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  • 1. Aberg, A. C.
    et al.
    Thorstensson, A.
    Tarassova, O.
    Halvorsen, Kjartan
    KTH, School of Technology and Health (STH).
    Calculations of mechanisms for balance control during narrow and single-leg standing in fit older adults: A reliability study2011In: Gait & Posture, ISSN 0966-6362, E-ISSN 1879-2219, Vol. 34, no 3, p. 352-357Article in journal (Refereed)
    Abstract [en]

    For older people balance control in standing is critical for performance of activities of daily living without falling. The aims were to investigate reliability of quantification of the usage of the two balance mechanisms M(1) 'moving the centre of pressure' and M(2) 'Segment acceleration' and also to compare calculation methods based on a combination of kinetic (K) and kinematic (Km) data, (K-Km), or Km data only concerning M(2). For this purpose nine physically fit persons aged 70-78 years were tested in narrow and single-leg standing. Data were collected by a 7-camera motion capture system and two force plates. Repeated measure ANOVA and Tukey's post hoc tests were used to detect differences between the standing tasks. Reliability was estimated by ICCs, standard error of measurement including its 95% Cl, and minimal detectable change, whereas Pearson's correlation coefficient was used to investigate agreement between the two calculation methods. The results indicated that for the tasks investigated, M(1) and M(2) can be measured with acceptable inter- and intrasession reliability, and that both Km and K-Km based calculations may be useful for M(2), although Km data may give slightly lower values. The proportional M(1) :M(2) usage was approximately 9:1, in both anterio-posterior (AP) and medio-lateral (ML) directions for narrow standing, and about 2:1 in the AP and of 1:2 in the ML direction in single-leg standing, respectively. In conclusion, the tested measurements and calculations appear to constitute a reliable way of quantifying one important aspect of balance capacity in fit older people.

  • 2. Adori, Csaba
    et al.
    Barde, Swapnali
    Bogdanovic, Nenad
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Institutet, Sweden.
    Reinscheid, Rainer R.
    Kovacs, Gabor G.
    Hokfelt, Tomas
    Neuropeptide S- and Neuropeptide S receptor-expressing neuron populations in the human pons2015In: Frontiers in Neuroanatomy, E-ISSN 1662-5129, Vol. 9Article in journal (Refereed)
    Abstract [en]

    Neuropeptide S (NPS) is a regulatory peptide with potent pharmacological effects. In rodents, NPS is expressed in a few pontine cell clusters. Its receptor (NPSR1) is, however, widely distributed in the brain. The anxiolytic and arousal promoting effects of NPS make the NPS NPSR1 system an interesting potential drug target in mood-related disorders. However, so far possible disease-related mechanisms involving NPS have only been studied in rodents. To validate the relevance of these animal studies for i.a. drug development, we have explored the distribution of NPS-expressing neurons in the human pons using in situ hybridization and stereological methods and we compared the distribution of NPS mRNA expressing neurons in the human and rat brain. The calculation revealed a total number of 22,317 +/- 2411 NPS mRNA-positive neurons in human, bilaterally. The majority of cells (84%) were located in the parabrachial area in human: in the extension of the medial and lateral parabrachial nuclei, in the Kolliker-Fuse nucleus and around the adjacent lateral lemniscus. In human, in sharp contrast to the rodents, only very few NPS-positive cells (5%) were found close to the locus coeruleus. In addition, we identified a smaller cell cluster (11% of all NPS cells) in the pontine central gray matter both in human and rat, which has not been described previously even in rodents. We also examined the distribution of NPSR1 mRNA-expressing neurons in the human pons. These cells were mainly located in the rostral laterodorsal tegmental nucleus, the cuneiform nucleus, the microcellular tegmental nucleus region and in the periaqueductal gray. Our results show that both NPS and NPSR1 in the human pons are preferentially localized in regions of importance for integration of visceral autonomic information and emotional behavior. The reported interspecies differences must, however, be considered when looking for targets for new pharmacotherapeutical interventions.

  • 3. Adori, Csaba
    et al.
    Glueck, Laura
    Barde, Swapnali
    Yoshitake, Takashi
    Kovacs, Gabor G.
    Mulder, Jan
    Magloczky, Zsofia
    Havas, Laszlo
    Boelcskei, Kata
    Mitsios, Nicholas
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Szolcsanyi, Janos
    Kehr, Jan
    Ronnback, Annica
    Schwartz, Thue
    Rehfeld, Jens F.
    Harkany, Tibor
    Palkovits, Miklos
    Schulz, Stefan
    Hokfelt, Tomas
    Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system: new aspects on Alzheimer's disease2015In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 129, no 4, p. 541-563Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease and other age-related neurodegenerative disorders are associated with deterioration of the noradrenergic locus coeruleus (LC), a probable trigger for mood and memory dysfunction. LC noradrenergic neurons exhibit particularly high levels of somatostatin binding sites. This is noteworthy since cortical and hypothalamic somatostatin content is reduced in neurodegenerative pathologies. Yet a possible role of a somatostatin signal deficit in the maintenance of noradrenergic projections remains unknown. Here, we deployed tissue microarrays, immunohistochemistry, quantitative morphometry and mRNA profiling in a cohort of Alzheimer's and age-matched control brains in combination with genetic models of somatostatin receptor deficiency to establish causality between defunct somatostatin signalling and noradrenergic neurodegeneration. In Alzheimer's disease, we found significantly reduced somatostatin protein expression in the temporal cortex, with aberrant clustering and bulging of tyrosine hydroxylase-immunoreactive afferents. As such, somatostatin receptor 2 (SSTR2) mRNA was highly expressed in the human LC, with its levels significantly decreasing from Braak stages III/IV and onwards, i.e., a process preceding advanced Alzheimer's pathology. The loss of SSTR2 transcripts in the LC neurons appeared selective, since tyrosine hydroxylase, dopamine beta-hydroxylase, galanin or galanin receptor 3 mRNAs remained unchanged. We modeled these pathogenic changes in Sstr2 (-/-) mice and, unlike in Sstr1 (-/-) or Sstr4 (-/-) genotypes, they showed selective, global and progressive degeneration of their central noradrenergic projections. However, neuronal perikarya in the LC were found intact until late adulthood (< 8 months) in Sstr2 (-/-) mice. In contrast, the noradrenergic neurons in the superior cervical ganglion lacked SSTR2 and, as expected, the sympathetic innervation of the head region did not show any signs of degeneration. Our results indicate that SSTR2-mediated signaling is integral to the maintenance of central noradrenergic projections at the system level, and that early loss of somatostatin receptor 2 function may be associated with the selective vulnerability of the noradrenergic system in Alzheimer's disease.

  • 4.
    Aghanoori, Mohamad-Reza
    et al.
    St Boniface Gen Hosp, Albrechtsen Res Ctr, Div Neurodegenerat Disorders, Winnipeg, MB, Canada.;Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada.;Univ Calgary, Cumming Sch Med, Dept Med Genet, 3330 Hosp Dr NW, Calgary, AB T2N 4N2, Canada..
    Agarwal, Prasoon
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST). Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada.;Univ Manitoba, Childrens Hosp Res Inst Manitoba, Winnipeg, MB, Canada..
    Gauvin, Evan
    St Boniface Gen Hosp, Albrechtsen Res Ctr, Div Neurodegenerat Disorders, Winnipeg, MB, Canada..
    Nagalingam, Raghu S.
    Univ Manitoba, Rady Fac Hlth Sci, Dept Physiol & Pathophysiol, Winnipeg, MB, Canada.;St Boniface Gen Hosp, Inst Cardiovasc Sci, Albrechtsen Res Ctr, Winnipeg, MB, Canada..
    Bonomo, Raiza
    Loyola Univ, Cellular & Mol Dept, Stritch Sch Med, Chicago, IL 60611 USA..
    Yathindranath, Vinith
    Univ Manitoba, Kleysen Inst Adv Med, Winnipeg, MB, Canada..
    Smith, Darrell R.
    St Boniface Gen Hosp, Albrechtsen Res Ctr, Div Neurodegenerat Disorders, Winnipeg, MB, Canada..
    Hai, Yan
    Univ Manitoba, Rady Fac Hlth Sci, Dept Biochem & Med Genet, Winnipeg, MB, Canada..
    Lee, Samantha
    Univ Manitoba, Rady Fac Hlth Sci, Dept Biochem & Med Genet, Winnipeg, MB, Canada..
    Jolivalt, Corinne G.
    Univ Calif San Diego, Dept Pathol, San Diego, CA USA..
    Calcutt, Nigel A.
    Univ Calif San Diego, Dept Pathol, San Diego, CA USA..
    Jones, Meaghan J.
    Univ Manitoba, Rady Fac Hlth Sci, Dept Biochem & Med Genet, Winnipeg, MB, Canada..
    Czubryt, Michael P.
    Univ Manitoba, Rady Fac Hlth Sci, Dept Physiol & Pathophysiol, Winnipeg, MB, Canada.;St Boniface Gen Hosp, Inst Cardiovasc Sci, Albrechtsen Res Ctr, Winnipeg, MB, Canada..
    Miller, Donald W.
    Univ Manitoba, Kleysen Inst Adv Med, Winnipeg, MB, Canada..
    Dolinsky, Vernon W.
    Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada.;Univ Manitoba, Childrens Hosp Res Inst Manitoba, Winnipeg, MB, Canada..
    Mansuy-Aubert, Virginie
    Loyola Univ, Cellular & Mol Dept, Stritch Sch Med, Chicago, IL 60611 USA..
    Fernyhough, Paul
    St Boniface Gen Hosp, Albrechtsen Res Ctr, Div Neurodegenerat Disorders, Winnipeg, MB, Canada.;Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada..
    CEBP beta regulation of endogenous IGF-1 in adult sensory neurons can be mobilized to overcome diabetes-induced deficits in bioenergetics and axonal outgrowth2022In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 79, no 4, article id 193Article in journal (Refereed)
    Abstract [en]

    Aberrant insulin-like growth factor 1 (IGF-1) signaling has been proposed as a contributing factor to the development of neurodegenerative disorders including diabetic neuropathy, and delivery of exogenous IGF-1 has been explored as a treatment for Alzheimer's disease and amyotrophic lateral sclerosis. However, the role of autocrine/paracrine IGF-1 in neuroprotection has not been well established. We therefore used in vitro cell culture systems and animal models of diabetic neuropathy to characterize endogenous IGF-1 in sensory neurons and determine the factors regulating IGF-1 expression and/or affecting neuronal health. Single-cell RNA sequencing (scRNA-Seq) and in situ hybridization analyses revealed high expression of endogenous IGF-1 in non-peptidergic neurons and satellite glial cells (SGCs) of dorsal root ganglia (DRG). Brain cortex and DRG had higher IGF-1 gene expression than sciatic nerve. Bidirectional transport of IGF-1 along sensory nerves was observed. Despite no difference in IGF-1 receptor levels, IGF-1 gene expression was significantly (P < 0.05) reduced in liver and DRG from streptozotocin (STZ)-induced type 1 diabetic rats, Zucker diabetic fatty (ZDF) rats, mice on a high-fat/ high-sugar diet and db/db type 2 diabetic mice. Hyperglycemia suppressed IGF-1 gene expression in cultured DRG neurons and this was reversed by exogenous IGF-1 or the aldose reductase inhibitor sorbinil. Transcription factors, such as NFAT1 and CEBP beta, were also less enriched at the IGF-1 promoter in DRG from diabetic rats vs control rats. CEBP beta overexpression promoted neurite outgrowth and mitochondrial respiration, both of which were blunted by knocking down or blocking IGF-1. Suppression of endogenous IGF-1 in diabetes may contribute to neuropathy and its upregulation at the transcriptional level by CEBP beta can be a promising therapeutic approach.

  • 5.
    Ahmed, Laeeq
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST).
    Edlund, Åke
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST).
    Laure, Erwin
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST).
    Whitmarsh, S.
    Parallel real time seizure detection in large EEG data2016In: IoTBD 2016 - Proceedings of the International Conference on Internet of Things and Big Data, SciTePress, 2016, p. 214-222Conference paper (Refereed)
    Abstract [en]

    Electroencephalography (EEG) is one of the main techniques for detecting and diagnosing epileptic seizures. Due to the large size of EEG data in long term clinical monitoring and the complex nature of epileptic seizures, seizure detection is both data-intensive and compute-intensive. Analysing EEG data for detecting seizures in real time has many applications, e.g., in automatic seizure detection or in allowing a timely alarm signal to be presented to the patient. In real time seizure detection, seizures have to be detected with negligible delay, thus requiring lightweight algorithms. MapReduce and its variations have been effectively used for data analysis in large dataset problems on general-purpose machines. In this study, we propose a parallel lightweight algorithm for epileptic seizure detection using Spark Streaming. Our algorithm not only classifies seizures in real time, it also learns an epileptic threshold in real time. We furthermore present "top-k amplitude measure" as a feature for classifying seizures in the EEG, that additionally assists in reducing data size. In a benchmark experiment we show that our algorithm can detect seizures in real time with low latency, while maintaining a good seizure detection rate. In short, our algorithm provides new possibilities in using private cloud infrastructures for real time epileptic seizure detection in EEG data.

