Parkinson’s disease (PD) is a movement disorder that is of basal ganglia origin. It is characterized by a severe loss of dopaminergic input to the striatum and symptoms such as bradykinesia, rigidity and tremor. There is growing evidence that PD is associated with pathological synchronous oscillatory activity in the basal ganglia, which primarily occurs in the 11-30 Hz range, the so-called beta band. The aim of this project was to better understand the oscillatory activity recorded from the basal ganglia of PD patients and to elucidate the significance of this activity in PD. To do this, neuronal firing and local field potentials (LFPs) were recorded from the subthalamic nucleus (STN) and globus pallidus internus (GPi) of PD patients undergoing stereotactic neurosurgery for implantation of therapeutic deep brain stimulation electrodes. Beta oscillatory LFP activity in the STN and GPi was found to be coherent with, and reflect to a certain degree, rhythmic activity in a population of local neurons. I have demonstrated for the first time that the degree of beta oscillatory firing in the STN, which is maximal in the motor portion, correlates with the patients’ benefit from dopaminergic medications, but not with baseline motor deficits. My study has also established that beta oscillatory firing in the STN does not positively correlate with the patients’ tremor scores and that during periods of tremor patients tend to have less beta oscillatory firing and increased neuronal oscillatory firing at the tremor frequency. Temporal examination of the LFPs recorded during periods of intermittent resting tremor revealed that stronger tremor is associated with increased LFP power in the low gamma range (35-55 Hz) and there is a decrease in the ratio of beta to gamma coherence. Similarly, a change in balance between oscillatory activities was observed during levodopa-induced dyskinesias. Finally, when the oscillatory activity in the GPi of PD patients was compared to that in dystonia I found that in dystonia, oscillatory LFP activity is less likely to reflect the neuronal firing. These findings indicate that beta oscillatory activity in the basal ganglia might reflect the degree of dopamine deficiency in the striatum and that the relative strength of oscillatory rhythms may play an important role in mediating the pathological features in PD.

Natriuretic peptides are a group of hormones, including atrial-, brain-, and C-type- natriuretic peptides (ANP, BNP, CNP). BNP can bind to two NP receptors (NPRs) denoted NPR-A (activates guanylyl cyclase) and NPR-C (activates inhibitory G- proteins). This study investigated the electrophysiological effects of BNP on isolated mouse atrial myocytes. Current-clamp experiments show that BNP had no effect on action potential (AP) parameters in basal conditions; however, when pre-stimulated with the ?-adrenergic receptor agonist isoproterenol (ISO), BNP prolonged AP duration. Voltage-clamp experiments demonstrate that BNP increased L-type calcium current (ICa,L) in the presence of ISO without altering cardiac potassium currents. The BNP effect on ICa,L was blocked by A71915 (a selective NPR-A antagonist), maintained in myocytes lacking NPR-C receptors and blocked by the phosphodiesterase-3 (PDE-3) inhibitor milrinone. These data demonstrate that BNP prolongs AP duration and increases ICa,L in atrial myocytes by activating NPR-A, increasing intracellular cGMP, and inhibiting PDE- 3.

Behavioural choices of animals as they acquire resources in the wild are well characterized by foraging theory; however, the neural mechanisms underlying these behaviours are not well understood. The goal of this thesis is to understand the brain mechanisms involved in selecting and executing such foraging behaviours. To do so, rhesus monkeys performed a novel visuosaccadic foraging task while we recorded the activity of single neurons in the intermediate layers of the superior colliculus (SCi). An important innovation of this task is that both target profitability – the measure of value in the simplest case of foraging theory – and saccade choice are measured separately. We hypothesized that target profitability is represented in the SCi in addition to its well characterized role in saccade planning and preparation. Visual Foraging Task: Monkeys harvested coloured dots representing prey items by fixating them for a pre-specified handling time. On each trial, multiple prey are presented, sharing identical physical attributes except that each was one of three colours. All prey of the same colour shared the same profitability [Profitability = reward magnitude (ml)/handling time (s)]. According to foraging theory, intake of reward is maximized if prey are selected in descending order of their profitability. Indeed, we found subjects gradually approached optimal efficiency. We computed an index of the relative subjective profitability of each prey colour, which compared the rank order with which monkeys chose prey of each colour. This subjective index of profitability was then compared to concomitant SC activity attributed to the prey item in the neuron’s response field (RF). First, we found that the amount of SC activity reflected the subjective profitability of the RF targets, and established that this effect was not simply a result of saccade goal planning. Second, profitability information remains dominant throughout the handling period until reward delivery, after which activity also became selective for upcoming saccades. Together, our results highlight the prominent role of target profitability in shaping SCi activity. We propose that profitability information in the SCi may play an important role in resolving competition between numerous target representations to choose the next saccade goal. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2011-02-21 15:37:43.468

