Pathway and biomarker discovery in a posttraumatic stress disorder mouse model

Kao, Chi-Ya (2015): Pathway and biomarker discovery in a posttraumatic stress disorder mouse model. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)

Abstract

Posttraumatic stress disorder (PTSD), a prevalent psychiatric disorder, is caused by exposure to a traumatic event. Individuals diagnosed for PTSD not only experience significant functional impairments but also have higher rates of physical morbidity and mortality. Despite intense research efforts, the neurobiological pathways affecting fear circuit brain regions in PTSD remain obscure and most of the previous studies were limited to characterization of specific markers in periphery or defined brain regions. In my PhD study, I employed proteomics, metabolomics and transcriptomcis technologies interrogating a foot shock induced PTSD mouse model. In addition, I studied the effects of early intervention of chronic fluoxetine treatment. By in silico analyses, altered cellular pathways associated with PTSD were identified in stress-vulnerable brain regions, including prelimbic cortex (PrL), anterior cingulate cortex (ACC), basolateral amygdala (BLA), central nucleus of amygdala(CeA), nucleus accumbens (NAc) and CA1 of the dorsal hippocampus. With RNA sequencing, I compared the brain transcriptome between shocked and control mice, with and without fluoxetine treatment. Differentially expressed genes were identified and clustered, and I observed increased inflammation in ACC and decreased neurotransmitter signaling in both ACC and CA1. I applied in vivo 15N metabolic labeling combined with mass spectrometry to study alterations at proteome level in the brain. By integrating proteomics and metabolomics profiling analyses, I found decreased Citric Acid Cycle pathway in both NAc and ACC, and dysregulated cytoskeleton assembly and myelination pathways in BLA, CeA and CA1. In addition, chronic fluoxetine treatment 12 hours after foot shock prevented altered inflammatory gene expression in ACC, and Citric Acid Cycle in NAc and ACC, and ameliorated conditioned fear response in shocked mice. These results shed light on the role of immune response and energy metabolism in PTSD pathogenesis. Furthermore, I performed microdialysis in medial prefrontal cortex and hippocampus to measure the changes in extracellular norepinephrine and free corticosterone (CORT) in the shocked mouse and related them to PTSD-like symptoms, including hyperaroual and contextual fear response. I found that increased free CORT was related to immediate stress response, whereas norepinephrine level, in a brain region specific manner, predicted arousal and contextual fear response one month after trauma. I also applied metabolomics analysis to investigate molecular changes in prefrontal microdialysates of shocked mice. Citric Acid Cycle, Glyoxylate and Dicarboxylate metabolism and Alanine, Aspartate and Glutamate metabolism pathways were found to be involved in foot shock induced hyperarousal. Taken together, my study provides novel insights into PTSD pathogenesis and suggests potential therapeutic applications targeting dysregulated pathways.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: PTSD mouse model, proteomics, metabolomics, transcriptomics, biomarker, fluoxetine
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Graduate School of Systemic Neurosciences (GSN)
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 15. Dezember 2015
• 1. Bericht­erstatter:in: Turck, Christoph