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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.

Genetic approaches to somatosensation

Abrahamsen, Bjarke January 2008 (has links)
Three approaches to understanding peripheral pain pathways are described in this thesis. Cre-loxP technology has been used to delete genes specifically in specialised sensory neurons that respond to tissue damage (nociceptors). The sodium channel selective Nav1.8 promoter is used to drive Cre expression. I used a mouse expressing diphtheria toxin A-chain downstream of a floxed stop signal, crossed with the Nayl.8Cre mouse to delete all cells expressing this channel. This lead to massive cell loss of nociceptive neurons, associated with altered pain behaviour. The mice lost cold, mechanical and inflammatory pain, but not thermal or neuropathic pain behaviour. These observations are consistent with modality specific pain pathways in the peripheral nervous system. Microarray analysis was used to identify the transcripts selectively expressed in the lost sensory neurons, providing potential new analgesic drug targets for inflammatory pain. In a further study exploiting knock out mice, I identified a line that had lost sensitivity to light touch, but was otherwise normal in terms of pain pathways. This sensory loss was due to the insertion of a LacZ cassette in a gene encoding Papin, a PDZ-protein of unknown function. Further analysis showed a loss of interactions between sensory neurons and mechanosensitive Merkel cells, and a loss of sensory neuron numbers. Finally, conditional deletion of Nav1.7 in mice, and global loss of Nav1.7 in man have been shown to lead to a loss of pain sensitivity. I used a recently discovered peptide blocker of Nav1.7 to examine the role of this channel in normal mice. I found that Nav1.7 block leads to a loss of mechanical, inflammatory and neuropathic pain, making this sodium channel a very attractive analgesic drug target.

Generation and modulation of network oscillations on the rodent prefrontal cortex in vitro

Glykos, Vasileios January 2013 (has links)
Fast network oscillations (~12-80 Hz) are recorded extensively in the mammalian cerebral cortex in vivo which local and distant neuronal populations orchestrate their firing activity to process cognitive-related information. The rat medial prefrontal cortex (mPFC) is considered to be functionally and anatomically homologous to the primate in vitro studies have demonstrated that the mPFC can sustain carbachol-induced persistent beta1 or kainate-induced transient low gamma frequency oscillations. We wished to establish an in vitro paradigm of carbachol (10 μM) / kainate (200 objective to investigate the distribution patterns and the mechanisms of these oscillations. Then we assessed the modulatory effects of the ascending catecholamine systems on fast network oscillations with exogenous application of Persistent fast network oscillations in the ventral mPFC were stronger, more rhythmic but slower (~25 Hz) than oscillations in the dorsal mPFC (~28 Hz). The regional difference in the oscillation amplitude was correlated to the strong regions in the mPFC, oscillations were stronger in layer 5. Oscillations relied on GABA, kainate but not AMPA receptors. In the ventral mPFC, network oscillations A were also dependent on NMDA receptor-mediated synaptic transmission. μM) reduced the oscillation strength and rhythmicity in the ventral mPFC. Instead, dopamine increased the power and rhythmicity of network oscillations in the dorsal mPFC. The region-dependent dopamine effect was correlated to the induced effects on synaptic inhibition and neuronal firing. μM) reduced the osc caused no effect on the dorsal mPFC.

Correlation between mass and unitary potentials evoked in the rat cerebral cortex by peripheral stimulation

Houchin, Jane January 1975 (has links)
Rats were anaesthetized with urethane or trilene. Electrical stimuli were applied to the forepaw and responses recorded from the primary somatosensory cortex. The cortical response and its variability were studied firstly in an attempt to identify and control variability in subsequent experiments. Depth and type of anaesthesia were relatively unimportant, but recording position was critical when results from different experiments were compared. The main variability was that due to interaction of evoked responses with ongoing spontaneous activity. It was found useful to divide all responses into two groups according to the presence or absence of ECoG activity at the time of stimulation. The variability of cortical evoked potentials in these experiments apparently reflected a cortical stabilizing mechanism. The suppression by ongoing cortical activity of a widespread surface positive/depth negative component in the response was associated with the suppression of unitary responses in the deep layers of the cortex. A simple postsynaptic modulation of evoked IPSPs may be largely responsible for the suppression of these action potential responses. Postsynaptic modulation of PSPs is also considered in the context of another cortical gating mechanism - direction specificity in responses to moving stimuli. A striking correlation was found between unitary action potentials, local negative waves and surface positive waves in both the stable and variable components of the response to forepaw stimulation, thus supporting the hypothesis that evoked potentials could, at least in part, be due to summation of soma action potentials. The expected contribution of soma action currents in pyramidal cells, to cortical surface potentials was estimated and found to be significant.

