Thesis (Ph. D.)--University of Oregon, 2000. / Typescript. Includes vita and abstract. Includes bibliographical references (leaves 140-159). Also available for download via the World Wide Web; free to University of Oregon users.

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published_or_final_version / Physiology / Doctoral / Doctor of Philosophy

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Thesis (Ph. D.)--Rutgers University, 2008. / "Graduate Program in Neuroscience." Includes bibliographical references (p. 94-112).

Thesis (M.Sc.) - University of Queensland, 2003. / Includes bibliography.

Thesis (M. A.)--University of North Texas, May, 2007. / Title from title page display. Includes bibliographical references.

Neurons transmit information through spikes in neural network through synaptic couplings. Given the prevalence of correlation among neural spike trains experimentally observed in different brain areas, it is of interest to study how neurons compute correlated input. Yet how it depends on the synaptic properties and conductance kinetics in neuronal interaction is very little known. Through simulation of leaky integrate-and-fire (LIF) neurons, we have studied the effects of excitatory and inhibitory synaptic decay times, level of background activities and higher-order conductance effects on the output correlation of different time scales for neurons receiving correlated excitatory input, and provided important understanding on the mechanism of how these factors influence neural computation of such correlated input. We showed that when the conductance effects are totally ignored, increasing excitatory synaptic decay time jitters output spike time and shapes the output correlation of short to medium time scale, while the output correlation of very long time scale is determined by the membrane time constant. When conductance effects are considered, this is no longer the case as the effective membrane time constant becomes comparable to the excitatory decay time. We found that the ratio of long-term correlation to short-term correlation (synchrony) increases with excitatory synaptic decay time and decreases with the level of input activities due to the combined effects of jittered spike time, which can be predicted from the time window and magnitude of the effects of a single input spike on membrane potential, and burst firing. In particular, it is possible for neurons with small excitatory synaptic decay time in high conductance state to respond to correlated input by solely giving extra precisely timed synchronous spikes without exhibiting correlation of longer time scale. In addition, we found that inhibitory synaptic decay time shapes correlation by controlling the relative contribution of excitatory and inhibitory input to output firing. As a result, both output correlation and synchrony increase with it. These results are qualitatively true for a wide range of input correlation and synaptic efficacies. Finally, we showed that fluctuations of conductance and membrane potential reduce output correlation, which can be explained by the reduced prevalence of burst firing. These results suggest that spike initiation dynamics of neurons can be well characterized by their synaptic decay times and the level of input activities. These properties are therefore expected to influence neurons’ ability to code temporal information. These results also hint that correlation, in particular that of long time scale, would be lower if more realistic biophysical features like neural adaptations and network circuitry with feed-forward or recurrent inhibition are considered. It suggests that studies using single LIF neurons tend to overestimate output correlation and underestimate the ability of neurons in producing precisely timed output.

Neuronal circuit output is dependent on the embedded synapses’ precise regulation of Ca2+ mediated release of neurotransmitter filled synaptic vesicles (SVs) in response to action potential (AP) depolarizations. A key determinant of SV release is the specific expression, organization, and abundance of voltage gated calcium channel (VGCC) subtypes at presynaptic active zones (AZs). In particular, the relative distance that SVs are coupled to VGCCs at AZs results in two different modes of SV release that dramatically impacts synapse release probability and ultimately the neuronal circuit output. They are: “Ca2+ microdomain,” SV release due to cooperative action of many loosely coupled VGCCs to SVs, or “Ca2+ nanodomain,” SV release due to fewer more tightly coupled VGCCs to SVs. VGCCs are multi-subunit complexes with the pore forming a1 subunit (Cav2.1), the critical determinant of the VGCC subtype kinetics, abundance, and organization at the AZ. Although in central synapses Cav2.2 and Cav2.1 mediate synchronous transmitter release, neurons express multiple VGCC subtypes with differential expression patterns between the cell body and the pre-synapse. The calyx of Held, a giant axosomatic glutamatergic presynaptic terminal that arises from the globular bushy cells (GBC) in the cochlear nucleus, exclusively uses Cav2.1 VGCCs to support the early stages of auditory processing. Due to its experimental accessibility the calyx provides unparalleled opportunities to gain mechanistic insights into Cav2.1 expression, organization, and SV release modes at the presynaptic terminal. Although many molecules are implicated in mediating Cav2.1 expression and SV to VGCC coupling through multiple binding domains on the C-terminus of the Cav2.1 a1 subunit, the underlying fundamental molecular mechanisms remain poorly defined. Here, using viral vector mediated approaches in combination with Cav2.1 conditional knock out transgenic mice, we demonstrate that that there a two independent pathways that control Cav2.1 expression and SV to VGCC coupling at the calyx of Held. These implications for the regulation of synaptic transmission in CNS synapses are discussed. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2016. / FAU Electronic Theses and Dissertations Collection

This thesis describes efforts at the interface of chemistry and neuroscience to design and characterize fluorescent probes capable of tracing neurotransmitters from individual release sites in brain tissue. As part of the Fluorescent False Neurotransmitters (FFNs) program, small organic fluorophores have been developed that undergo uptake into specific presynaptic release sites and synaptic vesicles by utilizing the native protein machinery, which can then be released during neuronal firing. The most advanced generation of FFNs are pH-sensitive, and display an increase in fluorescence when released from the acidic vesicular lumen into the extracellular space, called a “FFN Flash.” In Chapter 2, the utility of the dopamine-selective and pH-sensitive functionality of FFN102 to study the mechanisms that regulate changes in pre-synaptic plasticity, a critical component of neurotransmission was explored. This included using the FFN flash to quantitatively trace dopamine release, changes in the release probability of individual release sites, and changes in vesicular loading that can affect quantal size. The second goal of this thesis research, as detailed in Chapters 3 and 4, sought to expand the substrate scope of the FFN program to neurotransmitter systems other than dopamine. Described in Chapter 3, is the identification of a fluorescent phenylpyridinium, APP+, with excellent labeling for dopamine, norepinephrine, and serotonin neurons, however, the properties of the probe were found to be ill-suited for measuring neurotransmitter release. As a result, it was concluded that this class of compounds was not suitable for generating viable FFN leads. In contrast, Chapter 4 highlights the design, synthesis, and screening towards generating the novel noradrenergic-specific FFN, FFN270. This probe was further tested for application in acute murine brain slices where it labeled noradrenergic neurons, and was demonstrated to release upon stimulation. This chapter also describes the application of this compound in a series of in vivo experiments, where the ability to measure norepinephrine release from individual release sites was demonstrated in a living animal for the first time. This work opens the possibility for many exciting future FFN experiments studying the presynaptic regulation of neurotransmission in vivo.