Massey Documents by Type

Permanent URI for this communityhttps://mro.massey.ac.nz/handle/10179/294

Browse

Subject: search.filters.subject.Nervous system

Search Results

Now showing 1 - 7 of 7
  • Thumbnail Image
    Item
    Veterinarians' perspectives of neurology : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Veterinary Science at Massey University, Manawatū, New Zealand
    (Massey University, 2024-10-29) Shea, Anita
    Negative perspectives of neurology are commonly reported in medical education and have led to concerns regarding patient care and insufficient numbers of neurologists. Most of the proposed contributors to this “neurophobia” relate to intellectual difficulty learning and applying neurology knowledge. However, most studies to date have explored neurophobia superficially and differences between how neurophobia is defined and how it is measured challenge what the term means and our understanding of why it develops. Despite this lack of clarity, there are increasing numbers of reports that cite educational interventions to combat neurophobia. While the medical and veterinary professions share many similarities, there is very little research exploring neurophobia in veterinary medicine. It is unclear whether negative perspectives of neurology are common in veterinarians, and what contributes to the development of veterinarians’ perspectives of neurology. The overarching aims of this research were to better understand veterinarians’ perspectives of neurology, how and why they develop, and the effect they can have on further learning and clinical experiences. This research investigated veterinarians’ and veterinary students’ perspectives of neurology using a mixed method approach. Thematic analysis of semi-structured interviews explored how veterinarians’ experiences, and their reactions to those experiences, contributed to their overall attitude towards neurology. Statistical analysis of subsequent surveys of veterinarians and undergraduate veterinary students focused on those with negative or positive attitudes towards neurology to further explore these differing perspectives. The findings of all studies were integrated to obtain a holistic understanding of how similar inciting experiences can lead to different attitudes towards neurology. Intellectual difficulty learning and applying neurology was reported by most participants, regardless of their attitude towards neurology. Differences between participants with negative or positive attitudes towards neurology were often dictated by the individual’s affective responses to that difficulty, which in turn were shaped by personality traits, values, professional identity, and the ability of the individual to resolve internal conflict. Resolution of internal conflict could improve one’s attitude towards neurology. In contrast to medical literature on neurophobia, these findings suggest that an individual’s attitude towards neurology is determined by the way they react to intellectual difficulty, not the difficulty itself. This distinction has implications for educational interventions for any difficult subject, not just neurology.
  • Thumbnail Image
    Item
    On the higher-order smallest ring-star network of Chialvo neurons under diffusive couplings
    (American Institute of Physics, 2024-07-18) Nair AS; Ghosh I; Fatoyinbo HO; Muni SS
    Network dynamical systems with higher-order interactions are a current trending topic, pervasive in many applied fields. However, our focus in this work is neurodynamics. We numerically study the dynamics of the smallest higher-order network of neurons arranged in a ring-star topology. The dynamics of each node in this network is governed by the Chialvo neuron map, and they interact via linear diffusive couplings. This model is perceived to imitate the nonlinear dynamical properties exhibited by a realistic nervous system where the neurons transfer information through multi-body interactions. We deploy the higher-order coupling strength as the primary bifurcation parameter. We start by analyzing our model using standard tools from dynamical systems theory: fixed point analysis, Jacobian matrix, and bifurcation patterns. We observe the coexistence of disparate chaotic attractors. We also observe an interesting route to chaos from a fixed point via period-doubling and the appearance of cyclic quasiperiodic closed invariant curves. Furthermore, we numerically observe the existence of codimension-1 bifurcation points: saddle-node, period-doubling, and Neimark-Sacker. We also qualitatively study the typical phase portraits of the system, and numerically quantify chaos and complexity using the 0-1 test and sample entropy measure, respectively. Finally, we study the synchronization behavior among the neurons using the cross correlation coefficient and the Kuramoto order parameter. We conjecture that unfolding these patterns and behaviors of the network model will help us identify different states of the nervous system, further aiding us in dealing with various neural diseases and nervous disorders.
