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Browsing by study line "Neuroscience and psychobiology"

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  • Fan, Qiuyu (2020)
    Alzheimer’s disease (AD) is a neurodegenerative brain disorder in which the disease process may take decades until the symptoms become evident. To date, no ideal biomarker has emerged that would enable early detection of AD. Environmental and lifestyle factors are thought to affect the risk of developing AD, possibly through epigenetic mechanisms such as DNA methylation (DNAm). DNAm has been shown to differ in the blood and brain of subjects with AD compared with subjects without AD, suggesting that DNAm may be involved in the pathogenic process of AD. This study aims to detect the difference in blood DNAm at baseline between cases who later developed AD and controls who remained AD diagnosis-free during follow-up in a sample selected from a Finnish population-based cohort. Leucocyte genome-wide DNAm was profiled on approximately 850,000 CpG sites by using Infinium MethylationEPIC assay. Each CpG was regressed on the outcome of AD diagnosis during follow-up, controlling for subjects’ age at sampling, sex, smoking status, blood cell counts, working stress level, slide, and array. Specific differentially methylated positions (DMPs) were further explored using pathway analysis. Finally, the methylation level of the candidate gene (APOE) selected from the literature was compared with the sample of this study. After correction for multiple testing, the later diagnosis of AD was not significantly (adjusted p-value < 0.05) associated with methylation level at the baseline at any DNAm site. There was, however, a robust hypomethylation of DMPs among the cases, as 90.9% of the DMPs (p-value < 0.05) were hypomethylated in the case group. The 200 genes annotated by DMPs with the smallest p-values were involved in two neuronal pathways: “Axon guidance associated with semaphorins Homo sapiens” (p-value = 0.0058, adjusted p-value = 0.065) in Panther 2016 and “Semaphorin interactions Homo sapiens” (p-value = 0.00005, adjusted p-value = 0.078) in Reactome 2016. No significant difference existed in DNAm of the candidate gene (APOE) between cases and controls, while cg26190885 at the promoter region of APOE showed nominal significance (p-value = 0.04). In conclusion, no strong evidence was found to support the hypothesis that systemic changes in DNAm are involved in the pathogenesis of AD or that DNAm marks could be detected in blood before the symptoms become evident. A genome-wide pattern of hypomethylation measured by the Infinium MethylationEPIC assay was observed in the case group, serving as a venue for further investigations.
  • Jalkanen, Nelli (2020)
    Mitochondrial aminoacyl tRNA-synthetases (mt-aaRS) catalyse the charging of tRNAs with their cognate amino acids in mitochondria. Mutations in mt-aaRS cause tissue-specific mitochondrial diseases, especially affecting tissues with high energy expenditure like the nervous system, heart, and kidneys. However, disease mechanisms for the heterogeneous group of diseases have not yet been fully elucidated. Harnessing CRISPR-Cas9 genome editing in induced pluripotent stem cells (iPSC) provides an opportunity to model mt-aaRS mutations in vitro and investigate the effects of individual mutations on cellular phenotype. SARS2 encodes mitochondrial seryl tRNA-synthetase, and its c.1347 G>A mutation causes severe childhood-onset progressive spastic paresis. Here, CRISPR-Cas9 ribonucleoprotein (RNP) complex and associated donor template were used to induce homology directed repair (HDR) the genome of iPSC and knock-in the patient mutation. Guide RNAs were designed and tested for efficiency before electroporation into wild type iPSC. Clonal cell lines were made by low-density seeding and manual colony picking. The expression of pluripotency markers was measured by RT-qPCR. RT-qPCR and Western blot measured SARS2 mRNA expression and protein level respectively. The success and precision of genome editing were analysed by Sanger sequencing, comparing the performance of the different guide RNAs, and screening regions of potential off-target genome editing. Two genome-edited iPSC lines with the SARS2 c.1347 G>A mutation were successfully generated to model the patient mutation. The iPSC lines expressed pluripotency markers and contained no off-target genome editing and modelled the patient’s decrease in SARS2 protein level and mRNA expression. More evidence of differentiation ability is needed before differentiation into the affected cell type (motor neurons) and further disease modelling. The efficiency of CRISPR-Cas9 for genome editing, especially harnessing HDR in iPSC, is an area of future research.