Studying feature specific mechanisms of the human visual system

Kaul, C. E. January 2010 (has links)
What are the current limits of our knowledge of brain activity underlying vision and can I further this knowledge? In this thesis, I explore this basic question. I focus on those aspects of visual input that can be described as basic features of visual perception. Examples include orientation, color, direction of motion and spatial frequency. However, understanding how humans visually perceive the external world is closely related with the study of attention. Attention, that is, the selection of some aspects of the environment over others, is one of the most intensively studied areas in experimental psychology, yet its neural mechanisms remain largely elusive. This thesis focuses on three distinct topics at the border of feature specific visual perception and feature-specific visual attention. First, in a series of studies, I explore the influence of heightened attentional demand to a central task to feature-specific neural processing in the ignored periphery. I discover that heightened attentional demand does not influence feature-specific representations in early visual cortices. Second, I investigate the influence of feature-based attention on neural processing of early visual cortices. At the same time, I also probe the influence of a behavioral decision to deploy feature-specific attention in the imminent future. I find that feature-based attention operates independent of other types of attention. Additionally, results indicate that a behavioral decision to deploy feature-based attention alone, without visual stimulation present, is able to modulate neural activity in early visual cortices. Third, I examine the more complex feature of facial gender and where in the brain gender discrimination might receive neural processing. I find that, in an established network of face-selective brain areas, facial gender is represented in nearly all areas of that network. Finally, I discuss all findings in the light of the current state of research, for their scientific significance and for future research opportunities.

Effects of cholinesterase inhibition on brain function

Bentley, P. I. January 2011 (has links)
Pharmacological-functional imaging provides a non-invasive method by which the actions of neurotropic drugs on the human brain can be explored. Simply put, it assesses how neural activity patterns associated with cognitive functions of interest are modified by a drug challenge. Since one of the most widely-used cognitive-enhancing drugs in clinical practice are cholinesterase inhibitors, this thesis applies pharmacological functional imaging to the question of understanding how such drugs work - both in healthy people and dementia. The experiments in this thesis describe how brain activations – as revealed by functional magnetic resonance imaging (fMRI) – are modulated by the cholinesterase inhibitor physostigmine, during tasks designed to isolate sensory, attentional, and memory processes. While non-human and human psychophysical studies suggest that all three of these cognitive functions are under the control of the endogenous cortical cholinergic system, understanding how neurobiological models of cholinergic function translate into human brain activation modulations is unclear. One main question that is particularly relevant in this regard, that recurs through all the experiments, is how physostigmine-induced neuromodulations differ between sensory-driven ‘bottom-up’, and task-driven ‘top-down’, brain activations. The results are discussed with reference both to non-human physiological data and to existing human cholinergic-functional imaging studies (fifty studies published to date), which are themselves reviewed at the outset. Furthermore, assumptions based upon the physical and physiological principles of pharmacological functional imaging, being critical to interpretation, are discussed in detail within a general methods section.

Criteria and awareness in perceptual decision

Fleming, S. M. January 2011 (has links)
The immediacy of subjective experience belies the complex process of inference and categorisation that our brains undertake every moment of our waking lives, a process that allows the selection of the best course of action in the face of under-determined sensory input. There is much behavioural evidence that humans use the context in which decisions occur to actively shape links between perception and action. However, there are several remaining questions as to how this process occurs in the brain, and how such decision-making is linked to subjective reports, four of which are addressed in this thesis. It is unknown at which stage along the path from sensory to motor areas a loss function is integrated into the perceptual decision process. Using fMRI I show that asymmetries in value aect a fronto-parietal-basal ganglia network, rather than impacting upon the coding of visual categories. Theoretical models predict that the basal ganglia adjust the link between decision and action on the basis of contextual variables, but supporting empirical evidence is scarce. In two further imaging studies I show that the subthalamic nucleus modulates action control when default expectations are violated. That links between perception and action may be labile leads one to ask to what extent the observer has metacognitive access to these stages of the decision process, and which brain structures might mediate this access. I show that a second-order signal detection model can capture some, but not all, features of metacognitive condence. Finally, I show that individual dierences in metacognitive ability are associated with the structure of anterior prefrontal cortex. Comparing the levels of perceptual and metacognitive decision is critical for understanding how the mechanisms of decision-making are linked to awareness and self-report. The thesis concludes with a brief discussion of future challenges in this direction.

