Brain-wide activity mapping reveals the somatosensory cortex as a sex-specific regulator of hedonic feeding

Palatable food consumption engages reward circuitry and promotes neuroadaptations that contribute to overeating and obesity. While mesolimbic dopamine pathways are central to hedonic feeding models, the contribution of sensory cortical systems remains poorly understood. Here, we performed brain-wide activity mapping using Targeted Recombination in Active Populations (TRAP) and network analysis to define the distributed neural consequences of short-term high-fat diet (HFD) exposure in male and female mice. HFD increased caloric intake in both sexes, with females consuming significantly more than males. Brain-wide analysis revealed striking sex-specific adaptations: HFD increased activity-dependent labeling within isocortical areas in males, with the somatosensory cortex (SS) emerging as the most prominently modulated region. SS activity negatively correlated with HFD intake, driven by male mice. Network analysis using the SMARTTR pipeline demonstrated that HFD reorganized network activity in a sex-dependent manner, biasing male networks toward associative cortical-thalamic hubs, whereas female networks preferentially recruited subcortical and brainstem structures. To determine causality, we bidirectionally manipulated SS pyramidal neurons using chemogenetics during exposure to multiple diet conditions. Surprisingly, only inhibition of the SS altered palatable diet intake in males, whereas only activation reduced intake in females across diets and conditions. These findings establish the SS as a sex-specific regulator of palatable food consumption and demonstrate that similar behavioral outcomes emerge from distinct circuit architectures across sexes. Collectively, this study expands prevailing reward-centric models of hedonic feeding by identifying sensory cortical control as a critical component of diet-induced neuroadaptations and highlighting sex as a determinant of feeding-related circuit organization.