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Browsing by Subject "neuroplasticity"

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  • Kuutti, Mirjami (2022)
    In recent years, psychedelics have shown promise in the treatment of conditions like depression and addiction. The therapeutic effects of psychedelics have been linked to their ability to increase plasticity in the brain, an effect that has also been seen for antidepressants. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, which has an important role in the development of the nervous system, as well as promotion of neuronal survival and differentiation during adulthood. BDNF, through its receptor TrkB, has been implicated in antidepressant action, and BDNF-TrkB signalling is involved in many aspects of plasticity. Recently, antidepressants have been reported to bind directly to TrkB, and through this binding mediate their plasticity-enhancing, as well as behavioural effects. Psychedelics have been shown to increase structural and functional plasticity, but the mechanisms behind these effects are not fully understood. For example, the serotonergic receptor 5-HT2A is known to be behind the acute hallucinogenic effects of psychedelics, but its role in plasticity is still debated. The aim of this study was to investigate the mechanisms of LSD-induced plasticity. The dimerization of TrkB was examined after LSD treatment in the protein-fragment complementation assay (PCA). Phosphorylation of TrkB signalling markers mTOR and ERK, which have known effects on plasticity, was assessed in Western blot, and the total expression of BDNF was examined with the enzyme-linked immunosorbent assay (ELISA). The timeline of the effects was investigated, and the involvement of 5-HT2A in TrkB dimerization and the phosphorylation of ERK was assessed by combining LSD treatment with the 5-HT2A antagonist M100907. Dimerization was also assessed in a TrkB mutant (Y433F) that has previously been shown to disrupt antidepressant effects on plasticity. These experiments showed that LSD treatment increased TrkB dimerization as well as phosphorylation of mTOR and ERK. The Y433F mutation interfered with LSD-induced TrkB dimerization, but the effects of LSD on TrkB dimerization or ERK phosphorylation were not blocked by M100907. Together, these data suggest that 5-HT2A is not involved in LSD-induced promotion of TrkB dimerization or ERK phosphorylation. The increases in phosphorylation and dimerization were found to be most robust after a 1 h LSD treatment, however an increase in BDNF expression was seen in cortical neuron cultures only after a 24 h treatment with LSD. The results reported in this study support the view that 5-HT2A might not be needed for the plasticity-inducing effects of psychedelics. If this is true, the development of treatments that target plasticity without hallucinatory effects could be possible. Overall, this research provides insight into the mechanisms of LSD-induced plasticity and offers new and interesting directions for future research in the field.
  • Kaurinkoski, Katja Viivi Susanna (2024)
    Environmental enrichment (EE) can be defined as external stimulation by the physical or social surroundings. Like antidepressants, EE promotes neuronal plasticity in the brain, although the exact mechanisms of action are unknown. The aim of these experiments was to further elucidate the role of BDNF-TrkB in the behavioural outcomes of EE exposure. The effect of 10 weeks of environmental enrichment on neuroplasticity was investigated in female wildtype, BDNF-het, and hTrkB-Y433F mutant mice. Behavioural tests, open field, elevated plus maze, and novel object recognition, were conducted to assess memory, learning, and anxiety-like behaviour. Results were analysed in Excel and GraphPad Prism 9.0. with two-way ANOVA and Šídak’s posthoc test. EE affected the OF behaviour of WT and hTrkB-Y433F mice, but not BDNF-het mice. EE brought BDNF-het mice behaviour to the level of WT. Two-way ANOVA indicated that environment was the primary contributor for difference in results, as opposed to genotype. EE did not have a significant effect on EPM or NOR results in either mutant genotype. These results indicate that the BDNF-TrkB pathway, but not the TrkB receptor itself, plays a role in generating behavioural effects of EE. Further study is needed to elucidate the molecular mechanisms behind EE effect on plasticity. Studies separating components of EE would be interesting to see if any exhibit a stronger plasticity effect. Comparison of EE with other known plasticity promoters, ie: antidepressants and rapid-acting antidepressants, would be interesting particularly at a mechanistic level.