Jeffrey C. Petruska, Ph.D.
Laboratory of Neural Physiology & Plasticity
Associate Professor, Department of Anatomical Sciences & Neurobiology
Department of Neurological Surgery
Steering Committee – Interdisciplinary Program in Translational Neuroscience
Executive Committee - Interdisciplinary Program in Bioinformatics
Past-President, Louisville Chapter of the Society for Neuroscience (2017 Chapter of the Year!)
E-mail Jeffrey Petruska
In terms of biological principles, we investigate the cellular and molecular mechanisms regulating anatomical and electrophysiological plasticity of neurons, focusing on the peripheral nervous system and spinal cord. We are particularly interested in the interaction between, and co-regulation of, the anatomical and electrophysiological properties of neurons. We study these principles in the context of spinal cord injury and the spinal pain system (particularly in the context of damage to peripheral tissue which is a common and chronic issue for the SCI population and is an etiological factor in the development of chronic pain).
In terms of biomedical questions, we investigate:
1) the mechanisms controlling axonal collateral sprouting (growth of non-injured axons) in the adult nervous system, particularly considering how these mechanisms contrast with those of axonal regeneration (growth of injured axons);
2) the mechanisms and consequences of sensory neuron responses to damage of peripheral tissue (e.g., skin, muscle, viscera), particularly contrasting this with the response of sensory neurons to nerve injury;
3) the effects of spinal cord injury and post-SCI plasticity-inducing treatments on the function of motor and sensory neurons.
These hypothesis-driven projects are well-coordinated when viewed in the context of my long-term vision – understanding how sensory input to the spinal cord below an injury influences the function of the remaining circuitry. It is my proposition that the combined effects of spinal cord injury and inflammatory and/or tissue-damaging secondary conditions (e.g., systemic inflammation, pressure sores, bladder infection, bowel impaction) act in concert to induce “circuit dysfunction” in the spinal cord caudal to an injury due to an unchecked, overactive, and highly plastic spinal nociceptive system. Unfortunately, SCI-related secondary conditions are rarely considered in basic neuroscience research, in spite of their high degree of clinical relevance and importance to the SCI community. On the other hand, the status of spinal circuits below an injury is a topic of a great deal of basic science study, but principally in the context of acute lacerations intended to determine the role of specific tracts, and much less-so in the context of clinically-modelled SCI. The status of these circuits after SCI is increasingly more important with the accumulation of data demonstrating the efficacy of activity-dependent task-specific training (i.e., physical therapy), and the reliance of that therapy on both appropriate sensory input and “healthy” caudal spinal cord circuitry.
1) Mechanisms of adult axonal collateral sprouting
This project investigates the molecular-level regulation of adult axonal collateral sprouting – the extension of new axonal branches from non-injured neurons. Putative regulatory factors and pathways were identified principally from analysis of the transcriptome (mRNA microarray) using a “spared dermatome” model, where non-injured sensory neurons extend their axons into adjacent denervated skin (PMID: 26697387). This project has identified factors regulated specifically in axonal sprouting, as opposed to axonal regeneration, which represent a rational pathway from external signal to internal cytoskeletal response and transcriptional regulation. We have successfully validated many of these factors as playing a functional role in axon growth, in vivo and/or in vitro and are now examining their mechanisms of action. We are also determining the degree to which the genes expressed and regulated during sprouting overlap with those expressed and regulated during axonal regeneration.
2) Mechanisms and consequences of sensory neuron responses to tissue damage
This project investigates the mechanisms by which sensory neurons innervating injured tissue regulate genes associated with the cellular-stress response and with axonal regeneration (PMID:20627820), and which underlie electrophysiological properties associated with hyperalgesia and pain (PMID: 27264359). It also investigates the effects of this gene expression on the anatomical and electrophysiological properties of the affected sensory neurons. Our hypothesis is that tissue damage induces a long-term expression of the cellular-stress response in sensory neurons. Considering tissue damage-associated persistent pain in this context may account much more thoroughly and accurately for the the etiology than the current view, which considers it principally as an issue of tissue inflammation. We are also identifying clinically-applicable treatments which can reduce this injury/stress in an attempt to reduce the impact on the nervous system of damage to peripheral tissue.
