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Only recently has the rodent hippocampus been implicated in orexigenic appetitive processing1,2. This function has been found to be mediated at least in part by lateral hypothalamic inputs involving an orexigenic neuropeptide, melanin-concentrating hormone3. This circuit remains elusive in humans. Here, we combine tractography, intracranial electrophysiology, cortico-subcortical evoked potentials, and brain-clearing 3D histology to identify an orexigenic circuit involving the lateral hypothalamus converging in a hippocampal subregion. We found that low-frequency power is modulated by sweet-fat food cues and this modulation was specific to the dorsolateral hippocampus. Lastly, structural and functional analyses of this circuit in a human cohort exhibiting dysregulated eating behavior revealed connectivity that was inversely related to body mass index. Collectively, this multimodal approach describes an orexigenic subnetwork within the human hippocampus implicated in obesity and related eating disorders.

Introduction: Fragile X syndrome (FXS) is a debilitating neurogenetic disorder that can result in a multitude of impairments in cognition, memory, and learning. Case Presentation: a 25-year-old male with FXS participated in this study. The participant obtained scores in the non-spectrum range on the Autism Diagnostic Observation Scale and obtained an full scale IQ score of 57 (Verbal IQ = 23 and Nonverbal IQ = 34) on the Stanford-Binet Intelligence Scales (SB-5). On the Vineland Adaptive Behavior Scales, 2nd Edition (VABS-2) he obtained a composite score of 66. Pre-scan serum cortisol reactivity was 16.45 mcg/dL. Following a [18F]flumazenil (5mCi) intravenous bolus injection, the participant was scanned without sedation on a hybrid PET-MR system (Signa, GE Healthcare, Waukesha, WI) for 60 mins. List mode PET data, structural and diffusion MRI (DWI), and MR spectroscopy (MRS) were acquired simultaneously. Quantitative PET and DWI measures were extracted from 83 pre-defined regions of interest. MRS data was collected from two 20 cc voxels (thalamus and dorsolateral prefrontal cortex). Conclusion: This is the first study to investigate neuromolecular behavior in FXS without the use of sedation using PET-MR. Mapping the neuromolecular differences in FXS can lead to targeted treatments that can significantly improve quality of life for families and individuals with intellectual disabilities.