Laboratory of Neural Physiology and Plasticity – Petruska Lab
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 the spinal pain system and spinal cord injury.
In terms of biomedical questions, we investigate:
- Effects of spinal cord injury and post-SCI treatments on the function of motor and sensory neurons
- Mechanisms and consequences of sensory neuron responses to tissue damage
- Mechanisms and consequences of adult axonal collateral sprouting
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 secondary conditions 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.
Biomedical hypothesis-driven projects
1) 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. Secondarily, the electrophysiological parameters of motoneurons are related directly (i.e. from the same animals) to behavioral measures (step/swim kinematics, weight-support capacity) and molecular measures (levels of neurotrophins and neurotrophin receptors in relevant muscles, DRG, and spinal cord segments). Further, we determine the effects of post-SCI viral vector-mediated delivery of neurotrophic factors on these same parameters.
2) Mechanisms and consequences of sensory neuron responses to tissue damage
This project investigates the mechanisms by which sensory neurons innervating injured/inflamed tissue are induced to express injury/regeneration-like genes. It also investigates the effects of this gene expression on the anatomical and electrophysiological properties of the affected sensory neurons.
3) Mechanisms and consequences 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. This project has identified factors regulated specifically in sprouting, as opposed to regeneration, which represent a rational pathway from external signal to internal cytoskeletal response and transcriptional regulation.
Projects developing model systems and tools
1) “Functional reporter” gene for use with intracellular electrophysiology
This project aims to develop “functional reporters” – genes that can report on the genetic status of single cells to electrophysiological probes independent of optical detection. For example, frequently-used reporters such as GFP are undetectable by electrodes. Further, for applications such as in vivo electrophysiology in rodents and larger animals many targets are simply too deep to employ microscopy in parallel with electrophysiology. Thus, to enhance the throughput and analytical power of “blind” single-cell electrophysiology, I am developing a reporter gene that will signal in real time in a manner detectible by intracellular electrodes.
2) CTM reflex as a model system for investigating spinal nociception/pain, propriospinal neuron function, and plasticity in sensory and motor neurons.
This project characterizes the organization of the cutaneus trunci muscle (CTM) reflex system and develops it as a model system for testing hypotheses. It is already validated as a monitor for sensory neuron collateral sprouting through skin and for efficacy of anesthetic and analgesic agents.
Petruska, J.C., Kitay, B., Boyce, V.S., Kaspar, B.K., Pearse, D.D., Gage, F.H., Mendell, L.M. Intramuscular AAV delivery of NT-3 alters synaptic transmission to motoneurons in adult rats.(2010) European Journal of Neuroscience 32(6):997-1005 (PMID: 20849530)
Bevan, A.K., Hutchinson, K.R., Foust, K.D., Braun, L., McGovern, V.L., Schmelzer, L., Ward, J.G., Petruska, J.C., Lucchesi, P.A., Burghes, A.H.M., Kaspar, B.K. Early heart failure in the SMN delta-7 model of spinal muscular atrophy and correction by postnatal scAAV9-SMN delivery. (2010) Human Molecular Genetics 19(20):3895-905 (PMID: 20639395)
Hill, C.E., Harrison, B.J., Rau, K.K., Hougland, M.T., Bunge, M.B., Mendell, L.M., Petruska, J.C. Skin incision induces expression of axonal regeneration-related genes in adult rat spinal sensory neurons. (2010) Journal of Pain 11(11):1066-73 (PMID: 20627820)
Petruska, J.C. and Mendell, L.M. Nerve Growth Factor. (2009) In: Squire, L.R. (ed.) Encyclopedia of Neuroscience, volume 6, pp. 71-78. Oxford: Academic Press.
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 27:4460-4471
Tan, A.M., Petruska, J.C., Mendell, L.M. Levine, J.M. Sensory afferents regenerated after spinal cord injury remain in a chronic pathophysiological state. (2007) Experimental Neurology 206:257-268
Zhu, W., Galoyan, S.M., Petruska, J.C., Oxford, G.S., Mendell, L.M. A developmental switch in acute sensitization of small dorsal root ganglion (DRG) neurons to capsaicin or noxious heating by NGF. (2004) Journal of Neurophysiology 92:3148-3152
Arvanian, V.L., Bowers, W.J., Petruska, J.C., Motin, V., Manuzon, H., Narrow, W.C., Federoff, H.J., Mendell, L.M. Viral delivery of NR2D subunits reduces Mg2+ block of NMDA receptor and restores NT-3-induced potentiation of AMPA/kainate responses in maturing rat motoneuron. (2004) Journal of Neurophysiology 92:2394-2404
Aimone, J.B., et al. (Christopher Reeve Paralysis Foundation Research Consortium). Spatial and temporal gene expression profiling of the contused rat spinal cord. (2004) Exp. Neurology 189:204-21
Petruska, J.C. and Mendell, L.M. The many functions of nerve growth factor: Multiple actions on nociceptors. (2004) Neuroscience Letters 361:168-171
Garraway, S., Petruska, J.C., Mendell, L.M. BDNF sensitizes the response of lamina II neurons to high threshold primary afferent inputs. (2003) European Journal of Neuroscience 18:2467-2476
Galoyan, S.M., Petruska, J.C., Mendell, L.M. Mechanisms of sensitization of the responses of single dorsal root ganglion cells from adult rat to noxious heat. (2003) European Journal of Neuroscience 18:535-541
Petruska, J.C., Napaporn, J., Johnson, R. D., Cooper, B.Y. Chemical responsiveness and histochemical phenotype of electrophysiologically classified cells of the adult rat dorsal root ganglion. (2002) Neuroscience 115:15-30
Hubscher, C.H., Petruska, J.C., Rau, K.K., Johnson, R.D. Co-expression of P2X receptor subunits on rat nodose neurons that bind the isolectin GS-I-B4. (2001) NeuroReport 12:2995-2997
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
Petruska, J.C., Cooper, B.Y., Gu, J.G, Rau, K.K., Johnson, R.D. Distribution of P2x1, P2x2, and P2x3 receptor subunits in rat DRG: Relation to population markers and specific cell types. (2000) Journal of Chemical Neuroanatomy 20(2):141-162
Petruska, J.C., Mena, N., Naktasuka, T., Cooper, B.Y., Johnson, R.D., Gu, J.G. P2x1 receptor subunit immunoreactivity and ATP-evoked fast currents in adult rat dorsal root ganglia neurons. (2000) NeuroReport 11(16):3589-92
Petruska, J.C., Cooper, B.Y., Johnson, R.D., Gu, J.G. Distribution patterns of different P2x receptor phenotypes in acutely dissociated dorsal root ganglion neurons of adult rats. (2000) Experimental Brain Research 134(1):126-32
Petruska, J.C., Hubscher, C.H., Johnson, R.D. Anodally-focussed polarization of peripheral nerve allows discrimination of myelinated and unmyelinated fiber input to caudal brainstem nuclei. (1998) Experimental Brain Research 121(4):379-390
Petruska, J.C., Streit, W.J., Johnson, R.D. Localization of unmyelinated axons in rat skin and mucocutaneous tissue utilizing the isolectin GS-I-B4. (1997) Somatosensory and Motor Research 14(1):17-26