Characterisation of novel mutations within Heat Shock Protein 27 causing motor neuropathies

Innes, A. E. January 2012 (has links)
Charcot-Marie-Tooth disease (CMT) 2F and distal Hereditary Motor Neuropathy (dHMN) are peripheral motor axonopathies with limited sensory involvement, which usually present during the first decade of life. They are caused by mutations in heat shock protein 27 (Hsp27)/HSPB1, a highly conserved, ubiquitously expressed molecular chaperone. Hsp27 has several cytoprotective functions including the inhibition of apoptosis, protection against oxidative stress and promotion of axonal growth. In this Thesis, the effects of several pathogenic Hsp27 mutations were examined to elucidate their cellular effects in vitro and map these effects to different regions of the gene. The effects of Hsp27 mutations were first investigated in neuronal-like SH-SY5Y cells in vitro Analysis of cell survival and cellular morphology revealed that all mutations were cytotoxic under basal conditions. However, mutations located in the α-crystallin protein domain of Hsp27 resulted in a significant increase in the vulnerability of cells to cytoskeletal stressors and decreased neurite outgrowth. Using immunocytochemistry, interactions between mutant Hsp27 and cytoskeletal components were also examined. Mutations located in the Hsp27 α-crystallin domain increased co-localisation of Hsp27 with cytoskeletal elements. Although the mutation within the N-terminus did not have this effect it did result in the formation of distinct nuclear aggregates containing mutant Hsp27. The functional effects of Hsp27 mutations were investigated using lentiviral delivery of mutant Hsp27 in primary motoneurons. Examination of mitochondrial function showed that none of the Hsp27 mutants had any effect on mitochondrial membrane potential. The results presented in this Thesis show that disease-causing Hsp27 mutations have differential effects upon protein function in vitro depending upon the gene position of the mutation. Therefore, although all Hsp27 mutations in CMT patients result in motoneuron degeneration, these results suggest that this process may be initiated by different pathological mechanisms and that normal Hsp27 function is essential for the maintenance of motor-axonal function.

Investigating novel therapeutic approaches for sporadic inclusion body myositis (sIBM)

Ahmed, M. January 2012 (has links)
Sporadic inclusion body myositis (sIBM) is the most common acquired muscle disease affecting adults over the age of 50. Although the aetiology of this disease remains unclear, there is evidence for both inflammatory and myodegenerative processes in sIBM muscle pathology. In particular, abnormal protein aggregation is characteristic of affected muscle, with inclusion bodies incorporating amyloid-beta precursor protein (β-APP) among many others. Therapeutic interventions tested to date for sIBM have targeted the immune system; but none have been beneficial and sIBM currently remains untreatable. In this study, an in vitro model of the degenerative pathology seen in sIBM was established by over-expressing β-APP in primary muscle cultures. This resulted in the formation of inclusion bodies immuno-reactive for β-APP and other sIBM-relevant proteins, as well as increased cytotoxicity, proteasome dysfunction, mitochondrial abnormalities and TDP-43 mis-localisation; all observed in sIBM patient muscle. The heat shock response (HSR) is an acute endogenous cytoprotective mechanism that responds to misfolded proteins. Up-regulation of the HSR was examined by treatment with Arimoclomol, a co-inducer of the HSR, which showed beneficial effects in this in vitro model of IBM by significantly improving cell survival and attenuating cellular pathology. Since proteasome dysfunction has been implicated in sIBM pathology, I also examined the effects of pharmacological inhibition of the proteasome on muscle cells in culture. Proteasome inhibition did not result in the appearance of several key features of sIBM, suggesting that this is not a suitable approach to modeling sIBM. However, treatment with Arimoclomol was seen to significantly improve proteasome function and cell survival in these experiments. Using the β-APP model, eight novel pharmacological agents, with known anti-aggregation properties, were subsequently screened and one agent was found to significantly ameliorate the disease outcomes established in this model. The results of this Thesis show that β-APP over-expression in vitro recapitulates many of the characteristic features of sIBM and can be used successfully to screen potential therapies. In particular, Arimoclomol and one novel agent have been identified as potential therapeutic agents for IBM.