Learning and memory mechanisms that are normally related to natural rewards, such as long-term potentiation (LTP) and depression (LTD), may be usurped by the voluntary intake of drugs of abuse. The maladaptive behaviour that characterizes addiction is thought to arise from persistent changes in excitatory synaptic function in brain reward circuits. The oval region of the dorsal bed nucleus of the stria terminalis (ovBST) is one such region susceptible to drug-induced synaptic remodeling and is implicated in drug-driven behaviors, reinforcement and stress-induced relapse to drug-seeking. Using whole-cell voltage clamp recordings of ovBST neurons in brain slices prepared from adult Long-Evans rats, we demonstrated an unrestrained increase in AMPAR-mediated excitatory transmission with maintenance of cocaine self-administration. This is unlike self-administration of a natural reward, in which we observed an enhancement and then decline of AMPAR-mediated transmission with continued intake. Additionally, we demonstrate impairment in NMDAR-mediated LTD in ovBST neurons with cocaine self-administration. This impairment may be due to resilient GluN2B-containing NMDARs, as application of a GluN2B-antagonist rescued impaired LTD. Based on models of NMDAR-mediated bidirectional plasticity we suggest that a drug-induced de-regulation between GluN2A and GluN2B subunits impairs LTD, which may underlie the enhancement AMPAR-mediated transmission. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2012-05-31 09:46:39.312

No description available.

Extracellular potentials due to firing of action potentials are computed around cortical neurons and populations of cortical neurons. These extracellular potentials are calculated as a sum of contributions from ionic currents passing through the cell membrane at various locations using Maxwell's equations in the quasi-static limit. These transmembrane currents are found from simulations of anatomically reconstructed cortical neurons implemented as multi-compartmental models in the simulation tool NEURON. Extracellular signatures of action potentials of single neurons are calculated both in the immediate vicinity of the neuron somas and along vertical axes. For the neuronal populations only vertical axis distributions are considered. The vertical-axis calculations were performed to investigate the contributions of action potential firing to laminar-electrode recordings. Results for high-pass (750 - 3000 Hz) filtered potentials are also given to mimic multi-unit activity (MUA) recordings. Extracellular traces from single neurons and populations (both synchronous and asynchronous) of neurons are shown for three different neuron types: layer 3 pyramid, layer 4 stellate and layer 5 pyramid cell. The layer 3 cell shows a 'closed-field' configuration, while the layer 5 pyramid demonstrates an 'open-field' appearance for singe neuron simulations which is less apparent in population simulations. The layer 4 stellate cell seems to fall somewhere in between the open- and closed-field scenarios. Comparing single neuron and synchronous populations, the amplitudes of the extracellular traces increase as population radii increase, though the shapes are generally similar. Asynchronous populations produce small amplitudes due to a time convolution of various neuron contributions. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2005

The brain is protected by the blood brain barrier (BBB); areas lacking the BBB are termed circumventricular organs (CVOs). The SFO, a CVO is capable of detecting and responding to satiety signals that regulate energy balance. Insulin, a satiety signal, plays a role in energy balance and its actions at the SFO are unknown. The goal was to determine if cultured SFO neurons are electrophysiologically sensitive to insulin. Of 27 neurons tested 33% neurons hyperpolarized (-8.7 ± 1.7 mV), 37% neurons depolarized (10.5 ±2.8 mV) and 30% neurons (8 out of 27) showed no change in membrane potential. Input resistance changes indicated the modulation of two ion channels. Pharmacological data suggests hyperpolarization arises from the opening of KATP channels and depolarization results from the opening of non-selective cationic channels. Thus insulin modulates the electrical activity of SFO neurons and supports that the SFO is a sensor for maintaining energy homeostasis.

