Browsing by Subject "hippocampus"

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  • Alafuzoff, Aleksander (Helsingfors universitet, 2016)
    Background. Birth asphyxia is a pathological state that occurs if fetal gas exchange is disrupted for an extended period of time during delivery. Prolonged birth asphyxia causes brain damage and can even lead to death, but which in mild and moderate cases causes motor and cognitive disability. One of the brain regions often damaged is the hippocampus, which is known to play a major role in memory processing. Thus, damage to the hippocampus may in part explain the long-term cognitive consequences of birth asphyxia. In the neonatal brain hippocampal network activity is discontinuous, dominated by sharp waves and oscillatory bouts, of which the former are thought to be important for memory consolidation in the adult brain. Later in development sharp waves exhibit fast oscillations called ripples that organise hippocampal activity after learning. The aim of this thesis was to establish how sharp wave signalling in the neonatal hippocampus is affected by birth asphyxia. Methods. A rat model developed at the Laboratory of Neurobiology, University of Helsinki, was used to study birth asphyxia and a putative therapeutic strategy. Neonatal rat pups aged 5-8 days were used in the study. These animals were randomly assigned to one of four experimental groups: naive control, sham control, asphyxia, and graded restoration of normocapnia. Hippocampal network activity was measured in vivo under urethane anaesthesia using local field potential (LFP) recordings 24 hours after the asphyxic insult. Sharp waves were detected and analysed in terms of event counts, timing, size, shape and ripple properties. Results and conclusions. After asphyxia, sharp waves occurred more frequently within clusters than in isolation. In addition, sharp wave ripples were detected for the first time during early neonatal development. In asphyxiated animals, the number and magnitude of detected ripples was statistically significantly decreased. Interestingly, animals that underwent graded restoration of normocapnia after asphyxia were no different from controls, suggesting a protective effect of the treatment. The abnormal SPW development after birth asphyxia may form a mechanism contributing to the emergence of cognitive deficits.
  • Kartalou, Georgia-Ioanna; Salgueiro-Pereira, Ana Rita; Endres, Thomas; Lesnikova, Angelina; Casarotto, Plinio; Pousinha, Paula; Delanoe, Kevin; Edelmann, Elke; Castren, Eero; Gottmann, Kurt; Marie, Helene; Lessmann, Volkmar (2020)
    Therapeutic approaches providing effective medication for Alzheimer's disease (AD) patients after disease onset are urgently needed. Previous studies in AD mouse models suggested that physical exercise or changed lifestyle can delay AD-related synaptic and memory dysfunctions when treatment started in juvenile animals long before onset of disease symptoms, while a pharmacological treatment that can reverse synaptic and memory deficits in AD mice was thus far not identified. Repurposing food and drug administration (FDA)-approved drugs for treatment of AD is a promising way to reduce the time to bring such medication into clinical practice. The sphingosine-1 phosphate analog fingolimod (FTY720) was approved recently for treatment of multiple sclerosis patients. Here, we addressed whether fingolimod rescues AD-related synaptic deficits and memory dysfunction in an amyloid precursor protein/presenilin-1 (APP/PS1) AD mouse model when medication starts after onset of symptoms (at five months). Male mice received intraperitoneal injections of fingolimod for one to two months starting at five to six months. This treatment rescued spine density as well as long-term potentiation in hippocampal cornu ammonis-1 (CA1) pyramidal neurons, that were both impaired in untreated APP/PS1 animals at six to seven months of age. Immunohistochemical analysis with markers of microgliosis (ionized calcium-binding adapter molecule 1; Iba1) and astrogliosis (glial fibrillary acid protein; GFAP) revealed that our fingolimod treatment regime strongly down regulated neuroinflammation in the hippocampus and neocortex of this AD model. These effects were accompanied by a moderate reduction of A beta accumulation in hippocampus and neocortex. Our results suggest that fingolimod, when applied after onset of disease symptoms in an APP/PS1 mouse model, rescues synaptic pathology that is believed to underlie memory deficits in AD mice, and that this beneficial effect is mediated via anti-neuroinflammatory actions of the drug on microglia and astrocytes.