  • MacKeith, Ada (2019)
    Sleep difficulties have been on the rise for the past decade. Insomnia and sleep difficulties have associations with an increased risk of overall mortality, as well as with a diverse array of complex diseases, such as coronary heart disease, major depressive disorder, fibromyalgia and Alzheimer’s disease. Epigenomics provides information on how environmental factors influence the genome via epigenetic mechanisms, such as DNA methylation. Thus far, epigenome-wide association studies looking at the effects of sleep disturbances on the methylome have provided evidence of distinctive methylation patterns in insufficient sleep, involving biological processes related to neuroplasticity and neurodegeneration. However, more knowledge is needed to determine how the severity of sleeping difficulties influence the methylome. This thesis investigates the effects of increasing sleep difficulties on DNA methylation with an epigenome-wide association study. The study sample is derived from the Health 2000 general population survey. Subjects were divided into three different groups by their self-reported level of sleeping difficulty, and methylation measurements performed from whole blood samples utilizing the Illumina Infinium MethylationEPIC kit, encompassing >850,000 CpG sites. To identify differentially methylated sites, a multivariable regression model was used with age, gender, smoking, alcohol use, cell type distribution and plate and array data as covariates. None of the differentially methylated CpG sites identified remained significant after multiple testing correction. To gain more information regarding which biological processes the methylated sites may be part of, those CpG sites with an uncorrected p-value of <0.0005 were subjected to pathway analysis. Notable significant pathways included oxytocin- and serotonin receptor-mediated signalling pathways and Alzheimer’s disease-amyloid secretase pathway. Altogether, six pathways remained significant after multiple testing correction, with a total of 12 different genes appearing in them. Furthermore, a post-hoc regression analysis was conducted between these 12 genes and their corresponding CpG sites, and health-related quality of life questionnaire responses. Significant results included associations between sleep, and discomfort and symptoms (including pain). As an additional analysis, a database search was conducted to learn more about the genes’ functionality at the level of phenotype. Results included some variant trait associations to sleep, Alzheimer’s disease and cognitive performance. The associations to Alzheimer’s disease and cognitive performance warrant further research with a similar additive model, perhaps with a larger sample.
  • Hämäläinen, Lina-Maria (2023)
    Antiepileptic drugs (AED) are vital for treating epilepsy, but their use in pregnancy carries significant risks. Prenatal exposure to some AEDs like valproic acid increases the risk of teratogenicity and deficits in cognitive development in children. The impact of AEDs at different ages has been studied but their effect on the trajectory of cognitive development remains unknown. This study assessed the cognitive performance of children with prenatal AED exposure and unexposed controls using Bayley scales of infant and toddler development III (BSID-III) at 2 years and Weschler intelligence scales for children (WISC-IV) at 6 years of age. The association between 2- and 6-year outcomes was analyzed with separate ANCOVA models for each WISC-IV subscale. BSID-III subscales were used as the covariates and the models were adjusted for confounding factors. BSID-III scores in cognitive (B=6.70, p=0.01) and language (B=6.92, p=0.008) subscales were significantly associated with the WISC-IV working memory scores in controls but not in the exposed group. The groups were also found to differ in their intercorrelations between BSID-III subscale scores. Scores at 2 years were not associated with later results in exposed children as they were in controls. This may suggest that the cognitive development trajectory of AED-exposed children differs from that of unexposed controls, possibly following an alternate projection. Developmental trajectories should be considered when investigating the cognitive effects of prenatal AED exposure. The finding of lacking correlations of BSID-III subscales also raises cause for future investigation of the structure of cognition in AED exposed children.
