The intricate bidirectional communication between the brain and visceral organs is crucial for integrating internal interoceptive cues essential for survival. Gut-brain communication exemplifies a significant pathway where humoral and neural signals from the abdominal viscera relay metabolic information to the brain for maintaining energy balance. Beyond homeostatic functions, recent evidence suggests that these subtle gut-to-brain signals modulate higher-level cognitive processes like motivation, affect, learning, and memory. This understanding opens possibilities for developing minimally invasive autonomic neuromodulation therapies for metabolic and neurological disorders such as treatment-resistant depression, obesity, or diabetes. However, identifying the mechanisms underlying brain-viscera communication that influence neurocognitive states has been challenging due to a lack of suitable implantable, bio-integrated, multifunctional devices for long-term deployment in diverse organs of behaving animals. Traditional bio-integrated device fabrication relies on resource-intensive lithographic techniques from the semiconductor industry, requiring specialized cleanroom environments. The thin-film processing nature of lithography necessitates independent fabrication and manual assembly of individual device modalities, hindering rapid customization and scalability. This study introduces a novel strategy to address this technological gap, demonstrating its potential in experiments spanning neural circuits in the brain and gut.

Existing literature highlights the importance of understanding brain-gut interactions for various physiological and cognitive functions. Studies have shown the impact of gut microbiota and signaling on brain activity, affecting mood, behavior, and cognitive performance. However, research has been limited by the availability of suitable tools to investigate these complex interactions in vivo. Traditional methods, such as invasive surgeries and tethered devices, have limitations in studying freely behaving animals over extended periods. The lack of multifunctional devices capable of simultaneous optical stimulation, electrophysiological recording, and chemical delivery further hindered progress in this area. This research directly addresses these limitations by developing a novel platform for studying the interplay between the brain and gut.

This research developed multifunctional bioelectronic interfaces based on polymer fibers embedded with solid-state microelectronic components using thermal drawing. This top-down approach produced meters of microscale fibers capable of integrating multiple functionalities: µLEDs for optogenetics, thermal sensors for thermometry, microelectrodes for electrophysiology, and microfluidic channels for drug and gene delivery. The mechanical properties of the fibers were engineered for compatibility with both deep-brain and gastrointestinal tract implantation. For brain applications, a stiff yet flexible polycarbonate (PC) fiber was designed. For the gut, a much more compliant thermoplastic triblock elastomer poly(styrene-b-ethylene-co-butylene-b-styrene) (SEBS) fiber was created. A custom-designed modular wireless control circuit, NeuroStack, enabled real-time programmable optical stimulation and data transfer for recording local tissue temperature in untethered mice. The NeuroStack module consisted of a primary module with a microcontroller, battery, and wireless communication, and an optional intensity module for precise control of optical stimulation. The system allowed control of stimulation frequency, duty cycle, pulse shape, and intensity, and real-time temperature recording. In vivo experiments were conducted on mice with the fibers implanted in the brain (VTA) and gut (duodenum and ileum). Various behavioral assays were performed, including place preference assays and feeding behavior studies, alongside electrophysiological recordings and thermometry. The study also investigated the impact of optogenetic stimulation on vagal afferents and enteroendocrine cells, and how nutrient delivery affects VTA neuron activity.

The study successfully demonstrated the chronic implantation of multifunctional microelectronic fibers in both the brain and the gut of mice. In the brain (VTA), the fibers enabled longitudinal recording of spontaneous and optically evoked neural activity following viral vector delivery. Wireless programmable optogenetic stimulation of dopaminergic neurons elicited reward behavior. In the gut, the compliant fibers allowed targeted modulation of gastrointestinal neural circuitry, including epithelial sensory cells and vagal afferents. Wireless intraluminal gut optogenetics targeting enteroendocrine cells in the duodenum and ileum modulated feeding behavior. Optogenetic stimulation of vagal afferents from the gut lumen produced a rewarding phenotype, demonstrating direct modulation of CNS function from the intestine. The NeuroStack wireless module effectively controlled optical stimulation parameters and recorded temperature data in real-time. The fibers showed excellent biocompatibility with minimal immune response. The study further revealed that intestinal sucrose delivery positively modulated the firing rate of dopaminergic neurons in the VTA, suggesting a direct link between gut nutrient sensing and brain reward pathways.

This study's findings significantly advance the field of brain-viscera interoceptive signaling research. The development of multifunctional, wireless microelectronic fibers provides a powerful tool for investigating the complex interplay between the gut and the brain in freely moving animals. The ability to simultaneously modulate and record neural activity in multiple organs in real-time opens up unprecedented opportunities for understanding the neural mechanisms underlying various physiological processes and behavioral responses. The results demonstrate the feasibility of using this technology to study brain-gut interactions in relation to metabolic and neurological disorders, paving the way for new diagnostic and therapeutic approaches.

This study successfully developed and validated multifunctional microelectronic fibers and a wireless control module for multimodal interrogation of brain and gut neural circuits. This novel technology allows for wireless, programmable optogenetic stimulation and electrophysiological recording in freely behaving animals, revealing important insights into gut-brain communication and its impact on behavior. Future research can expand the application of these fibers to study other organ systems and neurological disorders, and improve the design for enhanced biocompatibility and longevity.

While the study demonstrated the significant potential of this technology, some limitations should be noted. The sample size for some experiments was relatively small. Long-term studies with larger sample sizes are needed to fully assess the long-term biocompatibility and efficacy of these fibers. Further research is needed to explore the potential effects of the fibers on gut motility and other physiological processes. The current system has limitations on the maximum operational duration; however, this can be easily improved with lighter, high capacity rechargeable batteries.