  • 6. Ahmed, Omar Jamil
    et al.
    McFarland, James
    Kumar, Arvind
    Brown University, United States.
    Reactivation in ventral striatum during hippocampal ripples: evidence for the binding of reward and spatial memories?2008In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 28, no 40, p. 9895-9897Article in journal (Refereed)
  • 7.
    Akkuratov, Evgeny E.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    The Biophysics of Na+,K+-ATPase in neuronal health and disease2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Na+,K+-ATPase is one of the most important proteins in the mammalian cell. It creates sodium and potassium gradients which are fundamental for the membrane potential and sodium-dependent secondary active transport. It has a second role in the cell as a receptor that by binding chemicals from the cardiotonic steroids family, the most knowledgeable of them is ouabain, triggers various signaling pathways in the cell which regulate gene activation, proliferation, apoptosis, etc. It has been shown that several severe neurological diseases are associated with mutations in the Na+,K+-ATPase encoding genes. Although Na+,K+-ATPase was discovered already in 1957 by the Danish scientist Jens Skou, the knowledge about the function of this enzyme  is still not complete.

     

    In the studies included in the thesis, we have learned more about the function of Na+,K+-ATPase in different aspects of health and disease. In study I we showed a mechanism of ouabain-dependent regulation of the NMDA receptor, one of the most important receptors in the nervous system, via binding with Na+,K+-ATPase. This allows us to look at the Na+,K+-ATPase as regulator via protein-protein interaction. In study II we investigated a different aspect of Na+,K+-ATPase functioning – to look at how binding of ouabain to Na+,K+-ATPase activates a number of signaling cascades by looking at the phosphoproteome status of the cells. This allows us to see the whole picture of ouabain-mediated cascades and further characterize them. In study III we focused on the role of Na+,K+-ATPase in severe epileptic encephalopathy caused by a mutation in the ATP1A1 gene. We performed a molecular and cellular study to describe how mutations affects protein structure and function and found that this mutation converts the ion pump to a nonspecific leak channel. In study IV we performed a translational study of the most common mutation for rapid-onset dystonia-parkinsonism. We studied how this mutation affects the nervous system on the protein-, cellular-, and organism level and found that the complete absence of ultraslow afterhyperpolarization (usAHP) could explain gait disturbances found in patients. In the on-going study we showed that Na+,K+-ATPase can oligomerize and that this effect is triggered by ouabain binding to the Na+,K+-ATPase. In this study, we utilized a novel fluorescence labelling approach and used biophysical techniques with single molecule sensitivity to track Na+,K+-ATPase interactions.

     

    In summary, we applied biophysical and molecular methods to study different aspects of the function of Na+,K+-ATPase, and gained insights that could be helpful not only for answering fundamental questions about Na+,K+-ATPase but also to find a treatment for patients with diseases associated with mutations in this protein.

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  • 8.
    Altay, Özlem
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Yang, Hong
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Yildirim, Serkan
    Department of Pathology, Faculty of Veterinary Medicine, Atatürk University, Erzurum 25240, Turkey;.
    Bayram, Cemil
    Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Atatürk University, Erzurum 25240, Turkey;.
    Bolat, Ismail
    Department of Pathology, Faculty of Veterinary Medicine, Atatürk University, Erzurum 25240, Turkey;.
    Oner, Sena
    Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, 25240, Turkey.
    Tozlu, Ozlem Ozdemir
    Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, 25240, Turkey.
    Arslan, Mehmet Enes
    Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, 25240, Turkey.
    Hacimuftuoglu, Ahmet
    Department of Medical Pharmacology, Faculty of Medicine, Atatürk University, Erzurum 25240, Turkey;.
    Shoaie, Saeed
    Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London, SE1 9RT, UK.
    Zhang, Cheng
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Borén, Jan
    Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, 413 45, Sweden.
    Uhlén, Mathias
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Turkez, Hasan
    Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum 25240, Turkey;.
    Mardinoglu, Adil
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London, SE1 9RT, UK.
    Combined Metabolic Activators with Different NAD+ Precursors Improve Metabolic Functions in the Animal Models of Neurodegenerative Diseases2024In: Biomedicines, E-ISSN 2227-9059, Vol. 12, no 4, article id 927Article in journal (Refereed)
    Abstract [en]

    Background: Mitochondrial dysfunction and metabolic abnormalities are acknowledged as significant factors in the onset of neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). Our research has demonstrated that the use of combined metabolic activators (CMA) may alleviate metabolic dysfunctions and stimulate mitochondrial metabolism. Therefore, the use of CMA could potentially be an effective therapeutic strategy to slow down or halt the progression of PD and AD. CMAs include substances such as the glutathione precursors (L-serine and N-acetyl cysteine), the NAD+ precursor (nicotinamide riboside), and L-carnitine tartrate. Methods: Here, we tested the effect of two different formulations, including CMA1 (nicotinamide riboside, L-serine, N-acetyl cysteine, L-carnitine tartrate), and CMA2 (nicotinamide, L-serine, N-acetyl cysteine, L-carnitine tartrate), as well as their individual components, on the animal models of AD and PD. We assessed the brain and liver tissues for pathological changes and immunohistochemical markers. Additionally, in the case of PD, we performed behavioral tests and measured responses to apomorphine-induced rotations. Findings: Histological analysis showed that the administration of both CMA1 and CMA2 formulations led to improvements in hyperemia, degeneration, and necrosis in neurons for both AD and PD models. Moreover, the administration of CMA2 showed a superior effect compared to CMA1. This was further corroborated by immunohistochemical data, which indicated a reduction in immunoreactivity in the neurons. Additionally, notable metabolic enhancements in liver tissues were observed using both formulations. In PD rat models, the administration of both formulations positively influenced the behavioral functions of the animals. Interpretation: Our findings suggest that the administration of both CMA1 and CMA2 markedly enhanced metabolic and behavioral outcomes, aligning with neuro-histological observations. These findings underscore the promise of CMA2 administration as an effective therapeutic strategy for enhancing metabolic parameters and cognitive function in AD and PD patients.

  • 9.
    Andersson, Sten
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Petersson, Marcus E.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Fransén, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Ionic mechanisms of action potential propagation velocity changes in peripheral C-fibers. Implications for pain2012In: BMC Neuroscience, E-ISSN 1471-2202, Vol. 13, no Suppl 1, p. P138-Article in journal (Refereed)
  • 10.
    Annelies, Nonneman
    et al.
    KU Leuven Univ Leuven, Dept Neurosci, Lab Neurobiol & Expt Neurol, Herestr 49, B-3000 Leuven, Belgium.;LBI, Herestr 49, B-3000 Leuven, Belgium.;Ctr Brain & Dis Res, VIB, Herestr 49, B-3000 Leuven, Belgium..
    Nathan, Criem
    Ctr Brain & Dis Res, VIB, Herestr 49, B-3000 Leuven, Belgium.;KU Leuven Univ Leuven, Dept Cardiovasc Sci, Ctr Mol & Vasc Biol, Herestr 49, B-3000 Leuven, Belgium.;KU Leuven Univ Leuven, Dept Human Genet, Herestr 49, B-3000 Leuven, Belgium..
    Lewandowski, Sebastian
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Clin Neurosci, S-17177 Stockholm, Sweden..
    Rik, Nuyts
    KU Leuven Univ Leuven, Dept Neurosci, Lab Neurobiol & Expt Neurol, Herestr 49, B-3000 Leuven, Belgium.;LBI, Herestr 49, B-3000 Leuven, Belgium.;Ctr Brain & Dis Res, VIB, Herestr 49, B-3000 Leuven, Belgium..
    Dietmar, Thal R.
    KU Leuven Univ Leuven, Dept Neurosci, Lab Neuropathol, Herestr 49, B-3000 Leuven, Belgium.;Univ Hosp Leuven, Dept Neurol, Herestr 49, B-3000 Leuven, Belgium..
    Frank, Pfrieger W.
    Univ Strasbourg, CNRS UPR 3212, Inst Cellular & Integrat Neurosci, F-67084 Strasbourg, France..
    John, Ravits
    Univ Calif San Diego, Dept Neurosci, 9500 Gilman Dr, San Diego, CA 92093 USA..
    Philip, Van Damme
    KU Leuven Univ Leuven, Dept Neurosci, Lab Neurobiol & Expt Neurol, Herestr 49, B-3000 Leuven, Belgium.;LBI, Herestr 49, B-3000 Leuven, Belgium.;Ctr Brain & Dis Res, VIB, Herestr 49, B-3000 Leuven, Belgium.;Univ Hosp Leuven, Dept Neurol, Herestr 49, B-3000 Leuven, Belgium..
    An, Zwijsen
    Ctr Brain & Dis Res, VIB, Herestr 49, B-3000 Leuven, Belgium.;KU Leuven Univ Leuven, Dept Cardiovasc Sci, Ctr Mol & Vasc Biol, Herestr 49, B-3000 Leuven, Belgium.;KU Leuven Univ Leuven, Dept Human Genet, Herestr 49, B-3000 Leuven, Belgium..
    Ludo, Van Den Bosch
    KU Leuven Univ Leuven, Dept Neurosci, Lab Neurobiol & Expt Neurol, Herestr 49, B-3000 Leuven, Belgium.;LBI, Herestr 49, B-3000 Leuven, Belgium.;Ctr Brain & Dis Res, VIB, Herestr 49, B-3000 Leuven, Belgium..
    Wim, Robberecht
    KU Leuven Univ Leuven, Dept Neurosci, Lab Neurobiol & Expt Neurol, Herestr 49, B-3000 Leuven, Belgium.;LBI, Herestr 49, B-3000 Leuven, Belgium.;Ctr Brain & Dis Res, VIB, Herestr 49, B-3000 Leuven, Belgium.;Univ Hosp Leuven, Dept Neurol, Herestr 49, B-3000 Leuven, Belgium..
    Astrocyte-derived Jagged-1 mitigates deleterious Notch signaling in amyotrophic lateral sclerosis2018In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 119, p. 26-40Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a late-onset devastating degenerative disease mainly affecting motor neurons. Motor neuron degeneration is accompanied and aggravated by oligodendroglial pathology and the presence of reactive astrocytes and microglia. We studied the role of the Notch signaling pathway in ALS, as it is implicated in several processes that may contribute to this disease, including axonal retraction, microgliosis, astrocytosis, oligodendrocyte precursor cell proliferation and differentiation, and cell death. We observed abnormal activation of the Notch signaling pathway in the spinal cord of SOD1(G93A) mice, a well-established model for ALS, as well as in the spinal cord of patients with sporadic ALS (sALS). This increased activation was particularly evident in reactive GFAP-positive astrocytes. In addition, one of the main Notch ligands, Jagged-1, was ectopically expressed in reactive astrocytes in spinal cord from ALS mice and patients, but absent in resting astrocytes. Astrocyte-specific inactivation of Jagged-1 in presymptomatic SOD1(G93A) mice further exacerbated the activation of the Notch signaling pathway and aggravated the course of the disease in these animals without affecting disease onset. These data suggest that aberrant Notch signaling activation contributes to the pathogenesis of ALS, both in sALS patients and SOD1(G93A) mice, and that it is mitigated in part by the upregulation of astrocytic Jagged-1.

  • 11.
    Arce, Luis
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.
    Serrano, Irene
    Division of Plant Science, Research School of Biology, Australian National University, Acton, Australian Capital Territory, Australia.
    Impact of childhood trauma on the epigenetics of anxiety disorder2023In: Revista de Psiquiatria Clínica, ISSN 0101-6083, E-ISSN 1806-938X, Vol. 50, no 6, p. 205-211Article in journal (Refereed)
    Abstract [en]

    The interaction of epigenetics, childhood trauma, and anxiety disorders is a fascinating area of scientific study with significant ramifications for clinical practice and mental health. This abstract captures the intricate interplay between these factors, emphasizing how early-life hardships leave persistent biochemical fingerprints on a person's genetic composition, perhaps influencing the emergence of anxiety disorders. Through epigenetic pathways, childhood trauma, which includes events like abuse, neglect, and persistent stress, might influence a person's sensitivity to anxiety. These processes, which control the expression of genes involved in stress response, neurotransmitter signaling, and emotional regulation, include DNA methylation, histone changes, and microRNA regulation. The disturbance of the hypothalamic-pituitary-adrenal (HPA) axis and neuroplasticity provide as more evidence of the effects of trauma-induced epigenetic modifications, which manifest as altered brain circuits and stress response mechanisms. This complex interaction highlights how nature and nurture interact dynamically, enhancing our knowledge of the many-faceted causes of anxiety disorders. A need for focused treatments and therapies that address the molecular causes of anxiety is made as a result of the recognition of the long-lasting impacts of childhood trauma, giving those who are afflicted hope for better mental health outcomes and resilience.

