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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

This doctoral dissertation examines the presence and function of the sense of smell in Early Modern Spanish literature. It studies the use of the olfactory in key works of the period and analyzes how each one reflects a certain contemporary aspect of Spanish culture and society. Though its role in literature has not been considered as widely as that of the other senses, smell's indubitable presence in the works and its unique qualities allow for a singular approach to the texts in question as they serve to preserve the beliefs, themes and trends of Renaissance and Golden Age Spain. This work analyzes four texts, one from the late Middle Ages and three from the Early Modern period: Fermoso cuento de una santa enperatrís que ovo en Roma & de su castidat (14th century); La Celestina, Fernando de Rojas (1499); Don Quijote, Miguel de Cervantes y Saavedra (1605 and 1615); "La inocencia castigada," María de Zayas (in Desengaños amorosos - 1647). These selected works permit an analysis of the function of smell within a variety of themes and across the span of the period. Serving to orient us in our search for literary scent, Chapter 1 presents considerations for the study of the olfactory in literature - how the senses have been perceived over time, how smell differs from the other senses and how smells are represented verbally. Chapter 2 deals with Fermoso cuento de una santa enperatrís que ovo en Roma & de su castidat and the way that the medieval saint-sinner dichotomy is reflected in pleasant and foul smells, respectively. Chapter 3 reviews the historical, cultural and social changes that took place in Iberia from the end of the Middle Ages into the Early Modern period to better understand changing perceptions and how they appear in literature during this time. Chapter 4 studies La Celestina and the title character's sensorial (olfactory) manipulation of others in the work. Chapter 5 looks at the role of smell, contrasted with the other senses, in Don Quijote's creation of Dulcinea. Chapter 6 analyzes the martyrdom of women in marriage as presented through smell in "La inocencia castigada." The epilogue briefly considers the role of smell in Lazarillo de Tormes and its implications for further study of the olfactory in literature. / Spanish

Human olfaction is significantly linked to memory, emotion, and learning. As the global population ages, subsequent physical and cognitive decline substantiates a need for more accessible technologies that improve quality of life for older adults. Olfactory disfunction, known to increase with age, is indicative of depression and loneliness, afflictions already prevalent among older communities. Reminiscence therapy presents a unique opportunity to combat loneliness utilizing olfactory cues. Calling on theories of embodied and tangible interaction, this thesis proposes the design of an olfactory radio, leveraging the strong connection between smell and memory to prompt reminiscence while reducing loneliness through the exchange of ‘scent-stories’. Results of the study highlight the potential of olfactory interaction to create meaningful, embodied experiences for older adults while promoting social connection. The paper concludes with a call for more multimodal and tangible approaches to human-computer interaction that better address the bodies for whom we design.

Genius loci has been described as "the spirit of place". The main interest in considering an urban monastery program is to create a place that embodies the spirit and culture of Tibetan Buddhism in the context of urban Washington, D.C. Given Tibet's unique culture that has developed over centuries without much Western influence, and it recent history of Chinese rule, religious persecution and infiltration of its language, culture and environment, the challenge of this program is to represent the traditions of Tibetan Buddhism in a modern language of architecture. / Master of Architecture

Infectious disease transmission is driven by a complex suite of drivers with behavior and landscape dynamics contributing to epidemics across host-pathogen systems. However, our understanding of the interaction between landscape, behavior, and infectious disease remains limited. In the banded mongoose (Mungos mungo), a novel tuberculosis pathogen, Mycobacterium mungi, has emerged in Northern Botswana that is transmitted through olfactory communication behaviors. Using this host-pathogen system, this thesis explores the influence of various land use areas along the human-wildlife interface on animal behavior, and ultimately, pathogen transmission potential. Using behavior data from remote sensing camera traps, a generalized linear mixed model identified vigilance behavior, land use, and their interaction as important factors in predicting olfactory behavior. Cluster and Classification and Regression Tree (CART) analysis of active den sites (n= 308, across 23 troops) identified the important characteristics of dens across land use areas. In human-modified environments, man-made den sites persisted longer than did natural dens which became unsuitable through environmental processes (e.g., collapse). We also document the occurrence of nighttime activity for this species, perceived to be strictly diurnal. These data provide information critical to the development of robust computational models and underscore the importance of both landscape and behavior in accurately predicting and managing infectious disease outbreaks. / M. S.