  • Thumbnail Image
    Item
    Characterising CG5846 (Peep) in Drosophila melanogaster neural function : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Biochemistry at Massey University, Manawatū, New Zealand
    (Massey University, 2024) Wilson, Sarah Jean
    Histone deacetylase 4 (HDAC4) is a transcriptional regulator that has been implicated in a number of neurodevelopmental and neurodegenerative diseases that are associated with intellectual disability, cognitive defects, and/or memory loss. Both the accumulation of nuclear HDAC4 and its loss-of-function have been linked to these conditions, therefore exploring HDAC4’s role in neuronal function is essential to understand the molecular mechanisms underlying these diseases. In Drosophila, overexpression of HDAC4 results in defects in morphogenesis of axons in the mushroom body, a structure essential for memory formation, as well as long-term memory defects and disruption to the development of the compound eye. The molecular mechanisms underlying these HDAC4-induced phenotypes are currently unknown. RNA-sequencing on fly heads in which HDAC4 was overexpressed has previously been performed and showed few genes were transcriptionally regulated by HDAC4. In addition, an enhancer/suppressor rough eye phenotype screen has also been performed which identified a number of genes that interact genetically in the same molecular pathway as HDAC4. To further investigate the molecular mechanisms underlying HDAC4 dysfunction, an RNA interference (RNAi) based candidate screen for potential HDAC4-interactors was performed, which involved quantification of developmental defects in the mushroom body and eye following RNAi knockdown of each candidate. It was hypothesised that if a phenotype resulting from RNAi knockdown was similar to that induced by HDAC4 overexpression, that candidate may function in similar molecular pathways. A single candidate-interactor was selected (CG5846, named Peep) for further investigation. On overexpression, Peep and HDAC4 co- distribute in nuclei of mushroom body neurons, however no physical interaction was detected. Furthermore, overexpression of Peep did not rescue the HDAC4-induced mushroom body or eye defects. Due to the uncharacterised nature of Peep, a thorough investigation was performed to assess the importance of Peep in survival, longevity, motor function, brain development, courtship learning and memory, and wing development. Peep was observed to be essential for survival of glial cells and for normal mushroom body development, which warrants further investigation. Reduced expression of Peep also resulted in a unique severe necrotic eye phenotype, and through this, Peep was shown to play a potential role in processes involved in regulating mitochondrial and proteasomal function, apoptosis and oxidative stress. These data provide the first documented characterisation of the functional role of Peep in Drosophila development and provide the basis for further investigation into the underlying molecular mechanisms involved in mushroom body and eye development.
  • Thumbnail Image
    Item
    Investigating HDAC4 aggregation in a Drosophila model of neuronal development : a dissertation presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Biochemistry at Massey University, Manawatū, New Zealand
    (Massey University, 2024-06-21) Hawley, Hannah Rose
    Histone deacetylase four (HDAC4) is essential in neuronal development and function, and dysregulation of HDAC4 has been observed in a number of neurodevelopmental and neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. In particular, its aberrant nuclear accumulation is a common feature among these diseases, and it has been observed that upon upregulation or accumulation in the nucleus, HDAC4 forms punctate foci in neuronal nuclei. Previous research in a Drosophila model determined that overexpression of HDAC4 disrupted both neuronal development and long-term memory, and this was largely mediated by the nuclear pool of HDAC4. Based on these data, it was hypothesised that aggregates of HDAC4 are responsible for the neurotoxicity that leads to disrupted neurodevelopment and memory. Therefore, this study aimed to determine whether the presence of HDAC4 nuclear aggregates correlated with neurodevelopmental deficits in a Drosophila model of neurodevelopment, and if so, how they mediate their toxic effects. The N-terminus of HDAC4 forms homo-oligomers in solution, and it was hypothesised that full-length HDAC4 similarly oligomerises, and that this is required for its aggregation in neuronal nuclei. Mutations predicted to prevent oligomerisation were introduced into the N- terminus of HDAC4 and were shown to significantly reduce aggregation of HDAC4 in Drosophila neurons. Furthermore, their presence also reduced the severity of HDAC4 overexpression-induced impairments in neurodevelopment. Conversely, stabilisation of oligomerisation increased aggregation and the severity of neurodevelopmental phenotypes, together indicating that aggregation positively correlates with the severity of neurodevelopmental deficits. HDAC4 aggregates have been previously shown to sequester the transcription factor MEF2, and further investigation revealed that the presence of MEF2 stabilised aggregation and increased the severity of defects in neuronal development. Importantly, targeting the interaction between HDAC4 and MEF2 reduced the severity of these defects. Other than MEF2, the composition of HDAC4 aggregates is unknown, and therefore immunoprecipitation-coupled mass spectrometry was performed on nuclear HDAC4 to identify candidate interactors of aggregates. This revealed a number of proteins with roles in neuronal development and function, as well as those involved in splicing and protein homeostasis, suggesting that aggregates may be impairing these processes to mediate toxicity. Together these data indicate that nuclear aggregation of HDAC4 impairs neurodevelopment, and may constitute a novel biomarker of disease or therapeutic target. Given the overlap in aetiology between neurodevelopmental and neurodegenerative diseases, further investigation of whether HDAC4 aggregation contributes to the severity and/or progression of neurodegenerative disorders is warranted.