  • 12.
    Asplund, Maria
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    Conjugated Polymers for Neural Interfaces: Prospects, possibilities and future challenges2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Within the field of neuroprosthetics the possibility to use implanted electrodes for communication with the nervous system is explored. Much effort is put into the material aspects of the electrode implant to increase charge injection capacity, suppress foreign body response and build micro sized electrode arrays allowing close contact with neurons. Conducting polymers, in particular poly(3,4-ethylene dioxythiophene) (PEDOT), have been suggested as materials highly interesting for such neural communication electrodes. The possibility to tailor the material both mechanically and biochemically to suit specific applications, is a substantial benefit with polymers when compared to metals. PEDOT also have hybrid charge transfer properties, including both electronic and ionic conduction, which allow for highly efficient charge injection.

     

    Part of this thesis describes a method of tailoring PEDOT through exchanging the counter ion used in electropolymerisation process. Commonly used surfactants can thereby be excluded and instead, different biomolecules can be incorporated into the polymer. The electrochemical characteristics of the polymer film depend on the ion. PEDOT electropolymerised with heparin was here determined to have the most advantageous properties. In vitro methods were applied to confirm non-cytotoxicity of the formed PEDOT:biomolecular composites. In addition, biocompatibility was affirmed for PEDOT:heparin by evaluation of inflammatory response and neuron density when implanted in rodent cortex.

     

    One advantage with PEDOT often stated, is its high stability compared to other conducting polymers. A battery of tests simulating the biological environment was therefore applied to investigate this stability, and especially the influence of the incorporated heparin. These tests showed that there was a decline in the electroactivity of PEDOT over time. This also applied in phosphate buffered saline at body temperature and in the absence of other stressors. The time course of degradation also differed depending on whether the counter ion was the surfactant polystyrene sulphonate or heparin, with a slightly better stability for the former.

     

    One possibility with PEDOT, often overlooked for biological applications, is the use of its semi conducting properties in order to include logic functions in the implant. This thesis presents the concept of using PEDOT electrochemical transistors to construct textile electrode arrays with in-built multiplexing. Using the electrolyte mediated interaction between adjacent PEDOT coated fibres to switch the polymer coat between conducting and non conducting states, then transistor function can be included in the conducting textile. Analogue circuit simulations based on experimentally found transistor characteristics proved the feasibility of these textile arrays. Developments of better polymer coatings, electrolytes and encapsulation techniques for this technology, were also identified to be essential steps in order to make these devices truly useful.

     

    In summary, this work shows the potential of PEDOT to improve neural interfaces in several ways. Some weaknesses of the polymer and the polymer electronics are presented and this, together with the epidemiological data, should point in the direction for future studies within this field.

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  • 13.
    Auffarth, Benjamin
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Understanding smell: the olfactory stimulus problem2013In: Neuroscience and Biobehavioral Reviews, ISSN 0149-7634, E-ISSN 1873-7528, Vol. 37, no 8, p. 1667-1679Article, review/survey (Refereed)
    Abstract [en]

    The main problem with sensory processing is the difficulty in relating sensory input to physiological responses and perception. This is especially problematic at higher levels of processing, where complex cues elicit highly specific responses. In olfaction, this relationship is particularly obfuscated by the difficulty of characterizing stimulus statistics and perception. The core questions in olfaction are hence the so-called stimulus problem, which refers to the understanding of the stimulus, and the structure–activity and structure–odor relationships, which refer to the molecular basis of smell. It is widely accepted that the recognition of odorants by receptors is governed by the detection of physico-chemical properties and that the physical space is highly complex. Not surprisingly, ideas differ about how odor stimuli should be classified and about the very nature of information that the brain extracts from odors. Even though there are many measures for smell, there is none that accurately describes all aspects of it. Here, we summarize recent developments in the understanding of olfaction. We argue that an approach to olfactory function where information processing is emphasized could contribute to a high degree to our understanding of smell as a perceptual phenomenon emerging from neural computations. Further, we argue that combined analysis of the stimulus, biology, physiology, and behavior and perception can provide new insights into olfactory function. We hope that the reader can use this review as a competent guide and overview of research activities in olfactory physiology, psychophysics, computation, and psychology. We propose avenues for research, particularly in the systematic characterization of receptive fields and of perception.

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    smell_review.pdf
  • 14.
    Auffarth, Benjamin
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Kaplan, Bernhard
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Anders, Lansner
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Map formation in the olfactory bulb by axon guidance of olfactory neurons2011In: Frontiers in Systems Neuroscience, E-ISSN 1662-5137, Vol. 5, no 0Article in journal (Refereed)
    Abstract [en]

    The organization of representations in the brain has been observed to locally reflect subspaces of inputs that are relevant to behavioral or perceptual feature combinations, such as in areas receptive to lower and higher-order features in the visual system. The early olfactory system developed highly plastic mechanisms and convergent evidence indicates that projections from primary neurons converge onto the glomerular level of the olfactory bulb (OB) to form a code composed of continuous spatial zones that are differentially active for particular physico?-chemical feature combinations, some of which are known to trigger behavioral responses. In a model study of the early human olfactory system, we derive a glomerular organization based on a set of real-world,biologically-relevant stimuli, a distribution of receptors that respond each to a set of odorants of similar ranges of molecular properties, and a mechanism of axon guidance based on activity. Apart from demonstrating activity-dependent glomeruli formation and reproducing the relationship of glomerular recruitment with concentration, it is shown that glomerular responses reflect similarities of human odor category perceptions and that further, a spatial code provides a better correlation than a distributed population code. These results are consistent with evidence of functional compartmentalization in the OB and could suggest a function for the bulb in encoding of perceptual dimensions.

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    Auffahrt Kaplan Lansner 2011 Map formation in the olfactory bulb by axon guidance of olfactory neurons.pdf
  • 15.
    Ayoglu, Burcu
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Mitsios, N.
    Khademi, M.
    Alfredsson, L.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Mulder, J.
    Olsson, T.
    Schwenk, Jochen
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Anoctamin 2, a novel autoimmune target candidate in multiple sclerosis2014In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 20, p. 49-50Article in journal (Other academic)
  • 16.
    Bahuguna, Jyotika
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST).
    Structure-Dynamics relationship in basalganglia: Implications for brain function2016Doctoral thesis, monograph (Other academic)
    Abstract [en]

    In this thesis, I have used a combination of computational models such as mean field and spikingnetwork simulations to study various sub-circuits of basal ganglia. I first studied the striatum(chapter 2), which is the input nucleus of basal ganglia. The two types of Medium SpinyNeurons (MSNs), D1 and D2-MSNs, together constitute 98% of the neurons in striatum. Thecomputational models so far have treated striatum as a homogenous unit and D1 and D2 MSNs asinterchangeable subpopulations. This implied that a bias in a Go/No-Go decision is enforced viaexternal agents to the striatum (eg. cortico-striatal weights), thereby assigning it a passive role.New data shows that there is an inherent asymmetry in striatal circuits. In this work, I showedthat striatum due to its asymmetric connectivity acts as a decision transition threshold devicefor the incoming cortical input. This has significant implications on the function of striatum asan active participant in influencing the bias towards a Go/No-Go decision. The striatal decisiontransition threshold also gives mechanistic explanations for phenomena such as L-Dopa InducedDyskinesia (LID), DBS-induced impulsivity, etc. In chapter 3, I extend the mean field model toinclude all the nuclei of basal ganglia to specifically study the role of two new subpopulationsfound in GPe (Globus Pallidus Externa). Recent work shows that GPe, also earlier consideredto be a homogenous nucleus, has at least two subpopulations which are dichotomous in theiractivity with respect to the cortical Slow Wave (SWA) and beta activity. Since the data for thesesubpopulations are missing, a parameter search was performed for effective connectivities usingGenetic Algorithms (GA) to fit the available experimental data. One major result of this studyis that there are various parameter combinations that meet the criteria and hence the presenceof functional homologs of the basal ganglia network for both pathological (PD) and healthynetworks is a possibility. Classifying all these homologous networks into clusters using somehigh level features of PD shows a large variance, hinting at the variance observed among the PDpatients as well as their response to the therapeutic measures. In chapter 4, I collaborated on aproject to model the role of STN and GPe burstiness for pathological beta oscillations as seenduring PD. During PD, the burstiness in the firing patterns of GPe and STN neurons are shownto increase. We found that in the baseline state, without any bursty neurons in GPe and STN,the GPe-STN network can transition to an oscillatory state through modulating the firing ratesof STN and GPe neurons. Whereas when GPe neurons are systematically replaced by burstyneurons, we found that increase in GPe burstiness enforces oscillations. An optimal % of burstyneurons in STN destroys oscillations in the GPe-STN network. Hence burstiness in STN mayserve as a compensatory mechanism to destroy oscillations. We also propose that bursting inGPe-STN could serve as a mechanism to initiate and kill oscillations on short time scales, asseen in the healthy state. The GPe-STN network however loses the ability to kill oscillations inthe pathological state.

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  • 17.
    Bahuguna, Jyotika
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. University of Freiburg, Germany.
    Aertsen, Ad
    University of Freiburg, Germany.
    Kumar, Arvind
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. University of Freiburg, Germany.
    Existence and control of Go/No-Go decision transition threshold in the striatum2015In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 11, no 4, article id e1004233Article in journal (Refereed)
    Abstract [en]

    A typical Go/No-Go decision is suggested to be implemented in the brain via the activation of the direct or indirect pathway in the basal ganglia. Medium spiny neurons (MSNs) in the striatum, receiving input from cortex and projecting to the direct and indirect pathways express D1 and D2 type dopamine receptors, respectively. Recently, it has become clear that the two types of MSNs markedly differ in their mutual and recurrent connectivities as well as feedforward inhibition from FSIs. Therefore, to understand striatal function in action selection, it is of key importance to identify the role of the distinct connectivities within and between the two types of MSNs on the balance of their activity. Here, we used both a reduced firing rate model and numerical simulations of a spiking network model of the striatum to analyze the dynamic balance of spiking activities in D1 and D2 MSNs. We show that the asymmetric connectivity of the two types of MSNs renders the striatum into a threshold device, indicating the state of cortical input rates and correlations by the relative activity rates of D1 and D2 MSNs. Next, we describe how this striatal threshold can be effectively modulated by the activity of fast spiking interneurons, by the dopamine level, and by the activity of the GPe via pallidostriatal backprojections. We show that multiple mechanisms exist in the basal ganglia for biasing striatal output in favour of either the `Go' or the `No-Go' pathway. This new understanding of striatal network dynamics provides novel insights into the putative role of the striatum in various behavioral deficits in patients with Parkinson's disease, including increased reaction times, L-Dopa-induced dyskinesia, and deep brain stimulation-induced impulsivity.

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  • 18.
    Barde, Swapnali
    et al.
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden.;Karolinska Inst, Dept Neurosci, Biomedicum, S-17177 Stockholm, Sweden..
    Aguila, Julio
    Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden.;Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden..
    Zhong, Wen
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Solarz, Anna
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Mei, Irene
    Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden..
    Prud'homme, Josee
    Douglas Mental Hlth Univ Inst, McGill Grp Suicide Studies, Verdun, PQ, Canada.;McGill Univ, Dept Psychiat, Montreal, PQ, Canada..
    Palkovits, Miklos
    Hungarian Acad Sci, Budapest, Hungary.;Semmelwe Univ, Human Brain Tissue Bank & Lab, H-1085 Budapest, Hungary..
    Turecki, Gustavo
    Douglas Mental Hlth Univ Inst, McGill Grp Suicide Studies, Verdun, PQ, Canada.;McGill Univ, Dept Psychiat, Montreal, PQ, Canada..
    Mulder, Jan
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Uhlen, Mathias
    Nagy, Corina
    Douglas Mental Hlth Univ Inst, McGill Grp Suicide Studies, Verdun, PQ, Canada.;McGill Univ, Dept Psychiat, Montreal, PQ, Canada..
    Mechawar, Naguib
    Douglas Mental Hlth Univ Inst, McGill Grp Suicide Studies, Verdun, PQ, Canada.;McGill Univ, Dept Psychiat, Montreal, PQ, Canada..
    Hedlund, Eva
    Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden.;Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden..
    Hokfelt, Tomas
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Substance P, NPY, CCK and their receptors in five brain regions in major depressive disorder with transcriptomic analysis of locus coeruleus neurons2024In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 78, p. 54-63Article in journal (Refereed)
    Abstract [en]

    Major depressive disorder (MDD) is a serious disease and a burden to patients, families and society. Rodent experiments and human studies suggest that several neuropeptide systems are involved in mood regulation. The aim of this study is two-fold: (i) to monitor, with qPCR, transcript levels of the substance P/tachykinin (TAC), NPY and CCK systems in bulk samples from control and suicide subjects, targeting five postmortem brain regions including locus coeruleus (LC); and (ii) to analyse expression of neuropeptide family transcripts in LC neurons of 'normal' postmortem brains by using laser capture microdissection with Smart-Seq2 RNA sequencing. qPCR revealed distinct regional expression patterns in male and female controls with higher levels for the TAC system in the dorsal raphe nucleus and LC, versus higher transcripts levels of the NPY and CCK systems in prefrontal cortex. In suicide patients, TAC, TAC receptors and a few NPY family transcript levels were increased mainly in prefrontal cortex and LC. The second study on 'normal' noradrenergic LC neurons revealed expression of transcripts for GAL, NPY, TAC1, CCK, and TACR1 and many other peptides (e.g. Cerebellin4 and CARTPT) and receptors (e.g. Adcyap1R1 and GPR173). These data and our previous results on suicide brains indicates that the tachykinin and galanin systems may be valid targets for developing antidepressant medicines. Moreover, the perturbation of neuropeptide systems in MDD patients, and the detection of further neuropeptide and receptor transcripts in LC, shed new light on signalling in noradrenergic LC neurons and on mechanisms possibly associated with mood disorders.