Les figures de neuroanatomie de ce mémoire peuvent être téléchargées en haute résolution. / Une voie neuronale sous-tendant la locomotion induite par la détection d’odorants a été découverte chez la lamproie (Derjean et al., 2010). Le signal olfactif est relayé du bulbe olfactif médian au tubercule postérieur, puis à la région locomotrice mésencéphalique et enfin aux cellules réticulospinales qui activent les réseaux locomoteurs spinaux. Des études récentes démontrent que le bulbe olfactif médian est sous l’influence d’une inhibition GABAergique tonique qui régule les réponses des cellules réticulospinales à la stimulation du nerf olfactif (Daghfous et al., 2013). Des mécanismes de modulation supplémentaires pourraient exister dans le bulbe olfactif de Petromyzon marinus puisqu’il contient aussi des fibres dopaminergiques. Chez tous les vertébrés étudiés, la dopamine joue un rôle important dans le traitement olfactif. Des techniques anatomiques (traçage et immunofluorescence) et physiologiques (enregistrements intracellulaires) ont été utilisées pour étudier la modulation dopaminergique de la voie olfacto-motrice. L’immunofluorescence ciblant la dopamine a révélé des fibres plus nombreuses dans la partie médiane du BO et à proximité de neurones de projection et de fibres olfactives. De plus, aucun corps cellulaire immunopositif n’a été détecté dans le bulbe olfactif. L’enregistrement des réponses synaptiques des cellules réticulospinales à la stimulation du nerf olfactif a été réalisé dans le cerveau isolé in vitro. L’injection locale de dopamine dans le bulbe olfactif médian diminue de moitié l’amplitude de réponse. Sous l’effet d’un antagoniste des récepteurs GABAA dans le bain ou localement dans le bulbe olfactif médian, les dépolarisations soutenues enregistrées sont supprimées par l’injection de dopamine. Cependant, l’injection individuelle ou combinée dans le bulbe olfactif médian d’antagonistes sélectifs des récepteurs D1 ou D2, soit le SCH 23390 et l’éticlopride, demeure sans effet significatif sur les réponses olfacto-motrices, indiquant l’absence d’activité dopaminergique tonique. Pour localiser les neurones responsables de cette modulation, des injections de traceur axonal ont été combinées avec l’immunofluorescence ciblant la dopamine. Des cellules dopaminergiques projetant au BO médian ont été observées dans les noyaux dopaminergiques du tubercule postérieur et de l’hypothalamus périventriculaire. Dans l’ensemble, nos résultats montrent anatomiquement et physiologiquement la présence d’une innervation dopaminergique dans le bulbe olfactif médian qui a une action inhibitrice sur le traitement olfacto-moteur. / A neural substrate underlying odor-evoked locomotion was revealed in lampreys (Derjean et al., 2010), involving a neural pathway extending from the medial part of the olfactory bulb to the posterior tuberculum. The signal is then relayed to the mesencephalic locomotor region and eventually reaches reticulospinal cells that activate the spinal locomotor networks. Recent research in the lab (Daghfous et al., 2013) shows that the medial olfactory bulb, is under a tonic GABAergic inhibition gating reticulospinal cell responses to olfactory nerve stimulation. Additional modulatory mechanisms might exist in the olfactory bulb of Petromyzon marinus as it also contains dopaminergic fibers. In every vertebrate studied to date, dopamine plays an important role in olfactory processing. Anatomical (axonal tracers and immunofluorescence) and physiological (intracellular recordings) techniques were used to investigate the dopaminergic modulation of the olfacto-motor pathway. Dopamine immunofluorescence showed scarce innervation of the olfactory bulb that was most abundant in the medial part and in close vicinity to projection neurons and olfactory nerve fibers. Additionally, no dopamine-immunoreactive cell bodies were detected in the olfactory bulb. Synaptic responses of reticulospinal cells to olfactory nerve stimulation were recorded in the isolated brain. Local injection of dopamine in the medial olfactory bulb induces an almost two-fold decrease of the synaptic responses. When GABAA receptor antagonist GABAzine was also injected in the medial olfactory bulb, the effect of dopamine was much more evident and could suppress large bursts of action potentials. However, D1 (SCH 23390) and D2 (Eticlopride) receptor antagonists injection in the medial olfactory bulb failed to alter the amplitude of reticulospinal cell responses to olfactory nerve stimulation, indicating that this modulation is not tonic. To locate the neurons responsible for this modulation, tracer injections combined with dopamine immunofluorescence were performed. Dopaminergic cells projecting to the medial olfactory bulb were found in the dopaminergic nuclei of the posterior tuberculum and the periventricular hypothalamus. Altogether, our results show anatomically and physiologically the presence of a dopaminergic innervation within the medial olfactory bulb that mediates inhibitory effects on olfacto-motor signaling.

