Biomedical Sciences ETDs

Publication Date

Fall 5-11-2019

Abstract

Previous studies have suggested that children with Fetal Alcohol Spectrum Disorder (FASD) display hypersensitivity to light touch. In support of this notion, we have demonstrated that applying a chronic constriction injury (CCI) to the sciatic nerve of rats that have prenatal alcohol exposure (PAE) results in heightened sensitivity to light touch, clinically termed allodynia. These observations coincided with heightened glial activation and enhanced peripheral immune reactivity. Considering allodynia is known to be mediated by both peripheral immune responses and spinal glial activation, it is reasonable to speculate that allodynia following PAE may be mediated through an alteration of immune reactivity. Thus, I hypothesized that PAE results in immune sensitization leading to enhanced susceptibility to developing allodynia.

To address the possibility that PAE creates susceptibility to developing neuropathy, a minor CCI was applied to rats that have been prenatally exposed to saccharin (Sac) or alcohol (PAE). Induction of allodynia occurs only in PAE rats with a minor injury. Interestingly, data acquired by immunohistochemistry (IHC) and subsequent microscopy analyses show that spinal astrocyte activation was altered compared to Sac rats. Furthermore, pharmacological blockade of spinal cytokines leading to reduced allodynia also demonstrate an alteration in the proinflammatory cytokine profile at the spinal cord and the sciatic nerve. Strikingly, PAE resulted in downregulation of normal IL-10 responses within the spinal cord and dorsal root ganglia (DRG) as shown by IHC. Additionally, satellite glial cells were activated in the DRG compared to controls which coincided with heightened expression of the proinflammatory cytokine IL-1b. Spinal cord IHC analysis of glutamate transporters demonstrated that PAE alone is sufficient to upregulate both glutamate transporter 1 (GLT-1) and the astrocyte specific transporter glutamate aspartate transporter (GLAST) followed by a downregulation after minor CCI. These data suggest that an increase in synaptic and peri-synaptic glutamate develops following minor injury that is regulated predominantly by glia. Interestingly, no significant change was seen in the neuronal specific transporter EAAC1 or in NMDA receptor subunits.

Collectively, the work described and presented in this dissertation demonstrates that PAE primes peripheral and spinal neuroimmune responses which lead to allodynia following minor CCI. Additionally, my data demonstrate that PAE may alter glutamate transporters in the spinal cord which may lead to continued heightened glial activation and increased cytokine actions following injury. Furthermore, our studies support the possibility that glial cells are sensitized as a consequence of PAE, which in turn influence neuronal activity. Taken together, the results from this work demonstrate that PAE leads to life-long susceptibility to developing allodynia.

Keywords

Neuropathic pain, FASD, PAE, astrocytes, microglia, spinal cord

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Dr. Erin D. Milligan

Second Committee Member

Dr. Kevin Caldwell

Third Committee Member

Dr. Jason Weick

Fourth Committee Member

Dr. Lauren Jantzie

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