Circuit-level control of forelimb motor behaviour and plasticity following injury

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The major output of the central nervous system (CNS) is to control movement via descending motor pathways that project from the brain to the spinal cord to orchestrate motoneuron activities. Their importance is strikingly obvious in cases of spinal cord injury, when severe paralysis can ensue because of their disruption. However, their specific roles in motor behaviour and ability to mediate motor system recovery following injury remain unclear. Here, we are embarking on a new research program aiming at an understanding of neural plasticity and functional compensation after spinal cord injury using chemogenetic and ontogenetic technologies. Specifically, we propose a series of initial experiments using a recently developed technology that allows non-invasive and transient silencing of specific neural circuits in vivo called Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) (PMID:17360345). DREADDs are bioengineered G-protein coupled receptors that can activate or silence neurons in response to ligands that do not activate other receptors within the body. These ligands can be administered non-invasively via intraperitoneal injection (short acting) or through drinking water (long acting). DREADD receptors can be targeted to specific neuronal populations in one of two ways. First, viruses encoding DREADDs can be administered such that only cells within the area of viral injection is generally infected. Second, by using cre-dependent constructs, specific anatomical projections can be targeted by employing a dual virus approach, wherein one cre-dependent virus is administered at the neuron's cell body and the second, cre-encoding virus is administered for retrograde infection at the neuron's axon/synaptic terminal (PMID: 26889809). We have used this approach successfully (PMID: 27053214). In the present project we will use the silencing DREADD hM4Di to specifically silence descending motor pathways implicated in forelimb motor control. The first objective of this grant is to elucidate the role of corticospinal, rubrospinal, and medullary reticulospinal ventral (MdV) pathways in motor behavioural function in the uninjured adult mouse CNS. The second objective is to elucidate the plasticity of rubrospinal and MdV pathways in mediating recovery following corticospinal tract injury at the level of the pyramid. We will assess the recovery of single food pellet reaching, ladder crossing, rotarod and grip strength in mice before and following the administration of CNO to silence these specific neuronal populations and make comparisons within the same animal such that each animal acts as its own control. This will reveal the functional involvement of specific neuronal projection systems in the execution of specific tasks, either in the normal uninjured state or after incomplete injury.