Detour pathways of descending motor systems

• Main Author: Mitchell, Emma
• Published: University of Glasgow 2016
• Subjects: 612.8; Q Science (General)
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.681879

The motor cortex makes a substantial contribution to contralateral limb function via the corticospinal tract (CST). The extent to which the motor cortex influences ipsilateral limb function is less clear. Interest in ipsilateral cortical control stems from studies of stroke survivors, demonstrating increased activation of the ipsilateral motor cortex during movement of the affected limb. This raises the possibility that ipsilateral pathways contribute to recovery of function following damage to the contralateral CST. The overarching aim of this thesis was to extend the knowledge of neural systems that might mediate ipsilateral actions of the motor cortex, both under normal circumstances and after stroke. In rodent models of stroke, there is evidence that CST axons originating from the non-ischaemic hemisphere sprout into the denervated (ipsilateral) side of the spinal cord, and the extent of sprouting correlates with the degree of motor recovery. However, it is yet to be confirmed whether the CST from the nonischaemic hemisphere establishes new terminals in the denervated (ipsilateral) side of the spinal cord to replace connections lost after stroke. Hence, the first major aim of this thesis was to assess for CST terminal remodelling between the non-ischaemic hemisphere and the denervated (ipsilateral) side of the cervical spinal cord following recovery from experimental stroke in the rat. Rats underwent 60 min middle cerebral artery occlusion (MCAo) or sham occlusion surgery. Behavioural testing was conducted prior to MCAo and postoperatively for 28 days to monitor functional deficit and recovery. At day 28, the anterograde tracer cholera toxin b (CTb) subunit was injected into the forelimb motor cortex of the non-ischaemic hemisphere. Spinal sections containing anterogradely labelled terminals were reacted with antibodies against CTb and immunoreactive terminals were quantified. MCAo was associated with loss of approximately 35% of CST axons originating from the ischaemic hemisphere and infarcts were localised to subcortical structures. Rats exhibited sensorimotor deficits in the early phase after MCAo but recovered over time such that there were no significant differences in sensorimotor performances between shamoperated and MCAo rats at post-operative day 28. Despite functional recovery demonstrated by MCAo rats, the number of CTb-labelled terminals in the II cervical spinal cord originating from the non-ischaemic hemisphere was not altered compared to shams. The results of this first study suggest that after subcortical stroke, the motor cortex from the non-ischaemic hemisphere does not contribute to recovery of the affected limb via increasing its direct CST connections to the denervated (ipsilateral) side of the spinal cord. If the motor cortex from the non-ischaemic hemisphere does take over control of ipsilateral spinal circuitry after stroke, it likely utilises an indirect route. In the intact animal, a number of indirect routes via which the motor cortex may gain access to ipsilateral spinal circuitry have been identified. These pathways are complex and involve intercalated neurons located in the brainstem and contralateral spinal cord. However, there are numerous putative indirect routes which have yet to be investigated. One such route involves contralaterally descending CST axons targeting spinal commissural interneurons (CINs), which in turn would either mono- or polysynaptically affect motor neurons on the opposite side of the spinal cord. CINs are a heterogeneous population of cells important for inter-limb coordination. Despite the importance of CINs to locomotion and their potential role in providing the motor cortex indirect access to ipsilateral spinal circuits, supraspinal input to CINs is poorly defined. Hence, the second major aim of this thesis was to characterise contacts to CINs from different supraspinal sources (the CST and reticulospinal tract (ReST)) in the cervical spinal cord of the intact rat. The CINs included i) those that issue longrange axonal projections to lumbar segments, termed long-descending propriospinal neurons (LDPNs), and ii) those that issue short-range axonal projections confined to a single segment, termed intrasegmental CINs. Axons were labelled anterogradely by injecting CTb into the forelimb motor cortex or medial longitudinal fasciculus (MLF), to label CST and ReST axons, respectively. Fluorogold (FG) was injected unilaterally into segments L1/L2 or C3/C4 in order to retrogradely label LDPNs or intrasegmental CINs, respectively. Spinal sections containing labelled cells and terminals were immunoreacted with various antibody combinations and were then examined with confocal microscopy. Both LDPNs and intrasegmental CINs received very few contacts from CST terminals but had significant numbers of contacts from ReST terminals. Use of vesicular glutamate and vesicular GABA transporters revealed that both cell types received approximately 80% of excitatory and 20% of inhibitory ReST contacts. III The results suggest that in the intact animal, the CST has a minimal direct influence on LDPNs and intrasegmental CINs but the ReST has a powerful direct influence. Therefore, following loss of CST axons (e.g. after stroke), the corticoreticulospinal- commissural pathway has the capacity to deliver information from the intact hemisphere to the denervated side of the spinal cord.