Browsing by Subject "Plasticity"

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  • Haikonen, Joni (Helsingin yliopisto, 2019)
    Kainate receptors are known to regulate neuronal function in the brain (Li, H., & Rogawski, M. A. (1998), Braga, M. F. et al. (2004), Lerma & Marques (2013), Carta, M (2014)). In the amygdala, they have been shown to affect synaptic transmission and plasticity, as well as glutamate and γ-aminobutyric acid (GABA) release (Li, H. et al. (2001). Braga, M. F. et al. (2003), Braga, M. F. et al. (2009), Aroniadou-Anderjaska, V. et al. (2012), Negrete‐Díaz, J. V. et al. (2012)), however, their role during development of the amygdala circuitry is not known. In the present study, we wished to understand how GluK1 kainate receptors regulate synaptic population activity and plasticity in the developing amygdala by using extracellular field recordings in P15-18 Wistar Han rat pup brain slices. Since field excitatory postsynaptic potentials (fEPSPs) are not commonly measured from the amygdala, we first sought to pharmacologically characterize the basic properties of the extracellular signal, recorded from the basolateral amygdala in response to stimulation of the external capsulae (EC). Having confirmed the validity of the fEPSP as a measure of postsynaptic population response, we were able to show that blocking GluK1 with (S)-1-(2-Amino-2-carboxyethyl)-3-(2-carboxy-5-phenylthiophene-3-yl-methyl)-5-methylpyrimidine-2,4-dione (ACET), a selective GluK1 antagonist, had no effect on the fEPSP. Furthermore, activation of GluK1 with RS-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid (ATPA), a GluK1 agonist, reduced the amplitude of the fEPSP, without affecting its slope, suggesting an increase in inhibitory signaling within the network. Blocking GABAergic activity with GABAA- receptor antagonist picrotoxin significantly reduced the effects of ATPA. Additionally, the increase in inhibitory signaling due to the activation of GluK1 was confirmed with whole-cell voltage clamp, by measuring spontaneous inhibitory postsynaptic current (sIPSC) frequency. Activation of GluK1 heavily increased sIPSC frequency in the basolateral amygdala neurons. Finally, we were also able to show that activation of GluK1 with ATPA strongly attenuates LTP induction. These results show that GluK1 kainate receptors play a vital role in the modulation of synaptic transmission and plasticity in the developing amygdala.
  • Antila, Hanna (Helsingfors universitet, 2012)
    Tissue plasminogen activator (tPA) is a serine protease that cleaves the inactive plasminogen to a broad-spectrum protease plasmin. Plasmin is involved in the degradation of blood clots by breaking down the fibrin network. In addition to it's role in the fibrinolytic system, tPA participates in the functions of the central nervous system. tPA is expressed in several brain areas and has been shown to be involved in neuronal plasticity. tPA's effects on brain plasticity are mediated in part via degradation of extracellular matrix proteins, but mainly via processing of brain-derived neurotrophic factor (BDNF). Plasmin cleaves pro-BDNF into BDNF that serves as primary endogenous ligand for TrkB neurotrophin receptor. TrkB signalling is strongly associated with the regulation of neuronal plasticity such as neurogenesis, synaptogenesis and long-term potentiation (LTP). On the contrary, pro-BDNF binds and activates p75 neurotrophin receptor that regulates many distinct, even opposite, effects on neuronal plasticity such as long-term depression and synapse refraction. Enhancement of brain plasticity is considered to be important for the therapeutic effects of antidepressant drugs and this is at least partially mediated via BDNF. Antidepressants activate TrkB receptors and increase BDNF protein levels in the rodent brain but the mechanism behind this remains obscure. Given that tPA is an important factor in the processing of BDNF, it is a possible mediator for antidepressants' neurotrophic effects. The effects of antidepressants on tPA activity have been previously studied only in the blood circulatory system. The aim of the experimental part of this Master's thesis was to examine the effects of antidepressant fluoxetine on tPA activity and protein levels in mouse hippocampus. Also the effects of fluoxetine on BDNF-TrkB signalling were studied. Fluoxetine was administered to mice acutely (30 mg/kg, i.p., 1 h) and chronically (0,08 mg/ml in drinking water, 3 weeks). tPA activity was studied using SDS-PAGE - and in situzymographies. TrkB activation, tPA and BDNF protein levels were measured using western blot. BDNF protein levels were also examined with ELISA method. No changes in tPA activity were found after acute fluoxetine treatment. In line with this result is the observation that also the BDNF levels remained unchanged. However, TrkB receptor activity was increased in fluoxetine treated mice. It seems possible that BDNF is not involved in the TrkB activation caused by acute fluoxetine treatment. Chronic fluoxetine treatment caused a significant increase in the BDNF protein levels compared to water-drinking control mice. This was not, however, associated with significant changes in TrkB activity. No changes in tPA activity were observed, which suggests that tPA is not involved in the increase of BDNF levels after chronic fluoxetine treatment. Interestingly, tPA antibody detected three distinct proteins in western blot of whose levels acute fluoxetine treatment regulated. However, more studies are needed to identify these proteins and to reveal the significance of such an effect of fluoxetine. According to this study, neither acute nor chronic fluoxetine treatment affects tPA activity in mouse hippocampus. However, environmental enrichment has been shown to enhance tPA activity and produce similar neurotrophic effects as chronic fluoxetine treatment. Therefore the result of this study concerning effect of chronic antidepressant treatment on tPA activity should be verified.
