• Login
    View Item 
    •   Home
    • Theses and Dissertations
    • PhD Dissertations
    • View Item
    •   Home
    • Theses and Dissertations
    • PhD Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of KAUSTCommunitiesIssue DateSubmit DateThis CollectionIssue DateSubmit Date

    My Account

    Login

    Quick Links

    Open Access PolicyORCID LibguideTheses and Dissertations LibguideSubmit an Item

    Statistics

    Display statistics

    Genome-wide Insights into the Targets and Mechanisms of Lactate Signaling in Cortical Neurons and an Investigation of the Astrocyte- Neuron Lactate Shuttle in Relation to the Gut Microbiota

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    Michael Margineanu Dissertation.pdf
    Size:
    20.95Mb
    Format:
    PDF
    Description:
    Michael Margineanu Dissertation
    Download
    Thumbnail
    Name:
    Michael Margineanu Supplementary Video 1.avi
    Size:
    7.290Mb
    Format:
    video/vnd.avi
    Description:
    Michael Margineanu supplementary file 1
    Download
    Thumbnail
    Name:
    Michael Margineanu Supplementary Video 2.avi
    Size:
    4.966Mb
    Format:
    video/vnd.avi
    Description:
    Michael Margineanu supplementary file 2
    Download
    View more filesView fewer files
    Type
    Dissertation
    Authors
    Margineanu, Michael B. cc
    Advisors
    Magistretti, Pierre J. cc
    Committee members
    Daffonchio, Daniele cc
    Hirt, Heribert cc
    Di Luca, Monica
    Program
    Bioscience
    KAUST Department
    Biological and Environmental Science and Engineering (BESE) Division
    Date
    2019-06
    Embargo End Date
    2020-07-21
    Permanent link to this record
    http://hdl.handle.net/10754/656128
    
    Metadata
    Show full item record
    Access Restrictions
    At the time of archiving, the student author of this dissertation opted to temporarily restrict access to it. The full text of this dissertation became available to the public after the expiration of the embargo on 2020-07-21.
    Abstract
    Lactate, a metabolic end product of glycolysis in mammals, has emerged as an important energy substrate for the brain. In addition to its energetic role, lactate was shown to modulate the excitability of neurons, to have a neuroprotective role and to participate in long-term memory formation. One previous investigation from our group reported that lactate modulates 4 synaptic plasticity-associated genes and potentiates the activity of the N-Methyl-D-aspartic acid (NMDA) receptor, a major receptor type involved in glutamatergic neurotransmission. The current thesis aimed at first to extend these findings by examining genome-wide transcriptional responses to this metabolite in cortical neurons. Using ribonucleic acid(RNA) sequencing to evaluate expression changes in protein-coding genes, we found that lactate modulates robustly after 1h, 20 genes involved in the mitogen-activated protein kinase (MAPK) signaling pathway and in synaptic plasticity in a NMDA receptor activitydependent manner and that nicotinamide adenine dinucleotide, reduced (NADH), but not pyruvate, reproduces the modulatory effects of lactate on 70% of all differentially expressed genes. In a time course experiment, genes modulated after lactate treatment for 6h and 24h were also identified; these are involved in 9 signaling pathways including circadian rhythm, drug addiction, and retrograde endocannabinoid signaling. Bioinformatics analyses indicated CREB1 and CREM as candidate master regulators of gene expression and the modulatory effect of lactate was prevented by inhibitors of Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity, indicating a role for this kinase in mediating lactate signaling. An examination of changes in dendritic spines’ morphology and density - a morphologicalcorrelate of synaptic plasticity – has shown that lactate modulated spine density changes induced by potassium chloride (KCl) and carbachol. An additional investigation described in this thesis indicated that different gut microbiota manipulations (germ-free, prebiotics, high-fat diet) regulated mRNA expression of genes involved in the Astrocyte-Neuron Lactate Shuttle (ANLS) - a metabolic cooperation mechanism between astrocytes and glutamatergic neurons. Overall, the results of this thesis help to establish a role for lactate as a signaling molecule in the brain, highlight mechanisms implicated in its signaling, and open new avenues for investigation of links between the gut microbiota and brain energy metabolism.
    Citation
    Margineanu, M. B. (2019). Genome-wide Insights into the Targets and Mechanisms of Lactate Signaling in Cortical Neurons and an Investigation of the Astrocyte- Neuron Lactate Shuttle in Relation to the Gut Microbiota. KAUST Research Repository. https://doi.org/10.25781/KAUST-6P4J3
    DOI
    10.25781/KAUST-6P4J3
    ae974a485f413a2113503eed53cd6c53
    10.25781/KAUST-6P4J3
    Scopus Count
    Collections
    Biological and Environmental Science and Engineering (BESE) Division; Bioscience Program; PhD Dissertations

    entitlement

     
    DSpace software copyright © 2002-2023  DuraSpace
    Quick Guide | Contact Us | KAUST University Library
    Open Repository is a service hosted by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items. For anonymous users the allowed maximum amount is 50 search results.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.