Cycle 1 project 9

Functional innervations of monoaminergic receptors after spinal cord injury

PhD student: Isabel Vollenweider, Colombia/Switzerland
Home Institute: Neuroscience Center Zürich; Principle Investigator: Grégoire Courtine
Host Institute: Bordeaux Neuroscience – Université Bordeaux Segalen; Principle Investigator: Erwan Bézard

Executive Summary
Descending monoaminergic inputs powerfully influence the spinal circuits that coordinate stepping in mammals. However, the anatomical and functional relationships between monoaminergic receptors and locomotor control remain poorly understood. Moreover, the impact of spinal cord injury (SCI) on monoaminergic receptor innervation, and its plasticity in response to effective neurorehabilitation interventions have not been evaluated thus far.

The objective of the current project is to investigate these research questions in adult rats with complete spinal cord transection.

1. In the first aim, we will assess serotonergic, dopaminergic, and noradrenergic innervation of locomotor-activated neurons within the lumbosacral spinal cord following hindlimb stepping enabled by electrical spinal cord stimulation and specific monoaminergic agonists. The underlying goal is to associate well-defined networks of monoaminergic-modulated locomotor circuits with distinct characteristics of gait.

2. In the second aim, we will correlate the progressive emergence of spasticity, abnormal reflexes, and degradation of function in spinal rats with time-dependent changes in monoaminergic receptor innervations. We hypothesize that a graded increase in monoaminergic receptor density on locomotor-activated neurons will contribute to functional deterioration in the 2 chronic stage after a severe spinal cord injury.

3. In the third aim, we will assess the capacity of neurorehabilitation to counteract detrimental changes in monoaminergic receptor innervations after SCI. Spinal rats will follow robotic locomotor training procedures enabled by electrical spinal cord stimulation and monoamine agonists. We previously showed that this multi-pronged neurorehabilitation allows the impressive recovery of full weight bearing locomotion in otherwise paralyzed spinal rats. Here, we surmise that use-dependent mechanisms will mediate a specific decrease in the density of monoaminergic receptor innervations on locomotor-activated lumbosacral neurons, which will correlate with functional improvements.

Results from the proposed studies will increase our basic understanding of spinal monoaminergic innervation and function. This knowledge will importantly contribute to paving the way towards the design of effective pharmacotherapy to improve function in severely paralyzed individuals. This doctoral fellowship will be integrated into a broader research program that aims at developing effective neuroprosthetic interfaces and pharmacological combinations to encourage neurorehabilitation and restore function after SCI and other debilitating neuromotor impairments.