  • 19. Bartonek, Asa
    et al.
    Lidbeck, Cecilia M.
    Pettersson, Robert
    KTH, School of Engineering Sciences (SCI), Mechanics, Structural Mechanics.
    Weidenhielm, Eva Brostrom
    Eriksson, Marie
    Gutierrez-Farewik, Elena
    KTH, School of Engineering Sciences (SCI), Mechanics, Structural Mechanics.
    Influence of heel lifts during standing in children with motor disorders2011In: Gait & Posture, ISSN 0966-6362, E-ISSN 1879-2219, Vol. 34, no 3, p. 426-431Article in journal (Refereed)
    Abstract [en]

    Heel wedges may influence standing posture but how and to what extent are unknown. Thirty-two children with motor disorders - 16 with arthrogryposis multiplex congenita (AMC) and 16 with cerebral palsy (CP) - and 19 control children underwent a three-dimensional motion analysis. Unassisted standing during 20s with shoes only and with heel lifts of 10,20 and 30 mm heights was recorded in a randomized order. The more weight-bearing limb or the right limb was chosen for analysis. In both the AMC and CP groups, significant changes were seen between various heel lifts in ankle, knee and pelvis, and in the control group in the ankle only. Between orthosis and non-orthosis users significant differences were seen between different heel lift conditions in ankle, knee and trunk in the AMC group and in the ankle in the CP group. Pelvis position changed toward less anterior tilt with increasing heel height, but led to increasing knee flexion in most of the children, except for the AMC Non-Ort group. Children with AMC and CP represent different motor disorders, but the heel wedges had a similar influence on pelvis, hip and knee positions in all children with CP and in the AMC orthosis users. A challenge is to apply heel heights adequate to each individual's orthopaedic and neurologic conditions to improve biomechanical alignment with respect to all body segments.

  • 20.
    Bayraktar, Abdulahad
    et al.
    Kings Coll London, Ctr Host Microbiome Interact, Fac Dent Oral & Craniofacial Sci, London SE1 9RT, England..
    Lam, Simon
    Kings Coll London, Ctr Host Microbiome Interact, Fac Dent Oral & Craniofacial Sci, London SE1 9RT, England..
    Altay, Özlem
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Li, Xiangyu
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Yuan, Meng
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Zhang, Cheng
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Arif, Muhammad
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Turkez, Hasan
    Ataturk Univ, Dept Med Biol, Fac Med, TR-25240 Erzurum, Turkey..
    Uhlén, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Shoaie, Saeed
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Kings Coll London, Ctr Host Microbiome Interact, Fac Dent Oral & Craniofacial Sci, London SE1 9RT, England.
    Mardinoglu, Adil
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Kings Coll London, Ctr Host Microbiome Interact, Fac Dent Oral & Craniofacial Sci, London SE1 9RT, England.
    Revealing the Molecular Mechanisms of Alzheimer's Disease Based on Network Analysis2021In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 22, no 21, article id 11556Article in journal (Refereed)
    Abstract [en]

    The complex pathology of Alzheimer's disease (AD) emphasises the need for comprehensive modelling of the disease, which may lead to the development of efficient treatment strategies. To address this challenge, we analysed transcriptome data of post-mortem human brain samples of healthy elders and individuals with late-onset AD from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) and Mayo Clinic (MayoRNAseq) studies in the AMP-AD consortium. In this context, we conducted several bioinformatics and systems medicine analyses including the construction of AD-specific co-expression networks and genome-scale metabolic modelling of the brain in AD patients to identify key genes, metabolites and pathways involved in the progression of AD. We identified AMIGO1 and GRPRASP2 as examples of commonly altered marker genes in AD patients. Moreover, we found alterations in energy metabolism, represented by reduced oxidative phosphorylation and ATPase activity, as well as the depletion of hexanoyl-CoA, pentanoyl-CoA, (2E)-hexenoyl-CoA and numerous other unsaturated fatty acids in the brain. We also observed that neuroprotective metabolites (e.g., vitamins, retinoids and unsaturated fatty acids) tend to be depleted in the AD brain, while neurotoxic metabolites (e.g., beta-alanine, bilirubin) were more abundant. In summary, we systematically revealed the key genes and pathways related to the progression of AD, gained insight into the crucial mechanisms of AD and identified some possible targets that could be used in the treatment of AD.

  • 21.
    Bayraktar, Abdulahad
    et al.
    Kings Coll London, Ctr Host Microbiome Interact, Fac Dent Oral & Craniofacial Sci, London SE1 9RT, England..
    Li, Xiangyu
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Bash Biotech Inc, 600 West Broadway, Suite 700, San Diego, CA 92101 USA..
    Kim, Woonghee
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Zhang, Cheng
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Turkez, Hasan
    Ataturk Univ, Fac Med, Dept Med Biol, Erzurum, Turkiye..
    Shoaie, Saeed
    Kings Coll London, Ctr Host Microbiome Interact, Fac Dent Oral & Craniofacial Sci, London SE1 9RT, England..
    Mardinoglu, Adil
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Kings Coll London, Ctr Host Microbiome Interact, Fac Dent Oral & Craniofacial Sci, London SE1 9RT, England..
    Drug repositioning targeting glutaminase reveals drug candidates for the treatment of Alzheimer's disease patients2023In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 21, no 1, article id 332Article in journal (Refereed)
    Abstract [en]

    Background

    Despite numerous clinical trials and decades of endeavour, there is still no effective cure for Alzheimer's disease. Computational drug repositioning approaches may be employed for the development of new treatment strategies for Alzheimer's patients since an extensive amount of omics data has been generated during pre-clinical and clinical studies. However, targeting the most critical pathophysiological mechanisms and determining drugs with proper pharmacodynamics and good efficacy are equally crucial in drug repurposing and often imbalanced in Alzheimer's studies.

    Methods

    Here, we investigated central co-expressed genes upregulated in Alzheimer's disease to determine a proper therapeutic target. We backed our reasoning by checking the target gene's estimated non-essentiality for survival in multiple human tissues. We screened transcriptome profiles of various human cell lines perturbed by drug induction (for 6798 compounds) and gene knockout using data available in the Connectivity Map database. Then, we applied a profile-based drug repositioning approach to discover drugs targeting the target gene based on the correlations between these transcriptome profiles. We evaluated the bioavailability, functional enrichment profiles and drug-protein interactions of these repurposed agents and evidenced their cellular viability and efficacy in glial cell culture by experimental assays and Western blotting. Finally, we evaluated their pharmacokinetics to anticipate to which degree their efficacy can be improved.

    Results

    We identified glutaminase as a promising drug target. Glutaminase overexpression may fuel the glutamate excitotoxicity in neurons, leading to mitochondrial dysfunction and other neurodegeneration hallmark processes. The computational drug repurposing revealed eight drugs: mitoxantrone, bortezomib, parbendazole, crizotinib, withaferin-a, SA-25547 and two unstudied compounds. We demonstrated that the proposed drugs could effectively suppress glutaminase and reduce glutamate production in the diseased brain through multiple neurodegeneration-associated mechanisms, including cytoskeleton and proteostasis. We also estimated the human blood-brain barrier permeability of parbendazole and SA-25547 using the SwissADME tool.

    Conclusions

    This study method effectively identified an Alzheimer's disease marker and compounds targeting the marker and interconnected biological processes by use of multiple computational approaches. Our results highlight the importance of synaptic glutamate signalling in Alzheimer's disease progression. We suggest repurposable drugs (like parbendazole) with well-evidenced activities that we linked to glutamate synthesis hereby and novel molecules (SA-25547) with estimated mechanisms for the treatment of Alzheimer's patients.

  • 22.
    Bekkouche, Bo
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST). KTH.
    Classification of Neuronal Subtypes in the Striatum and the Effect of Neuronal Heterogeneity on the Activity Dynamics2016Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Clustering of single-cell RNA sequencing data is often used to show what states and subtypes cells have. Using this technique, striatal cells were clustered into subtypes using different clustering algorithms. Previously known subtypes were confirmed and new subtypes were found. One of them is a third medium spiny neuron subtype. Using the observed heterogeneity, as a second task, this project questions whether or not differences in individual neurons have an impact on the network dynamics. By clustering spiking activity from a neural network model, inconclusive results were found. Both algorithms indicating low heterogeneity, but by altering the quantity of a subtype between a low and high number, and clustering the network activity in each case, results indicate that there is an increase in the heterogeneity. This project shows a list of potential striatal subtypes and gives reasons to keep giving attention to biologically observed heterogeneity.

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  • 23.
    Belic, Jovana
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST).
    Untangling Cortico-Striatal Circuitry and its Role in Health and Disease - A computational investigation2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The basal ganglia (BG) play a critical role in a variety of regular motor and cognitive functions. Many brain diseases, such as Parkinson’s diseases, Huntington’s disease and dyskinesia, are directly related to malfunctions of the BG nuclei. One of those nuclei, the input nucleus called the striatum, is heavily connected to the cortex and receives afferents from nearly all cortical areas. The striatum is a recurrent inhibitory network that contains several distinct cell types. About 95% of neurons in the striatum are medium spiny neurons (MSNs) that form the only output from the striatum. Two of the most examined sources of GABAergic inhibition into MSNs are the feedback inhibition (FB) from the axon collaterals of the MSNs themselves, and the feedforward inhibition (FF) via the small population (1-2% of striatal neurons) of fast spiking interneurons (FSIs). The cortex sends direct projections to the striatum, while the striatum can affect the cortex only indirectly through other BG nuclei and the thalamus. Understanding how different components of the striatal network interact with each other and influence the striatal response to cortical inputs has crucial importance for clarifying the overall functions and dysfunctions of the BG.

        In this thesis I have employed advanced experimental data analysis techniques as well as computational modelling, to study the complex nature of cortico-striatal interactions. I found that for pathological states, such as Parkinson’s disease and L-DOPA-induced dyskinesia, effective connectivity is bidirectional with an accent on the striatal influence on the cortex. Interestingly, in the case of L-DOPA-induced dyskinesia, there was a high increase in effective connectivity at ~80 Hz and the results also showed a large relative decrease in the modulation of the local field potential amplitude (recorded in the primary motor cortex and sensorimotor striatum in awake, freely behaving, 6-OHDA lesioned hemi-parkinsonian rats) at ~80 Hz by the phase of low frequency oscillations. These results suggest a lack of coupling between the low frequency activity of a presumably larger neuronal population and the synchronized activity of a presumably smaller group of neurons active at 80 Hz.

        Next, I used a spiking neuron network model of the striatum to isolate the mechanisms underlying the transmission of cortical oscillations to the MSN population. I showed that FSIs play a crucial role in efficient propagation of cortical oscillations to the MSNs that did not receive direct cortical oscillations. Further, I have identified multiple factors such as the number of activated neurons, ongoing activity, connectivity, and synchronicity of inputs that influenced the transfer of oscillations by modifying the levels of FB and FF inhibitions. Overall, these findings reveal a new role of FSIs in modulating the transfer of information from the cortex to striatum. By modulating the activity and properties of the FSIs, striatal oscillations can be controlled very efficiently. Finally, I explored the interactions in the striatal network with different oscillation frequencies and showed that the features of those oscillations, such as amplitude and frequency fluctuations, can be influenced by a change in the input intensities into MSNs and FSIs and that these fluctuations are also highly dependent on the selected frequencies in addition to the phase offset between different cortical inputs.

        Lastly, I investigated how the striatum responds to cortical neuronal avalanches. Recordings in the striatum revealed that striatal activity was also characterized by spatiotemporal clusters that followed a power law distribution albeit, with significantly steeper slope. In this study, an abstract computational model was developed to elucidate the influence of intrastriatal inhibition and cortico-striatal interplay as important factors to understand the experimental findings. I showed that one particularly high activation threshold of striatal nodes can reproduce a power law-like distribution with a coefficient similar to the one found experimentally. By changing the ratio of excitation and inhibition in the cortical model, I saw that increased activity in the cortex strongly influenced striatal dynamics, which was reflected in a less negative slope of cluster size distributions in the striatum.  Finally, when inhibition was added to the model, cluster size distributions had a prominently earlier deviation from the power law distribution compared to the case when inhibition was not present. 