  • Aitta-aho, Teemu; Maksimovic, Milica; Dahl, Kristiina; Sprengel, Rolf; Korpi, Esa R. (2019)
    Gene-targeted mice with deficient AMPA receptor GluA1 subunits (Gria1-/- mice) show robust hyperlocomotion in a novel environment, suggesting them to constitute a model for hyperactivity disorders such as mania, schizophrenia and attention deficit hyperactivity disorder. This behavioral alteration has been associated with increased neuronal activation in the hippocampus, and it can be attenuated by chronic treatment with antimanic drugs, such as lithium, valproic acid, and lamotrigine. Now we found that systemic cannabidiol strongly blunted the hyperactivity and the hippocampal c-Fos expression of the Gria1-/- mice, while not affecting the wild-type littermate controls. Acute bilateral intra-dorsal hippocampal infusion of cannabidiol partially blocked the hyperactivity of the Gria1-/- mice, but had no effect on wild-types. The activation of the inhibitory DREADD receptor hM4Gi in the dorsal hippocampus by clozapine-N-oxide robustly inhibited the hyperactivity of the Gria1-/- mice, but had no effect on the locomotion of wild-type mice. Our results show that enhanced neuronal excitability in the hippocampus is associated with pronounced novelty-induced hyperactivity of GluA1 subunit-deficient mice. When this enhanced response of hippocampal neurons to novel stimuli is specifically reduced in the hippocampus by pharmacological treatment or by chemogenetic inhibition, Gria1-/- mice recover from behavioral hyperactivity, suggesting a hippocampal dysfunction in hyperactive behaviors that can be treated with cannabidiol.
  • Lensu, Sanna; Waselius, Tomi; Penttonen, Markku; Nokia, Miriam S. (2019)
    Hippocampal dentate spikes (DSs) are short-duration, large-amplitude fluctuations in hilar local field potentials and take place while resting and sleeping. During DSs, dentate gyms granule cells increase firing while CA1 pyramidal cells decrease firing. Recent findings suggest DSs play a significant role in memory consolidation after training on a hippocampus-dependent, nonspatial associative learning task. Here, we aimed to find out whether DSs are important in other types of hippocampus-dependent learning tasks as well. To this end, we trained adult male Sprague-Dawley rats in a spatial reference memory task, a fixed interval task, and a pattern separation task. During a rest period immediately after each training session, we either let neural activity to take place as usual, timed electrical stimulation of the ventral hippocampal commissure (vHC) to immediately follow DSs, or applied the vHC stimulation during a random neural state. We found no effect of vHC stimulation on performance in the spatial reference memory task or in the fixed interval task. Surprisingly, vHC stimulation, especially contingent on DSs, improved performance in the pattern separation task. In conclusion, the behavioral relevance of hippocampal processing and DSs seems to depend on the task at hand. It could be that in an intact brain, offline memory consolidation by default involves associating neural representations of temporally separate but related events. In some cases this might be beneficial for adaptive behavior in the future (associative learning), while in other cases it might not (pattern separation). NEW & NOTEWORTHY The behavioral relevance of dentate spikes seems to depend on the learning task at hand. We suggest that dentate spikes are related to associating neural representations of temporally separate but related events within the dentate gyrus. In some cases this might be beneficial for adaptive behavior in the future (associative learning), while in other cases it might not (pattern separation).
  • Luchkina, Natalia V.; Huupponen, Johanna; Clarke, Vernon R. J.; Coleman, Sarah K.; Keinanen, Kari; Taira, Tomi; Lauri, Sari E. (2014)
  • Hedström, Anna (Helsingin yliopisto, 2020)
    The ability to regulate release of noradrenaline, dopamine and GABA is one of the most important roles of the nicotinic receptors. The release of neurotransmitters following stimulation of nicotinic receptors is addressed in the thesis, with focus on dopamine and noradrenaline. Release of neurotransmitters, mediated through nicotinic receptors, has been researched using various methods, including brain slices, microdialysis and synaptosomes. Research using synaptosomes have provided valuable information regarding nicotinic receptors and their ability to regulate neurotransmitter release. Research using receptor specific antagonists have provided information regarding the stoichiometry of nicotinic receptor in different regions of the brain. The primary focus in the thesis, was the characterization of [3H]dopamine release following stimulation of nicotinic receptors with varenicline and acetylcholine, using synaptosomes from mouse striatum. Using a-conotoxin-MII, the [3H]dopamine release was divided into a-conotoxin- MII-resistant and -sensitive release. [3H]Dopamine release was mediated through a6b2*- and a4b2*-receptors from striatal synaptosomes. The involvement of other receptors could not be ruled out, but based on these results and results from previous studies, the involvement of other nicotinic receptors is supposedly low.
