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Olfactory function plays an important role in health and well-being. Deficits have been associated with a greater risk of cognitive decline, dementia, and death, indicating that olfactory ability may be an early marker of cognitive impairment and indicator of brain integrity. In the progression of cognitive impairment related to dementia, intraindividual variability in cognition may precede cognitive decline as an early risk factor, indicating that individuals with more variability in their cognitive performance may have an increased risk of cognitive impairment. Despite a significant amount of literature examining the relationship between olfaction and cognitive decline, to the best of our knowledge, no study has yet examined whether olfaction is associated with the earlier marker of cognitive decline, intraindividual variability in cognition. Project 1. In data drawn from the Rush Memory and Aging Project (N=1501), multistate models were used to estimate the association of olfactory identification with transition patterns through cognitive states including non-impaired cognitive functioning, clinically diagnosed mild cognitive impairment and dementia, and death. Additionally, multinomial regression models were fit to estimate life expectancies for overall and cognitively unimpaired years of life, relative to olfactory identification scores. This dissertation aims to contribute to the current body of literature suggesting potential for the use of olfactory identification as a clinically administered marker for the early detection of cognitive decline and risk of dementia. Project 2. In data collected by our lab (N=65), multilevel models were used to examine whether olfactory identification scores were associated with the magnitude and rate of change of intraindividual variability (IIV) in cognitive functioning. This dissertation aims to address whether olfactory identification is associated with IIV in cognition using self-administered mobile cognitive testing in a 14-day micro-longitudinal study. / Graduate

The olfactory system is believed to be the oldest sensory system. It developed to detect and analyse chemical information in the form of odours, and its organisation follows the same principles in almost all living animals - insects as well as mammals. Likely, the similarities are due to parallel evolution - the same type of organisation has arisen more than once. Therefore, the olfactory system is often assumed to be close to optimally designed for its tasks. Paradoxically, the workings of the olfactory system are not yet well known, although several milestone discoveries have been made during the last decades. The most well-known is probably the disovery of the olfactory receptor gene family, announced in 1991 by Linda Buck and Richard Axel. For this and subsequent work, they were awarded a Nobel Prize Award in 2004. This achievement has been of immense value for both experimentalists and theorists, and forms the basis of the current understanding of olfaction. The olfactory system has long been a focus for scientific interest, both experimental and theoretical. Ever since the field of computational neuroscience was founded, the functions of the olfactory system have been investigated through computational modelling. In this thesis, I present the basis of a biologically realistic model of the olfactory system. Our goal is to be able to represent the whole olfactory system. We are not there yet, but we have some of the necessary building blocks; a model of the input from the olfactory receptor neuron population and a model of the olfactory bulb. Taking into account the reported variability of geometrical, electrical and receptor-dependent neuronal characteristics, we have been able to model the frequency response of a population of olfactory receptor neurons. By constructing several olfactory bulb models of different size, we have shown that the size of the bulb network has an impact on its ability to process noisy information. We have also, through biochemical modelling, investigated the behaviour of the enzyme CaMKII which is known to be critical for early olfactory adaptation (suppression of constant odour stimuli). / Luktsystemet anses allmänt vara det äldsta sensoriska systemet. Det utvecklades för att upptäcka och analysera kemisk information i form av lukter, och det är organiserat efter samma principer hos nästan alla djurarter: insekter så väl som däggdjur. Troligen beror likheterna på parallell evolution -- samma organisation har uppstått mer än en gång. Därför antas det ofta att luktsystemet är nära optimalt anpassat för sina arbetsuppgifter. Paradoxalt nog är luktsystemets arbetssätt ännu inte väl känt, även om flera banbrytande framsteg gjorts de senaste decennierna. Det mest välkända är nog upptäckten av genfamiljen av luktreceptorer, som tillkännagavs 1991 av Linda Buck och Rikard Axel. För detta och efterföljande arbete belönades de med Nobelpriset år 2004. Upptäckten har varit mycket värdefull för både experimentalister och teoretiker, och formar grunden för vår nuvarande förståelse av luktsystemet. Luktsystemet har länge varit ett fokus för vetenskapligt intresse, både experimentellt och teoretiskt. Ända sedan fältet beräkningsbiologi grundades har luktsystemet undersökts genom datormodellering. I denna avhandling presenterar jag grunden för en biologiskt realistisk modell av luktsystemet. Vårt mål är att kunna representera hela luktsystemet. Så långt har vi ännu inte nått, men vi har några av de nödvändiga byggstenarna: en modell av signalerna från populationen av luktreceptorceller, och en modell av luktbulben. Genom att ta hänsyn till nervcellernas rapporterade variationer i geometriska, elektriska och receptor-beroende karaktärsdrag har vi lyckats modellera svarsfrekvenserna från en population av luktreceptorceller. Genom att konstruera flera olika stora modeller av luktbulben har vi visat att storleken på luktbulbens cellnätverk påverkar dess förmåga att behandla brusig information. Vi har också, genom biokemisk modellering, undersökt beteendet hos enzymet CaMKII, som är kritiskt viktigt för adaptering (undertryckning av ständigt närvarande luktstimuli) i luktsystemet.