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  • 24.
    Ben Khedher, Nidhal
    et al.
    Univ Hail, Coll Engn, Dept Mech Engn, Hail 81451, Saudi Arabia.;Univ Monastir, Natl Sch Engn Monastir, Lab Thermal & Energet Syst Studies LESTE, Monastir 5000, Tunisia..
    Shahabadi, Mohammad
    Univ Oklahoma, Sch Aerosp & Mech Engn, Norman, OK 73019 USA..
    Alghawli, Abed Saif
    Prince Sattam Bin Abdulaziz Univ, Comp Sci Dept, Al Aflaj 11912, Saudi Arabia..
    Hulme-Smith, Christopher
    KTH, School of Industrial Engineering and Management (ITM), Materials Science and Engineering, Process.
    Mehryan, Seyed Abdollah Mansouri
    Islamic Azad Univ, Yasooj Branch, Young Researchers & Elite Club, Yasuj 7591493686, Iran..
    Numerical Study of the Flow and Thermomagnetic Convection Heat Transfer of a Power Law Non-Newtonian Ferrofluid within a Circular Cavity with a Permanent Magnet2022In: Mathematics, E-ISSN 2227-7390, Vol. 10, no 15, article id 2612Article in journal (Refereed)
    Abstract [en]

    The aim of this study is to analyze the thermo-magnetic-gravitational convection of a non-Newtonian power law ferrofluid within a circular cavity. The ferrofluid is exposed to the magnetic field of a permanent magnet. The finite element method is employed to solve the non-dimensional controlling equations. A grid sensitivity analysis and the validation of the used method are conducted. The effect of alterable parameters, including the power law index, 0.7 <= n <= 1.3, gravitational Rayleigh number, 10(4) <= Ra-T <= 10(6), magnetic Rayleigh number, 10(5) <= Ra-M <= 10(8), the location of the hot and cold surfaces, 0 <= lambda <= pi/2, and the length of the magnet normalized with respect to the diameter of the cavity, 0.1 <= L <= 0.65, on the flow and heat transfer characteristics are explored. The results show that the heat transfer rate increases at the end of both arcs compared to the central region because of buoyancy effects, and it is greater close to the hot arc. The location of the arcs does not affect the heat transfer rate considerably. An increase in the magnetic Rayleigh number contributes to stronger circulation of the flow inside and higher heat transfer. When the Kelvin force is the only one imposed on the flow, it enhances the heat transfer for magnets of length 0.2 <= L <= 0.3.

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  • 25.
    Benjaminsson, Simon
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Lansner, Anders
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Nexa: A scalable neural simulator with integrated analysis2012In: Network, ISSN 0954-898X, E-ISSN 1361-6536, Vol. 23, no 4, p. 254-271Article in journal (Refereed)
    Abstract [en]

    Large-scale neural simulations encompass challenges in simulator design, data handling and understanding of simulation output. As the computational power of supercomputers and the size of network models increase, these challenges become even more pronounced. Here we introduce the experimental scalable neural simulator Nexa, for parallel simulation of large-scale neural network models at a high level of biological abstraction and for exploration of the simulation methods involved. It includes firing-rate models and capabilities to build networks using machine learning inspired methods for e. g. self-organization of network architecture and for structural plasticity. We show scalability up to the size of the largest machines currently available for a number of model scenarios. We further demonstrate simulator integration with online analysis and real-time visualization as scalable solutions for the data handling challenges.

  • 26.
    Bergström, Sofia
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Oijerstedt, Linn
    Swedish FTD Initiat, Stockholm, Sweden.;Karolinska Univ Hosp, Theme Aging, Unit Hereditary Dementias, Dept Neurobiol Care Sci & Soc,Div Neurogeriatr,Ka, Solna, Sweden.;Karolinska Univ Hosp, Unit Hereditary Dementias, Theme Aging, Solna, Sweden..
    Remnestål, Julia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Olofsson, Jennie
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Ullgren, Abbe
    Swedish FTD Initiat, Stockholm, Sweden.;Karolinska Univ Hosp, Theme Aging, Unit Hereditary Dementias, Dept Neurobiol Care Sci & Soc,Div Neurogeriatr,Ka, Solna, Sweden..
    Seelaar, Harro
    Erasmus MC, Dept Neurol, Rotterdam, Netherlands..
    van Swieten, John C.
    Erasmus MC, Dept Neurol, Rotterdam, Netherlands..
    Synofzik, Matthis
    Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany.;Univ Tubingen, Ctr Neurol, Tubingen, Germany.;Ctr Neurodegenerat Dis DZNE, Tubingen, Germany..
    Sanchez-Valle, Raquel
    Univ Barcelona, Inst Invest Biomed August Pi I Sunyer, Hosp Clin, Alzheimers Dis & Other Cognit Disorders Unit,Neur, Barcelona, Spain..
    Moreno, Fermin
    Donostia Univ Hosp, Dept Neurol, Cognit Disorders Unit, San Sebastian, Gipuzkoa, Spain.;Biodonostia Hlth Res Inst, Neurosci Area, San Sebastian, Gipuzkoa, Spain..
    Finger, Elizabeth
    Univ Western Ontario, Dept Clin Neurol Sci, London, ON, Canada..
    Masellis, Mario
    Univ Toronto, Sunnybrook Hlth Sci Ctr, Sunnybrook Res Inst, Toronto, ON, Canada..
    Tartaglia, Carmela
    Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON, Canada..
    Vandenberghe, Rik
    Katholieke Univ Leuven, Lab Cognit Neurol, Dept Neurosci, Leuven, Belgium.;Univ Hosp Leuven, Neurol Serv, Leuven, Belgium.;Katholieke Univ Leuven, Leuven Brain Inst, Leuven, Belgium..
    Laforce, Robert
    Univ Laval, CHU Quebec, Dept Sci Neurol, Clin Interdisciplinaire Mem, Quebec City, PQ, Canada.;Univ Laval, Fac Med, Quebec City, PQ, Canada..
    Galimberti, Daniela
    Fdn IRCCS Osped Policlin, Milan, Italy.;Univ Milan, Ctr Dino Ferrari, Milan, Italy..
    Borroni, Barbara
    Univ Brescia, Ctr Neurodegenerat Disorders, Dept Clin & Expt Sci, Brescia, Italy..
    Butler, Chris R.
    Univ Oxford, Nuffield Dept Clin Neurosci, Med Sci Div, Oxford, England.;Imperial Coll London, Dept Brain Sci, London, England..
    Gerhard, Alexander
    Univ Manchester, Wolfson Mol Imaging Ctr, Div Neurosci & Expt Psychol, Manchester, Lancs, England.;Univ Duisburg Essen, Dept Geriatr Med, Duisburg, Germany.;Univ Duisburg Essen, Dept Nucl Med, Duisburg, Germany..
    Ducharme, Simon
    McGill Univ, Douglas Mental Hlth Univ Inst, Dept Psychiat, Montreal, PQ, Canada.;McGill Univ, McConnell Brain Imaging Ctr, Montreal Neurol Inst, Montreal, PQ, Canada..
    Rohrer, Jonathan D.
    UCL Inst Neurol, Dementia Res Ctr, Dept Neurodegenerat Dis, Queen Sq, London, England..
    Manberg, Anna
    Univ Toronto, Sunnybrook Hlth Sci Ctr, Sunnybrook Res Inst, Toronto, ON, Canada..
    Graff, Caroline
    Swedish FTD Initiat, Stockholm, Sweden.;Karolinska Univ Hosp, Theme Aging, Unit Hereditary Dementias, Dept Neurobiol Care Sci & Soc,Div Neurogeriatr,Ka, Solna, Sweden.;Karolinska Univ Hosp, Unit Hereditary Dementias, Theme Aging, Solna, Sweden..
    Nilsson, Peter
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study2021In: Molecular Neurodegeneration, E-ISSN 1750-1326, Vol. 16, no 1, article id 79Article in journal (Refereed)
    Abstract [en]

    Background A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. Methods A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. Results When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). Conclusion In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD.

  • 27.
    Bergström, Sofia
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Remnestål, Julia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Yousef, Jamil
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Olofsson, Jennie
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Markaki, Ioanna
    Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden.
    Carvalho, Stephanie
    Sorbonne Université Institut du Cerveau ‐ Paris Brain Institute ‐ ICM, Assistance‐Publique Hôpitaux de Paris INSERM CNRS Hôpital Pitié‐Salpêtrière Department of Neurology Centre d’Investigation Clinique Neurosciences Paris France.
    Corvol, Jean‐Christophe
    Sorbonne Université Institut du Cerveau ‐ Paris Brain Institute ‐ ICM, Assistance‐Publique Hôpitaux de Paris INSERM CNRS Hôpital Pitié‐Salpêtrière Department of Neurology Centre d’Investigation Clinique Neurosciences Paris France.
    Kultima, Kim
    Department of Medical Sciences Clinical Chemistry Uppsala University Uppsala Sweden.
    Kilander, Lena
    Department of Public Health and Caring Sciences Geriatrics Uppsala University Uppsala Sweden.
    Löwenmark, Malin
    Department of Public Health and Caring Sciences Geriatrics Uppsala University Uppsala Sweden.
    Ingelsson, Martin
    Department of Public Health and Caring Sciences Geriatrics Uppsala University Uppsala Sweden.
    Blennow, Kaj
    Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology The Sahlgrenska Academy University of Gothenburg;Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Mölndal Sweden.
    Zetterberg, Henrik
    Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology The Sahlgrenska Academy University of Gothenburg;Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Mölndal Sweden;Department of Neurodegenerative Disease UCL Institute of Neurology London UK;UK Dementia Research Institute at UCL London UK.
    Nellgård, Bengt
    Anesthesiology and Intensive Care Medicine Sahlgrenska University Hospital Mölndal Sweden;Department of Anesthesiology and Intensive Care Medicine Institute of Clinical Sciences The Sahlgrenska Academy University of Gothenburg.
    Brosseron, Frederic
    Universitätsklinikum Bonn Germany;German Center for Neurodegenerative Diseases (DZNE) Bonn Germany.
    Heneka, Michael T.
    Universitätsklinikum Bonn Germany.
    Bosch, Beatriz
    Alzheimer’s and other cognitive disorders Unit. Service of Neurology Hospital Clínic de Barcelona Institut d'Investigació Biomèdica August Pi i Sunyer University of Barcelona Barcelona Spain.
    Sanchez‐Valle, Raquel
    Alzheimer’s and other cognitive disorders Unit. Service of Neurology Hospital Clínic de Barcelona Institut d'Investigació Biomèdica August Pi i Sunyer University of Barcelona Barcelona Spain.
    Månberg, Anna
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Svenningsson, Per
    Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden.
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Multi‐cohort profiling reveals elevated CSF levels of brain‐enriched proteins in Alzheimer’s disease2021In: Annals of Clinical and Translational Neurology, E-ISSN 2328-9503, Vol. 8, no 7, p. 1456-1470Article in journal (Refereed)
    Abstract [en]

    Objective: Decreased amyloid beta (Ab) 42 together with increased tau and phospho-tau in cerebrospinal fluid (CSF) is indicative of Alzheimer’s disease (AD). However, the molecular pathophysiology underlying the slowly progressive cognitive decline observed in AD is not fully understood and it is not known what other CSF biomarkers may be altered in early disease stages. Methods: We utilized an antibody-based suspension bead array to analyze levels of 216 proteins in CSF from AD patients, patients with mild cognitive impairment (MCI), and controls from two independent cohorts collected within the AETIONOMY consortium. Two additional cohorts from Sweden were used for biological verification. Results: Six proteins, amphiphysin (AMPH), aquaporin 4 (AQP4), cAMP-regulated phosphoprotein 21 (ARPP21), growth-associated protein 43 (GAP43), neurofilament medium polypeptide (NEFM), and synuclein beta (SNCB) were found at increased levels in CSF from AD patients compared with controls. Next, we used CSF levels of Ab42 and tau for the stratification of the MCI patients and observed increased levels of AMPH, AQP4, ARPP21, GAP43, and SNCB in the MCI subgroups with abnormal tau levels compared with controls. Further characterization revealed strong to moderate correlations between these five proteins and tau concentrations. Interpretation: In conclusion, we report six extensively replicated candidate biomarkers with the potential to reflect disease development. Continued evaluation of these proteins will determine to what extent they can aid in the discrimination of MCI patients with and without an underlying AD etiology, and if they have the potential to contribute to a better understanding of the AD continuum.