  • Komulainen, Emilia; Varidaki, Artemis; Kulesskaya, Natalia; Mohammad, Hasan; Sourander, Christel; Rauvala, Heikki; Coffey, Eleanor T. (2020)
    The protein kinase JNK1 exhibits high activity in the developing brain, where it regulates dendrite morphology through the phosphorylation of cytoskeletal regulatory proteins. JNK1 also phosphorylates dendritic spine proteins, and Jnk1-/- mice display a long-term depression deficit. Whether JNK1 or other JNKs regulate spine morphology is thus of interest. Here, we characterize dendritic spine morphology in hippocampus of mice lacking Jnk1-/- using Lucifer yellow labelling. We find that mushroom spines decrease and thin spines increase in apical dendrites of CA3 pyramidal neurons with no spine changes in basal dendrites or in CA1. Consistent with this spine deficit, Jnk1-/- mice display impaired acquisition learning in the Morris water maze. In hippocampal cultures, we show that cytosolic but not nuclear JNK, regulates spine morphology and expression of phosphomimicry variants of JNK substrates doublecortin (DCX) or myristoylated alanine-rich C kinase substrate-like protein-1 (MARCKSL1), rescue mushroom, thin, and stubby spines differentially. These data suggest that physiologically active JNK controls the equilibrium between mushroom, thin, and stubby spines via phosphorylation of distinct substrates.
  • Virachit, Sophie; Mathews, Kathryn J.; Cottam, Veronica; Werry, Eryn; Galli, Emilia; Rappou, Elisabeth; Lindholm, Pӓivi; Saarma, Mart; Halliday, Glenda M.; Weickert, Cynthia Shannon; Double, Kay L. (2019)
    Growth factors can facilitate hippocampus-based learning and memory and are potential targets for treatment of cognitive dysfunction via their neuroprotective and neurorestorative effects. Dementia is common in Parkinson's disease (PD), but treatment options are limited. We aimed to determine if levels of growth factors are altered in the hippocampus of patients with PD, and if such alterations are associated with PD pathology. Enzyme-linked immunosorbent assays were used to quantify seven growth factors in fresh frozen hippocampus from 10 PD and nine age-matched control brains. Western blotting and immunohistochemistry were used to explore cellular and inflammatory changes that may be associated with growth factor alterations. In the PD hippocampus, protein levels of glial cell line-derived neurotrophic factor were significantly decreased, despite no evidence of neuronal loss. In contrast, protein levels of fibroblast growth factor 2 and cerebral dopamine neurotrophic factor were significantly increased in PD compared to controls. Levels of the growth factors epidermal growth factor, heparin-binding epidermal growth factor, brain-derived neurotrophic factor and mesencephalic astrocyte-derived neurotrophic factor did not differ between groups. Our data demonstrate changes in specific growth factors in the hippocampus of the PD brain, which potentially represent targets for modification to help attenuate cognitive decline in PD. These data also suggest that multiple growth factors and direction of change needs to be considered when approaching growth factors as a potential treatment for cognitive decline.
  • Sierra-Torre, Virginia; Plaza-Zabala, Ainhoa; Bonifazi, Paolo; Abiega, Oihane; Diaz-Aparicio, Irune; Tegelberg, Saara; Lehesjoki, Anna-Elina; Valero, Jorge; Sierra, Amanda (2020)
    Objective Microglial phagocytosis of apoptotic cells is an essential component of the brain regenerative response during neurodegeneration. Whereas it is very efficient in physiological conditions, it is impaired in mouse and human mesial temporal lobe epilepsy, and now we extend our studies to a model of progressive myoclonus epilepsy type 1 in mice lacking cystatin B (CSTB). Methods We used confocal imaging and stereology-based quantification of apoptosis and phagocytosis of the hippocampus ofCstbknockout (KO) mice, an in vitro model of phagocytosis and siRNAs to acutely reduceCstbexpression, and a virtual three-dimensional (3D) model to analyze the physical relationship between apoptosis, phagocytosis, and active hippocampal neurons. Results Microglial phagocytosis was impaired in the hippocampus ofCstbKO mice at 1 month of age, when seizures arise and hippocampal atrophy begins. This impairment was not related to the lack of Cstb in microglia alone, as shown by in vitro experiments with microglial Cstb depletion. The phagocytosis impairment was also unrelated to seizures, as it was also present inCstbKO mice at postnatal day 14, before seizures begin. Importantly, phagocytosis impairment was restricted to the granule cell layer and spared the subgranular zone, where there are no active neurons. Furthermore, apoptotic cells (both phagocytosed and not phagocytosed) inCstb-deficient mice were at close proximity to active cFos(+)neurons, and a virtual 3D model demonstrated that the physical relationship between apoptotic cells and cFos(+)neurons was specific forCstbKO mice. Significance These results suggest a complex crosstalk between apoptosis, phagocytosis, and neuronal activity, hinting that local neuronal activity could be related to phagocytosis dysfunction inCstbKO mice. Overall, these data suggest that phagocytosis impairment is an early feature of hippocampal damage in epilepsy and opens novel therapeutic approaches for epileptic patients based on targeting microglial phagocytosis.
