Anatomy and Neuroscience - Theses
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ItemInvestigating regulation of vagally-evoked respiratory responses by the parabrachial complex in the mouse( 2022)The presence of respiratory irritants or infection can promote aberrant activity of central nervous system (CNS) neural circuits, which conduct interoceptive and homeostatic activity. Dysfunctional action in these CNS circuits contribute to morbidity in disease and decrease in quality of life. Incomplete understanding of CNS respiratory sensory relay circuits likely precludes effective medical treatment in instances of aberrant neural activity. Thus far, our understanding of respiratory relay aspects of the parabrachial complex (PBC) is unassessed. The PBC has been known to relay pain, thermoregulatory, gustatory, fluid and salt intake, and other sensory inputs to forebrain regions. Additionally, the PBC is known to receive respiratory-relevant sensory information to its pontine respiratory group (PRG) division, which in turn regulates respiratory pattern. However, the potential of the PBC in relaying vagally-derived respiratory-relevant information to forebrain regions has not been assessed. This thesis investigated physiological, neurochemical, and neuroanatomical components of the PBC in mice to assess its role in relaying vagal sensory information. To achieve this, a novel methodological approach was developed to facilitate physiological investigation of changes in respiratory rate, in response to electrical stimulation of the vagus nerve (eVNS), combined with muscimol inhibition of select PBC areas. Investigation identified region-dependent modulation of eVNS-induced activity by the PBC, with distinct roles for the medial parabrachial (MPB) and lateral parabrachial (LPB). Muscimol microinjection into the caudal LPB resulted in the complete abolishment of eVNS-induced apnoea. Inhibition of the caudal or intermediate MPB potentiated eVNS-induced tachypnoea, with inhibition of intermediate MPB regions additionally increasing the eVNS frequency required to induce apnoea. Given these physiological findings, the neurochemical phenotypes and neuroanatomical connectivity of the PBC were next investigated with immunohistochemistry and viral tracing, with an emphasis on description of the caudal PBC, a less understood subregion. The immunohistochemical findings obtained here suggest that the caudal LPB appears to be a unique entity, distinct from the intermediate and rostral LPB, due to the absence of CGRP or ChAT somal labelling in the caudal LPB which was present in the intermediate and rostral LPB. Additionally, calbindin immunolabelling identified a previously undescribed ‘axonal bundle’ principally present in caudal PBC regions. Viral tracing used here did not allow a discrete investigation of the caudal PBC and its connectivity in isolation, yet replicated projection patterns of the PBC that had previously been comprehensively assessed only in rats. Overall, this thesis has identified the caudal PBC to be a novel region of vagal sensory relay, deserving of future investigation.
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ItemThe role of neuronal TrkB in central nervous system myelination( 2019)Myelin, the specialised membrane surrounding many axons in the nervous system, is vital for the normal sensory and motor function as well as high order function such as learning and memory. Despite the importance of myelin in neural development and functions, little is known whether neuronally expressed molecules can promote the central nervous system (CNS) myelinating process. Through selectively deleting the expression of neurotrophin receptor TrkB in neurons in vivo (TrKB cKO), I have found that neuronal TrkB is essential for oligodendroglial cell production and lineage progression in multiple CNS regions including the lumbar spinal cord white matter tracts, cerebral cortex and corpus callosum and importantly de novo myelination, independent of axonal number and calibre in vivo. I have performed ultrastructural analysis of myelinated axons and found that TrkB cKO mice have significantly fewer myelinated axons compared to control mice during early postnatal development, indicative of delayed initiation of myelination. The analysis of myelin thickness via G ratio has revealed thinner myelin membranes in TrkB cKO mice compared to littermate control mice during development, persisting to late adulthood (n=3 mice/genotype/timepoint). This hypomyelinating phenotype has resulted in impaired myelin function, as evident by reduced optomoter responses in TrkB cKO mice compared to control mice. Moreover, I have found that TrkB cKO mice have significantly fewer oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes in both white and grey matter regions throughout postnatal development and into adulthood compared to littermate controls. A 24-hour EdU labelling experiment has demonstrated that neuronal TrkB expression is required for oligodendroglial production. Interestingly, the overall number of astrocytes and microglia has remained unchanged after neuronal TrkB deletion, suggesting a specific effect upon oligodendroglial lineage cells and myelination. In addition, assessment of neuronal morphology revealed no significant difference in overall dendritic branching including the number of primary and secondary processes. Taken together, results of this PhD study identify that TrkB is a novel neuronal signal that instructs oligodendroglial lineage development and de novo myelination within different neural circuits, indicating a new mechanism that underpins nervous system plasticity.