Detour pathways of descending motor systems

Mitchell, Emma (2016) Detour pathways of descending motor systems. PhD thesis, University of Glasgow.

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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
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.
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.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: stroke, spinal cord, detour circuits.
Subjects: Q Science > Q Science (General)
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
Supervisor's Name: Dewar, Dr. D. and Maxwell, Professor D.J.
Date of Award: 2016
Depositing User: Emma J Mitchell
Unique ID: glathesis:2016-7168
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 24 Mar 2016 14:41
Last Modified: 12 Apr 2016 08:21

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