  • Thumbnail Image
    Item
    Characterising the responses of farm mammals to a thoracic squeeze and the relationship to tonic immobility : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Veterinary Science at Massey University, Manawatū, New Zealand
    (Massey University, 2023) Holdsworth, Sophia Ellen
    Applying compression to the thorax of newborn farm mammals causes immobility accompanied by reduced responsiveness. Traditionally, this response was proposed to arise in neonatal foals due to the ‘thoracic squeeze’ mimicking the compression occurring during birth. Recent findings regarding the responses to the squeeze suggest a link to Tonic Immobility (TI). TI is a temporary and reversible state of reduced responsiveness and immobility with characteristic physiological changes. It is elicited by the collective actions of handling and sustained physical contact with additional pressure (restraint) and may be facilitated by inversion. TI is reported in young and adult animals of numerous species. The aim of this thesis was to examine whether responses to the thoracic squeeze are consistent with TI. First, behavioural responses to a squeeze were explored in lambs, with a focus on determining whether responses persisted beyond the neonatal period. Cortisol responses of healthy neonatal piglets to the squeeze were then investigated to explore similarities in Hypothalamic-Pituitary-Adrenal responses between the squeeze and TI. The final study examined electroencephalographic (EEG) responses of healthy neonatal piglets to a thoracic squeeze under light anaesthesia, to determine whether the squeeze causes changes in brain activity or exerts anti-nociceptive effects such as those reported during TI. The results demonstrated that responses to a thoracic squeeze persist beyond the neonatal period in lambs, and responses are generalised across multiple mammalian species. Furthermore, cortisol responses of piglets to a thoracic squeeze followed a similar pattern to that previously observed during TI in other species. Also consistent with some TI studies, the initial handling and restraint required to apply the squeeze appeared to induce the cortisol response in piglets. No inferences could be made about the effects of a thoracic squeeze on state of awareness in neonatal piglets, or the squeeze’s effect on nociception due to methodological limitations. Nevertheless, the results of this research support the hypothesis that the thoracic squeeze may be classified as a stimulus for inducing TI. Further work is required to characterise the effects of the squeeze on awareness and nociception and to explore the affective experiences of animals subjected to the squeeze.