  • Ahveninen, Lotta (2022)
    Objectives. Ageing is accompanied by neurobiological changes, such as changes in grey matter (GM) volume and cortical thickness, that mediate a gradual cognitive decline, which can, in turn, be potentially offset by stimulating leisure activities. Choir singing is an especially feasible musical activity with positive effects on physiological, psychological, cognitive, and social functioning in old age. Research investigating the effects of choir singing on the ageing brain is limited. As part of the Brain, Ageing, and Vocal Expression (BRAVE) project, this study aimed to investigate the effect of ageing and choir singing on GM structure. Methods. Using a cross-sectional design and voxel-based morphometry (VBM) and surface-based morphometry (SBM), this study compared GM structure between young (20-39 years; n=35), middle-aged (40-59 years; n=34), and old (60-90 years; n=31) participants and investigated the interaction of age and choir singing on GM structure with amateur choir singer (n=54) and controls (n=46). Results and conclusions. Age had a significant and widespread effect on GM structure, with old participants showing lower GM volume and cortical thickness than young (in bilateral sensorimotor, auditory/language, visual, and limbic areas, midbrain, and cerebellum) and middle-aged (in right visual cortex, thalamus, hippocampus and left auditory cortex) participants. Middle-aged participants also showed lower GM volume and cortical thickness than young participants (in bilateral sensorimotor, language, and visual areas, basal ganglia, cerebellum, and right hippocampus and amygdala). These results corroborate the current understanding of neurobiological ageing. No significant interaction of age and choir singing was found on GM structure, which could be explained by methodological factors. Further research is needed to determine whether choir singing can support brain structure or function across healthy ageing.
  • Rinne, Nea (2022)
    Aims: Reading ability is a fundamental skill in the modern society, yet some individuals have difficulties in learn-ing to read and write. There is a lot of variability in reading skills, and one reason that can cause reading difficulty is a neurodevelopmental disorder called dyslexia. It is the most common learning disability, and the core deficit in dyslexia lies in word decoding, which is the process of connecting letter combinations into their corresponding auditory representations. Dyslexia is familial and is recognized to have strong genetic background. A dozen dyslexia susceptibility genes have been suggested, but DYX1C1, DCDC2 and KIAA0319 have been associated with dyslexia most commonly. The function of these genes is however not yet fully understood. In previous studies variation in these genes have been linked to struc-tural brain alterations in left hemispheric regions where language is mostly processed. The aim of this study was to examine the connection between dyslexia susceptibility genes DCDC2, DYX1C1 and KI-AA0319 and variation in brain activity during reading tasks in the left middle temporal gyrus (MTG), infe-rior Frontal Gyrus (IFG) and intraparietal sulcus (IPS), by combining functional magnetic resonance imag-ing data and genetic data in a neurotypical population. Previous studies have reported that weaker reading skills are associated with decreased brain activity in these regions, and reading incongruent sentences has been associated with increased brain activity in the left IFG and MTG. Methods: During fMRI, participants were presented with sentences with illogical and logical endings, and judged them as either congruent or incongruent, in distracted and undistracted conditions. Auditory speech stimuli were used as distractor. Regions of Interest analyses were conducted to examine brain activation in the aforementioned brain regions during distracted and non-distracted reading separately for different allelic groups in single nucleotide polymorphisms of the three genes. Results and Conclusions: DYX1C1 showed significant interaction with brain activation in the IPS. A significant interaction of DCDC2 with logic was found in the IFG and IPS showing that individuals carrying susceptibility alleles have reduced brain activation when reading incongruent sentences. Additionally, DCDC2 showed inter-action with distraction in the IFG, as individuals carrying susceptibility alleles had reduced brain activa-tion when a speech distractor was presented. In the MTG, there was a significant interaction of DCDC2 with logic and distractor showing that in different allelic groups, speech distractor modulated the activa-tion elicited by incongruent sentences in different ways. These results provide a link between variation in dyslexia susceptibility genes and brain activation during reading. Previous studies have mostly linked dyslexia susceptibility genes to structural brain alterations, and dyslexia and lower reading skills have been linked to variation in brain activity. The current study therefore expands the current understanding of genetic basis on reading and linguistic processing.