  • 28.
    Berthet, Pierre
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST). Karolinska Institute, Stockholm, Sweden.
    Lindahl, Mikael
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST). Karolinska Institute, Stockholm, Sweden.
    Tully, Philip
    Hällgren Kotaleski, Jeanette
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST). Karolinska Institute, Stockholm, Sweden.
    Lansner, Anders
    Functional Relevance of Different Basal Ganglia Pathways Investigated in a Spiking 1 Model with Reward Dependent PlasticityManuscript (preprint) (Other academic)
  • 29.
    Berthet, Pierre
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. Stockholm Univ, Sweden; Karolinska Inst, Sweden.
    Lindahl, Mikael
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. Karolinska Inst, Sweden.
    Tully, Philip J.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. Karolinska Inst, Sweden; Univ Edinburgh, Scotland.
    Hellgren-Kotaleski, Jeanette
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. Karolinska Inst, Sweden.
    Lansner, Anders
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. Stockholm Univ, Sweden; Karolinska Inst, Sweden.
    Functional Relevance of Different Basal Ganglia Pathways Investigated in a Spiking Model with Reward Dependent Plasticity2016In: Frontiers in Neural Circuits, E-ISSN 1662-5110, Vol. 10, article id 53Article in journal (Refereed)
    Abstract [en]

    The brain enables animals to behaviorally adapt in order to survive in a complex and dynamic environment, but how reward-oriented behaviors are achieved and computed by its underlying neural circuitry is an open question. To address this concern, we have developed a spiking model of the basal ganglia (BG) that learns to dis-inhibit the action leading to a reward despite ongoing changes in the reward schedule. The architecture of the network features the two pathways commonly described in BG, the direct (denoted D1) and the indirect (denoted D2) pathway, as well as a loop involving striatum and the dopaminergic system. The activity of these dopaminergic neurons conveys the reward prediction error (RPE), which determines the magnitude of synaptic plasticity within the different pathways. All plastic connections implement a versatile four-factor learning rule derived from Bayesian inference that depends upon pre- and post-synaptic activity, receptor type, and dopamine level. Synaptic weight updates occur in the D1 or D2 pathways depending on the sign of the RPE, and an efference copy informs upstream nuclei about the action selected. We demonstrate successful performance of the system in a multiple-choice learning task with a transiently changing reward schedule. We simulate lesioning of the various pathways and show that a condition without the D2 pathway fares worse than one without D1. Additionally, we simulate the degeneration observed in Parkinson's disease (PD) by decreasing the number of dopaminergic neurons during learning. The results suggest that the D1 pathway impairment in PD might have been overlooked. Furthermore, an analysis of the alterations in the synaptic weights shows that using the absolute reward value instead of the RPE leads to a larger change in D1.

  • 30.
    Bicanski, Andrej
    et al.
    School of Engineering, École Polytechnique Fédérale de Lausanne.
    Ryczko, Dimitri
    Département de Physiologie, Université de Montréa.
    Knuesel, Jérémie
    School of Engineering, École Polytechnique Fédérale de Lausanne.
    Harischandra, Nalin
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Charrier, Vanessa
    INSERM U862, Neurocentre Magendie, Université Bordeaux.
    Ekeberg, Örjan
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Cabelguen, Jean-Marie
    Neurocentre Magendie, Bordeaux University, Bordeaux Cedex, France.
    Ijspeert, Auke Jan
    School of Engineering, École Polytechnique Fédérale de Lausanne.
    Decoding the mechanisms of gait generation in salamanders by combining neurobiology, modeling and robotics2013In: Biological Cybernetics, ISSN 0340-1200, E-ISSN 1432-0770, Vol. 107, no 5, p. 545-564Article, review/survey (Refereed)
    Abstract [en]

    Vertebrate animals exhibit impressive locomotor skills. These locomotor skills are due to the complex interactions between the environment, the musculo-skeletal system and the central nervous system, in particular the spinal locomotor circuits. We are interested in decoding these interactions in the salamander, a key animal from an evolutionary point of view. It exhibits both swimming and stepping gaits and is faced with the problem of producing efficient propulsive forces using the same musculo-skeletal system in two environments with significant physical differences in density, viscosity and gravitational load. Yet its nervous system remains comparatively simple. Our approach is based on a combination of neurophysiological experiments, numerical modeling at different levels of abstraction, and robotic validation using an amphibious salamander-like robot. This article reviews the current state of our knowledge on salamander locomotion control, and presents how our approach has allowed us to obtain a first conceptual model of the salamander spinal locomotor networks. The model suggests that the salamander locomotor circuit can be seen as a lamprey-like circuit controlling axial movements of the trunk and tail, extended by specialized oscillatory centers controlling limb movements. The interplay between the two types of circuits determines the mode of locomotion under the influence of sensory feedback and descending drive, with stepping gaits at low drive, and swimming at high drive.

  • 31. Binda, Francesca
    et al.
    Spaeth, Ludovic
    Kumar, Arvind
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST).
    Isope, Philippe
    Excitation and Inhibition Delays within a Feedforward Inhibitory Pathway Modulate Cerebellar Purkinje Cell Output in Mice2023In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 43, no 33, p. 5905-5917Article in journal (Refereed)
    Abstract [en]

    The cerebellar cortex computes sensorimotor information from many brain areas through a feedforward inhibitory (FFI) microcircuit between the input stage, the granule cell (GC) layer, and the output stage, the Purkinje cells (PCs). Although in other brain areas FFI underlies a precise excitation versus inhibition temporal correlation, recent findings in the cerebellum highlighted more complex behaviors at GC-molecular layer interneuron (MLI)-PC pathway. To dissect the temporal organization of this cerebellar FFI pathway, we combined ex vivo patch-clamp recordings of PCs in male mice with a viral-based strategy to express Channelrhodopsin2 in a subset of mossy fibers (MFs), the major excitatory inputs to GCs. We show that although light-mediated MF activation elicited pairs of excitatory and inhibitory postsynaptic currents in PCs, excitation (E) from GCs and inhibition (I) from MLIs reached PCs with a wide range of different temporal delays. However, when GCs were directly stimulated, a low variability in E/I delays was observed. Our results demonstrate that in many recordings MF stimulation recruited different groups of GCs that trigger E and/or I, and expanded PC temporal synaptic integration. Finally, using a computational model of the FFI pathway, we showed that this temporal expansion could strongly influence how PCs integrate GC inputs. Our findings show that specific E/I delays may help PCs encoding specific MF inputs.SIGNIFICANCE STATEMENT Sensorimotor information is conveyed to the cerebellar cortex by mossy fibers. Mossy fiber inputs activate granule cells that excite molecular interneurons and Purkinje cells, the sole output of the cerebellar cortex, leading to a sequence of synaptic excitation and inhibition in Purkinje cells, thus defining a feedforward inhibitory pathway. Using electrophysiological recordings, optogenetic stimulation, and mathematical modeling, we demonstrated that different groups of granule cells can elicit synaptic excitation and inhibition with various latencies onto Purkinje cells. This temporal variability controls how granule cells influence Purkinje cell discharge and may support temporal coding in the cerebellar cortex.

  • 32. Björkman, Eva
    et al.
    Zagal, Juan Cristobal
    Lindeberg, Tony
    KTH, Superseded Departments (pre-2005), Numerical Analysis and Computer Science, NADA.
    Roland, Per E.
    Evaluation of design options for the scale-space primal sketch analysis of brain activation images2000In: : HBM'00, published in Neuroimage, volume 11, number 5, 2000, 2000, Vol. 11, p. 656-656Conference paper (Refereed)
    Abstract [en]

    A key issue in brain imaging concerns how to detect the functionally activated regions from PET and fMRI images. In earlier work, it has been shown that the scale-space primal sketch provides a useful tool for such analysis [1]. The method includes presmoothing with different filter widths and automatic estimation of the spatial extent of the activated regions (blobs).

    The purpose is to present two modifications of the scale-space primal sketch, as well as a quantitative evaluation which shows that these modifications improve the performance, measured as the separation between blob descriptors extracted from PET images and from noise images. This separation is essential for future work of associating a statistical p-value with the scale-space blob descriptors.

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  • 33.
    Blackwell, Kim T.
    et al.
    George Mason Univ, Krasnow Inst Adv Study, Fairfax, VA 22030 USA. lackwell, Kim T..
    Salinas, Armando G.
    Tewatia, Parul
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    English, Brad
    Hellgren Kotaleski, Jeanette
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lovinger, David M.
    Molecular mechanisms underlying striatal synaptic plasticity: relevance chronic alcohol consumption and seeking2019In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 49, no 6, p. 768-783Article in journal (Refereed)
    Abstract [en]

    The striatum, the input structure of the basal ganglia, is a major site learning and memory for goal-directed actions and habit formation. iny projection neurons of the striatum integrate cortical, thalamic, d nigral inputs to learn associations, with cortico-striatal synaptic asticity as a learning mechanism. Signaling molecules implicated in naptic plasticity are altered in alcohol withdrawal, which may ntribute to overly strong learning and increased alcohol seeking and nsumption. To understand how interactions among signaling molecules oduce synaptic plasticity, we implemented a mechanistic model of gnaling pathways activated by dopamine D1 receptors, acetylcholine ceptors, and glutamate. We use our novel, computationally efficient mulator, NeuroRD, to simulate stochastic interactions both within and tween dendritic spines. Dopamine release during theta burst and 20-Hz imulation was extrapolated from fast-scan cyclic voltammetry data llected in mouse striatal slices. Our results show that the combined tivity of several key plasticity molecules correctly predicts the currence of either LTP, LTD, or no plasticity for numerous perimental protocols. To investigate spatial interactions, we imulate two spines, either adjacent or separated on a 20-mu m ndritic segment. Our results show that molecules underlying LTP hibit spatial specificity, whereas 2-arachidonoylglycerol exhibits a atially diffuse elevation. We also implement changes in NMDA ceptors, adenylyl cyclase, and G protein signaling that have been asured following chronic alcohol treatment. Simulations under these nditions suggest that the molecular changes can predict changes in naptic plasticity, thereby accounting for some aspects of alcohol use sorder.

  • 34.
    Blom, Hans
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Bernhem, Kristoffer
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Institutet, Sweden.
    Sodium pump organization in dendritic spines2016In: NEUROPHOTONICS, ISSN 2329-423X, Vol. 3, no 4, article id 041803Article in journal (Refereed)
    Abstract [en]

    Advancement in fluorescence imaging with the invention of several super-resolution microscopy modalities (e.g., PALM/STORM and STED) has opened up the possibility of deciphering molecular distributions on the nanoscale. In our quest to better elucidate postsynaptic protein distribution in dendritic spines, we have applied these nanoscopy methods, where generated results could help improve our understanding of neuronal functions. In particular, we have investigated the principal energy transformer in the brain, i.e., the Na+; K+-ATPase (or sodium pump), an essential protein responsible for maintaining resting membrane potential and a major controller of intracellular ion homeostasis. In these investigations, we have focused on estimates of protein amount, giving assessments of how variations may depend on labeling strategies, sample analysis, and choice of nanoscopic imaging method, concluding that all can be critical factors for quantification. We present a comparison of these results and discuss the influences this may have for homeostatic sodium regulation in neurons and energy consumption.

  • 35.
    Blom, Hans
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Experimental Biomolecular Physics.
    Ronnlund, Daniel
    KTH, School of Engineering Sciences (SCI), Applied Physics, Experimental Biomolecular Physics.
    Scott, Lena
    Spicarova, Zuzana
    Widengren, Jerker
    KTH, School of Engineering Sciences (SCI), Applied Physics, Experimental Biomolecular Physics.
    Bondar, Alexander
    Aperia, Anita
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Spatial distribution of Na+-K+-ATPase in dendritic spines dissected by nanoscale superresolution STED microscopy2011In: BMC Neuroscience, E-ISSN 1471-2202, Vol. 12, p. 16-Article in journal (Refereed)
    Abstract [en]

    Background: The Na+,K+-ATPase plays an important role for ion homeostasis in virtually all mammalian cells, including neurons. Despite this, there is as yet little known about the isoform specific distribution in neurons. Results: With help of superresolving stimulated emission depletion microscopy the spatial distribution of Na+,K+-ATPase in dendritic spines of cultured striatum neurons have been dissected. The found compartmentalized distribution provides a strong evidence for the confinement of neuronal Na+,K+-ATPase (alpha 3 isoform) in the postsynaptic region of the spine. Conclusions: A compartmentalized distribution may have implications for the generation of local sodium gradients within the spine and for the structural and functional interaction between the sodium pump and other synaptic proteins. Superresolution microscopy has thus opened up a new perspective to elucidate the nature of the physiological function, regulation and signaling role of Na+,K+-ATPase from its topological distribution in dendritic spines.