A rearing methodology for dogwood borer was developed, using standardized procedures at each developmental stage. These methods enabled the establishment of a laboratory colony and efficient production of synchronized cohorts of each of its lifestages throughout the year for specific experimental needs. The behavioral repertoire shown by mated female dogwood borer in an apple orchard was characterized and quantified and the diel periodicity with which those behaviors occurred was determined. Mated females were easily recognized, based on their characteristic casting flight directed toward areas below the graft union of apple trees, and were observed more frequently during the late afternoon and evening. Casting flight, probing with the ovipositor, and oviposition were the most frequent behaviors observed, but the duration of those behaviors was relatively short compared with the much lengthier periods of resting behavior that typically occurred within the canopy. Data from a previous, three-year study in two newly planted apple orchards were subjected to geostatistical analyses to examine the temporal and spatial patterns of infestation by larval dogwood borer and to gain further information about the spatial scales at which oviposition occurs. There were moderate to high degrees of aggregation of dogwood borer infestations on neighboring apple trees, with ranges of spatial dependence from 7.50–19.87 m. No directionality was observed in the spatial autocorrelation of infestation and it appears that females utilized oviposition sites equally along and across orchard rows. The aggregated nature of infestations requires that random, independent samples must be taken from a number of sample pairs at distances greater than the range of spatial dependence to ensure that sample data are not autocorrelated. Alternatively, an efficient sampling program for mapping dogwood borer infestation can be achieved by limiting sample points to distances within the range of spatial dependence. These sample points can be used in interpolating algorithms, such as kriging, to predict infestation at unsampled locations in space for use in site-specific pest management programs. The external morphology of male and female dogwood borer antennae and their sensilla were examined using light and scanning electron microscopy to characterize, measure and compare the types, number, and distribution of sensilla. Although the general shape and size of male and female antennae were similar, those from females possessed a greater number of generally smaller antennal flagellomeres. The flagellum of both male and female antennae contained seven sensillum types including auricillica, basiconica, chaetica, coeloconica, squamiformia, styloconica, and three subtypes of sensilla trichoidea. With the exception of sensilla basiconica, which were present in roughly equal numbers on male and female antennae, all other sensillum types were significantly more abundant on female antennae. The antennae of female dogwood borer appear well equipped to perceive olfactory stimuli, based on the types and number of sensilla present. Coupled gas chromatography and electroantennogram detection (GC-EAD) analyses of headspace collections from damaged and undamaged tissues from apple and dogwood trees were conducted to examine and compare the antennal responsiveness of female dogwood borer to host plant volatiles. A total of 16 and 9 compounds from apple and dogwood tissues, respectively, consistently elicited an antennal response in females. There were no differences in the response of antennae from virgin and mated females, and the amplitude of the female response to host odors was greater than that of males. Six compounds were identified from the headspace collections from apple trees, four of which (octanal, nonanal, decanal, and methyl salicylate) were identified from all apple tissues sampled. A novel compound,α-bergamotene, was identified from injured apple bark, from apple burr knots infested with dogwood borer larvae and from larval dogwood borer frass, and appears to be produced by apple trees in response to injury. Another novel compound, methyl-2,4-decadienoate, was identified from infested burr knot tissue and appears to be produced in response to an insect-plant interaction. Two compounds, hexanoic and nonanoic acid, were identified from headspace collections from dogwood trees. Numerous approaches were used to examine the behavioral response of mated female dogwood borer to host plant headspace collections and to individual compounds from those collections that elicited a strong and repeatable antennal response. Under both natural and semi-natural conditions in the field and in laboratory bioassays, neither attraction/orientation or consistent oviposition were documented and it is apparent that correlating the electrophysiological and behavioral responses of mated female dogwood borer to olfactory stimuli from their host plants will require further research on bioassay development. / Ph. D.

