My dedication to spinal cord injury (SCI) comes from both my clinical and academic experiences. As a clinician, I specialized in improving the overall function of persons with SCI and teaching other clinicians specialized treatments for SCI. As an academic, I have had extensive and broad research experiences in SCI. I started working in human SCI research first examining bone mineral density changes post injury at the University of Iowa and then studying the spinal circuitry changes occurring post SCI that contribute to spams at the Rehabilitation Institute of Chicago. My experience with human SCI research and my experiences in the clinic prompted my return to academia full-time to use research to improve the lives of individuals with spinal cord injury (SCI) as my main focus. During my PhD with Jack Kessler, MD, my emphasis was toward interventions. I used developmental neurobiological approaches to attenuating or solving SCI including neural and oligodendritic replacement with embryonic stem cells and axon regeneration with growth factors and development-inspired nanotechnology materials. In performing these studies with my experience as a physical therapist, I saw a great need to develop specific quantitative behavioral tests so we can prove not only that our interventions work, but how exactly they contribute to function. My postdoctoral fellowship with Matt Tresch, PhD, aimed at developing such tests. At present, we have pioneered several new techniques for looking at in vivo mouse behaviors including chronic multi-muscle EMG recordings and single motor unit recordings in the mouse. The spectrum of neuroscientific areas and techniques in which I have experience is quite broad, however, the one piece that is missing is the ability to examine neuronal function using cellular electrophysiology. My short-term career goal is to fill this gap. This proposal provides the expertise and protected time for this learning to occur. Once I am able to perform the techniques listed in my proposal and combine these with my previous experimental knowledge and clinical experience, I will be uniquely qualified for my long-term goal of producing a comprehensive, translatable spinal cord injury research program that is based on novel therapeutics and a basic science understanding of how recovery can be improved, not only on a cellular basis, but on a systems basis as well. Mentorship for this award and for the beginning of my career is found here at Northwestern as well as at outside institutions. I began my position as an Assistant Professor in the Departments of Physical Therapy and Human Movement Sciences Physiology at Northwestern University in 2013. The PTHMS and Physiology departments are very supportive of my research, as my position requires at most 20% teaching and research space within the Physiology Department. I have shared space and equipment with my consultant, Matt Tresch, PhD for my proposed in vivo behavioral experiments as well as for space and equipment for the proposed in vitro cellular electrophysiology experiments from my mentor, CJ Heckman, PhD. Again, my goal is always to design my experiments to be as clinically relevant as possible and my clinical experience supports this goal, but my chairperson and consultant Jules Dewald, PT, PhD, will also be evaluating my work for translatability as this is clearly a strength for him. Finally, two outstandng researchers, Ron Harris-Warrick, PhD at Cornell University and Claire Meehan, PhD at the University of Copenhagen will provide mentoring outside of Northwestern. They have both graciously invited me to their laboratories to learn their novel and unique in vitro cellular electrophysiology techniques to answer the questions posed in my proposal. The inception of this proposal started at the beginning of my professional journey when working in human SCI with Brian Schmit, PhD and in the clinic with SCI patients and aims to understand the cellular changes underlying spams after SCI so as to provide better treatments. Spasms are caused by hyperexcitability in both interneurons and motoneurons. Normally, descending neuromodulatory pathways, especially the serotonergic raphespinal system, control excitability of both types of spinal neurons. The loss of this serotonergic input to the spinal cord has several consequences, all of which potentially contribute to spasms following SCI. First, following complete transection, the loss of this serotonergic input to the ventral spinal cord causes motoneurons to increase expression of constitutively active serotonin receptors. This adaptation causes motoneurons to become intrinsically hyperexcitable and to become supersensitive to any residual serotonin. In addition to these effects on ventrally located motoneurons, the loss of raphespinal inputs to the dorsal spinal cord releases interneurons from serotonergic inhibition, increasing interneuron excitability and supersensitivity. Each of these alterations can contribute to the expression of spasms following SCI. However, their specific contributions will depend on the nature of the spinal injury. For example, the supersensitivity of neurons to serotonin might play a smaller role following complete SCI than following incomplete SCI where some residual raphespinal systems remain intact. Similarly, injuries that preferentially affect dorsal or ventral raphespinal systems might differentially involve hyperexcitability in motoneurons or disinhibition of interneurons. Our proposal uses an unparalleled range of unique mouse preparations and novel therapeutics to test how these cellular alterations underlie the variability seen in spasms post SCI and provide directions for therapeutic intervention.

Public Health Relevance

Spinal cord injury (SCI) causes paralysis but also induces severe alterations to reflexes, resulting in debilitating involuntary muscle contractions or spasms. Our hypothesis is that the mechanisms underlying these reflex alterations are not identical across people with SCI but vary systematically with both the severity and location of injury. This goal of this proposal is to determine how the severity and location of injury affects the development of spasms post SCI and, therefore, how we can create better therapies that are specific to SCI and specific to the patient.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Scientist Development Award - Research & Training (K01)
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National Institute of Child Health and Human Development Initial Review Group (CHHD)
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Marden, Susan F
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Northwestern University at Chicago
Physical Medicine & Rehab
Schools of Medicine
United States
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Quinlan, Katharina A; Kajtaz, Elma; Ciolino, Jody D et al. (2017) Chronic electromyograms in treadmill running SOD1 mice reveal early changes in muscle activation. J Physiol 595:5387-5400
Tysseling, V M; Klein, D A; Imhoff-Manuel, R et al. (2017) Constitutive activity of 5-HT2C receptors is present after incomplete spinal cord injury but is not modified after chronic SSRI or baclofen treatment. J Neurophysiol 118:2944-2952
Johnson, Michael D; Thompson, Christopher K; Tysseling, Vicki M et al. (2017) The potential for understanding the synaptic organization of human motor commands via the firing patterns of motoneurons. J Neurophysiol 118:520-531
Thaweerattanasinp, Theeradej; Heckman, Charles J; Tysseling, Vicki M (2016) Firing characteristics of deep dorsal horn neurons after acute spinal transection during administration of agonists for 5-HT1B/1D and NMDA receptors. J Neurophysiol 116:1644-1653