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    NKA-STED
  • 36.
    Brandi, Maya
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. KTH, School of Computer Science and Communication (CSC), Centres, Centre for High Performance Computing, PDC.
    Brocke, Ekaterina
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Talukdar, Husain A.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Hanke, Michael
    KTH, School of Computer Science and Communication (CSC), Numerical Analysis, NA.
    Bhalla, Upinder S.
    National Centre for Biological Sciences, Bangalore, India.
    Hällgren-Kotaleski, Jeanette
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Djurfeldt, Mikael
    KTH, School of Computer Science and Communication (CSC), Centres, Centre for High Performance Computing, PDC.
    Connecting MOOSE and NeuroRD through MUSIC: towards a communication framework for multi-scale modeling2011In: Twentieth Annual Computational Neuroscience Meeting: CNS*2011, Springer Science+Business Media B.V., 2011Conference paper (Refereed)
  • 37. Brette, Romain
    et al.
    Rudolph, Michelle
    Carnevale, Ted
    Hines, Michael
    Beeman, David
    Bower, James M.
    Diesmann, Markus
    Morrison, Abigail
    Goodman, Philip H.
    Harris, Frederick C., Jr.
    Zirpe, Milind
    Natschlaeger, Thomas
    Pecevski, Dejan
    Ermentrout, Bard
    Djurfeldt, Mikael
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Lansner, Anders
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Rochel, Olivier
    Vieville, Thierry
    Muller, Eilif
    Davison, Andrew P.
    El Boustani, Sami
    Destexhe, Alain
    Simulation of networks of spiking neurons: A review of tools and strategies2007In: Journal of Computational Neuroscience, ISSN 0929-5313, E-ISSN 1573-6873, Vol. 23, no 3, p. 349-398Article, review/survey (Refereed)
    Abstract [en]

    We review different aspects of the simulation of spiking neural networks. We start by reviewing the different types of simulation strategies and algorithms that are currently implemented. We next review the precision of those simulation strategies, in particular in cases where plasticity depends on the exact timing of the spikes. We overview different simulators and simulation environments presently available (restricted to those freely available, open source and documented). For each simulation tool, its advantages and pitfalls are reviewed, with an aim to allow the reader to identify which simulator is appropriate for a given task. Finally, we provide a series of benchmark simulations of different types of networks of spiking neurons, including Hodgkin-Huxley type, integrate-and-fire models, interacting with current-based or conductance-based synapses, using clock-driven or event-driven integration strategies. The same set of models are implemented on the different simulators, and the codes are made available. The ultimate goal of this review is to provide a resource to facilitate identifying the appropriate integration strategy and simulation tool to use for a given modeling problem related to spiking neural networks.

  • 38.
    Brocke, Ekaterina
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Djurfeldt, Mikael
    KTH, School of Computer Science and Communication (CSC), Centres, Centre for High Performance Computing, PDC.
    Efficient spike communication in the MUSIC multi-simulation framework2011In: Twentieth Annual Computational Neuroscience Meeting: CNS*2011, Springer Science+Business Media B.V., 2011Conference paper (Refereed)
  • 39.
    Broome, M.
    et al.
    Karolinska Institutet.
    Hokfelt, T.
    Terenius, L.
    Peptide YY (PYY)-immunoreactive neurons in the lower brain stem and spinal cord of rat1985In: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 125, no 2, p. 349-352Article in journal (Refereed)
  • 40.
    Brusini, Irene
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Methods for the analysis and characterization of brain morphology from MRI images2022Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Brain magnetic resonance imaging (MRI) is an imaging modality that produces detailed images of the brain without using any ionizing radiation. From a structural MRI scan, it is possible to extract morphological properties of different brain regions, such as their volume and shape. These measures can both allow a better understanding of how the brain changes due to multiple factors (e.g., environmental and pathological) and contribute to the identification of new imaging biomarkers of neurological and psychiatric diseases. The overall goal of the present thesis is to advance the knowledge on how brain MRI image processing can be effectively used to analyze and characterize brain structure.

    The first two works presented in this thesis are animal studies that primarily aim to use MRI data for analyzing differences between groups of interest. In Paper I, MRI scans from wild and domestic rabbits were processed to identify structural brain differences between these two groups. Domestication was found to significantly reshape brain structure in terms of both regional gray matter volume and white matter integrity. In Paper II, rat brain MRI scans were used to train a brain age prediction model. This model was then tested on both controls and a group of rats that underwent long-term environmental enrichment and dietary restriction. This healthy lifestyle intervention was shown to significantly affect the predicted brain age trajectories by slowing the rats' aging process compared to controls. Furthermore, brain age predicted on young adult rats was found to have a significant effect on survival.

    Papers III to V are human studies that propose deep learning-based methods for segmenting brain structures that can be severely affected by neurodegeneration. In particular, Papers III and IV focus on U-Net-based 2D segmentation of the corpus callosum (CC) in multiple sclerosis (MS) patients. In both studies, good segmentation accuracy was obtained and a significant correlation was found between CC area and the patient's level of cognitive and physical disability. Additionally, in Paper IV, shape analysis of the segmented CC revealed a significant association between disability and both CC thickness and bending angle. Conversely, in Paper V, a novel method for automatic segmentation of the hippocampus is proposed, which consists of embedding a statistical shape prior as context information into a U-Net-based framework. The inclusion of shape information was shown to significantly improve segmentation accuracy when testing the method on a new unseen cohort (i.e., different from the one used for training). Furthermore, good performance was observed across three different diagnostic groups (healthy controls, subjects with mild cognitive impairment and Alzheimer's patients) that were characterized by different levels of hippocampal atrophy.

    In summary, the studies presented in this thesis support the great value of MRI image analysis for the advancement of neuroscientific knowledge, and their contribution is mostly two-fold. First, by applying well-established processing methods on datasets that had not yet been explored in the literature, it was possible to characterize specific brain changes and disentangle relevant problems of a clinical or biological nature. Second, a technical contribution is provided by modifying and extending already-existing brain image processing methods to achieve good performance on new datasets.

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  • 41.
    Brusini, Irene
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Carneiro, Miguel
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet CIBIO, InBIO, P-4485661 Vairao, Portugal.;Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal..
    Wang, Chunliang
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Rubin, Carl-Johan
    Uppsala Univ, Sci Life Lab Uppsala, Dept Med Biochem & Microbiol, S-75236 Uppsala, Sweden..
    Ring, Henrik
    Uppsala Univ, Dept Neurosci, S-75236 Uppsala, Sweden..
    Afonso, Sandra
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet CIBIO, InBIO, P-4485661 Vairao, Portugal..
    Blanco-Aguiar, Jose A.
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet CIBIO, InBIO, P-4485661 Vairao, Portugal.;CSIC, Inst Invest Recursos Cineget IREC, Ciudad Real 13005, Spain.;UCLM, CSIC, Ciudad Real 13005, Spain..
    Ferrand, Nuno
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet CIBIO, InBIO, P-4485661 Vairao, Portugal.;Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal.;Univ Johannesburg, Dept Zool, ZA-2006 Auckland Pk, South Africa..
    Rafati, Nima
    Uppsala Univ, Sci Life Lab Uppsala, Dept Med Biochem & Microbiol, S-75236 Uppsala, Sweden..
    Villafuerte, Rafael
    CSIC, IESA, Cordoba 14004, Spain..
    Smedby, Örjan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Damberg, Peter
    Karolinska Univ Hosp, Karolinska Expt Res & Imaging Ctr, S-17176 Solna, Sweden..
    Hallbook, Finn
    Uppsala Univ, Dept Neurosci, S-75236 Uppsala, Sweden..
    Fredrikson, Mats
    Uppsala Univ, Dept Psychol, S-75236 Uppsala, Sweden.;Karolinska Inst, Dept Clin Neurosci, S-17177 Stockholm, Sweden..
    Andersson, Leif
    Uppsala Univ, Sci Life Lab Uppsala, Dept Med Biochem & Microbiol, S-75236 Uppsala, Sweden.;Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA.;Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden..
    Changes in brain architecture are consistent with altered fear processing in domestic rabbits2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 28, p. 7380-7385Article in journal (Refereed)
    Abstract [en]

    The most characteristic feature of domestic animals is their change in behavior associated with selection for tameness. Here we show, using high-resolution brain magnetic resonance imaging in wild and domestic rabbits, that domestication reduced amygdala volume and enlarged medial prefrontal cortex volume, supporting that areas driving fear have lost volume while areas modulating negative affect have gained volume during domestication. In contrast to the localized gray matter alterations, white matter anisotropy was reduced in the corona radiata, corpus callosum, and the subcortical white matter. This suggests a compromised white matter structural integrity in projection and association fibers affecting both afferent and efferent neural flow, consistent with reduced neural processing. We propose that compared with their wild ancestors, domestic rabbits are less fearful and have an attenuated flight response because of these changes in brain architecture.

  • 42.
    Brusini, Irene
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging. Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden..
    MacNicol, Eilidh
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Neuroimaging, London, England..
    Kim, Eugene
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Neuroimaging, London, England..
    Smedby, Örjan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Wang, Chunliang
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Westman, Eric
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden..
    Veronese, Mattia
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Neuroimaging, London, England.;Univ Padua, Dept Informat Engn, Padua, Italy..
    Turkheimer, Federico
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Neuroimaging, London, England..
    Cash, Diana
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Neuroimaging, London, England..
    MRI-derived brain age as a biomarker of ageing in rats: validation using a healthy lifestyle intervention2022In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 109, p. 204-215Article in journal (Refereed)
    Abstract [en]

    The difference between brain age predicted from MRI and chronological age (the so-called BrainAGE) has been proposed as an ageing biomarker. We analyse its cross-species potential by testing it on rats undergoing an ageing modulation intervention. Our rat brain age prediction model combined Gaussian process regression with a classifier and achieved a mean absolute error (MAE) of 4.87 weeks using cross-validation on a longitudinal dataset of 31 normal ageing rats. It was then tested on two groups of 24 rats (MAE = 9.89 weeks, correlation coefficient = 0.86): controls vs. a group under long-term environmental enrichment and dietary restriction (EEDR). Using a linear mixed-effects model, BrainAGE was found to increase more slowly with chronological age in EEDR rats ( p = 0 . 015 for the interaction term). Cox re-gression showed that older BrainAGE at 5 months was associated with higher mortality risk ( p = 0 . 03 ). Our findings suggest that lifestyle-related prevention approaches may help to slow down brain ageing in rodents and the potential of BrainAGE as a predictor of age-related health outcomes.

  • 43. Bujan, Alejandro
    et al.
    Aertsen, Ad
    Kumar, Arvind
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. University of Freiburg, Freiburg, Germany .
    Role of Input Correlations in Shaping the Variability and Noise Correlations of Evoked Activity in the Neocortex2015In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 35, no 22, p. 8611-8625Article in journal (Refereed)
    Abstract [en]

    Recent analysis of evoked activity recorded across different brain regions and tasks revealed a marked decrease in noise correlations and trial-by-trial variability. Given the importance of correlations and variability for information processing within the rate coding paradigm, several mechanisms have been proposed to explain the reduction in these quantities despite an increase in firing rates. These models suggest that anatomical clusters and/or tightly balanced excitation-inhibition can generate intrinsic network dynamics that may exhibit a reduction in noise correlations and trial-by-trial variability when perturbed by an external input. Such mechanisms based on the recurrent feedback crucially ignore the contribution of feedforward input to the statistics of the evoked activity. Therefore, we investigated how statistical properties of the feedforward input shape the statistics of the evoked activity. Specifically, we focused on the effect of input correlation structure on the noise correlations and trial-by-trial variability. We show that the ability of neurons to transfer the input firing rate, correlation, and variability to the output depends on the correlations within the presynaptic pool of a neuron, and that an input with even weak within-correlations can be sufficient to reduce noise correlations and trial-by-trial variability, without requiring any specific recurrent connectivity structure. In general, depending on the ongoing activity state, feedforward input could either increase or decrease noise correlation and trial-by-trial variability. Thus, we propose that evoked activity statistics are jointly determined by the feedforward and feedback inputs.

