Janina Seubert

Persistent preoccupation with food in the absence of metabolic need ("food noise") is increasingly recognized as a key driver of overeating in obesity and is strongly reduced by pharmacological treatments with GLP-1 agonists. Despite its clinical relevance, the behavioral and neural mechanisms underlying this effect remain poorly understood, limiting the ability to predict treatment response and personalize interventions. Through three interconnected aims, this project aims to establish olfactory food cue responsiveness as a behavioral endophenotype of persistent food preoccupation in obesity and probe its causal relationship with impaired metabolic regulation of cortical coding of food rewards as well as cortical-mesolimbic connectivity. Focusing on olfactory food cues, which provide a direct and ecologically valid probe of perceptual food reward processing in humans, the project modulates metabolic state (hunger/satiety) to see how it shapes sensory responsiveness to food cues and reward-seeking behavior. The target group consists of adults with severe obesity, with and without persistent food preoccupation, as well as healthy-weight control participants. A clinical cohort of patients initiating treatment with appetite-regulating pharmaceuticals will be followed longitudinally in aim 3. Research integrating mesolimbic metabolic processing, sensory neuroscience, and obesity treatment remains unaddressed by existing programs, and will be made possible by the applicant's unique skillset in perceptual psychophysics and neuroimaging, and their clinical collaborations. Going forward, the results gained from this project can provide a foundation for clinical trials emphasizing personalized treatment plans based on neurobehavioral response profiles to food stimuli, and help investigate development of these markers over the life span to identify risk groups for maladaptive eating behavior before they lead to pathological changes in body weight regulation.

Human food consumption habits pose a fundamental problem for public health and environmental sustainability, but the complex interactions between homeostatic needs and the desire to eat remain poorly understood. This project aims to delineate the mechanisms by which metabolic states (hunger/satiety) regulate reward attribution to sensory food stimuli, making it difficult to resist flavorful meals when we are hungry and to continue eating when we are full. Study 1 will behaviorally assess the specificity of metabolic modulation to the olfactory modality and the food content of the anticipatory reward stimulus, and probe implicit effects on reward-seeking behavior with the help of a novel ecologically relevant adaption of the incentive delay paradigm. Study 2 will use multivariate fMRI analyses to identify differences in perceptual stimulus encoding during hunger and satiety, and determine invigorating effects of anticipatory food reward on sensory-striatal connectivity. We will then seek to understand the impact of dysregulation in this circuitry for disturbed eating behavior

the final two studies will, on a behavioral and neuroanatomical level, pinpoint the stages of anticipatory reward regulation where eating disorder patients show deficits relative to controls. Taken together, this project will answer fundamental questions about human food intake regulation, and provide a starting point for development of intervention strategies for dysregulated food consumption behavior.

To change human diets is an urgent global health and sustainability goal

yet, overcoming preferences for familiar food flavors in favor of healthier or more sustainable options remains a major challenge. Odor-taste associative learning is the principal perceptual support process for flavor preference formation and retrieval. Mechanistic insight into the cortical processes that transfer appetitive properties of an odor from the mouth onto environmental objects is, however, almost completely absent. As a result, fundamental questions about the processes that drive the acquisition of new flavor preferences, and their regulation by signals from the digestive tract, still remain to be answered. OLFLINK will uncover processes that link olfactory perception inside and outside the mouth across three nested levels of investigation that are usually studied in separation. In doing so, I propose to discover key factors that facilitate or hinder acquisition of new flavor preferences. Specifically, I will 1: determine the distributed CODE by which odors acquire and evoke taste associations (WP1), 2: delineate the cortical CONTROL mechanisms that facilitate encoding and retrieval of odor-taste associations in the light of contextual variability (WP2), and 3: determine the interactions with digestive feedback that REGULATE this flexible coding system during flavor preference acquisition and retrieval (WP3). This final step especially provides insight into the body’s ability to adjust learning and retrieval of food preferences based on nutritional needs, and has potential to transform our thinking about the biological basis of maladaptive eating patterns. The novel insights from OLFLINK will fill the knowledge gap that currently exists between the mechanisms driving perceptual experiences during food consumption and the subsequent evaluation of food in the outside world, and will inspire the development of novel interventions to facilitate dietary changes over the life course.