Background: Hyposmia is an early symptom of Parkinson’s Disease (PD) that often predates motor symptoms by years. Hyposmia has been shown to have a more consistent link to idiopathic PD than to other movement disorders. Olfaction has the potential to be used as a biomarker for PD, either through clinical evaluation or imaging. Objectives: This study uses functional magnetic resonance imaging (fMRI) to assess differences in olfaction pathways between anosmic early PD patients and age and gender-matched controls. Methods: 12 PD patients and 12 age- and gender-matched control subjects were recruited from the subject panel of a previous UMMS study on olfaction and PD. All PD patients were determined to be anosmic, and all controls were determined to have normal olfaction for their age and gender. All subjects underwent fMRI including periods with and without odorant exposure. Statistical analysis was performed using SPM8, using a general linear model to calculate BOLD signal changes for each scent relative to room air. A random effect model was used to infer general population effects. Results: Control subjects showed significant activation in the piriform cortex, anterior olfactory nucleus, insula, hippocampus and temporal lobe, all regions associated with olfactory processing. Relative to control subjects, PD patients showed no significant BOLD activation in the olfactory pathways of the brain. In response to a citrus scent, PD patients showed activation in the superior and middle frontal lobe, as well as the cingulate gyrus. In response to a cinnamon scent, PD patients showed significant activation in the precuneus and paracentral lobule as well as lower levels of activation in the frontal lobe. PD patients showed no significant areas of activation in response to a mint scent. Conclusion: Our results suggest that anosmic PD patients do not show activation of the olfactory pathways in the brain on exposure to these odorants. Taken together with previous studies, this suggests that BOLD activation in these regions of the brain can reflect clinical olfactory capability. In addition, PD patients show areas of increased activation, particularly in the frontal lobe. These distinct patterns of BOLD activation allow us to consider the feasibility of fMRI as a biomarker for diagnosis and evaluation of PD.

This thesis focuses on several aspects of olfactory processing in Drosophila. In chapter I and II, I will discuss how odorants are encoded in the brain. In both insects and mammals, olfactory receptor neurons (ORNs) expressing the same odorant receptor gene converge onto the same glomerulus. This topographical organization segregates incoming odor information into combinatorial maps. One prominent theory suggests that insects and mammals discriminate odors based on these distinct combinatorial spatial codes. I tested the combinatorial coding hypothesis by engineering flies that have only one class of functional ORNs and therefore cannot support combinatorial maps. These files can be taught to discriminate between two odorants that activate the single functional class of ORN and identify an odorant across a range of concentrations, demonstrating that a combinatorial code is not required to support learned odor discrimination. In addition, these data suggest that odorant identity can be encoded as temporal patterns of ORN activity. Behaviors are influenced by motivational states of the animal. Chapter III of this thesis focuses on understanding how motivational states control behavior. Appetitive memory in Drosophilaprovides an excellent system for such studies because the motivational state of hunger promotes reliance on learned appetitive cues whereas satiety suppresses it. We found that activation of neuropeptide F (dNPF) neurons in fed flies releases appetitive memory performance from satiety-mediated suppression. Through a GAL4 screen, we identified six dopaminergic neurons that are a substrate for dNPF regulation. In satiated flies, these neurons inhibit mushroom body output, thereby suppressing appetitive memory performance. Hunger promotes dNPF release, which blocks the inhibitory dopaminergic neurons. The motivational drive of hunger thus affects behavior through a hierarchical inhibitory control mechanism: satiety inhibits memory performance through a subset of dopaminergic neurons, and hunger promotes appetitive memory retrieval via dNPF-mediated disinhibition of these neurons. The aforementioned studies utilize sophisticated genetic tools for Drosophila. In chapter IV, I will talk about two new genetic tools. We developed a new technique to restrict gene expression to different subsets of mushroom body neurons with unprecedented precision. We also adapted the light-activated adenylyl cyclase (PAC) from Euglena gracilis as a light-inducable cAMP system for Drosophila. This system can be used to induce cAMP synthesis in targeted neurons in live, behaving preparations.