  • Järvinen, Elli Katariina (2021)
    Ischemic stroke is a complex disease involving multiple pathophysiological mechanisms. To date, many therapeutic intervention strategies such as anti-inflammatory treatments have been tested, but none of them has been successful. Previous studies have shown that mesencephalic astrocyte-derived neurotrophic factor (MANF) improves stroke recovery and increases the expression of phagocytosis related genes. In this study, the phagocytic and inflammatory effect of monocyte chemoattractant protein 1 (MCP-1), macrophage colony-stimulating factor (M-CSF), complement component 3 (C3), adhesion G protein-coupled receptor E1 (ADGRE1), MER receptor tyrosine kinase (MerTK) and mesencephalic astrocyte-derived neurotrophic factor (MANF) on microglia were studied simultaneously for the first time. The phagocytosis related genes were transiently transfected into a microglial cell line and studied in vitro utilizing phagocytosis assay, fluorescence-activated cell sorting, Western blot and enzyme-linked immunosorbent assay. MCP-1, M-CSF and C3a were shown to enhance microglial phagocytosis without inducing a pro-inflammatory response. In addition, MerTK induces phagocytosis and the synthesis of pro-inflammatory cytokines. In conclusion, the real therapeutic potential of MCP-1, M-CSF, C3a and MerTK in stroke treatment should be further characterized and tested in vivo.
  • Haapaniemi, Hele (2022)
    The prevalence of major depressive disorder is increasing despite the increased standard of living. The prevailing hypothesis to explain depression is that there is an unbalance in information processing in relevant brain networks. Antidepressants (SSRIs, SNRIs) have been shown to induce a juvenile-like plasticity state (iPlasticity) in the brain that helps in rewiring the affected neuronal networks when combined with beneficial environmental stimuli (e.g. psychotherapy). However, it takes weeks to see the beneficial effects of conventional antidepressants on mood and they bring relief only to approximately two-thirds of the patients. There is an urgent need for more efficient and rapid-acting antidepressants. Preliminary data suggests that psychedelics may have potential to respond to this need. It is thought that the therapeutic effect of psychedelics rises from the molecular effects leading to structural and functional plasticity and behavioral changes. Molecular effects of psychedelics are believed to arise from the activation of serotonin 2A (5-HT2A) receptors. It is well established that serotonin 2A (5-HT2A) receptor activation lies behind the hallucinogenic effects of psychedelics, but its role in drug-induced plasticity is currently under debate. Signaling of brain-derived neurotrophic factor (BDNF) through its receptor TrkB has been proposed to underlie the plasticity-promoting effects of psychedelics. However, the mechanisms leading to increased BDNF/TrkB signaling after psychedelic administration are poorly understood. This thesis aimed to study the molecular mechanisms associated with psychedelic-induced plasticity in cortical neuronal cultures. The timeline of the effects of LSD was studied by analyzing the phosphorylation of neurotrophic signaling markers downstream of TrkB (mTOR and ERK) in primary neuronal cultures using Western blot. The role of the 5-HT2A receptor was assessed by combining 5-HT2A antagonist M100907 pretreatment with LSD treatment, followed by Western blot analyses of the same signaling markers mTOR and ERK. The degree of molecular effects of psychedelics was compared to the effects of classical antidepressant fluoxetine. Protein-fragment complementation assay (PCA) was used to evaluate the dimerization of the TrkB receptor in the presence of psychedelics and classical antidepressants. In this context, Western blot was also used to assess the phosphorylation of the plasticity-related BDNF signaling markers ERK and two tyrosines of TrkB receptor (Y515 and Y816) that mediate recruitment of neurotrophic signaling pathways. We found that psychedelic treatment promoted phosphorylation of mTOR and ERK significantly. These effects were not affected by pretreatment with M100907, indicating activation of BDNF/TrkB signaling by psychedelics is independent from 5-HT2A activation. Psychedelics were also shown to cause a significant increase in dimerization of TrkB whereas increase caused by fluoxetine was not significant. Lastly, psychedelics were shown to cause increase in phosphorylation of TrkB and ERK that were comparable to those induced by fluoxetine. These results highlight the potential of psychedelics to promote BDNF-mediated neurotrophic signaling associated with juvenile-like plasticity. Interestingly, the results show recruitment of BDNF/TrkB downstream signaling independently from 5-HT2A activation, which suggests that plasticity-promoting effects of psychedelics might be detached from their hallucinogenic effects.
