Patrick Sheets, Ph.D.
Assistant Professor, Pharmacology & Toxicology
Ph.D., Pharmacology, Indiana University School of Medicine, Indianapolis, IN (2007)
Post-Doc, Neurobiology, Northwestern University, Chicago, IL (2012)
Elucidating Alterations to Supraspinal Circuitry Caused by Neuropathic and Inflammatory Pain.
The major objective of my laboratory is to understand the mechanisms by which neuropathic and inflammatory pain alter the morphology, intrinsic physiology, neuromodulation, and connectivity of circuitry encompassing 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, virtually nothing is known regarding 1) the functional organization of local or long-range inputs of mPFC-PAG-amygdala circuits and 2) the specific mechanisms by which neuropathic and inflammatory pain alter the neurophysiology and synaptic function of mPFC-PAG-amygdala circuitry. These are critical unknowns that 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, 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.
Cheriyan J, Kaushik M, Ferreira AN, Sheets PL (2016). Specific targeting of the basolateral amygdala to projectionally defined pyramidal neurons in prelimbic and infralimbic cortex eNeuro. Mar 31; 3(2). PMID: 27022632.
Ferreira AN, Yousuf H, Dalton S, Sheets PL (2015). Highly differentiated cellular and circuit properties of mPFC neurons projecting to the periaqueductal gray and amygdala. Frontiers of Cellular Neuroscience. Apr 28; 9:161. PMID: 25972785.
Balsara RD, Ferreira AN, Donahue DL, Castellino FJ, Sheets PL (2014). Probing NMDA NR2A and NR2B subunit expression and distribution in cortical neurons. Neuropharmacology. Epub ahead of print. Apr;79:542-9. PMID: 24440368.
Yasvoina MV, Genc B, Jara JH, Sheets PL, Quinlan K, Milosevic A, Heckman CJ, Shepherd GMG, Ozdinler PH (2013). Visualization of vulnerable corticospinal and a subset of degeneration-resistant spinal motor neurons by genetic labeling in UCHL1-eGFP and hSOD1G93A-UeGFP mice reveal increased autophagy along the apical dendrites of diseased CSMN in the motor cortex. Journal of Neuroscience. May1;33(18):7890-7904. PMID: 23637180.
Brittain MK, Brustovetsky T, Sheets PL, Brittain JM, Khanna R, Cummins TR, Brustovetsky N (2012). Delayed calcium dysregulation in neurons requires both the NMDA receptor and the reverse Na(+)/Ca(2+) exchanger. Neurobiology of Disease. Jan 10 Epub ahead of print. PMID: 22249110.
Sheets PL, Suter BA, Kiritani T, Chan CS, Surmeier DJ, Shepherd GMG (2011). Corticospinal-specific HCN expression in mouse motor cortex: Ih-dependent integration of layer 2/3 excitatory synaptic inputs as a candidate microcircuit mechanism involved in motor control. Journal of Neurophysiology. Jul 27 Epub ahead of print. PMID: 21795621.
Sheets PL, Jarecki BW, Cummins TR (2011). Lidocaine stabilizes Nav1.7 in a configuration that decreases transition to the slow inactivated state of the channel. British Journal of Pharmacology. 164(2b): 719-30. PMID: 21232038.
Anderson CT, Sheets PL*, Kiritani T, Shepherd GM (2010). Sublayer-specific microcircuits of corticospinal and corticostriatal neurons in motor cortex. Nature Neuroscience. Jun;13(6):739-44. PMID: 20436481 *Equal contribution.
R01 NS094389 Prefrontal circuitry and pain.