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Permanent link (DOI): https://doi.org/10.7939/R3ZK55Z98

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Role of Aromatic L-Amino Acid Decarboxylase (AADC) after Spinal Cord Injury Open Access

Descriptions

Other title
Subject/Keyword
chronic spinal cord injury
pericyte
5-HTP
5-HT1B receptor
AADC
impaired blood flow
basal vessel tone
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Li, Yaqing
Supervisor and department
David J Bennett, Centre for Neuroscience, U of Alberta
Examining committee member and department
Richard B. Stein, Centre for Neuroscience, U of Alberta
Glen B. Baker, Department of Psychiatry, U of Alberta
Karim Fouad, Centre for Neuroscience, U of Alberta
Shawn Hochman, Department of Physiology, Emory University
Department
Centre for Neuroscience
Specialization

Date accepted
2015-12-10T13:35:02Z
Graduation date
2016-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Spinal cord transection leads to elimination of brainstem-derived monoamine fibers that normally synthesize most of the monoamines in the spinal cord, including serotonin (5-HT) and noradrenaline (NA). Such spinal cord injury (SCI) thus leads to the loss of monoamines, as well as monoamine-synthesizing enzymes, including tryptophan hydroxylase (TPH) and aromatic L-amino acid decarboxylase (AADC). However, several studies suggest that after SCI the spinal cord spontaneously recovers AADC, but not other monoamine synthesizing enzymes. Thus, we explore here the mechanisms and outcomes of this plasticity in AADC. AADC alone cannot produce 5-HT, but it can produce 5-HT when its precursor, 5-HTP, is made available. As well, AADC can produce trace amines (like tryptamine) directly from dietary amino acids (like tryptophan). In the first chapter of this thesis, we used an immunolabelling method to determine locations of recovered AADC after SCI. We found that AADC is ectopically upregulated in microvasculature, especially in pericytes on capillaries, and in certain AADC-containing interneurons in the spinal cord caudal to lesion. We then tested the action of AADC on motoneurons and muscle spasms (long-lasting reflexes, LLRs) by both in vivo and in vitro methods, and we found that the upregulated spinal AADC in both vessels and interneurons produced functional amounts of 5-HT from exogenously applied 5-HTP, which increased both motoneuron and LLR activity. However, we found that this AADC was not capable of endogenously producing functional classic monoamines, like 5-HT, leaving the endogenous function of spinal AADC uncertain. Thus in chapter 3 we examined whether spinal AADC was able to endogenously produce functional trace amines. Initially, we found no direct effect of physiological trace amine on motoneurons and spasms, and thus we turned to investigating blood vessel function, because vessel AADC was highly upregulated . Blood vessels in the central nervous system (CNS) are controlled by neuronal activity, including widespread vessel constrictions induced by brainstem-derived monoamines (5-HT and NA), and local vessel dilation mediated by glutamatergic neuron activity. SCI eliminates this monoamine innervation of vessels, and thus we examined whether trace amines could replace this lost innervation. Using infrared differential interference contrast (IR-DIC) microscopy, we found that AADC produced trace amines (TAs, like tryptamine) from dietary amino acids (tryptophan) and this in turn led to constrictions of capillaries adjacent to pericytes. These TA-induced constrictions were mediated by 5-HT1B and alpha2 adrenergic receptors. These receptors play a critical role in compensating for the loss of classic monoamines, and restoring microvessel tone. However, we also found that this vessel tone was excessive, with spinal cord oxygenation and blood flow about half of normal after SCI (in vivo). This led to the cord below the injury being in a chronic state of hypoxia. Blocking monoamine receptors or AADC, or briefly inhaling pure oxygen, produced long-term relief from hypoxia and improved motor functions, including locomotion.
Language
English
DOI
doi:10.7939/R3ZK55Z98
Rights
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
Y. Li, L. Li, M.J. Stephens, D. Zenner, K.C. Murray, I.R. Winship, R. Varek, G.B. Baker, K. Fouad and D.J. Bennett. Synthesis, transport, and metabolism of serotonin formed from exogenously applied 5-HTP after spinal cord injury in rat. J Neurophysio vol 111: 145-163, 2014

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