  • Sandelin, Amanda (2022)
    Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an evolutionarily conserved protein with pleiotropic therapeutic effects in several disease models, including Parkinson’s disease (PD), diabetes and stroke. PD is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and many GWAS-based genes predisposing for PD are involved in oxidative stress. MANF has been shown to alleviate oxidative stress in PD models, however, the role of MANF in the antioxidant defense and mitochondrial respiration is not fully understood. By performing bulk RNA sequencing on wildtype and MANF knockout (MANF-KO) human embryonic stem cells (hESCs), we uncovered several genes involved in antioxidant defense to be up- or downregulated in MANF-KO hESC. Here we report that MANF-KO hESCs do not express the evolutionary conserved antioxidant enzyme catalase. We show that the loss of catalase makes the MANF-KO hESCs more vulnerable to hydrogen peroxide indued oxidative stress, and that MANF-KO hESCs have a reduced maximal respiration and spare respiratory capacity. Additionally, we examined if the loss of catalase in MANF-KO hESCs inhibits the differentiation of the cells to human dopaminergic neurons in vitro. We show that MANF-KO hESCs differentiate to TH+/MAP2+ cells despite a sustained deficiency of catalase, but the MANF-KO DA cultures tend to have a reduced spare respiratory capacity and higher basal glycolytic activity. To elucidate the structure-to-function relationship of MANF we utilize molecular dynamics simulations in combination with spin relaxation data from nuclear magnetic resonance spectroscopy. By examining the two-domain nature of MANF in different intracellular conditions we provide insight of the biological relevance of MANF interactions. Here we show that MANF conformational ensemble is more compact than previously reported. By simulating MANF in the presence of calcium and ATP, in neutral and low pH, we observed competitive binding of ATP and calcium to MANF. This study provides novel evidence of a regulatory role of MANF in the cellular antioxidant defense and explores the biological relevance of ATP and calcium binding to MANF.
  • Harkki, Juliana Sade Maria (2020)
    Background: Alcohol dependence is a chronic severe substance use disorder that has devastating personal and public health consequences. The efficacy of the current pharmacotherapy options for the treatment of alcohol dependence are modest at best, therefore better alternatives are greatly needed. Lysergic acid diethylamide (LSD) has shown promise in treatment of alcohol dependence in several clinical trials. A sigle high dose of LSD has been suggested to have a treatment effect that last for at least six months, indicating a remarkably better efficacy than the currently available methods. LSD itself has been reported to have a low addiction potential. In mouse models, acute LSD has been demonstrated to reduce ethanol consumption. Yet, the mechanism of action behind these effects has remained largely unknown. LSD is an agonist of serotonin’s 5-HT2A and 5-HT2C receptors which have been shown to modulate the dopaminergic activity of the reward circuitry, a crucial brain area in the initiation of addiction. Intracranial self-stimulation (ICSS) is a procedure for a quantitative assessment of reward behavior in animal models. In ICSS, laboratory rodents self-administer electric stimulation to the dopaminergic pathways of the reward circuitry inducing a reinforcing effect similar to drug reward. Aim: The aim of the current body of work was to use ICSS to assess the acute effects of LSD on reward behavior in C57BL/6JRj mice. This was done to improve the understanding of the mechanism of action of LSD and to evaluate whether the ethanol-consumption-reducing effect of LSD in mice is mediated through the reward mechanism. Methods: Bipolar electrodes targeting the medial forebrain bundle were implanted in the brains of C57BL/6JRj mice in a stereotaxic surgery. The animals were trained to acquire the self-stimulation in the discrete-trial current-intensity procedure. First, the possible dose-dependent acute effects were tested with three different doses of LSD. Next, the acute effect of LSD on amphetamine-induced changes in ISCC were tested. Lastly, a small preliminary test on the effects of LSD on lipopolysaccharide (LPS) -induced changes on ICSS were conducted. Results and conclusions: Acute LSD did not affect reward behavior in ICSS on any of the tested doses. Accordingly, LSD did not affect the facilitation of ICSS induced by acute amphetamine. The results of the LPS experiment were likely to be skewed by the development of tolerance to LPS, therefore the evaluation of the possible effect of LSD was not possible. These findings suggest that the previously reported LSD-induced reduction in ethanol consumption in mice, is not mediated through alteration of the reward mechanism. At the same time, these findings provide further evidence supporting the suggestion that LSD itself does not induce facilitation of the reward circuitry needed for the development of addiction.
