Jay A. Gottfried, M.D., Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): This is a request for an NIDCD K08 Mentored Clinical Scientist Development Award for Jay A. Gottfried, MD, PhD, under the mentorship of Dr. M.-Marsel Mesulam, MD, Professor of Neurology, Northwestern University, and the co-mentorship of Dr. Lawrence Marks, PhD, Professor of Psychology, Yale University. Clarifying the biological links between physical and perceptual attributes of odor is a critical issue in olfactory neuroscience. Why does one volatile organic compound "smell" like chocolate, and another like cheese? There has been little systematic research to address these questions. The long-term objective of the proposed project is to understand the nature of odor coding in the human brain. Functional neuroimaging techniques will be combined with olfactory paradigms of cross-adaptation, perceptual learning, and classical conditioning to characterize the neural response properties of primary olfactory (piriform) cortex. These studies will be complemented by olfactory psychophysics approaches to assess the behavioral influence of sensory experience and associative learning on odor quality perception and discrimination. - As part of the career development plan, Dr. Gottfried will learn new skills in human olfactory psychophysics (Dr. Marks), gain additional training in neuroimaging (Drs. Apkarian, Gitelman, Parrish), and receive supervision in behavioral neuroscience (Dr. Mesulam) and clinical neuropsychology (Dr. Weintraub), all complemented by didactic instruction in sensory information theory, statistics, experimental design, and MRI physics. The knowledge acquired during this project should allow Dr. Gottfried to develop into an independent clinician-investigator in human olfaction specializing in functional imaging applications that span the interface between basic olfactory neuroscience and clinical behavioral neurology. Abnormalities in the sense of smell figure prominently in a number of neurological disorders, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. Therefore, a systematic understanding of olfactory function in healthy subjects may lead to new insights concerning the pathophysiology, diagnosis, and perhaps even treatment of these neurodegenerative conditions. By helping to clarify how smells are represented in the intact human brain, the proposed research may have important utility in enlightening our understanding of Alzheimer's disease and other neurological disorders. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): A central goal of neuroscience is to clarify how the brain transforms sensory inputs into perceptual representations. Curiously, even though odor stimuli are at the heart of goal-directed behavior, including feeding, mating, and maternal bonding (for both human and non-human species), very little is known about the neural transformations that create olfactory percepts out of airborne molecules. Because most odors are complex mixtures of different molecules, an important challenge of olfactory systems is to re-assemble these parts into coherent perceptual wholes, or objects, that are perceptually anchored to their original sources in the environment. Understanding how the human brain encodes, discriminates, and categorizes olfactory objects is a key research focus in our lab. An advantage to studying humans is that they can talk and provide ratings of their sensory experiences, offering a highly tractable way to relate brain activity patterns directly to perception. In work proposed here, we will leverage our current strengths in olfactory psychophysics, functional magnetic resonance imaging (fMRI), and pattern-based imaging analysis with new methodological, experimental, and computational approaches to dissect the components of odor perceptual processing at the behavioral and neural levels. By effectively deconstructing either the odor stimulus or the olfactory system, we will be able to gain unique insights into the functional organization of odor object coding and recognition. Specific studies will explore where conscious perception of an odor arises in the human brain, how higher- order regions contribute to perceptual coding and categorization, and whether the brain has access to individual elements of a behaviorally salient food odor. Complementary studies will investigate the role of familiarity, reward learning, and levels of prior belief on the emergence and modulation of odor object patterns and connectivity in olfactory and non-olfactory brain areas. Together these experiments will bring novel understanding of how the human brain overcomes the challenges of recognizing odor objects, and will highlight the key regions that are instrumental in supporting odor perception. In addition, our findings should usefully inform the human neurobiology of the other sensory systems, and should contribute valuable basic information that could help guide development of future diagnostic strategies in patients with Alzheimer's disease and Parkinson's disease, which are associated with olfactory perceptual deficits in their earliest stages.

