Fatigue Symptoms Influence Effort-Based Decision-Making in Major Depressive Disorder.

The drug discovery process of analgesics is often constrained by a lack of human in vitro models that can specifically target the nerve fibers responsible for pain signal transmission. To overcome this limitation, we have established a model using human stem cell-derived sensory neurons in a microfluidic culture platform that allows compartmentalization of the cell soma and the signal transmitting processes. We use this system to demonstrate that signal transmission can be selectively blocked by targeting channels that contribute to signaling in these fibers. This model provides a transformative tool for screening potential analgesics and studying human pain mechanisms directly. Latest estimates suggest that 20%-30% of the global population suffers from some form of chronic pain including high impact pain but the current pain treatments are often ineffective or associated with severe side effects. Evaluation of analgesic efficacy in drug discovery has relied primarily on rodent-based pre-clinical models, but they have shown poor translational success, leading to high failure rates in clinical trials. This translational gap may be due to species differences in nociceptor populations and pain-related ion channel expression, such as voltage-gated sodium channels. Therefore, human-relevant in vitro models offer a promising alternative to improve understanding of human molecular pain mechanisms and advance analgesic drug discovery. Primary human dorsal root ganglia (DRG) neurons, which transmit pain signals to the spinal cord neurons, are considered to have higher physiological relevance, but are difficult to obtain due to their limited availability. Human induced pluripotent stem cells (hiPSC) offer an alternative, as they can be differentiated into functional sensory neurons (hiPSC-SNs), expressing key nociceptor pain targets such as Nav1.7, Nav1.8, TRPA1 and TRPV1. However, conventional hiPSC-SN cultures have significant limitations in that they fail to capture the physiological complexity of pain signaling. They lack the compartmentalization needed to separate cell bodies from their processes, which is fundamental to understanding how nociceptive signals are carried from the periphery to the central nervous system. We have shown that microfluidic culture systems overcome these limitations by providing a structured environment that allows processes to be physically separated from cell bodies, enabling targeted pharmacological studies solely on sensory axonal function. Small, well-defined chambers enable independent manipulation of axonal and cell body environments across distinct compartments. This setup allows for localized drug application, enables the investigation of axon-specific signaling, supports synaptic connectivity, and better recapitulates the anatomical organization of peripheral pain system.