Doctoral theses
Search command : Author="Ραϊσάκη"
And Author="Μαρία"
Current Record: 42 of 1070
|
|
| Identifier |
000453410 |
| Title |
The role of RGS4 and RGS9 proteins in neuropathic pain stress and depression |
| Alternative Title |
Ο ρόλος των πρωτεϊνών RGS4 και RGS9-2 στο νευροπαθητικό πόνο, το άγχος και την κατάθλιψη |
|
Author
|
Μήτση, Βασιλική
|
|
Thesis advisor
|
Ζαχαρίου, Βενετία
|
|
Reviewer
|
Ηλιόπουλος, Ιωάννης
Τσατσάνης, Χρήστος
Μπίτσιος, Παναγιώτης
Ηλιόπουλος, Αριστείδης
Ζαγανάς, Ιωάννης
|
| Abstract |
The first part of the present thesis, focuses on the striatal protein Regulator of G-protein signaling 9-2 (RGS9-2) which plays a key modulatory role in opioid, monoamine, and other G-protein–coupled receptor responses. Here, we use the murine spared-nerve injury (SNI) model of neuropathic pain to investigate the mechanism by which RGS9-2 in the nucleus accumbens (NAc), a brain region involved in mood, reward, and motivation, modulates the actions of tricyclic antidepressants (TCAs), such as desipramine. Prevention of RGS9-2 action in the NAc increases the efficacy of the TCA desipramine and dramatically accelerates its onset of action. By controlling the activation of effector molecules by G protein α and βγ subunits, RGS9-2 affects several protein interactions, phosphoprotein levels, and the function of the epigenetic modifier histone deacetylase 5, which are important for TCA responsiveness. Furthermore, information from RNA-sequencing analysis revealed that RGS9-2 in the NAc affects the expression of many genes known to be involved in nociception, analgesia, and antidepressant drug actions, providing novel information on NAc-specific cellular mechanisms that mediate the actions of TCAs in neuropathic pain states. The second part of the present thesis focuses on RGS4 protein which plays a prominent role in physiological and pharmacological responses by controlling multiple intracellular pathways. Our earlier work identified dynamic but distinct roles of RGS4 in the efficacy of monoamine-targeting vs fast-acting antidepressants. Using the chronic variable stress (CVS) paradigm in mice, we demonstrate that stress-induced behavioral abnormalities are associated with downregulation of RGS4 in the medial prefrontal cortex (mPFC). Knockout of RGS4 (RGS4KO) increases susceptibility to mCVS, as mutant mice develop behavioral abnormalities following shorter stressful periods. Resting state fMRI (rsfMRI) experiments indicate that stress susceptibility in RGS4KO mice is associated with changes in connectivity between the mediodorsal thalamus (MD-THL) and the mPFC. Notably, prevention of RGS4 action enhances the antidepressant efficacy of ketamine in the CVS paradigm. RNA-sequencing analysis of naïve and CVS mPFC revealed that RGS4KO triggers unique gene expression signatures and affects several intracellular pathways associated with major depression. Our analysis suggests that ketamine treatment in the RGS4KO group triggers changes in pathways implicated in synaptic activity and responses to stress, including pathways associated with axonal guidance and myelination. Overall, we show that reduction of RGS4 activity triggers unique gene expression adaptations that underlie emotional and sensory manifestations of chronic stress and that RGS4 is a negative modulator of ketamine actions.
|
| Language |
English |
| Subject |
Ketamine |
|
RNA-SEQ |
|
Κεταμίνη |
|
Ρυθμιστές G σηματοδότησης |
| Issue date |
2023-04-05 |
| Collection
|
School/Department--School of Medicine--Department of Medicine--Doctoral theses
|
|
|
Type of Work--Doctoral theses
|
| Permanent Link |
https://elocus.lib.uoc.gr//dlib/0/5/7/metadata-dlib-1674121388-718333-27378.tkl
|
| Views |
659 |
|
Digital Documents
|
|
No permission to view document.
It won't be available until: 2025-03-31
|
Collections
