules and novel treatment approaches to promote restoration and protection of selectively vulnerable populations of neurons in the HD brain. Rapid advances in vectorology and gene-based medicine over the past decade have opened the way for safe and efficient delivery of biotherapeutics to the CNS. With numerous factors known to regulate the development, plasticity and maintenance of the mammalian nervous system many proteins have emerged as potential therapeutic agents to alleviate HD progression. This investigative study utilised gene delivery vectors derived from the non-pathogenic adeno-associated virus (AAV) to direct high-level expression of brain-derived neurotrophic factor (BDNF), glial cell-line derived neurotrophic factor (GDNF), Bcl-xL or X-linked inhibitor of apoptosis protein (XIAP) within the rodent striatum. Maintenance of the basal ganglia and functional behaviour deficits were assessed following excitotoxic insult of the striatum by quinolinic acid (QA), a neurotoxic model of HD pathology. Enhanced striatal expression of BDNF prior to QA-induced lesioning provided maintenance of the striosome-matrix organisation of the striatum, attenuating impairments of sensorimotor behaviour with a 36-38% increase in the maintenance of DARPP-32 / krox-24 expressing striatal neurons, reduced striatal atrophy and increased maintenance of striatonigral projections. Higher levels of BDNF however induced seizures and weight-loss highlighting the need to provide regulatable control over biotherapeutic protein expression. Continuous high-expression of BDNF or GDNF resulted in a downregulation of intracellular signal mediating proteins including DARPP-32, with AAV-GDNF not found to enhance the overall maintenance of striatal neurons. Neither of the anti-apoptotic factors provided significant protection of transduced striatal neurons but tended towards ameliorating QA-induced behavioural deficits, displaying behaviour – pathology correlations with the survival of parvalbumin-expressing neurons in the globus pallidus. The results of this thesis suggest BDNF as a promising putative biotherapeutic for HD, but emphasises the requirement to control expression following gene delivery, and for further elucidation of the physiological impact that enhanced expression of endogenous factors has on the host cells. Additionally the maintenance of neural networks beyond the caudate-putamen will be vital to ensuring efficient clinical outcomes for HD. / Auckland Medical Research Foundation. Foundation for Research, Science and Technology. The University of Auckland.

Progressive degeneration in the central nervous system (CNS) of Huntington’s disease (HD) patients is a relentless debilitating process, resulting from the inheritance of a single gene mutation. With limited knowledge of the underlying pathological molecular mechanisms, pharmaceutical intervention has to-date not provided any effective clinical treatment strategies to attenuate or compensate the neuronal cell death. Attention has therefore turned to biotherapeutic molecules and novel treatment approaches to promote restoration and protection of selectively vulnerable populations of neurons in the HD brain. Rapid advances in vectorology and gene-based medicine over the past decade have opened the way for safe and efficient delivery of biotherapeutics to the CNS. With numerous factors known to regulate the development, plasticity and maintenance of the mammalian nervous system many proteins have emerged as potential therapeutic agents to alleviate HD progression. This investigative study utilised gene delivery vectors derived from the non-pathogenic adeno-associated virus (AAV) to direct high-level expression of brain-derived neurotrophic factor (BDNF), glial cell-line derived neurotrophic factor (GDNF), Bcl-xL or X-linked inhibitor of apoptosis protein (XIAP) within the rodent striatum. Maintenance of the basal ganglia and functional behaviour deficits were assessed following excitotoxic insult of the striatum by quinolinic acid (QA), a neurotoxic model of HD pathology. Enhanced striatal expression of BDNF prior to QA-induced lesioning provided maintenance of the striosome-matrix organisation of the striatum, attenuating impairments of sensorimotor behaviour with a 36-38% increase in the maintenance of DARPP-32 / krox-24 expressing striatal neurons, reduced striatal atrophy and increased maintenance of striatonigral projections. Higher levels of BDNF however induced seizures and weight-loss highlighting the need to provide regulatable control over biotherapeutic protein expression. Continuous high-expression of BDNF or GDNF resulted in a downregulation of intracellular signal mediating proteins including DARPP-32, with AAV-GDNF not found to enhance the overall maintenance of striatal neurons. Neither of the anti-apoptotic factors provided significant protection of transduced striatal neurons but tended towards ameliorating QA-induced behavioural deficits, displaying behaviour – pathology correlations with the survival of parvalbumin-expressing neurons in the globus pallidus. The results of this thesis suggest BDNF as a promising putative biotherapeutic for HD, but emphasises the requirement to control expression following gene delivery, and for further elucidation of the physiological impact that enhanced expression of endogenous factors has on the host cells. Additionally the maintenance of neural networks beyond the caudate-putamen will be vital to ensuring efficient clinical outcomes for HD. / Auckland Medical Research Foundation. Foundation for Research, Science and Technology. The University of Auckland.

