Matthew Ramer
Relevant Thesis-Based Degree Programs
Graduate Student Supervision
Doctoral Student Supervision
Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
Remyelination occurs after spinal cord injury (SCI) but its functional relevance isunclear. We assessed the necessity of myelin regulatory factor (Myrf) in remyelination aftercontusive SCI by deleting the gene from platelet-derived growth factor receptor alpha positive(PDGFRα-positive) oligodendrocyte precursor cells (OPCs) in mice prior to SCI. While OPCproliferation and density were not altered by Myrf inducible knockout after SCI, theaccumulation of new oligodendrocytes was prevented. This greatly inhibited myelin regenerationresulting in a loss of myelinated axons at the lesion epicenter. However, spontaneous locomotorrecovery after SCI was not altered by remyelination failure. In controls with functional MYRF,locomotor recovery preceded the onset of substantial oligodendrocyte myelin regeneration. Wenext assessed locomotor recovery in a severe model of SCI where fewer axons were spared. Hereanimals were still able to recover despite the inhibition of remyelination. We noticed that ionchannels were redistributed in demyelinated axons. Further testing showed knockout animalswere able to show conduction properties similar to that of control animals. Collectively, thesedata demonstrate that MYRF expression in PDGFRα-positive cell derived oligodendrocytes isindispensable for oligodendrocyte myelin regeneration following contusive SCI, thatremyelination is not required for spontaneous recovery of stepping in moderate or severeinjuries, and that demyelinated axons redistribute voltage gated ion channels and conductionproperties similar to that of unmyelinated axons.
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Spinal cord injury (SCI) interrupts communication between the brain and peripheral organs resulting in profound and long-lasting effects, including clinically important dysfunction of the pelvic viscera (PV). Sensory and autonomic peripheral neurons innervating the PV are contained in the dorsal root ganglia (DRG) and pelvic ganglia (PG), respectively. Previous studies have identified changes in these neurons after SCI, but questions remain about the relationship between injury level and changes in peripheral targets and ganglia. In this dissertation, I addressed these questions using male Wistar rats with a high thoracic transection (T3x), which eliminates the majority of supraspinal connections to sympathetic preganglionics (including those innervating the splanchnic bed and adrenal glands), or a high lumbar transection (L2x), which preserve these connections but directly damage neurons innervating the pelvic peripheral ganglia and PV. I examined gene expression changes in DRGs and PGs one month post-T3x using RNA sequencing and found indications for unexpected neuron-target interactions, including changes in growth factor signaling and cell communication. In the PG, decreased expression of tyrosine hydroxylase (TH) after T3x was supported by atrophy of sympathetic (TH-positive) neurons. SCI results in bladder hypertrophy, and though L2x resulted in increased bladder weights compared to both T3x and naïve animals, the expression of TH in the PG decreased and TH-positive neuron hypertrophy was only transient. These results indicate a more complex relationship between target size and neurotrophism than generally accepted. Examination of PV changes after high and low SCI revealed different patterns of bladder activity. Two days after injury, there was augmented bladder activity at low intravesical pressures in L2x compared to T3x and naïve animals. I found that disrupting signal transmission through the PG did not change the bladder activity patterns, however, bilateral adrenalectomy concurrent to L2x resulted in bladder activity patterns that more closely resembled the T3x injury. Further to this, circulating catecholamine levels were higher in animals with intact innervation to the adrenal gland, implicating adrenal function in bladder changes after SCI. The findings in this thesis highlight the importance of studying injury level both from the perspective of both local circuitry and systemic changes.
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No abstract available.
No abstract available.
Master's Student Supervision
Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
Peripheral nerve injuries (PNIs) occur in 1-3% of patients with any trauma. While peripheral axons have the ability to regenerate at ~1-3 mm/day, the distance over which they must do so means lengthy recovery times associated with regenerative failure due to a decline in supporting cells’ ability to maintain axon growth. Successful axonal regeneration depends heavily upon the neuronal response to injury, and that of myeloid cells recruited to the damaged nerve. In injured regeneration-competent neurons, the transcriptomic changes that occur mirror those observed in hypoxia; hypoxia inducible factors (HIFs) effect some of these. HIF activity is governed in turn by the HIF-hydroxylases, prolyl hydroxylase domain (PHD) proteins and factor inhibiting HIF (FIH). Under normoxic conditions, HIF-hydroxylases act as master regulators of the hypoxia response, targeting HIFs for proteasomal degradation. I hypothesized that deleting any or all of the PHDs (PHD1, 2, and 3), or inhibiting PHDs pharmacologically, would induce a hypoxia response and enhance axonal regeneration and functional recovery following PNI. I used global PHD1 knockout, global PHD3 knockout, and heterozygous PHD2 transgenic mice, as well as non-transgenic mice treated with dimethyloxalylglycine (DMOG), a pan-HIF-hydroxylase inhibitor. Using sciatic nerve models of injury, I assessed functional recovery at various time points post-injury using behavioural assays. I characterized macrophage and axon densities in the nerves after injury and assessed DMOG-induced changes in macrophage phenotype using FACS, RT-PCR and immunohistochemistry. I found that deletion of PHD1 or PHD3, or inhibition of all three PHDs resulted in earlier functional recovery after injury, increased macrophage infiltration in the injured nerve, an M2-skewed macrophage phenotype, and enhanced axonal regrowth. Additionally, deletion of any of the PHDs, or their inhibition by DMOG, resulted in improved electromyographical responses of the nerve one-month post-injury. These findings suggest that nerve repair can be aided by hypoxia-independent induction of the hypoxia response.