  • Laukkanen, Liina (2021)
    This study investigated the in vitro and in vivo effects of direct angiotensin II (ANG) receptor type 2 (AGTR2) agonist Compound 21 (C21). The blockade of ANG receptor type 1 (AGTR1) by AGTR1 antagonists has long been associated with antidepressant and anxiolytic effects. Furthermore, it has been suggested that the therapeutic effects of the AGTR1 antagonists are partially dependent on enhancing the signaling through neuroprotective AGTR2. This suggests that as a specific AGTR2 agonist C21 could be used as a potential therapeutic tool to treat mood disorders that would greatly benefit from new effective treatments. Brain-derived neurotrophic factor (BDNF) is a neurotrophic that binds to tropomyosin receptor kinase B (TRKB). This study aimed to test how C21 affects BDNF:TRKB signaling that has been shown to regulate the therapeutic effects of different antidepressants that act on mood disorders. In vitro effects of C21 on BDNF:TRKB signaling were investigated with ELISA in the cortical cell cultures. Acute AGTR2 stimulation significantly elevated the amount of surface TRKB whereas a prolonged treatment of C21 for three consecutive days induced activation of TRKB. Similarly, combined treatment of C21 and a non-therapeutic treatment of BDNF induced TRKB activation, further linking the AGTR2 stimulation by this compound to the BDNF:TRKB signaling. In vivo effects of C21 on conditioned and unconditioned fear were investigated in mice by using contextual fear conditioning and elevated plus-maze (EPM) respectively. The therapeutic effect of C21 protected mice from conditioned fear but failed to provide similar results for unconditioned fear in the EPM. Interestingly, these stress-protective effects of AGTR2 stimulation were lost in the BDNF-deficient animals. To conclude, AGTR2 stimulation by C21 elevates the amount of surface TRKB that enhances the BDNF:TRKB signaling similar to antidepressants, which further leads to the therapeutic, stress-protective effects. Furthermore, these AGTR2-induced effects were absent without exposure to stress or when BDNF was diminished, indicating that both fear conditioning and BDNF are crucially involved. This study suggests that the AGTR2 is indeed a potential therapeutic target for treating mood disorders, and that in the future C21 could be translated for this use. To achieve this result, the cell types that regulate this effect need to be identified.
  • Sokka, Laura (2021)
    Lactase is a digestive enzyme, and its principal function is to break down lactose, a disaccharide found in milk. The main site for lactase expression is the intestines, however, it is also expressed in other tissues, including the brain. Because the primary substrate, lactose, is not present in the central nervous system, it can be assumed that lactase serves another function besides lactose breakdown outside the digestive system. In C57BL/6NCrl mice, lactase expression is higher in the ventral hippocampus after chronic social defeat stress in comparison to controls. This suggests that lactase expression is to some extent affected by stress. Although lactose metabolism is only necessary for mammals, some other animals – including the zebrafish (Danio rerio) – possess a gene that codes for lactase. Research on the zebrafish lactase gene is scarce, and the expression pattern of its two transcripts, the primary lct-201 and the secondary lct-202, is not known. This study focused on measuring lactase expression in adult wild type zebrafish – both on the gene and on the protein level as enzymatic activity. The effect of stress on lactase expression was also examined by applying two different stress models: netting handling stress as a form of physiological stress, and chronic social defeat as a model for psychosocial stress. Real-time polymerase chain reaction (q-RT-PCR) showed lct-201 expression in all five tissues investigated in this study – the forebrain, the mid-hindbrain, higher intestines, lower intestines, and skeletal muscle, whereas lct-202 was only expressed in the higher and lower intestines. The expression level of lct-201 in the muscle was only fifth of that in the lower intestines. Lactase activity assay on the whole brain and whole intestines displayed enzymatic activity in both tissues, with the activity in the intestines being more than seven-fold compared to the brain. q-RT-PCR on both stressed and control fish whole brain and intestines revealed higher lactase expression in the stressed fish intestines, however, the effect was only seen with a primer pair targeting both transcripts simultaneously, and not for either of them separately. Lactase expression was on average approximately 40 % higher in physiologically and 55 % higher in psychosocially stressed fish in comparison to their respective controls. Neither physiological nor psychosocial stress affected lactase expression in the brain. These findings suggest that the two zebrafish lactase transcripts have distinct expression patterns, which might imply different functional roles for lct-201 and lct-202. Furthermore, these results indicate that lactase is expressed in the zebrafish brain, suggesting that it has a specific function in the central nervous system. Based on the findings in this study, lactase gene expression might be connected to experienced stress – both physiological and psychosocial.
