Role of oligodendrogenesis in memory consolidation ​

Memory is an incredibly complex phenomenon of which only the tip of the iceberg has been scratched. Initially, it was known to regulate ion synaptogenesis marking the formation of new connections, thus new memories. Although, it was lately discovered that it is not the only mechanism involved in memory. As a matter of fact, oligodendrogenesis (ODG) has lately been considered as another participant. Differently from synaptogenesis, it is not involved in memory formation, rather it has a more stabilizing and consolidating role, especially regarding remote memory. It has been observed that ODG responds in an experienced-related manner, as shown by contextual fear conditioning tests. There is an increase in ODG when the association between the fear-evoking event and the neutral stimulus is solidified. Moreover, inhibition of ODG leads to weakening of this association, due to which there is a strong reduction in freezing responses. This phenotype can be rescued by the pharmacological compound clemastine fumarate, which is capable of increasing ODG and maintaining the association through time. Conditional knock-out mice for Myrf factor (a transcriptional factor essential for OPC differentiation) that were treated with clemastine fumarate were able to ameliorate the behavioural response in long-term retrieval tests. Furthermore, it has been observed that the impairment of new oligodendrocytes (OLs) formation doesn't affect recent memory and already existing myelin. Thus, it can only influence newly formed experience-related myelin. The exact mechanism by which the formation of new OLs is capable of maintaining memory is still partially mysterious. However, some answers may have been found through the analysis of the ripple-spindle waves – which states that new myelin leads to an increase in synchronization between different neural circuits belonging to different areas of the encephalon. Therefore, ODG enables a stronger consolidation of memory. Regulation of ODG is incredibly important for its interplay with the rest of the neural environment. It has been observed that Oligodendrocyte Progenitor Cells (OPCs) can respond to a variety of factors as they possess receptors for neurotransmitter, hormones and signalling molecules. Along with these, stress is a major risk factor for a variety of mood and anxiety disorders, including depression and post-traumatic stress disorder (PTSD). OPCs possess glucocorticoid receptors (GRs) and are thus capable of responding directly to glucocorticoids (GCs, the stress hormones) by increasing their activity. Thus, unhealthy activation of ODG in response to chronic stress can cause an alarming increase of white matter, potentially leading to cognitive impairment a vulnerability to various disorders. ODG thus has a more complex role in the nervous system than originally thought, especially regarding memory, as opposed to previous assumptions that described it being the supporting, passive partner of axons. The data presented in this thesis underlines this fact, exploring the stimuli that lead to ODG activation and the molecules that can regulate it. ​