The major objective of the laboratory of Patrick Sheets, PhD, is to understand the mechanisms by which neuropathic, surgical and inflammatory pain alter the morphology, intrinsic physiology, neuromodulation, and connectivity of supraspinal circuits with a major focus on the medial prefrontal cortex (mPFC), periaqueductal gray (PAG), and amygdala. Importantly, circuits comprising the mPFC are essential in processing emotional components of our everyday experiences, and therefore, are implicated in the affective component, or unpleasantness, of pain. Additionally, mPFC circuits are associated with depression and anxiety, which are common co-morbidities of neuropathic pain. The PAG is a link in the primary pain-modulating network essential for endogenous analgesia and autonomic response to pain. In humans, the mPFC-PAG pathway is associated with emotional modulation of pain. The amygdala serves as a key node that integrates information essential for connecting pain and emotion. Signaling of reciprocal pathways between the PAG and amygdala is critical for neuronal processing involved in nociception. However, many unknowns remain regarding 1) the functional organization of local or long-range inputs of mPFC-PAG-amygdala circuits nor 2) the specific mechanisms by which neuropathic and inflammatory pain alter the neurophysiology and synaptic function of cortical circuitry including the mPFC-PAG-amygdala pathway. These critical unknowns need to be resolved for understanding the mechanisms that drive dysfunction of neural activity in neuropathic and inflammatory pain. Our lab is currently using a multifaceted approach (retrograde labeling, slice electrophysiology, laser scanning photostimulation, high-resolution imaging, optogenetics, and behavior) to resolve these critical unknowns. The rationale for our work is that identifying the neural mechanisms through which neuropathic and inflammatory pain alters circuit function in cognitive and emotional networks of the brain (specifically mPFC-PAG-amygdala) will produce critical knowledge regarding the affective and emotional dimensions of pain. Such an understanding can lead to novel strategies for therapeutic intervention and improvement of clinical guidelines.