Crucial spinal circuit changes that mediate locomotor benefits and deficits following combined therapies after spinal cord injury

Drexel University, Philadelphia PA

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Abstract

ABSTRACT Severe spinal cord injury (SCI) often spares spinal circuitries innervating the hindlimbs but results in the loss of motor control below the injury due to compromised descending innervation of the cord. Plasticity after injury leads to the development of hyperreflexia and spasticity over time. Although hyperreflexia can be beneficial initially, facilitating motor output and locomotor function, it disrupts functional gains in the longer-term. The sensory afferents and their transmission within the cord are thought to be a primary mechanistic contributor to both regained locomotor function and hyperreflexia following SCI. Thus, identification of the mechanistic balance point between afferent input promoting locomotion and contributing to pathology, including hyperreflexia, after SCI is crucial to maximizing functional recovery. During the prior funding period, we demonstrated that viral delivery of brain derived neurotrophic factor (AAV-BDNF) below the lesion dramatically improves weight- supported stepping in subsets of rats and mice with complete thoracic spinal cord injury but hyperreflexia interferes with functional gains in other subsets over time. This provides a powerful experimental model where the same treatment strategy leads to beneficial and detrimental outcomes. In this renewal application, we will test the overarching hypothesis that spatial variations in plasticity and excitability across the cord due to viral BDNF contribute to functional variation in both locomotor patterns and expression of pathological reflexes. Experiments will be performed in two highly complementary neurophysiology labs with expertise in chronic recordings and rehabilitation in rats and intracellular and genetics techniques in mice. To obtain precisely controlled effects in spinal circuitry in both rodent models, we use complete SCI, eliminating descending control driven effects below the lesion, and focusing on spinal and afferent driven plasticity. The complete SCI will provide clean and unambiguous data which can subsequently guide other therapeutic work in more directly clinically translatable animal models. Using mouse and rat data together, we will determine the structural, synaptic, circuit, and synergy-related plasticity associated with the recovery of stepping, and interfering hyperflexion and hyperextension, after complete SCI. Further, the critical windows and critical neural elements supporting both locomotor improvements and the development of pathological reflexes will be determined. The establishment of the structural, synaptic, and circuit differences underlying functional locomotor gains, hyperflexion, and hyperextension will greatly contribute to mechanistic understanding of both function and pathology, and has the potential to reveal testable structural or electrophysiological biomarkers for specific pathologies. Additionally, the determination of timing, critical neuronal elements, and the mechanistic interactions of these circuits with both AAV-BDNF driven plasticity and with epidural stimulation will together reveal key therapeutic targets and potential neuromodulation-based treatment strategies to enhance locomotor function.