  • Valtonen, Jussi; Gregory, Emma; Landau, Barbara; McCloskey, Michael (2014)
  • Acosta, H.; Kantojärvi, K.; Hashempour, N.; Pelto, J.; Scheinin, N. M.; Lehtola, S. J.; Lewis, J. D.; Fonov, V. S.; Collins, D. L.; Evans, A.; Parkkola, R.; Lahdesmaki, T.; Saunavaara, J.; Karlsson, L.; Merisaari, H.; Paunio, T.; Karlsson, H.; Tuulari, J. J. (2020)
    Psychiatric disease susceptibility partly originates prenatally and is shaped by an interplay of genetic and environmental risk factors. A recent study has provided preliminary evidence that an offspring polygenic risk score for major depressive disorder (PRS-MDD), based on European ancestry, interacts with prenatal maternal depressive symptoms (GxE) on neonatal right amygdalar (US and Asian cohort) and hippocampal volumes (Asian cohort). However, to date, this GxE interplay has only been addressed by one study and is yet unknown for a European ancestry sample. We investigated in 105 Finnish mother-infant dyads (44 female, 11-54 days old) how offspring PRS-MDD interacts with prenatal maternal depressive symptoms (Edinburgh Postnatal Depression Scale, gestational weeks 14, 24, 34) on infant amygdalar and hippocampal volumes. We found a GxE effect on right amygdalar volumes, significant in the main analysis, but nonsignificant after multiple comparison correction and some of the control analyses, whose direction paralleled the US cohort findings. Additional exploratory analyses suggested a sex-specific GxE effect on right hippocampal volumes. Our study is the first to provide support, though statistically weak, for an interplay of offspring PRS-MDD and prenatal maternal depressive symptoms on infant limbic brain volumes in a cohort matched to the PRS-MDD discovery sample.
  • Karpova, Nina N.; Lindholm, Jesse Saku Olavi; Kulesskaya, Natalia; Onishchenko, Natalia; Vahter, Marie; Popova, Dina; Ceccatelli, Sandra; Castren, Eero (2014)
  • Yoon, Dae Wui; Kwon, Hyuk Nam; Jin, Xing; Kim, Jin Kwan; Lee, Seung Ku; Park, Sunghyouk; Yun, Chang-Ho; Shin, Chol (2019)
    Sleep fragmentation (SF) commonly occurs in several pathologic conditions and is especially associated with impairments of hippocampus-dependent neurocognitive functions. Although the effects of SF on hippocampus in terms of protein or gene levels were examined in several studies, the impact of SF at the metabolite level has not been investigated. Thus, in this study, the differentially expressed large-scale metabolite profiles of hippocampus in a rat model of SF were investigated using untargeted metabolomics approaches. Forty-eight rats were divided into the following 4 groups: 4-day SF group, 4-day exercise control (EC) group, 15-day SF group, and 15-day EC group (n = 12, each). SF was accomplished by forced exercise using a walking wheel system with 30-s on/90-s off cycles, and EC condition was set at 10-min on/30-min off. The metabolite profiles of rat hippocampi in the SF and EC groups were analyzed using liquid chromatography/mass spectrometry. Multivariate analysis revealed distinctive metabolic profiles and marker signals between the SF and corresponding EC groups. Metabolic changes were significant only in the 15-day SF group. In the 15-day SF group, L-tryptophan, myristoylcarnitine, and palmitoylcarnitine were significantly increased, while adenosine monophosphate, hypoxanthine, L-glutamate, L-aspartate, L-methionine, and glycerophosphocholine were decreased compared to the EC group. The alanine, aspartate, and glutamate metabolism pathway was observed as the common key pathway in the 15-day SF groups. The results from this untargeted metabolomics study provide a perspective on metabolic impact of SF on the hippocampus.