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Anticonvulsants like pregabalin (PGB) are the first-line treatment for neuropathic pain caused by traumatic injury and non-traumatic diseases of the central nervous system. Recent evidence from a human cohort study suggests that early use of pregabalin after spinal cord injury (SCI) may result in improved motor scores, however, it is unknown to what extent changes in spinal neural circuitry are involved. Backwards translation into a rat model is the first step towards understanding these possible changes. Using a rat model of unilateral cervical contusion, I examined the effect of pregabalin treatment on both motor and sensory function. For four weeks post-injury, rats were given daily pregabalin or filtered water via oral gavage. Motor function was scored using the Montoya staircase assessment (MSA) of fine motor skills. Additionally, pruritus and noxious mechanosensation were assessed through behavioural evidence of scratching and the Randall-Selitto analgesy-meter, respectively. I found no evidence of improved motor scores in the affected forelimb following MSA analysis with the early administration of pregabalin. There was an unexpected deterioration of motor function contralateral to injury, and this was mitigated by early PGB treatment. Additionally, I found that self-injurious scratching, often occurring in animals with this type of injury, was greatly reduced in those treated with PGB. Finally, results of the Randall-Selitto analgesy-meter indicate a protective effect of (PGB) even after its discontinuation. Our findings suggest that in rats with a unilateral SCI, pregabalin treatment has an at-time effect on pruritus and neuropathic pain, a possible protective effect on mechanosensory nociception, and contrary to a human cohort study, does not improve ipsilateral motor outcomes with early administration.
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Spinal cord injury (SCI) is a devastating insult to the nervous system with implications for locomotor, autonomic and sensory function. Past studies indicate that passively moving the lower limbs may be beneficial for locomotor recovery after SCI, however the literature lacks in studies addressing autonomic and sensory ramifications of passive exercise. I used a well-established passive exercise model, which consists of cycling the hind-limbs of adult male Wistar rats with complete transection SCI at the third thoracic segment (T3), beginning 5 days after injury and continuing for 4 weeks (5 days / week, 1 hour total cycling/day). I measured Hoffman (H)-reflex latency and motoneuron recruitment after the cycling intervention. Latency of the H-wave was shorter in duration and motoneuron recruitment was enhanced after SCI when compared to uninjured controls. Exercise did not affect these properties. I performed histological analysis of parvalbumin-expressing neurons of lumbar (L) and sacral (S) dorsal root ganaglia (DRGs). Proprioceptive neurons at L1/L2 and L4/L5 levels demonstrated somal size decreases after SCI and further decreases with exercise, while there was no change at the L6/S1 level. This effect may be due to exercise-induced changes in neurotrophic support of proprioceptive neurons by target tissues. The autonomic/cardiovascular effects of passive exercise are largely unknown. I focused on two common cardiovascular conditions associated with SCI, autonomic dysreflexia (AD) and orthostatic hypotension (OH). AD occurs in individuals with an injury above T6, and is marked by massive spikes in blood pressure (BP) due to a normally-innocuous stimulus below the injury level. OH is a large drop in BP upon being seated upright, assessed via tilting the animal to a 90 degree head-up position. Passive exercise led to a 50% reduction in AD severity, as measured by beat-to-beat BP measurements and an established method for inducing AD. In contrast, I found no change in OH severity with exercise. Lumbosacral nociceptors expressing the capsaicin receptor (TRPV1), which have previously been implicated in AD and demonstrate hypertrophy after SCI, decrease in soma size after the exercise intervention. This may also indicate exercise-induced altered neurotrophic support.
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Spinal cord injury (SCI) has the potential to disrupt autonomic pathways in the spinal cord leading to a range of autonomic dysfunctions. The cardiovascular (CV) and metabolic sequelae can restrict the lives of individuals with SCI and contribute to the deterioration of their cardiometabolic health. Here I investigated the whole-body CV and metabolic ramifications of experimental SCI in rats. Complete thoracic SCI was performed at two different levels in order to determine whether these outcomes demonstrated a level dependence. High-(T3) and low-(T10) thoracic SCI both result in flaccid hindlimb paralysis, but have different effects on the level of supraspinal autonomic control. CV and metabolic function were assessed at several times post-injury to investigate changes over time. Animals with acute high-thoracic SCI displayed resting hypotension that resolved with time post-injury. However, their capacity to control blood pressure (BP) in response to physiological stimuli remained deficient; animals with high-thoracic SCI displayed pronounced orthostatic hypotension (OH) and severe episodes of sensory stimulation-induced hypertension known as autonomic dysreflexia (AD). The resting BP and heart rate of animals with low-thoracic SCI, and their ability to respond to orthostatic stress, was indistinguishable from sham controls. Lipid metabolism was also disordered by SCI in a level-dependent pattern. Animals with high-thoracic SCI carried increased white adipose tissue and had higher circulating triacylglycerol levels compared to animals with low-thoracic SCI and sham controls. However, there was no difference in the distribution of cholesterol-carrying lipoproteins. Carbohydrate metabolism in animals with SCI did not support the diabetic profile suggested by the lipid results. Overall, animals with SCI were more sensitive to glucose and insulin than sham-injured animals. The pronounced ketone response to fasting in animals with high-thoracic SCI suggests that there are diverse effects on substrate metabolism.This work introduces simple tests that can be performed to investigate several important and understudied autonomic outcomes of SCI. The results reveal the importance of the intact autonomic nervous system in regulating CV and metabolic function. The disparity between motor and autonomic function encourages modifying our current conventions so that we stratify subjects by their autonomic injury level and their motor deficits.
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