Progressive degeneration in the central nervous system (CNS) of Huntington’s disease (HD) patients is a relentless debilitating process, resulting from the inheritance of a single gene mutation. With limited knowledge of the underlying pathological molecular mechanisms, pharmaceutical intervention has to-date not provided any effective clinical treatment strategies to attenuate or compensate the neuronal cell death. Attention has therefore turned to biotherapeutic molecules and novel treatment approaches to promote restoration and protection of selectively vulnerable populations of neurons in the HD brain. Rapid advances in vectorology and gene-based medicine over the past decade have opened the way for safe and efficient delivery of biotherapeutics to the CNS. With numerous factors known to regulate the development, plasticity and maintenance of the mammalian nervous system many proteins have emerged as potential therapeutic agents to alleviate HD progression. This investigative study utilised gene delivery vectors derived from the non-pathogenic adeno-associated virus (AAV) to direct high-level expression of brain-derived neurotrophic factor (BDNF), glial cell-line derived neurotrophic factor (GDNF), Bcl-xL or X-linked inhibitor of apoptosis protein (XIAP) within the rodent striatum. Maintenance of the basal ganglia and functional behaviour deficits were assessed following excitotoxic insult of the striatum by quinolinic acid (QA), a neurotoxic model of HD pathology. Enhanced striatal expression of BDNF prior to QA-induced lesioning provided maintenance of the striosome-matrix organisation of the striatum, attenuating impairments of sensorimotor behaviour with a 36-38% increase in the maintenance of DARPP-32 / krox-24 expressing striatal neurons, reduced striatal atrophy and increased maintenance of striatonigral projections. Higher levels of BDNF however induced seizures and weight-loss highlighting the need to provide regulatable control over biotherapeutic protein expression. Continuous high-expression of BDNF or GDNF resulted in a downregulation of intracellular signal mediating proteins including DARPP-32, with AAV-GDNF not found to enhance the overall maintenance of striatal neurons. Neither of the anti-apoptotic factors provided significant protection of transduced striatal neurons but tended towards ameliorating QA-induced behavioural deficits, displaying behaviour – pathology correlations with the survival of parvalbumin-expressing neurons in the globus pallidus. The results of this thesis suggest BDNF as a promising putative biotherapeutic for HD, but emphasises the requirement to control expression following gene delivery, and for further elucidation of the physiological impact that enhanced expression of endogenous factors has on the host cells. Additionally the maintenance of neural networks beyond the caudate-putamen will be vital to ensuring efficient clinical outcomes for HD. / Auckland Medical Research Foundation. Foundation for Research, Science and Technology. The University of Auckland.