Aedes aegypti mosquitoes are found globally and also act as the primary vector of Zika, dengue, and Chikungunya viruses, for which there are limited treatment options and no vaccines available. The use of insecticides as the main control strategy against diseases transmitted by this mosquito, is increasingly challenged by emerging resistance. Thus, there is a dire need for the development of novel approaches informed by an improved understanding of mosquito biology, to control mosquito populations and, ultimately, disease transmission. Rhythmic biological processes in mosquitoes help optimize resource exploitation by coordinating behaviors and physiology with fluctuating environmental conditions. Such synchronization enables organisms to adjust their physiology, metabolism, and behavior to predictable external cycles. In mosquitoes, circadian rhythmicity has been demonstrated in their biting and oviposition behavior, as well as their locomotor activity. However, little is known regarding how responses to long-range host cues are modulated by the circadian system. Here we show that both antennal sensitivity and olfactory behavior are time-of-day and odor-specific in Ae. aegypti females. Global transcriptomic analysis in whole heads of Ae. aegypti females reveal chemosensory genes differentially expressed throughout the day, providing insight into the molecular mechanisms behind daily variations in olfactory sensitivity and behaviors. We additionally show an odor-induced activation of mosquito behavior. Mosquito locomotion and behavior are also mediated by physiological state, and activity decreases after blood-feeding. Since the central clock components have been shown in other organisms to be redox-sensitive, we explored the role that diet heme plays in mediating behavioral changes following blood ingestion using artificial blood diets. We found that the transcription of the timekeeping gene period is reduced in the head immediately after feeding on a meal containing hemoglobin, but peripheral period transcription is reduced throughout the course of digestion following ingestion of a protein meal independent of hemoglobin inclusion. Overall, our results show that Ae. aegypti behavioral rhythms mediated by rhythmic gene expression are plastic and susceptible to external host cues and host blood digestion. This work can be leveraged for future studies investigating mosquito host-seeking and blood digestion to identify novel targets for vector control. / Doctor of Philosophy / Female mosquitoes rely on blood-feeding in order to produce eggs, but can unfortunately act as vectors of disease if they transmit pathogens when biting. Insecticides are currently our strongest main tool for controlling mosquito disease vectors such as Aedes aegypti, the yellow fever mosquito. However, increasing cases of insecticide resistance present new challenges in vector control, and new strategies to prevent vector-borne disease are needed. The Ae. aegypti mosquito is found globally and transmits Zika, dengue, and Chikungunya viruses, for which there are limited treatment options and no vaccines available. Mosquitoes exhibit rhythms in their gene expression and behaviors such as biting and activity patterns, in order to optimize energy efficiency and coordinate their biology and behaviors with daily fluctuations in the environment. However, it is unknown how their responses to human host odor cues are modulated by their central timekeeping system in the brain. Mosquitoes primarily find a human host via their sense of smell, or olfaction. Odor molecules in the air, emitted by humans, can be detected by mosquitoes' antennae. Here we show that both antennal sensitivity and behavioral responses to odors are time of day and odor-specific in Ae. aegypti females. We quantified gene transcripts in whole heads of Ae. aegypti females as a measure of gene expression, which revealed that genes involved in odor detection are expressed differently throughout the day, providing insight into the molecular mechanisms behind behavioral observations. We also show that mosquito behavior can be activated by odor exposure, and that their behavioral patterns can be influenced for multiple days following exposure. Mosquito behavior is also influenced by blood-feeding, which reduces mosquito activity and flight. Time-keeping genes in the fly brain have been shown to be sensitive to oxidative stress. Blood contains the protein hemoglobin, which can lead to oxidative stress when digested. Using artificial blood diets that allowed us to include or exclude hemoglobin in the meal, we found that the transcription of the timekeeping gene period is reduced in the head immediately after feeding on a diet containing hemoglobin, but is reduced in the rest of the body throughout the course of digestion following ingestion of a protein meal, whether hemoglobin was included or not. This work can be leveraged for future studies investigating mosquitoes' rhythms in host-seeking and blood digestion to identify new effective targets for vector control.