Background & Aims
Old and new evidence suggests that the primary somatosensory cortex (S1) plays a significant role in encoding sensory components of nociception (e.g. localization and discrimination) (Vierck et al., 2017). However, layer-specific contributions of S1 circuitry to the modulation of nociception remain largely unexplored. In this context, we aim to characterize the electrophysiological, anatomical, and behavioral relevance of the layer 5 pyramidal tract of the hind-limb S1 (S1HL) in nociception, with a focus on its monosynaptic targeting of the ventrolateral periaqueductal gray (vlPAG) and lumbar dorsal horn (LDH). These two regions have been extensively implicated in both acute and chronic pain states, but the relevance of their monosynaptic input from the pyramidal tract, which is generally well-positioned to modulate behavior as a primary cortical output pathway (Mease and Gonzalez, 2021), has not been elucidated.
Methods
To achieve our aims, we employ viral techniques for directed optogenetic and chemogenetic manipulation of the pyramidal tract or its recipient cells in the vlPAG or LDH. We pair this with high-yield in vivo extracellular electrophysiological recordings and behavioral readouts of pain in the complete Freund’s adjuvant (CFA) model of inflammatory pain. To elucidate the molecular characterization of pyramidal tract recipient cells in the vLPAG and LDH, we use viral tracing techniques and in situ hybridization (RNAScope).
Results
Here, we report that optogenetic and chemogenetic excitation of the S1HL pyramidal tract elicits an antinociceptive effect, characterized by a reduction in sensitivity to mechanical peripheral stimulation in an inflammatory pain model. This manipulation also elicited a conditioned place preference, suggesting an effect on both sensory and affective components of pain. We show that S1HL pyramidal tract targets LDH neurons primarily in laminae IV (21.1%) and V (44.1%), and that approximately 75% of all recipient cells in the LDH are positive for at least one inhibitory marker (PAX2, GlyT2, or pENK), with 33% of all recipient cells being positive for both PAX2 and GlyT2. In the vlPAG, we found that approximately 48% of S1HL pyramidal tract recipient cells are glutamatergic.
Conclusions
Thus far, we conclude that the S1HL pyramidal tract elicits antinociceptive effects, and that these may in part be driven by monosynaptic targeting of the vlPAG and LDH. Stimulation of glutamatergic cells in the vlPAG has previously been shown to reduce pain (Samineni et al.,2017), as has stimulation of inhibitory cells in the LDH (Petitjean et al., 2015), and we show that both of these populations are targeted by the S1HL pyramidal tract. Ongoing behavioral and electrophysiological studies will determine the relevance of these pyramidal tract recipient populations on the processing of nociceptive information.
References
Mease, R. A., & Gonzalez, A. J. (2021). Corticothalamic Pathways From Layer 5: Emerging Roles in Computation and Pathology. Frontiers in neural circuits, 15, 730211.
Petitjean H, Pawlowski SA, Fraine SL, Sharif B, Hamad D, Fatima T, Berg J, Brown CM, Jan LY, Ribeiro-da-Silva A, Braz JM, Basbaum AI, Sharif-Naeini R. Dorsal Horn Parvalbumin Neurons Are Gate-Keepers of Touch-Evoked Pain after Nerve Injury. Cell Rep. 2015 Nov 10;13(6):1246-1257.
Samineni VK, Grajales-Reyes JG, Copits BA, O’Brien DE, Trigg SL, Gomez AM, Bruchas MR, Gereau RW 4th. Divergent Modulation of Nociception by Glutamatergic and GABAergic Neuronal Subpopulations in the Periaqueductal Gray. eNeuro. 2017 Mar 29;4(2):ENEURO.0129-16.2017.
Vierck, C. J., Whitsel, B. L., Favorov, O. V., Brown, A. W., & Tommerdahl, M. (2013). Role of primary somatosensory cortex in the coding of pain. Pain, 154(3), 334–344.
Presenting Author
Antonio J. Gonzalez
Poster Authors
Topics
- Mechanisms: Biological-Molecular and Cell Biology