Progressive degeneration in the central nervous system (CNS) of Huntington’s disease (HD) patients is a relentless debilitating process, resulting from the inheritance of a single gene mutation. With limited knowledge of the underlying pathological molecular mechanisms, pharmaceutical intervention has to-date not provided any effective clinical treatment strategies to attenuate or compensate the neuronal cell death. Attention has therefore turned to biotherapeutic molecules and novel treatment approaches to promote restoration and protection of selectively vulnerable populations of neurons in the HD brain. Rapid advances in vectorology and gene-based medicine over the past decade have opened the way for safe and efficient delivery of biotherapeutics to the CNS. With numerous factors known to regulate the development, plasticity and maintenance of the mammalian nervous system many proteins have emerged as potential therapeutic agents to alleviate HD progression. This investigative study utilised gene delivery vectors derived from the non-pathogenic adeno-associated virus (AAV) to direct high-level expression of brain-derived neurotrophic factor (BDNF), glial cell-line derived neurotrophic factor (GDNF), Bcl-xL or X-linked inhibitor of apoptosis protein (XIAP) within the rodent striatum. Maintenance of the basal ganglia and functional behaviour deficits were assessed following excitotoxic insult of the striatum by quinolinic acid (QA), a neurotoxic model of HD pathology. Enhanced striatal expression of BDNF prior to QA-induced lesioning provided maintenance of the striosome-matrix organisation of the striatum, attenuating impairments of sensorimotor behaviour with a 36-38% increase in the maintenance of DARPP-32 / krox-24 expressing striatal neurons, reduced striatal atrophy and increased maintenance of striatonigral projections. Higher levels of BDNF however induced seizures and weight-loss highlighting the need to provide regulatable control over biotherapeutic protein expression. Continuous high-expression of BDNF or GDNF resulted in a downregulation of intracellular signal mediating proteins including DARPP-32, with AAV-GDNF not found to enhance the overall maintenance of striatal neurons. Neither of the anti-apoptotic factors provided significant protection of transduced striatal neurons but tended towards ameliorating QA-induced behavioural deficits, displaying behaviour – pathology correlations with the survival of parvalbumin-expressing neurons in the globus pallidus. The results of this thesis suggest BDNF as a promising putative biotherapeutic for HD, but emphasises the requirement to control expression following gene delivery, and for further elucidation of the physiological impact that enhanced expression of endogenous factors has on the host cells. Additionally the maintenance of neural networks beyond the caudate-putamen will be vital to ensuring efficient clinical outcomes for HD. / Auckland Medical Research Foundation. Foundation for Research, Science and Technology. The University of Auckland.

Progressive degeneration in the central nervous system (CNS) of Huntington’s disease (HD) patients is a relentless debilitating process, resulting from the inheritance of a single gene mutation. With limited knowledge of the underlying pathological molecular mechanisms, pharmaceutical intervention has to-date not provided any effective clinical treatment strategies to attenuate or compensate the neuronal cell death. Attention has therefore turned to biotherapeutic molecules and novel treatment approaches to promote restoration and protection of selectively vulnerable populations of neurons in the HD brain. Rapid advances in vectorology and gene-based medicine over the past decade have opened the way for safe and efficient delivery of biotherapeutics to the CNS. With numerous factors known to regulate the development, plasticity and maintenance of the mammalian nervous system many proteins have emerged as potential therapeutic agents to alleviate HD progression. This investigative study utilised gene delivery vectors derived from the non-pathogenic adeno-associated virus (AAV) to direct high-level expression of brain-derived neurotrophic factor (BDNF), glial cell-line derived neurotrophic factor (GDNF), Bcl-xL or X-linked inhibitor of apoptosis protein (XIAP) within the rodent striatum. Maintenance of the basal ganglia and functional behaviour deficits were assessed following excitotoxic insult of the striatum by quinolinic acid (QA), a neurotoxic model of HD pathology. Enhanced striatal expression of BDNF prior to QA-induced lesioning provided maintenance of the striosome-matrix organisation of the striatum, attenuating impairments of sensorimotor behaviour with a 36-38% increase in the maintenance of DARPP-32 / krox-24 expressing striatal neurons, reduced striatal atrophy and increased maintenance of striatonigral projections. Higher levels of BDNF however induced seizures and weight-loss highlighting the need to provide regulatable control over biotherapeutic protein expression. Continuous high-expression of BDNF or GDNF resulted in a downregulation of intracellular signal mediating proteins including DARPP-32, with AAV-GDNF not found to enhance the overall maintenance of striatal neurons. Neither of the anti-apoptotic factors provided significant protection of transduced striatal neurons but tended towards ameliorating QA-induced behavioural deficits, displaying behaviour – pathology correlations with the survival of parvalbumin-expressing neurons in the globus pallidus. The results of this thesis suggest BDNF as a promising putative biotherapeutic for HD, but emphasises the requirement to control expression following gene delivery, and for further elucidation of the physiological impact that enhanced expression of endogenous factors has on the host cells. Additionally the maintenance of neural networks beyond the caudate-putamen will be vital to ensuring efficient clinical outcomes for HD. / Auckland Medical Research Foundation. Foundation for Research, Science and Technology. The University of Auckland.