Anxiety disorders are highly prevalent and often refractory to existing treatments, motivating the development of alternative neuromodulatory strategies. Peripheral bioelectronic approaches targeting the gut-brain axis, such as vagus nerve stimulation (VNS), demonstrate that modulation of visceral afferent pathways can influence central emotional circuits. Gastric electrical stimulation (GES) is a clinically established therapy for gastrointestinal motility disorders. While the stomach is densely innervated by vagal afferents, the effect of GES on anxiety-related behavior has not been systematically examined. We sought to identify neural pathways engaged by GES and the effects of continuous chronic GES on behavior. To do this, we developed a gastric stimulation platform for rodents, a fully implantable, untethered system enabling chronic neuromodulation in freely moving rats. We combined this with cross-species whole-brain activity mapping in mice to interrogate circuit-level mechanisms. Using open field and elevated plus mazes, together with machine-learning-based behavioral tracking and multivariate modeling, we show that acute GES induces a robust, context-dependent anxiogenic phenotype characterized by reduced exploration and increased freezing, particularly in novel open-field environments. In contrast, chronic GES produces a divergent post-stimulation behavioral profile marked by enhanced exploratory behavior relative to acutely stimulated animals, indicating temporally dynamic reorganization of anxiety-related behavior. Principal component analysis and hierarchical clustering further revealed that stimulation reshapes the multivariate structure of behavioral features rather than shifting animals along a single anxiety continuum. Whole-brain c-Fos mapping revealed anatomically distributed modulation of limbic-cortical networks following gastric stimulation, including suppression of ventral medial entorhinal cortex, excitation of nucleus tractus solitarii, and heterogeneous recruitment of amygdalar and hippocampal subregions. These circuit-level patterns align with the behavioral dissociation between contextual exploration and explicit threat avoidance, providing convergent cross-species evidence that gastric stimulation engages distributed anxiety-related networks. Together, these findings establish the first freely moving behavioral model of chronic gastric neuromodulation, demonstrate temporally dynamic and context-sensitive effects on anxiety-like behavior, and provide system-level validation that the stomach can serve as a viable peripheral access point for modulating central emotional circuits.
Daood, M., Memon, R., Rout, S., Elgengihy, B., Nossa, A., Feldman, R., Elbeh, M., Usmani, S., Ramadi, K. B.
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