MRI has been applied to directly detecting neuronal activity. The direct detection of multiple dendrite sites within the brain offers an important tool in the analysis of the brain for mapping cognition. In this, multiple dendrite contributions can be applied with the same model between the parallel and anti-parallel orientations depending on a spatial depolarization and re-polarization wave. Once the strength of the dendritic contribution was calculated, the spatially dependent phase shifts were theoretically modeled. In the construction of this column the dendrites were modeled as having cylindrical symmetry, uniform current density, and the intracellular current was taken as the primary current contribution to the volume dendrite model. The method examined the system using the known volume density of the dendrites treated with the current dipole model over a voxel. The maximum effect of the field strength, phase, and percent signal change was theoretically calculated. The maximum field was calculated as 1.07 nT, the maximum phase was calculated as 2.14 mrad, and the maximum percent signal increase was calculated as 0.217 %. / Overview of the basics of MRI imaging -- Overview of neural activation and imaging of the activation -- Theory and methods -- Results. / Department of Physics and Astronomy

Glutamate is the primary excitatory neurotransmitter in the central nervous system. Extracellular glutamate concentrations are tightly regulated to avoid over-stimulation of glutamate receptors, which leads to a cascade of deleterious processes collectively known as excitotoxicity. Excitotoxicity is common to several neurodegenerative disorders and CNS injuries, including stroke and Alzheimer’s disease (AD). The projects described in this thesis were designed to uncover novel protective pathways in excitotoxic neurodegeneration. Excessive activation of the DNA repair enzyme, poly(ADP-ribose) polymerase-1 (PARP-1), is a convergence point for neuron death signaling in excitotoxic pathways. In AD, the peptide amyloid-β1-42 (Aβ1-42) is aberrantly produced, leading to excitotoxic neuron death in vitro. To investigate links between Aβ1-42 and PARP, we treated cultured cortical neurons with Aβ1-42 and determined whether PARP-1 contributes to neuron death. Increased neuron death was observed after Aβ1-42 exposure. A non-selective PARP-1/2 inhibitor significantly reduced Aβ1-42-induced death while elimination of PARP-1 alone was not neuroprotective. This suggests that PARP-2 or combined effects of PARP-1 and PARP-2 are required for Aβ1-42-induced neuron death. A hallmark of PARP over-activation is depletion of intracellular NAD+ and ATP levels, yet nearly all studies examining adenine nucleotide levels use separate biochemical samples to measure nucleotides individually. We developed two HPLC methods for simultaneous separation of NAD+, ATP, ADP and AMP. We determined that PARP-1 activation in astrocytes leads to near complete NAD+ depletion, followed by partial loss of ATP pools and total adenine nucleotide pools. Finally, we hypothesized that conjugated linoleic acid (CLA), a naturally occurring polyunsaturated fatty acid, is capable of enhancing neuron survival after an excitotoxic insult. Cultured cortical neurons were exposed to glutamate in the presence and absence of CLA. CLA levels likely achievable in human plasma and brain tissue during dietary supplementation regimens, protected neurons against glutamate excitotoxicity when given during or up to five hours after glutamate exposure. Several markers of mitochondrial damage and intrinsic apoptosis were examined. CLA stabilized mitochondrial membrane potential and permeability, shedding light on the mechanism of CLA neuroprotection. Overall, our research suggests a role for PARP in Aβ1-42 toxicity and identifies a novel role for CLA in neuroprotection following excitotoxicity.

Mitofusin 1 and 2 are outer-mitochondrial membrane proteins that have been shown to be involved in fusion. Mitofusin 2 has also been associated with apoptosis and development. When Mfn1 and Mfn2 were each conditionally knocked out from the cerebellum, Purkinje cells in Mfn2 deficient cerebellum during development had undergone neurodegeneration. Mutations in Mfn2 have also been associated with the Charcot Marie Tooth Type 2A (CMT2A). We want to asses the effect Mfn2 and Mfn1 might have on the development of other regions of the brain such as the telencephalon. We generated Mfn1 and Mfn2 conditional knockouts in the telencephalon by crossing them with Foxg1 Cre - a cre expressed in the telencephalon. We found that Mfn1 deficient mice have lost their corpus callosum at the midline, but survive over 6 months with a decrease in progenitor cells postnatally. Mfn2 deficient mice die between P9 and P12 with a decrease in progenitor cells postnatally and a decrease in number of neurons in the cortex. Therefore, our results suggest that Mfn1 and Mfn2 play a significant role in the development of the telencephalon.

Signal processing in the visual system is mediated by classic neurotransmission and neuropeptidergic modulatory pathways. In Dipteran insects, especially in the fruitfly Drosophila melanogaster, the morphology of the visual system is very well described. However neurotransmitter and neuropeptidergic circuits within the optic lobe neuropil are only partially known. Using several transgenic fly lines and antibodies we determined the localization of the classical neurotransmitters GABA, acetylcholine and glutamate in the visual system, and their putative targets via detecting several neurotransmitter receptors. We paid particular attention to the peripheral neuropil layer called the lamina, where the light signals are filtered, channeled and amplified (Paper I). We discovered four new types of efferent tangential neurons branching distally to the lamina. Among them was the first neuropeptidergic neuron (LMIo) in this region of Drosophila. The LMIo expresses myoinhibitory peptide (MIP) and has its cell body located close to the main lateral clock neurons that express the neuropeptide pigment-dispersing factor (PDF)(Paper II). Since in other Dipteran species PDF is expressed in processes distally to the lamina, we performed comparative anatomical studies of the MIP, PDF, Ion Transport Peptide (ITP) and serotonin (5-HT) distribution in the visual system of the flies Drosophila and Calliphora. Our data suggest that PDF signaling distal to the lamina of the blowfly might be replaced by MIP signaling in the fruitfly, while ITP and 5-HT expression is conserved in the two species (Paper III). Serotonin is crucial in light adaptation during the daily light-dark cycles. We analyzed putative serotonergic circuits in the lamina. We found that LMIo neurons express the inhibitory receptor 5-HT1A, while 5-HT1B and 5-HT2 are both expressed in the epithelial glia of the lamina. Another novel wide-field neuron with lamina branches expresses the excitatory serotonin receptor 5-HT7. Our studies have identified a fairly complex neuronal circuitry in the tangential plexus above the lamina. (Paper IV). Finally we tested circadian locomotor activity rhythms in flies with the GABAB receptor knocked down on the lateral PDF-expressing clock neurons. We observed significant changes in the activity periods and diminished strength of rhythmicity during DD suggesting a modulatory role of GABA in clock function (Paper V). / At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: Manuscript. Paper 5: Manuscript.

Thesis (Ph. D.)--Case Western Reserve University, 2007. / [School of Medicine] Department of Neurosciences. Includes bibliographical references.

Thesis (Ph.D.)--University of Melbourne, Howard Florey Institute of Experimental Physiology and Medicine and Dept. of Anatomy and Cell Biology, 2003. / Typescript (photocopy). Includes bibliographical references (leaves 108-130).

Thesis (Ph. D.)--University of Oregon, 2007. / Typescript. Includes vita and abstract. Includes bibliographical references (leaves 107-114). Also available for download via the World Wide Web; free to University of Oregon users.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 5 uppsatser.

Diss. (sammanfattning) Linköping : Univ., 2001. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 4 uppsatser.