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The Laboratory for the Systems Neuroscience of Pain
The Mercer Lindsay lab is dedicated to dissecting the neural circuits that process pain and control movement, with a particular focus on the modulatory role of the endogenous opioid system within these circuits. By unraveling how the brain’s sensorimotor pathways and opioid signaling interact during chronic pain and analgesia, we aim to develop innovative, non-addictive therapeutic interventions for pain treatment.
Figure 1. Sensorimotor circuits and neural-behavioral responses underlying pain perception and behavior.
Left: Diagram illustrating the key brain circuits involved in sensorimotor integration related to pain. Sensory inputs enter via trigeminal ganglion (TG) and spinal trigeminal nucleus (SpV), relayed through thalamic nuclei (Po, VPM), and processed in primary somatosensory cortex (S1) and motor cortex (MC). Descending modulatory pathways involve the rostroventral medulla (RVM) and gigantocellular nucleus (GI). The inset schematic summarizes the flow from sensory input to muscle output.
Right: Neural and behavioral responses to a pain stimulus. The heatmap shows pain-evoked firing rate modulation of RVM neurons recorded with Neuropixels probes, aligned to pain stimulus onset (dashed line). Right panels show concurrent neck muscle activity measured with EMG, and head/nose and eye movements quantified using DeepLabCut pose estimation. These data illustrate coordinated sensorimotor responses evoked by pain.
Abbreviations: MC, motor cortex; S1, primary somatosensory cortex; Po, posterior thalamic nucleus; VPM, ventral posteromedial nucleus of thalamus; PrV, principal sensory trigeminal nucleus; TG, trigeminal ganglion; SpV, spinal trigeminal nucleus; RVM, rostroventral medulla; GI, gigantocellular nucleus; EMG, electromyography.
Scientific Problem
Chronic pain is a pervasive and debilitating condition affecting millions worldwide. It arises from complex interactions within neural circuits that integrate sensory input, motor output, and neuromodulatory signals. While most pain research has focused on sensory pathways, the role of motor circuits in driving pain and analgesia is less well understood. For example, the motor cortex (MC) corticofugal projections are best known for driving coordinated, complex movements. Yet, clinical evidence shows that stimulating these pathways in patients can provide effective pain relief. Morover, this analgesic effect depends on endogenous opioid signaling, which implies that the motor cortex has an intrinsic mechanism to induce non-addictive analgesia through opioid peptide release.
Our goal is to understand how motor circuit activity directly and indirectly modulates pain pathways that drive the sensory, emotional, and cognitive aspects of pain experience.
Our Approach
To dissect how motor circuits influence pain and analgesia, we employ a broad suite of neuroscience techniques:
1. Circuit Mapping and Connectivity: Using viral tracing, genetic reporter mice, and multiplexed molecular labeling, we map connections between motor and pain circuits alongside detailed expression profiles of endogenous opioid receptors and peptides.
2. Neural Activity Dynamics: Employing high-density Neuropixels electrophysiology, calcium imaging, and machine learning-based behavioral tracking (e.g., DeepLabCut), we record and analyze neural and motor responses in preclinical models of chronic pain.
3. Pharmacological and Genetic Manipulations: By applying intracranial opioid receptor agonists and antagonists, and using knockout models, we test the necessity and sufficiency of opioid signaling in modulating pain.
