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Beyond Neurons: The role of the oligodendrocyte-specific gene CNP1 in major depressive disorder

Edgar, Nicole M. (2011) Beyond Neurons: The role of the oligodendrocyte-specific gene CNP1 in major depressive disorder. Doctoral Dissertation, University of Pittsburgh.

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    Abstract

    Altered oligodendrocyte structure and function is implicated in major mental illnesses, including low density and reduced expression of oligodendrocyte-specific gene transcripts in major depressive disorder (MDD). These features are also observed in the unpredictable chronic mild stress (UCMS) and chronic corticosterone (CORT) rodent models of the illness; however, whether oligodendrocyte changes are a causal component of MDD is not known. The oligodendrocyte-specific gene 2'-3'-cyclic nucleotide-3'-phosphodiesterase (CNP1) is a key component of axoglial communication and has previously been implicated in psychiatric disorders. A recent study in our lab found decreased levels of CNP1 in the amygdala (a central region of mood regulation) of human post-mortem MDD subjects and mice exposed to UCMS. In an attempt to determine whether altered CNP1 (or disrupted oligodendrocyte integrity) represents a causal factor in MDD, we investigated MDD-related features in mice lacking CNP1 (CNP1KO mice). In terms of technical development, we: 1) initiated use of a novel Z-score normalization procedure to counteract variability and extract a more comprehensive and translational view of our behavioral analyses, and 2) propose that the fear conditioning paradigm can be used to assess corticolimbic dysfunctions relating to mechanisms of MDD. Together, our studies in CNP1KO mice reveal a surprising profile of behavioral resilience that is accompanied by patterns of amygdala-related dysfunction. In addition, we show robust upregulation of oligodendrocyte and immune related transcripts in the basolateral amygdala of CNP1KO mice. This pattern is suggestive of compensatory changes for oligodendrocyte structure/function and indicative of an association between oligodendrocytes and immune function. Together, these studies demonstrate that disruption of oligodendrocyte function (via CNP1 ablation) can impact circuits mediating emotionality in mice resulting in abnormal affective behaviors. However, downstream molecular changes combined with the observation of longterm detrimental consequences in these mice (e.g. neurodegeneration), is suggestive of a maladaptive role for CNP1 in MDD.


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    Item Type: University of Pittsburgh ETD
    ETD Committee:
    ETD Committee TypeCommittee MemberEmail
    Committee ChairCard, J. Patrickcard@pitt.edu
    Committee MemberLewis, Davidlewisda@upmc.edu
    Committee MemberSibille, Etiennesibilleel@upmc.edu
    Committee MemberThiels, Flohthiels@neurobio.pitt.edu
    Committee MemberHomanics, GreggHomanicsGE@anes.upmc.edu
    Committee MemberLucki, Irwinlucki@mail.med.upenn.edu
    Title: Beyond Neurons: The role of the oligodendrocyte-specific gene CNP1 in major depressive disorder
    Status: Unpublished
    Abstract: Altered oligodendrocyte structure and function is implicated in major mental illnesses, including low density and reduced expression of oligodendrocyte-specific gene transcripts in major depressive disorder (MDD). These features are also observed in the unpredictable chronic mild stress (UCMS) and chronic corticosterone (CORT) rodent models of the illness; however, whether oligodendrocyte changes are a causal component of MDD is not known. The oligodendrocyte-specific gene 2'-3'-cyclic nucleotide-3'-phosphodiesterase (CNP1) is a key component of axoglial communication and has previously been implicated in psychiatric disorders. A recent study in our lab found decreased levels of CNP1 in the amygdala (a central region of mood regulation) of human post-mortem MDD subjects and mice exposed to UCMS. In an attempt to determine whether altered CNP1 (or disrupted oligodendrocyte integrity) represents a causal factor in MDD, we investigated MDD-related features in mice lacking CNP1 (CNP1KO mice). In terms of technical development, we: 1) initiated use of a novel Z-score normalization procedure to counteract variability and extract a more comprehensive and translational view of our behavioral analyses, and 2) propose that the fear conditioning paradigm can be used to assess corticolimbic dysfunctions relating to mechanisms of MDD. Together, our studies in CNP1KO mice reveal a surprising profile of behavioral resilience that is accompanied by patterns of amygdala-related dysfunction. In addition, we show robust upregulation of oligodendrocyte and immune related transcripts in the basolateral amygdala of CNP1KO mice. This pattern is suggestive of compensatory changes for oligodendrocyte structure/function and indicative of an association between oligodendrocytes and immune function. Together, these studies demonstrate that disruption of oligodendrocyte function (via CNP1 ablation) can impact circuits mediating emotionality in mice resulting in abnormal affective behaviors. However, downstream molecular changes combined with the observation of longterm detrimental consequences in these mice (e.g. neurodegeneration), is suggestive of a maladaptive role for CNP1 in MDD.
    Date: 11 August 2011
    Date Type: Completion
    Defense Date: 23 June 2011
    Approval Date: 11 August 2011
    Submission Date: 04 August 2011
    Access Restriction: No restriction; The work is available for access worldwide immediately.
    Patent pending: No
    Institution: University of Pittsburgh
    Thesis Type: Doctoral Dissertation
    Refereed: Yes
    Degree: PhD - Doctor of Philosophy
    URN: etd-08042011-110435
    Uncontrolled Keywords: depression; emotionality; myelin; stress; UCMS; Cnp; oligodendrocyte
    Schools and Programs: School of Medicine > Neurobiology
    Date Deposited: 10 Nov 2011 14:57
    Last Modified: 11 Jun 2012 12:54
    Other ID: http://etd.library.pitt.edu/ETD/available/etd-08042011-110435/, etd-08042011-110435

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