Characterization of brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), expression and function in the spinal nociceptive circuitry in a model of chronic neuropathic pain
2021-08
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Characterization of brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), expression and function in the spinal nociceptive circuitry in a model of chronic neuropathic pain
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2021-08
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Abstract
Brain derived neurotrophic factor (BDNF) is widely studied for its role inplasticity that underlies learning and memory, and the maladaptive plasticity that gives
rise to chronic pain. BDNF acts through its receptor, tropomyosin kinase B (TrkB), to
initiate signaling cascades that result in time-, sex-, region-specific changes in
nociceptive circuitry due to nerve injury. Despite great interest in the role of BDNF in
neuroplasticity responsible for producing chronic pain states, including neuropathic pain,
very few studies include more than one timepoint, region, sex, and methods to evaluate
the presence and activity of BDNF. These gaps in the literature are especially problematic
when considering reported sex-dependent or contradictory effects of BDNF on pain
behaviors. Understanding the scope and exact mechanism of BDNF-TrkB signaling in
neuropathic pain is crucial for the development of novel pain therapies that are safe,
effective, and unbiased.
My thesis work focuses on providing a comprehensive assessment of BDNF and
TrkB expression and function which includes both sexes, multiple regions of the
nociceptive pathway, cell types, and timepoints after nerve injury. Using a highly
sensitive in situ hybridization method, I show that changes in BDNF and TrkB mRNA in
DRG and spinal cord are time- and sex-dependent. Although males had higher amounts
of TrkB protein in dorsal horn (DH) of the spinal cord, the degree of TrkB activation due
to injury was comparable between the sexes. A novel TrkB specific inhibitor, ANA-12,
modestly but significantly reduced hypersensitivity in males in a time-dependent manner
but not in females. Further investigation into this revealed that ANA-12, instead of
inhibiting TrkB activity, increased DH TrkB phosphorylation in both sexes. Finally, the
role of microglia in BDNF-TrkB signaling was investigated and although BDNF mRNA
was not detected in any microglial profiles in DH, TrkB mRNA was reliably identified in
DH microglia after nerve injury. The microglial TrkB phosphorylation was elevated in
DH of injured animals pointing to a functional role. To test that hypothesis, I generated a
tamoxifen inducible microglia specific TrkB knockout line and conducted behavioral
experiments to evaluate the effect of microglial TrkB on pain behaviors. No behavioral
differences were detected at any timepoint in either sex. Surprisingly, tissue analysis
revealed an elevation in BDNF and TrkB along with the surface area of microglia in DH
indicating increased microglial activation in response to microglial TrkB deletion. These
data collectively suggest that BDNF-TrkB activity is region, sex, and time-dependent and
highlights the importance of validating not just the tools used, but also the effect of the
manipulations on the underlying process that is being studied.
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University of Minnesota Ph.D. dissertation. 2021. Major: Neuroscience. Advisor: Lucy Vulchanova. 1 computer file (PDF); vi, 116 pages.
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Gore, Reshma. (2021). Characterization of brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), expression and function in the spinal nociceptive circuitry in a model of chronic neuropathic pain. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/224971.
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