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.
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Dissecting circuit changes to inhibitory circuits of the medial prefrontal cortex (mPFC) in mouse models of both acute and chronic pain
For this project, the lab uses transgenic breeding strategies to identify specific subtypes of inhibitory interneurons in the mPFC; specifically those expressing somatostatin (SOM+) or parvalbumin (PV+). This approach allows for a multi-faceted analysis (electrophysiology, circuit mapping, high-resolution imaging, protein expression) aimed at understanding how acute or chronic pain alters the function of specific inhibitory neurons in the mPFC. These methods are useful for examining the dynamics of circuits in slice, and allow the laboratory to measure pain-induced changes in local inhibitory connections to specific subclasses of excitatory neurons in the mPFC including mPFC-PAG and mPFC-amygdalar neurons.
Elucidating a role for lipid signaling in supraspinal pain modulation
Neurons in the central amygdala (CeA) contribute to pain modulation. However, the heterogeneity of these neurons and their contribution to the sensory-discriminative and/or emotional-affective dimensions of chronic pain are not understood, nor is their neurochemical modulation. The goal of this project is to 1) use transgenic mouse lines, retrograde labeling, electrophysiology, optogenetics, and behavior to test the hypotheses that CeA circuits are comprised of heterogeneous populations of neurons (based on intrinsic excitability, molecular markers, and long-range connectivity) that are differentially sensitized in various models of acute and chronic pain. 2) Test the hypotheses that the bioactive lysophospholipid, sphingosine-1-phosphate (S1P) differentially alters CeA neurons based on their molecular and intrinsic identity and that reducing S1P signaling reverses the sensitization of CeA neurons altered in various models of pain. 3) Determine if modulation of S1P receptor signaling in the CeA attenuates pain behavior.
Understanding how mPFC neurons expressing the endogenous opioid dynorphin (mPFCDyn+ neurons) play a functional role in pain processing and affective behaviors
Dynorphin (Dyn) is the endogenous opioid peptide that binds with high affinity to kappa opioid receptors (KORs), which are associated with mediating the negative valence (i.e. aversion component) of pain. Chronic pain increases transcription of Dyn in the mPFC, and injection of Dyn derivatives into the mPFC evokes placed aversion. These findings support the notion that Dyn+ mPFC circuits play a critical role in modulating negative valence associated with pain. Unfortunately, significant gaps in knowledge remain regarding 1) how Dyn-KOR signaling regulates the activity of mPFC circuits, 2) how mPFC Dyn+ circuit dynamics are altered in response to acute and chronic pain, and 3) how mPFC Dyn+ circuit activity modulates sensory and affective behaviors associated with pain. Addressing these knowledge gaps is critical for a complete understanding of how the brain assigns negative valence to pain, which is essential for developing new strategies aimed at treating sensory pain, affective pain and pain-associated comorbidities including anxiety, depression, mood-disorders and cognitive deficits.
Investigating the role of corticostriatal circuitry in both pain and alcohol disorders
Alcohol consumption and chronic pain are strongly comorbid. Relative to the general population, patients with chronic pain are twice as likely to meet the criteria of alcohol use disorder. Similarly, chronic alcohol intake can exacerbate chronic pain progression and can heighten pain during abstinence. This suggests a potential overlap in alcohol and pain circuits, which facilitates a positive feedback loop that contributes the high incidence of comorbidity. Unfortunately, how these neural circuits are regulated in comorbid conditions of chronic pain and alcoholism is poorly understood. Lack of such knowledge is a serious problem because it prohibits a broader understanding of functional neural networks that may worsen both pain experience and alcohol dependence. The long-term goal of this project is to delineate the overlapping mechanisms of alcohol addiction and pain pathology so we can improve strategies for therapeutic approaches.
Meet the faculty and students in the Sheets Lab.
Funding and Publications
Work in the Sheets Lab is currently funded by multiple grants.