During embryonic development a variety of tissues and organs such as the lung, eye, and kidney are being formed. The generation of functional organs is regulated by reciprocal cell-cell interactions. Via the secretion of soluble molecules one type of cells affect the fate of their neighboring cells. A central issue in organogenesis is how a cell interprets such extrinsic signals and adopts a specific fate, and how the cell in response to this signal establishes reciprocal signaling. Transcription factors play a critical role in this process and my thesis focuses on the role of the LIM-homeodomain transcription factor, Lhx2, in the development of three different organ systems, the liver, the hematopoietic system and the olfactory system. The liver is formed from endoderm of the ventral foregut and mesenchyme of the septum transversum (st) and its development depends upon signaling interactions between these two tissues. As the liver becomes a distinct organ it is colonized by hematopoietic cells and serves as hematopoietic organ until birth. The fetal liver provides a microenvironment that supports the expansion of the entire hematopoietic system (HS) including the hematopoietic stem cells (HSCs). Liver development in Lhx2-/- embryos is disrupted leading to a lethal anemia due to insufficient support of hematopoiesis. To further investigate the role of Lhx2 in liver development I analyzed gene expression from the Lhx2 locus during liver development in wild-type and Lhx2-/- mice. Lhx2 is expressed in the liver associated st mesenchymal cells that become integrated in the liver and contribute to a subpopulation of hepatic stellate cells in adult liver. Lhx2 is not required for the formation of these mesenchymal cells, suggesting that the phenotype in Lhx2-/- livers is due to the presence of defective mesenchymal cells. The putative role of Lhx2 in the expansion of the HS was examined by introducing Lhx2 cDNA into embryonic stem cells differentiated in vitro. This approach allowed for the generation of immortalized multipotent hematopoietic progenitor cell (HPC) lines that share many characteristics with normal HSCs. The Lhx2-dependent generation of HSC-like cell lines suggests that Lhx2 plays a role in the maintenance and/or expansion of the HS. To isolate genes putatively linked to Lhx2 function, genes differentially expressed in the HPC lines were isolated using a cDNA subtraction approach. This allowed for the identification of a few genes putatively linked to Lhx2 function, as well as several stem cell-specific genes. The antagonist of Wnt signalling, Dickkopf-1 (Dkk-1), was identified in the former group of genes as it showed a similar expression pattern in the fetal liver, as that of Lhx2 and expression of Dkk-1 in fetal liver and in HPC lines appeared to be regulated by Lhx2. This suggests that Dkk-1 plays a role in liver development and/or HSC physiology during embryonic development. During development of the olfactory epithelium (OE) neuronal progenitors differentiate into mature olfactory sensory neurons (OSNs) that are individually specified into over a thousand different subpopulations, each expressing a unique odorant receptor (OR) gene. The expression of Lhx2 in olfactory neurons suggested a potential role for Lhx2 in the development of OSNs. To address this OE from Lhx2-/- and wild-type mice was compared. In the absence of functional Lhx2 neuronal differentiation was arrested prior to onset of OR expression. Lhx2 is thus required for the development of OSN progenitors into functional, individually specified OSNs. Thus, Lhx2 trigger a variety of cellular responses in different organ systems that play important roles in organ development in vivo and stem cell expansion in vitro.