DESCRIPTION (provided by applicant): It is increasingly clear that olfactory perception is impaired in a wide variety of neurological and neuropsychiatric disorders. However, this growing clinical appreciation for the human sense of smell is offset by a poor basic understanding of its anatomy and physiology. Even the most fundamental assumptions remain unexplored: Is the human olfactory pathway really ipsilateral? Where exactly is primary olfactory cortex? How fast is odor information transmitted through the human olfactory brain? The major aim of this exploratory research project is to investigate odor-evoked patterns of electroencephalographic (EEG) activity directly from the surface of the human brain in patients with medically intractable epilepsy and to map the olfactory cortex with electrical cortical stimulation and cortico-cortical evoked potentials. The highly accurate placement of a high-density invasive electrode array around the temporal and orbitofrontal cortices during standard surgical exploration offers a unique window into the functional anatomy of the olfactory system which has been largely unexplored. Work proposed here will yield a more comprehensive basic understanding of human olfaction, help in diagnosis and prediction of functional outcome in epilepsy patients, and open up new avenues for monitoring disease onset and progression in other neurological disorders involving the sense of smell. PUBLIC HEALTH RELEVANCE: Abnormalities in the sense of smell have particular clinical relevance for a wide variety of neurological and neuropsychiatric disorders, including complex partial epilepsy, Alzheimer's disease, Parkinson's disease, and schizophrenia. In many instances, perceptual deficits of odor discrimination arise early in the course of illness, likely due to the initial accumulation of neuropathological lesions in olfactory limbic regions of the brain. In combining electrocorticography techniques with olfactory psychophysical approaches in patients with medically refractory epilepsy, the proposed research offers a unique window into the fundamental organization of the human olfactory system. Findings from this work may directly guide the development of new tools for lesion localization in epilepsy and for the prediction of functional outcome in epilepsy patients who are being considered for surgical intervention. The work proposed here will additionally provide new insights into monitoring onset and progression of other neurological diseases in which olfactory perceptual impairments are an early sign.

DESCRIPTION (provided by applicant): It is increasingly clear that olfactory perception is impaired in a wide variety of neurological and neuropsychiatric disorders. However, this growing clinical appreciation for the human sense of smell is offset by a poor scientific understanding at the physiological level. Indeed, much of our basic knowledge about the human olfactory system is inferred from studies in rodents and insects, but whether the cortical computations established in animals are relevant for humans is largely unknown. The major aim of this research project is to elucidate the spatiotemporal mechanisms of odor processing in the human olfactory system. In collaboration with the Comprehensive Epilepsy Center and Functional Neurosurgery teams at Northwestern, we will record odor-evoked patterns of electroencephalographic (EEG) activity directly from the human brain in patients with medically intractable seizures. The highly accurate placement of high-density invasive electrodes around the medial temporal and orbital frontal lobes during standard surgical exploration offers a unique window into the functional anatomy of the olfactory system with unparalleled temporal and spatial resolution. Studies are designed to compare odor-evoked oscillatory activity profiles in the olfactory bulb, olfactory (piriform) cortex, and orbitofrontal cortex, and to understand how these different brain regions interact to support olfactory categorical perception and coding. Work proposed here will yield a more comprehensive basic research understanding of human olfaction, particularly with regard to its temporal dynamics, and will provide a direct link to non human animal studies. From a clinical translational perspective, this project may help in diagnosis and prediction of functional outcome in epilepsy patients, and open up new avenues for monitoring disease onset and progression in other neurological disorders involving the sense of smell.

DESCRIPTION (provided by applicant): The sense of smell in humans is pivotal for stimulating appetite, guiding food selection, avoiding spoiled foods and noxious chemicals, and enhancing overall quality of life. Disorders in the sense of smell are commonly observed in Alzheimer's disease and Parkinson's disease, with early accumulation of neuropathological lesions in the peripheral olfactory system including sensory neurons of the nasal mucosa and their projections to the olfactory bulb. Despite the critical contributions of these structures to olfactory perceptual processing, and their widespread involvement in neurodegenerative disorders, we have only a rudimentary understanding of the molecular and cellular components of the human peripheral olfactory system. Moreover, it remains unclear whether the wealth of information available about olfaction in model organisms applies to the anatomical, physiological, and functional properties of the human olfactory system. In research proposed here, we will leverage our complementary strengths in mouse olfactory genetics (Dr. Bozza) and human olfactory neurobiology (Dr. Gottfried) to comprehensively characterize the human peripheral olfactory system with a research breadth and specificity not previously attempted. This work will exploit advanced next-generation sequencing, novel trans vivo gene targeting, immunohistochemistry, electrophysiology, in vivo calcium imaging, and access to human biopsy and post-mortem tissue samples, to study the expression, function, and topographical mapping of human odorant receptor genes. Specific experiments will (1) measure the expression and determine the structure of chemosensory genes including olfactory receptors (ORs) and trace amine- associated receptors (TAARs) in the human olfactory epithelium, (2) characterize the odor response profiles of human odorant receptors when expressed in mouse olfactory sensory neurons, and (3) define the spatial distribution of receptor-specific projections of human olfactory sensory neurons from the epithelium to the olfactory bulb. Together these studies will advance our understanding of the functional organization of the human olfactory system, and will set the stage for clarifying how individual chemoreceptor genes influence odor perception. Finally, by defining the functional organization of olfactory pathways in neurologically intact individuals, this work will serve as a valuable starting point for investigating the impact of neurodegenerative disease on olfactory gene expression, circuit anatomy and sensory function.