  • Lehto, Jani (2023)
    Neuropathic pain is a chronic pain condition, which affects the life quality of almost 10% of the adult population of Europe. Current treatments for neuropathic pain are either not effective enough or have severe adverse effects, which leads to an urgent need for novel and efficient treatment options. Serotonin receptors 5-HT2A have been shown to modulate GABAA receptor activity via KCC2 mediated pathways, which has been suggested to be a possible mechanism behind neuropathic pain. 5-HT2AR agonists LSD and psilocybin activate 5-HT2ARs and acts as a potential novel therapy for neuropathic pain. The aims of this study were to investigate whether 5-HT2AR agonists modulate mechanical allodynia in healthy mice and whether a single administration of 5-HT2AR agonists can reduce mechanical allodynia in mice after SNI. To see whether 5-HT2AR agonists induce mechanical allodynia in healthy mice, baseline response to mechanical stimulus was measured with von Frey filaments with different target forces (0.07 G, 0.16 G, 0.4 G, 0.6 G and 1 G). Mice were treated with LSD, psilocybin, or saline, and after 5 minutes, the von Frey measurements were taken again. The allodynia was induced with SNI, where the common peroneal nerve and tibial nerve were ligated and cut, leaving the sural nerve intact. The development of mechanical allodynia was measured with von Frey filaments before the surgery and on post-operative day 14. On post-operative day 14, after the von Frey measurements, the mice were injected with LSD, psilocybin, pregabalin or saline. After 5 min, post-treatment measurements were performed. The experiments showed that 5-HT2AR agonists do not modulate mechanical allodynia in healthy mice. In SNI mice, psilocybin showed reduced mechanical allodynia between pre- and post-treatment measurements in 0.6 G and in 1 G, while LSD in 0.6 G. When comparing the average effects of 5-HT2AR agonists to allodynia and pain, psilocybin reduced the mechanical allodynia and pain, while LSD only had an effect on pain. The results suggest that 5-HT2AR agonists have analgesic effects after single administration in mice. Overall, this thesis provides insight into the therapeutic potential of 5-HT2AR agonists in the treatment of neuropathic pain and provides interesting viewpoints for the future research in the field.
  • Maiju, Savolainen (2023)
    Myelin is a lipid-rich substance wrapped around nerve axons that can be adaptively modified in response to neuronal activity and experience. Recent research has revealed myelination of parvalbumin (PV) inhibitory interneurons, critical for brain oscillations and balance. Defects in PV interneuron myelination have been linked to psychiatric disorders, like schizophrenia. Tropomyosin receptor kinase B (TrkB) signaling has been shown to be important for myelination. Moreover, fluoxetine, an antidepressant, binds to TrkB receptors in PV interneurons, enhancing plasticity. While previous studies support the importance of PV interneuron mediated TrkB signaling for anti-depressant induced neural plasticity, its effect on PV interneuron myelination remains unexplored. The objective of this thesis was to investigate whether TrkB signaling, and fluoxetine affect the overall and PV-interneuron specific myelination in the medial prefrontal cortex (mPFC) in mice. Using immunohistochemical analysis, we assessed myelin changes through node of Ranvier morphology and myelin immunostaining intensity in control and in mice with heterozygous conditional TrkB deletion in PV interneurons (hereafter referred to as TrkB KO), with or without fluoxetine. We found that fluoxetine increases node length in TrkB KO mice, while reduced TrkB signaling shortens paranodes in PV neurons compared to controls. Our findings also depict that fluoxetine and PV-mediated TrkB signaling do not alter the overall myelination of the mPFC. The findings of this work provide mechanistic insights into PV interneuron myelination in the mPFC, with potential implications for demyelinating and psychiatric conditions where PV myelination plays a role.