  • 44.
    Bulovaite, Edita
    et al.
    Univ Edinburgh, Ctr Clin Brain Sci, Genes Cognit Program, Edinburgh EH16 4SB, Scotland..
    Qiu, Zhen
    Univ Edinburgh, Ctr Clin Brain Sci, Genes Cognit Program, Edinburgh EH16 4SB, Scotland..
    Kratschke, Maximilian
    Univ Edinburgh, Ctr Clin Brain Sci, Genes Cognit Program, Edinburgh EH16 4SB, Scotland..
    Zgraj, Adrianna
    Univ Edinburgh, Ctr Clin Brain Sci, Genes Cognit Program, Edinburgh EH16 4SB, Scotland..
    Fricker, David G.
    Univ Edinburgh, Ctr Clin Brain Sci, Genes Cognit Program, Edinburgh EH16 4SB, Scotland..
    Tuck, Eleanor J.
    Univ Edinburgh, Ctr Clin Brain Sci, Genes Cognit Program, Edinburgh EH16 4SB, Scotland..
    Gokhale, Ragini
    Univ Edinburgh, Ctr Clin Brain Sci, Genes Cognit Program, Edinburgh EH16 4SB, Scotland..
    Koniaris, Babis
    Univ Edinburgh, Ctr Clin Brain Sci, Genes Cognit Program, Edinburgh EH16 4SB, Scotland.;Edinburgh Napier Univ, Sch Comp, Edinburgh EH10 5DT, Scotland..
    Jami, Shekib A.
    Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Los Angeles, CA 90095 USA.;Univ Calif Los Angeles, Brain Res Inst, Integrat Ctr Learning & Memory, Los Angeles, CA 90095 USA..
    Merino-Serrais, Paula
    UPM, Lab Cajal Circuitos Cort, Ctr Tecnol Biomed, Madrid 28223, Spain.;CSIC, Inst Cajal, Madrid 28002, Spain..
    Husi, Elodie
    Univ Geneva, Fac Med, Dept Basic Neurosci, CH-1211 Geneva, Switzerland..
    Mendive-Tapia, Lorena
    Univ Edinburgh, Ctr Inflammat Res, Edinburgh EH16 4TJ, Scotland..
    Vendrell, Marc
    Univ Edinburgh, Ctr Inflammat Res, Edinburgh EH16 4TJ, Scotland..
    O'Dell, Thomas J.
    DeFelipe, Javier
    Komiyama, Noboru H.
    Univ Edinburgh, Ctr Clin Brain Sci, Genes Cognit Program, Edinburgh EH16 4SB, Scotland.;Univ Edinburgh, Ctr Discovery Brain Sci, Simons Initiat Developing Brain SIDB, Edinburgh EH8 9XD, Scotland.;Univ Edinburgh, Patrick Wild Ctr Res Autism, Ctr Discovery Brain Sci, Fragile Syndrome & Intellectual Disabil 10, Edinburgh EH8 9XD, Scotland.;Univ Edinburgh, Muir Maxwell Epilepsy Ctr, Edinburgh EH8 9XD, Scotland..
    Holtmaat, Anthony
    Univ Geneva, Fac Med, Dept Basic Neurosci, CH-1211 Geneva, Switzerland..
    Fransén, Erik
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Grant, Seth G. N.
    Univ Edinburgh, Ctr Clin Brain Sci, Genes Cognit Program, Edinburgh EH16 4SB, Scotland.;Univ Edinburgh, Ctr Discovery Brain Sci, Simons Initiat Developing Brain SIDB, Edinburgh EH8 9XD, Scotland..
    A brain atlas of synapse protein lifetime across the mouse lifespan2022In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 110, no 24, p. 4057-+Article in journal (Refereed)
    Abstract [en]

    The lifetime of proteins in synapses is important for their signaling, maintenance, and remodeling, and for memory duration. We quantified the lifetime of endogenous PSD95, an abundant postsynaptic protein in excitatory synapses, at single-synapse resolution across the mouse brain and lifespan, generating the Protein Lifetime Synaptome Atlas. Excitatory synapses have a wide range of PSD95 lifetimes extending from hours to several months, with distinct spatial distributions in dendrites, neurons, and brain regions. Synapses with short protein lifetimes are enriched in young animals and in brain regions controlling innate behaviors, whereas synapses with long protein lifetimes accumulate during development, are enriched in the cortex and CA1 where memories are stored, and are preferentially preserved in old age. Synapse protein lifetime increases throughout the brain in a mouse model of autism and schizophrenia. Protein lifetime adds a further layer to synapse diversity and enriches prevailing concepts in brain development, aging, and disease.

  • 45.
    Carannante, Ilaria
    et al.
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Johansson, Yvonne
    UCL, Sainsbury Wellcome Ctr Neural Circuits & Behav, London, England..
    Silberberg, Gilad
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Hellgren Kotaleski, Jeanette
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST). KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Data-Driven Model of Postsynaptic Currents Mediated by NMDA or AMPA Receptors in Striatal Neurons2022In: Frontiers in Computational Neuroscience, E-ISSN 1662-5188, Vol. 16, article id 806086Article in journal (Refereed)
    Abstract [en]

    The majority of excitatory synapses in the brain uses glutamate as neurotransmitter, and the synaptic transmission is primarily mediated by AMPA and NMDA receptors in postsynaptic neurons. Here, we present data-driven models of the postsynaptic currents of these receptors in excitatory synapses in mouse striatum. It is common to fit two decay time constants to the decay phases of the current profiles but then compute a single weighted mean time constant to describe them. We have shown that this approach does not lead to an improvement in the fitting, and, hence, we present a new model based on the use of both the fast and slow time constants and a numerical calculation of the peak time using Newton's method. Our framework allows for a more accurate description of the current profiles without needing extra data and without overburdening the comptuational costs. The user-friendliness of the method, here implemented in Python, makes it easily applicable to other data sets.

  • 46.
    Carannante, Ilaria
    et al.
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Scolamiero, Martina
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Mathematics of Data and AI.
    Hjorth, J. J. Johannes
    Kozlov, Alexander
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST). Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Bekkouche, Bo
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST).
    Guo, Lihao
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST).
    Kumar, Arvind
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST).
    Chachólski, Wojciech
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Mathematics (Div.).
    Hellgren Kotaleski, Jeanette
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST). Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    The impact of Parkinson’s disease on striatal network connectivity and cortico-striatal drive: an in-silico studyManuscript (preprint) (Other academic)
    Abstract [en]

    Striatum, the input stage of the basal ganglia, is important for sensory-motor integration, initiation and selection of behaviour, as well as reward learning. Striatum receives glutamatergic inputs from mainly cortex and thalamus. In rodents, the striatal projection neurons (SPNs), giving rise to the direct and the indirect pathway (dSPNs and iSPNs, respectively), account for 95% of the neurons and the remaining 5% are GABAergic and cholinergic interneurons. Interneuron axon terminals as well as local dSPN and iSPN axon collaterals form an intricate striatal network. Following chronic dopamine depletion as in Parkinson’s disease (PD), both morphological and electrophysiological striatal neuronal features are altered. Our goal with this \textit{in-silico} study is twofold: a) to predict and quantify how the intrastriatal network connectivity structure becomes altered as a consequence of the morphological changes reported at the single neuron level, and b) to investigate how the effective glutamatergic drive to the SPNs would need to be altered to account for the activity level seen in SPNs during PD. In summary we find that the richness of the connectivity motifs is significantly decreased during PD, while at the same time a substantial enhancement of the effective glutamatergic drive to striatum is present.  

  • 47.
    Cardoso, Gabriel
    et al.
    Centre de Mathématiques appliquées, Ecole polytechnique, IHU Liryc, fondation Bordeaux Université, Univ Bordeaux, CRCTB U4045, INSERM, Centre de Mathématiques Appliquées, Ecole polytechnique, IHU Liryc, Fondation Bordeaux Université, Univ Bordeaux, CRCTB U4045, INSERM.
    Samsonov, Sergey
    HSE University, HSE University.
    Thin, Achille
    UMR MIA, AgroParisTech, UMR MIA, AgroParisTech.
    Moulines, Eric
    Centre de Mathématiques appliquées, Ecole polytechnique, Centre de Mathématiques Appliquées, Ecole Polytechnique.
    Olsson, Jimmy
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Mathematical Statistics.
    BR-SNIS: Bias Reduced Self-Normalized Importance Sampling2022In: Advances in Neural Information Processing Systems 35 - 36th Conference on Neural Information Processing Systems, NeurIPS 2022, Neural Information Processing Systems Foundation , 2022Conference paper (Refereed)
    Abstract [en]

    Importance Sampling (IS) is a method for approximating expectations under a target distribution using independent samples from a proposal distribution and the associated importance weights. In many applications, the target distribution is known only up to a normalization constant, in which case self-normalized IS (SNIS) can be used. While the use of self-normalization can have a positive effect on the dispersion of the estimator, it introduces bias. In this work, we propose a new method, BR-SNIS, whose complexity is essentially the same as that of SNIS and which significantly reduces bias without increasing the variance. This method is a wrapper in the sense that it uses the same proposal samples and importance weights as SNIS, but makes clever use of iterated sampling-importance resampling (i-SIR) to form a bias-reduced version of the estimator. We furnish the proposed algorithm with rigorous theoretical results, including new bias, variance and high-probability bounds, and these are illustrated by numerical examples.

  • 48.
    Cenci, M. Angela
    et al.
    Basal Ganglia Pathophysiology Unit, Department Experimental Medical Science, Lund University, Lund, Sweden.
    Kumar, Arvind
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST).
    Cells, pathways, and models in dyskinesia research2024In: Current Opinion in Neurobiology, ISSN 0959-4388, E-ISSN 1873-6882, Vol. 84, article id 102833Article, review/survey (Refereed)
    Abstract [en]

    L-DOPA-induced dyskinesia (LID) is the most common form of hyperkinetic movement disorder resulting from altered information processing in the cortico-basal ganglia network. We here review recent advances clarifying the altered interplay between striatal output pathways in this movement disorder. We also review studies revealing structural and synaptic changes to the striatal microcircuitry and altered cortico-striatal activity dynamics in LID. We furthermore highlight the recent progress made in understanding the involvement of cerebellar and brain stem nuclei. These recent developments illustrate that dyskinesia research continues to provide key insights into cellular and circuit-level plasticity within the cortico-basal ganglia network and its interconnected brain regions.

  • 49.
    Chakravarty, Kingshuk
    et al.
    Tata Consultancy Serv, TCS Res, Kolkata 700160, India..
    Roy, Sangheeta
    Tata Consultancy Serv, TCS Res, Kolkata 700160, India..
    Sinha, Aniruddha
    Tata Consultancy Serv, TCS Res, Kolkata 700160, India..
    Nambu, Atsushi
    Natl Inst Physiol Sci, Div Syst Neurophysiol, Okazaki, Aichi 4448585, Japan.;SOKENDAI Grad Univ Adv Studies, Dept Physiol Sci, Okazaki, Aichi 4448585, Japan..
    Chiken, Satomi
    Natl Inst Physiol Sci, Div Syst Neurophysiol, Okazaki, Aichi 4448585, Japan.;SOKENDAI Grad Univ Adv Studies, Dept Physiol Sci, Okazaki, Aichi 4448585, Japan..
    Hellgren Kotaleski, Jeanette
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST). Karolinska Inst, Dept Neurosci, SE-17177 Stockholm, Sweden..
    Kumar, Arvind
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST).
    Transient Response of Basal Ganglia Network in Healthy and Low-Dopamine State2022In: eNeuro, E-ISSN 2373-2822, Vol. 9, no 2, p. ENEURO.0376-21.2022-, article id 0376-21.2022Article in journal (Refereed)
    Abstract [en]

    The basal ganglia (BG) are crucial for a variety of motor and cognitive functions. Changes induced by persistent low-dopamine (e.g., in Parkinson's disease; PD) result in aberrant changes in steady-state population activity (beta band oscillations) and the transient response of the BG. Typically, a brief cortical stimulation results in a triphasic response in the substantia nigra pars reticulata (SNr; an output of the BG). The properties of the triphasic responses are shaped by dopamine levels. While mechanisms underlying aberrant steady state activity are well studied, it is still unclear which BG interactions are crucial for the aberrant transient responses in the BG. Moreover, it is also unclear whether mechanisms underlying the aberrant changes in steady-state activity and transient response are the same. Here, we used numerical simulations of a network model of BG to identify the key factors that determine the shape of the transient responses. We show that an aberrant transient response of the SNr in the low-dopamine state involves changes in the direct pathway and the recurrent interactions within the globus pallidus externa (GPe) and between GPe and subthalamic nucleus (STN). However, the connections from D2-type spiny projection neurons (D2-SPN) to GPe are most crucial in shaping the transient response and by restoring them to their healthy level, we could restore the shape of transient response even in low-dopamine state. Finally, we show that the changes in BG that result in aberrant transient response are also sufficient to generate pathologic oscillatory activity in the steady state.

  • 50.
    Chang, Weipang
    et al.
    Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden..
    Pedroni, Andrea
    Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden..
    Hohendorf, Victoria
    Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden..
    Giacomello, Stefania
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Hibi, Masahiko
    Nagoya Univ, Grad Sch Sci, Div Biol Sci, Nagoya, Aichi 4648602, Japan..
    Koester, Reinhard W.
    Tech Univ Carolo Wilhelmina Braunschweig, Zool Inst, Cellular & Mol Neurobiol, D-38106 Braunschweig, Germany..
    Ampatzis, Konstantinos
    Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden..
    Functionally distinct Purkinje cell types show temporal precision in encoding locomotion2020In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 117, no 29, p. 17330-17337Article in journal (Refereed)
    Abstract [en]

    Purkinje cells, the principal neurons of cerebellar computations, are believed to comprise a uniform neuronal population of cells, each with similar functional properties. Here, we show an undiscovered heterogeneity of adult zebrafish Purkinje cells, revealing the existence of anatomically and functionally distinct cell types. Dual patch-clamp recordings showed that the cerebellar circuit contains all Purkinje cell types that cross-communicate extensively using chemical and electrical synapses. Further activation of spinal central pattern generators (CPGs) revealed unique phase-locked activity from each Purkinje cell type during the locomotor cycle. Thus, we show intricately organized Purkinje cell networks in the adult zebrafish cerebellum that encode the locomotion rhythm differentially, and we suggest that these organizational properties may also apply to other cerebellar functions.

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