3) Effects of spinal cord injury and post-SCI treatments on motoneuron function
This project investigates the effects of graded contusion SCI on the electrophysiological properties of hindlimb motoneurons and sensory neurons. Secondarily, we compare the electrophysiological properties directly (i.e. from the same animals) to behavioral measures (reflexes, step/swim kinematics, weight-support capacity) and molecular measures (levels of neurotrophins and neurotrophin receptors in relevant muscles, DRG, and spinal cord segments)(PMID:23316162). Further, we determine the effects of viral vector-mediated delivery of neurotrophic factors on these same parameters before (PMID:20849530) and after SCI. We have determined that treatment with certain trophic factors can significantly enhance behavioral recovery, and these assessments are aimed at identifying the mechanisms of this improvement.
4) Development of novel local anesthetic agents
This project arose from a serendipitous finding. We discovered that an existing FDA-approved drug had local anesthetic actions which were unrelated to its intended purpose or known mechanisms of action. It structure is very different from other known local anesthetics, suggesting it may have a different mechanism of action, and may offer a new avenue of development for this important family of clinical tools. More intriguing yet is that some motoneurons appear to be resistant to the conduction block, opening the possibility of developing a new kind of local anesthetic - one that may prevent pain yet may spare at least some motor function (imagine not drooling and still being able to talk after leaving the dentist!). We are currently engaged with medicinal chemists, anesthesiologists, and the Office of Technology Transfer to best develop this opportunity and hopefully provide some clinical or scientific benefit as soon as possible.
Rau, K.K., Hill, C.E., Harrison, B.J., Venkat, G., Koenig, H.M., Cook, S.B., Rabchevsky, A.G., Taylor, B.K., Hai, T., Petruska, J.C. (2016) Cutaneous tissue damage induces long-lasting nociceptive sensitization and regulation of cellular stress- and nerve injury-associated genes in sensory neurons. Experimental Neurology 283(Pt A):413-27 (PMID: 27264359)
Harrison, B.J., Venkat, G., Lamb, J.L., Hutson, T.H., Drury, C., Rau, K.K., Bunge, M.B., Mendell, L.M., Gage, F.H., Johnson, R.D., Hill, C.E., Rouchka, E.C., Moon, L.D., and Petruska, J.C. (2016) The Adaptor Protein CD2AP Is a Coordinator of Neurotrophin Signaling-Mediated Axon Arbor Plasticity. Journal of Neuroscience 36(15):4259-75 (PMID: 27076424)
Harrison, B.J., Flight, R.M., Gomes, C., Venkat, G., Ellis, S.R., Sankar, U., Twiss, J.L., Rouchka, E.C., and Petruska, J.C. (2014) IB4-binding sensory neurons in the adult rat express a novel 3’ UTR-extended isoform of CaMK4 that is associated with its localization to axons. Journal of Comparative Neurology 522(2):308-36 (PMID: 23817991)
Petruska, J.C.*, Barker, D.F., Garraway, S.M., Trainer, R., Fransen, J.W., Seidman, P.A., Soto, R.G., Mendell, L.M., Johnson, R.D. (2014) “Organization of sensory input to the nociceptive-specific cutaneous trunk muscle reflex in rat, an effective experimental system for examining nociception and plasticity.” Journal of Comparative Neurology 522(5):1048-71 (PMID: 23983104)
Petruska, J.C., Ichiyama, R.M., Jindrich, D., Crown, E.D., Tansey, K.E., Roy, R.R., Edgerton, V.R., Mendell, L.M. Changes in Motoneuron Properties and Synaptic Inputs Related to Step Training Following Spinal Cord Transection in Rats. (2007) Journal of Neuroscience 27:4460-44713 (PMID: 17442831)
Petruska, J.C., Napaporn, J., Johnson, R. D., Gu J.G. and Cooper, B.Y. Subclassified acutely dissociated cells of rat DRG: Histochemistry and patterns of capsaicin, proton and ATP activated currents (2000) Journal of Neurophysiology 84(5):2365-2379 (PMID: 11067979)