Leucine rich repeat kinase 2 in the pathogenesis of Parkinson's disease

Papkovskaia, T. D. January 2013 (has links)
The Leucine Rich Repeat kinase 2 (LRRK2) G2019S mutation is the most common genetic cause of Parkinons's disease (PD) which is clinically and pathologically indistinguishable from idiopathic PD. The effects of the G2019S mutation were explored in primary fibroblasts and SHSY5Y cells expressing wild type or G2019S LRRK2. LRRK2 was predominantly in the cytosol and small vesicular fraction of lymphoblasts and SHSY5Y cells with some localized to the mitochondria in overexpressing cells. While we could detect LRRK2 in various mouse and marmoset brain regions LRRK2 protein levels were higher in fibroblast and lymphoblast cultures. LRRK2 cellular distribution, mRNA and protein expression were not affected by the mutation. Mitochondrial abnormalities are a common feature in PD. To determine whether mitochondrial function is compromised in mutant cells, a detailed bioenergetic assessment was carried out on both G2019S cell models. An increase in basal and oligomycin inhibited respiration rates, reduced mitochondrial membrane potential and cellular ATP levels was observed for G2019S fibroblasts with similar changes observed in the neuroblastoma G2019S model. Respiratory rates and membrane potential were restored with LRRK2 kinase inhibition. Our data is consistent with reversable uncoupling of oxidative phosphorylation. Investigating transcriptional levels of mitochondrial uncoupling proteins (UCP) identified a G2019S dependent increase in UCP2 and 4 in fibroblasts and SHSY5Y cells. Upstream of this transcriptional event, an interaction between LRRK2 and the negative regulator of PGC1α expression, HDAC5 was investigated for both the wild type and G2019S protein. We have identified a role for endogenous LRRK2 in regulating mitochondrial bioenergetics with a kinase dependent gain of function for the G2019S mutation consistent with partial uncoupling of oxidative phosphorylation. LRRK2 G2019S enhanced the HDAC5 association which may be responsible for increased PGC1α expression and the downstream UCP transcription linked with the observed mitochondrial phenotype.

Prion pathology in the brainstem : clinical target areas in prion disease

Mirabile, I. January 2012 (has links)
Prion diseases are fatal transmissible neurodegenerative disorders characterized by spongiform changes, neuronal loss, reactive astrocytosis, and deposition of disease associated prion protein (PrP). Our aim was to investigate "clinical target areas" for prion disease, responsible for disease onset, progression, and the clinical phenotype, using PrP overexpressing MloxP and PrP depleted NFH-Cre/MloxP transgenic mouse lines. Upon infection with different prion strains NFH-Cre/MloxP mice have significantly longer survival than MloxP mice (first set of experiments: Me7, ~29 weeks vs. ~17 weeks; Mouse-adapted BSE , ~33 weeks vs. ~20 weeks; second set of experiments: RML, ~35 weeks vs.12 weeks; Me7 ~29 weeks, vs. ~17 weeks; MRC2 ~31 weeks vs. ~22 week). As we found that the first pathological changes in the brains of Me7 and Mouse–adapted BSE infected mice are localized in the brainstem, and clinical signs of prion disease point to brainstem failure, we quantitatively scored spongiosis, abnormal PrP accumulation and astrogliosis at early and late stage of disease in specific brainstem nuclei of RML and Me7 infected MloxP and NFH-Cre/MloxP mice. The first target areas showing abnormal PrP accumulation and gliosis in both prion infections are the locus coeruleus (LC), the nucleus of the solitary tract (NTS) and the pre-Bötzinger complex (PBC). We then studied the pathology progression, scoring prion pathology in these and other brainstem nuclei of infected MloxP and NFH-Cre/MloxP mice in the course of the disease. We show that neural degeneration in the LC, NTS, and PBC correlate with clinical signs characteristic of terminally ill mice. We therefore propose that these areas are potential clinical target areas of prion disease. We also studied the spatial and temporal characteristics of Cre-mediated recombination. With immunohistochemistry in reporter mice, we estimated that in the LC, NTS, and PBC, Cre-mediated recombination is 60% or lower, and this can explain why mice proceed to terminal stage of the disease. In NFH-Cre/MloxP mice we found that recombination is a progressive event and in the hippocampus it is complete by 5 weeks post-natally, differently from previous data. Finally, we produced anti PrP RNAi –encoding lentivirus which could be used as focal therapy in the clinical target areas we propose.

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