Effect of dopamine on synchronous neuronal oscillations in the globus pallidus-subthalamic nucleus network

Changes in the pattern of activity of neurones within the basal ganglia are relevant in the pathophysiology and symptoms of Parkinson’s disease. The globus pallidus (GP) – subthalamic nucleus (STN) network has been proposed to form a pacemaker driving regenerative synchronous bursting activity. In order to test whether this activity can be sustained in vitro a 20o parasagittal slice of mouse midbrain was developed which preserved functional connectivity between the STN and GP. Mouse STN and GP cells were characterised electrophysiologically by the presence or absence of a voltage sag in response to hyperpolarising current steps indicative of Ih and the presence of rebound depolarisations. The presence of evoked and spontaneous post-synaptic GABA and glutamatergic currents indicated functional connectivity between the STN and GP. In control slices, STN cells fired action potentials at a regular rate, activity which was unaffected by bath application of the GABAA receptor antagonist picrotoxin (50 μM) or the glutamate receptor antagonist CNQX (10 μM). Paired extracellular recordings of STN cells showed uncorrelated firing. Oscillatory burst activity was induced pharmacologically using the glutamate receptor agonist, NMDA (20 μM), in combination with the potassium channel blocker apamin (50 -100 nM). The burst activity was unaffected by bath application of picrotoxin or CNQX while paired STN recordings showed uncorrelated activity indicating that the activity is not produced by the neuronal network. Thus, no regenerative activity is evident in this mouse brain preparation, either in control slices or when bursting is pharmacologically induced, suggesting the requirement of other afferent inputs that are not present in the slice. Using single-unit extracellular recording, dopamine (30 μM) produced an excitation of STN cells. This excitation was independent of synaptic transmission and was mimicked by both the Dl-like receptor agonist SKF38393 (10 μM) and the D2-like receptor agonist quinpirole (10 μM). However, the excitation was partially reduced by the D1-like antagonist SCH23390 (2 μM) but not by the D2-like antagonists sulpiride (10 μM) and eticlopride (10 μM). Using whole-recordings, dopamine was shown to induce membrane depolarisation. This depolarisation was caused either by a D1-like receptor mediated increase in a conductance which reversed at -34 mV, consistent with a non-specific cation conductance, or a D2-like receptor mediated decrease in conductance which reversed around -100 mV, consistent with a potassium conductance. Bath application of dopamine altered the pattern of the burst-firing produced by NMDA an apamin towards a more regular pattern. This effect was associated with a decrease in amplitude and ll1crease in frequency of TTX-resistant plateau potentials which underlie the burst activity.

Failure analysis of cold-formed steel sections

The purlin-sheeting system has been the subject of numerous theoretical and experimental investigations over the past 30 years, but the complexity of the problem has led to great difficulty in developing a sound and general model. The primary aim of the thesis is to investigate the failure behaviours of cold-formed zed and channel sections for use in purlin-sheeting systems. Both the energy method and finite strip method are used to develop an approach to investigate cold-formed zed and channel section beams with partial-lateral restraint from the metal sheeting when subjected to a uniformly distributed transverse load. The stress analysis of cold-formed zed and channel section beams with partially-lateral restraint from the metal sheeting when subjected to a uniformly distributed transverse load is investigated firstly by using the analytical model based on the energy method in which the restraint actions of the sheeting are modelled by using two springs representing the translational and rotational restraints. The numerical results have showed that the two springs have significantly different influences on the stresses of the beams. The influence of the two springs has also been found to depend on the anti-sag bar and the position of the loading line. A novel method is presented for analysing the elastic local buckling behaviour of cold-formed zed and channel section beams with partial-lateral restraint from metal sheeting when subjected to a uniformly distributed transverse load, which is carried out by inputting the cross sectional stresses with the largest compressive stress into the finite strip analysis. By using the presented novel method, individual influences of warning stress, partially lateral restraints from the sheeting and the dimensions of the cross section and position of the loading line on the buckling behaviour are investigated.