Parkinson’s disease (PD) is a movement disorder that is of basal ganglia origin. It is characterized by a severe loss of dopaminergic input to the striatum and symptoms such as bradykinesia, rigidity and tremor. There is growing evidence that PD is associated with pathological synchronous oscillatory activity in the basal ganglia, which primarily occurs in the 11-30 Hz range, the so-called beta band. The aim of this project was to better understand the oscillatory activity recorded from the basal ganglia of PD patients and to elucidate the significance of this activity in PD. To do this, neuronal firing and local field potentials (LFPs) were recorded from the subthalamic nucleus (STN) and globus pallidus internus (GPi) of PD patients undergoing stereotactic neurosurgery for implantation of therapeutic deep brain stimulation electrodes. Beta oscillatory LFP activity in the STN and GPi was found to be coherent with, and reflect to a certain degree, rhythmic activity in a population of local neurons. I have demonstrated for the first time that the degree of beta oscillatory firing in the STN, which is maximal in the motor portion, correlates with the patients’ benefit from dopaminergic medications, but not with baseline motor deficits. My study has also established that beta oscillatory firing in the STN does not positively correlate with the patients’ tremor scores and that during periods of tremor patients tend to have less beta oscillatory firing and increased neuronal oscillatory firing at the tremor frequency. Temporal examination of the LFPs recorded during periods of intermittent resting tremor revealed that stronger tremor is associated with increased LFP power in the low gamma range (35-55 Hz) and there is a decrease in the ratio of beta to gamma coherence. Similarly, a change in balance between oscillatory activities was observed during levodopa-induced dyskinesias. Finally, when the oscillatory activity in the GPi of PD patients was compared to that in dystonia I found that in dystonia, oscillatory LFP activity is less likely to reflect the neuronal firing. These findings indicate that beta oscillatory activity in the basal ganglia might reflect the degree of dopamine deficiency in the striatum and that the relative strength of oscillatory rhythms may play an important role in mediating the pathological features in PD.

No description available.

Invertebrate T-type calcium channels cloned from the great pond snail, Lymnaea Stagnalis (LCav3) possess highly sodium permeant ion channel currents by means of alternative splicing of exon 12. Exon 12 is located on the extracellular turret and the descending helix between segments 5 and segments 6, upstream of the ion selectivity filter in Domain II. Highly-sodium permeant T-type channels are generated without altering the selectivity filter locus, the primary regulatory domain known to govern ion selectivity for calcium and sodium channels. Comparisons of exon 12 sequences between invertebrates and vertebrate T-type channels reveals a conserved pattern of cysteine residues. Calcium-selective mammalian T-type channels possess a single cysteine in exon 12 in comparison to invertebrate T-type channels with either a tri- or penta- cysteine framework. Cysteine residues in exon 12 were substituted with a neutral amino acid, alanine in LCav3 channels harbouring exon 12a and 12b to mimic the turret structure of vertebrate T-type channels. The results generated T-type channels that were even more sodium-permeable than the native T-type channels in snails. Furthermore, permeant divalent ions similar in structure to calcium (eg. barium) were unable to sufficiently block the monovalent ion current of channels lacking cysteines in Domain II, suggesting that the pore is highly sodium permeant, and has weak affinity and block by permeant divalent ions other than calcium. Besides ion selectivity, the cysteine mutated T-type channels were 10 to 100 fold more sensitive to inhibition by nickel and zinc, respectively. The cysteine mutation data highly suggests that the cysteines form an extracellular structure that regulates ion selectivity and shields T-type channels from block by nickel and zinc. In addition, we replaced exon 12 from the sodium permeant snail T-type channel with exon 12 from human Cav3.2 channels. The snail T-type channel with exon 12 from human T-type channels produced a T-type channel that was modestly sodium permeable, but did not confer the high calcium permeability of Cav3.2 channels. These findings suggest that the cysteine containing extracellular domains in exon 12 are not sufficient to generate calcium selective channels similar to human Cav3.2 and likely work in concert with other extracellular domains to regulate the calcium or sodium selectivity of T-type channels.