Introduction: Cholinergic network modulation is carried out through the neurotransmitter acetylcholine (ACh) and expression of α4β2 nicotinic acetylcholine recetors (nAChRs) in central brain regions responsible for the detection of external sensory stimuli through thalamic and basal forebrain circuits but also within mesolimbic reward signaling. Alterations in α4β2 availability could therefore contribute to pathologically increased eating behavior leading to obesity. Investigations of task-related cholinergic neurotransmission in vivo in human obesity comparing baseline versus stimulus conditions have yet to be established. Objective: Aim of this exploratory study was to investigate the neurobiological mechanisms of cholinergic signaling and its ramifications on eating behavior to possibly identify α4β2 as a pharmacological target in obesity therapy approaches. Primary outcome measure was the distribution volume calculated from PET data by VOI-based analyses. We compared α4β2 nAChR availability in OB (participants with obesity) with NW (normal weight participants) under baseline and stimulus conditions. Secondary, we explored whether changes in eating behavior measured by VAS (visual analogue scores) are correlated with changes in α4β2 nAChR availability. We also hypothesized that this relationship differs between resting state and stimulus conditions in both NW as well as OB. Materials and Methods: Study population consisted of 16 study participants with OB (N=16; mean BMI 37.8±3.18 kg/m2; 10 females; mean age 40.6±14.0; range from 20-62 years) and 14 NW (N=14; mean BMI 21.8±1.90 kg/m2; 11 females; mean age 28.1±7.58; range from 19-45 years), all mentally healthy and non-smokers. Every participant underwent simultaneous PET-MR imaging (mMR Siemens) under baseline and stimulus conditions, applying a standard set of salient food items. Calculations of VT was based on the bolus-infusion protocol. This includes investigation of VT as the ratio between mean (-)-[18F]flubatine in brain tissue and mean plasma (-)-[18F]flubatine in venous blood samples at 120 until 165 minutes post injection. During each visit VAS data were obtained. Results: No significant group differences in VT between NW and OB under baseline conditions were found, while OB showed a trend towards lower VT in the Nucleus basalis of Meynert (NBM; NW: mean VT= 11.6; OB: mean VT=10.2; mean difference= 1.35; p= 0.119). Under stimulus conditions, OB demonstrate higher thalamic VT (Thalamus; NW: mean VT= 25.1; OB: mean VT= 28.8; mean difference: -3.63; p= 0.028). Additionally, OB showed a tendency to greater VT mean differences between resting state and stimulus conditions compared with NW. Correlational analyses revealed statistically significant positive correlation (r= 0.61) between HPT and VAS “satiety” in NW and a significant negative correlation (r= -0.59) between NAc and VAS “disinhibition” in OB. Conclusion: These first in-human data suggest substantial changes in cholinergic signaling in brain circuits that process external sensory stimuli with high-incentive properties such as visual food cues in obesity. If confirmed in an extended population with larger sample size and including seed-based fMR imaging investigations, the α4β2 nAChR represent a promising target for pharmacological intervention as a non-invasive alternative to surgical procedures to combat the obesity epidemic.:2. Table of Contents 2. TABLE OF CONTENTS 2 3. ABBREVIATIONS 2 LIST OF FIGURES 4 LIST OF TABLES 6 4. INTRODUCTION 6 4.1 OBESITY AND THE CENTRAL CHOLINERGIC SYSTEM 7 4.2 CHOLINERGIC NEUROTRANSMISSION 9 4.3 STRUCTURE AND RECEPTOR KINETICS OF NACHR 11 4.4 TOPOGRAPHY OF CENTRAL NACHR 13 4.5 CHOLINERGIC NEUROMODULATION 15 4.5.1 Cholinergic Neuromodulation and Cognitive Processes 16 4.5.2 Cholinergic Neuromodulation and Reward 19 4.5.3 Cholinergic Neuromodulation and Eating Behavior 21 4.6. POSITRON EMISSION TOMOGRAPHY (PET) AS A MOLECULAR IMAGING TECHNIQUE FOR MEASURING NACHR IN VIVO 23 4.6.1 PET Imaging 23 4.6.2 Imaging of α4β2 Nicotinic Acetylcholine Receptors 23 4.6.3 (-)-[18F]flubatine: a specific α4β2 nAChR radiotracer 25 4.7 VOLUMES OF INTEREST (VOI) 33 5. OBJECTIVE 34 6. MATERIALS AND METHODS 35 6.1 ETHICS STATEMENT 35 6.2 STUDY DESIGN 35 6.3 STUDY PARTICIPANTS 36 6.4 VISUAL ANALOGUE SCALE (VAS) 38 6.5 PET/MR IMAGING 39 6.6 IMAGING DATA AND BLOOD PLASMA ANALYSIS 43 6.7 STATISTICAL ANALYSIS 45 7. RESULTS 46 7.1 EPIDEMIOLOGICAL DATA 46 7.2 BASELINE AND STIMULUS VT CALCULATIONS 47 7.3 INTRA-INDIVIDUAL VT ASSESSMENT BETWEEN BASELINE AND STIMULUS CONDITIONS 53 7.4 CORRELATIONAL ANALYSES OF VAS VERSUS VT 57 8. DISCUSSION 63 9. SUMMARY 70 10. REFERENCES 72 11. ANLAGEN 81