  • Tolmacheva, Aleksandra; Savolainen, Sarianna; Kirveskari, Erika; Brandstack, Nina; Mäkelä, Jyrki P.; Shulga, Anastasia (2019)
    Objectives Long-term paired associative stimulation (PAS) is a non-invasive combination of transcranial magnetic stimulation and peripheral nerve stimulation and leads to improved hand motor function in individuals with incomplete traumatic tetraplegia. Spinal cord injuries (SCIs) can also be induced by neurological diseases. We tested a similar long-term PAS approach in patients with nontraumatic neurological SCI. Methods In this case series five patients with nontraumatic tetraplegia received PAS to the weaker upper limb 3 to 5 times per week for 6 weeks. Patients were evaluated with manual muscle testing (MMT) before and immediately after therapy and at the 1- and 6-month follow ups. Patients were also evaluated for spasticity, hand mechanical and digital dynamometry, pinch, and Box and Blocks tests. Results All patients had improved MMT values at all post-PAS evaluations. The mean±standard error MMT increase was 1.44±0.37 points (p=0.043) immediately after PAS, 1.57±0.4 points (p=0.043) at the 1-month follow-up, and 1.71±0.47 points (p=0.043) at the 6-month follow up. The pinch, digital dynamometry values, and Box and Blocks test results also improved in all patients. Conclusions Long-term PAS may be a safe and effective treatment for improving hand function in patients with nontraumatic tetraplegia. Significance This is the first report demonstrating the therapeutic potential of PAS for neurological SCI.
  • Kohtala, S.; Alitalo, O.; Rosenholm, M.; Rozov, S.; Rantamäki, T. (2021)
    Several studies have demonstrated the effectiveness of ketamine in rapidly alleviating depression and suicidal ideation. Intense research efforts have been undertaken to expose the precise mechanism underlying the antidepressant action of ketamine; however, the translation of findings into new clinical treatments has been slow. This translational gap is partially explained by a lack of understanding of the function of time and circadian timing in the complex neurobiology around ketamine. Indeed, the acute pharmacological effects of a single ketamine treatment last for only a few hours, whereas the antidepressant effects peak at around 24 hours and are sustained for the following few days. Numerous studies have investigated the acute and long-lasting neurobiological changes induced by ketamine; however, the most dramatic and fundamental change that the brain undergoes each day is rarely taken into consideration. Here, we explore the link between sleep and circadian regulation and rapid -acting antidepressant effects and summarize how diverse phenomena associated with ketamine's antidepressant actions - such as cortical excitation, synaptogenesis, and involved molecular determinants - are intimately connected with the neurobiology of wake, sleep, and circadian rhythms. We review several recently proposed hypotheses about rapid antidepressant actions, which focus on sleep or circadian regulation, and discuss their implications for ongoing research. Considering these aspects may be the last piece of the puzzle necessary to gain a more comprehensive understanding of the effects of rapid-acting antidepressants on the brain. (c) 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://
  • Salmi, Juha; Nyberg, Lars; Laine, Matti (2018)
    The present meta-analytic study examined brain activation changes following working memory (WM) training, a form of cognitive training that has attracted considerable interest. Comparisons with perceptual-motor (PM) learning revealed that WM training engages domain-general large-scale networks for learning encompassing the dorsal attention and salience networks, sensory areas, and striatum. Also the dynamics of the training-induced brain activation changes within these networks showed a high overlap between WM and PM training. The distinguishing feature for WM training was the consistent modulation of the dorso- and ventrolateral prefrontal cortex (DLPFC/VLPFC) activity. The strongest candidate for mediating transfer to similar untrained WM tasks was the frontostriatal system, showing higher striatal and VLPFC activations, and lower DLPFC activations after training. Modulation of transfer-related areas occurred mostly with longer training periods. Overall, our findings place WM training effects into a general perception-action cycle, where some modulations may depend on the specific cognitive demands of a training task.