  • Thumbnail Image
    Item
    Investigating the role of HDAC4 in Drosophila neuronal function : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy (PhD) in Genetics at Massey University, Manawatū, New Zealand
    (Massey University, 2022) Tan, Wei Jun
    HDAC4 plays an essential role in brain functions including neurodevelopment and memory formation, and increased levels of HDAC4 have also been associated with neurodegenerative disorders including Alzheimer’s disease. Histone deacetylases are enzymes that are traditionally known to regulate gene expression in the nucleus, however in neurons, HDAC4 shuttles between the nucleus and cytoplasm with a predominant distribution in the cytoplasm. Although studies have identified potential differences in subcellular function in which accumulation of nuclear HDAC4 has been shown to promote neurodegeneration, while cytoplasmic HDAC4 is neuroprotective, the mechanistic pathways through which it acts are still unknown. Therefore, this project aimed to determine the importance of nuclear and cytoplasmic pools of HDAC4 to the neurological functions of Drosophila melanogaster, as well as to determine the domains within the protein that are required for its function(s). This was carried out by expressing HDAC4 with mutations that resulted in altered subcellular distribution or carrying mutations in binding domain/motifs that have previously been shown to be important for HDAC4 function. Increased expression of wild-type HDAC4 disrupted development of the retina and the mushroom body (MB, a brain structure derived from Kenyon cells which are crucial for learning and memory), and expression of each mutant revealed the importance of specific domains/motifs to HDAC4 function in these tissues. Of interest, impairments to MB formation were exacerbated by mutation of the ankyrin-binding site and by mutation of serine residues that promote nuclear exit when phosphorylated (i.e. resulting in restriction to the nucleus). Mutation of the MEF2-binding site ameliorated these phenotypes, suggesting that HDAC4 acts through MEF2 to regulate MB development. However, while deacetylase activity was found to be dispensable in the MB, an active deacetylase domain was required in order for the phenotype to manifest in the retina, and mutation of the MEF2-binding site had no impact on the deficits caused by nuclear restriction of HDAC4 and mutation of the ankyrin-binding domain. Together these data indicate that HDAC4 acts through varying mechanism(s) depending on the cell type. Transcriptional changes in the Drosophila brain resulting from the expression of HDAC4 or its mutant variants was also explored using RNA-Seq. However only wild-type HDAC4 resulted in a large number of differentially expressed genes and the low level of differential gene expression in HDAC4 variants suggests that non-transcriptional processes may be involved in the induction of phenotypes caused by expression of these mutants. Additionally, further analysis of genes that were differentially regulated revealed a number of processes related to mitochondrial energy production. These findings have provided new insights into the role of HDAC4 in Drosophila neurodevelopment which opens up additional research avenues to focus on in the future.
  • Thumbnail Image
    Item
    Investigating the role of HDAC4 subcellular distribution in Drosophila development and memory : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy (PhD) in Biochemistry at Massey University, Manawatū, New Zealand
    (Massey University, 2019) Main, Patrick James
    The class IIa histone deacetylase HDAC4 has been previously demonstrated to play an essential role in brain development, learning and memory. However, the molecular pathways through which it acts are unknown. HDAC4 undergoes activity-dependent nucleocytoplasmic shuttling, disruption of the balance of nuclear and cytoplasmic HDAC4 has been identified as a factor in developmental and neurodegenerative disorders. This project used Drosophila melanogaster as a model to investigate the effects of altered subcellular distribution of HDAC4 on neural development and memory formation through the overexpression of Drosophila HDAC4 and wild-type human HDAC4 (hHDAC4), as well as nuclear- and cytoplasm-localising mutants of hHDAC4 named 3SA and L175A, respectively. The nuclear or cytoplasmic abundance of HDAC4 was adjusted by expressing the mutants during development or in adult flies. It was established that increased nuclear abundance of hHDAC4 in the brain impaired long-term memory and development, whereas increasing the cytoplasmic abundance did not. Further investigation showed that, contrary to vertebrate models, HDAC4 does not appear to repress memory in Drosophila through inactivation of MEF2 or CREB. Investigation of the transcriptomic changes induced by nuclear and cytoplasmic HDAC4 via RNASeq on RNA isolated from fly heads showed that L175A unexpectedly up-regulates the expression of genes in transcription and DNA synthesis. The relatively low number of transcriptional changes induced by 3SA suggested that it may be acting through largely transcriptionally independent means to impair memory and development in Drosophila. The localisation of HDAC4 to punctate foci in nuclei, potentially forming protein aggregates similar to Marinesco bodies seen in Parkinson’s Disease warrants further investigation. This project has shown that nuclear but not cytoplasmic HDAC4 impairs development and memory in Drosophila. Furthermore, cytoplasmic HDAC4 may play a role in transcriptional regulation of neurons, possibly regulation metabolic activity, suggesting that the activity-dependent nucleocytoplasmic shuttling of HDAC4 may not be primarily to remove HDAC4 from the nucleus and but instead to return HDAC4 to the cytoplasm.