| 1. |
- Borisovsky, Gilad, et al.
(författare)
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Results of congenital cataract surgery with and without intraocular lens implantation in infants and children
- 2013
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Ingår i: Graefe's Archives for Clinical and Experimental Ophthalmology. - : Springer Science and Business Media LLC. - 0721-832X .- 1435-702X. ; 251:9, s. 2205-2211
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Tidskriftsartikel (refereegranskat)abstract
- Operations for congenital cataract in children in the past had resulted in aphakia. Improvement in surgical tools and techniques as well as in intraocular lens (IOL) implantation has led to correction of the aphakia by IOL implantation. We report the outcome of cataract surgery with and without IOL on these children in our institution between 1991-2008. In this retrospective cohort study, the medical records of all children who underwent surgery for congenital cataract were reviewed. The final study group included 144 children (218 eyes). Postoperative visual acuity (VA) was tested either by Teller Acuity Cards (in preverbal children) or by the Snellen chart. Data on VA status and postoperative complications were retrieved. Patients with bilateral cataract had better postoperative VA than patients with unilateral cataract (logMAR 0.559 +/- 0.455 vs. 0.919 +/- 0.685, respectively, P < 0.001). Children who underwent IOL implantation had better postoperative VA than those who did not, but the type of surgery had no significant effect after correction for the child's age at surgery (P = 0.346). Secondary cataract occurred more frequently in the extra-capsular cataract extraction (ECCE) + IOL implantation group than in the ECCE only group (20.6 % vs. 8.3 %, respectively, P = 0.018). Patients with bilateral cataract had better postoperative VA compared with those with unilateral cataract. The type of surgery had no effect on final VA, but there was a higher rate of secondary cataract in the ECCE + IOL patients compared to the ECCE only patients.
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| 2. |
- Carannante, Ilaria, et al.
(författare)
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Data-Driven Model of Postsynaptic Currents Mediated by NMDA or AMPA Receptors in Striatal Neurons
- 2022
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Ingår i: Frontiers in Computational Neuroscience. - : Frontiers Media SA. - 1662-5188. ; 16
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Daniel, Chammiran, et al.
(författare)
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Alu elements shape the primate transcriptome by cis-regulation of RNA editing
- 2014
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 15:2
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Tidskriftsartikel (refereegranskat)abstract
- Background: RNA editing by adenosine to inosine deamination is a widespread phenomenon, particularly frequent in the human transcriptome, largely due to the presence of inverted Alu repeats and their ability to form double-stranded structures - a requisite for ADAR editing. While several hundred thousand editing sites have been identified within these primate-specific repeats, the function of Alu-editing has yet to be elucidated. Results: We show that inverted Alu repeats, expressed in the primate brain, can induce site-selective editing in cis on sites located several hundred nucleotides from the Alu elements. Furthermore, a computational analysis, based on available RNA-seq data, finds that site-selective editing occurs significantly closer to edited Alu elements than expected. These targets are poorly edited upon deletion of the editing inducers, as well as in homologous transcripts from organisms lacking Alus. Sequences surrounding sites near edited Alus in UTRs, have been subjected to a lesser extent of evolutionary selection than those far from edited Alus, indicating that their editing generally depends on cis-acting Alus. Interestingly, we find an enrichment of primate-specific editing within encoded sequence or the UTRs of zinc finger-containing transcription factors. Conclusions: We propose a model whereby primate-specific editing is induced by adjacent Alu elements that function as recruitment elements for the ADAR editing enzymes. The enrichment of site-selective editing with potentially functional consequences on the expression of transcription factors indicates that editing contributes more profoundly to the transcriptomic regulation and repertoire in primates than previously thought.
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| 4. |
- Dorst, Matthijs C., et al.
(författare)
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Polysynaptic inhibition between striatal cholinergic interneurons shapes their network activity patterns in a dopamine-dependent manner
- 2020
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Striatal activity is dynamically modulated by acetylcholine and dopamine, both of which are essential for basal ganglia function. Synchronized pauses in the activity of striatal cholinergic interneurons (ChINs) are correlated with elevated activity of midbrain dopaminergic neurons, whereas synchronous firing of ChINs induces local release of dopamine. The mechanisms underlying ChIN synchronization and its interplay with dopamine release are not fully understood. Here we show that polysynaptic inhibition between ChINs is a robust network motif and instrumental in shaping the network activity of ChINs. Action potentials in ChINs evoke large inhibitory responses in multiple neighboring ChINs, strong enough to suppress their tonic activity. Using a combination of optogenetics and chemogenetics we show the involvement of striatal tyrosine hydroxylase-expressing interneurons in mediating this inhibition. Inhibition between ChINs is attenuated by dopaminergic midbrain afferents acting presynaptically on D2 receptors. Our results present a novel form of interaction between striatal dopamine and acetylcholine dynamics.
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| 5. |
- Eberle, Andrea B., et al.
(författare)
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An Interaction between RRP6 and SU(VAR)3-9 Targets RRP6 to Heterochromatin and Contributes to Heterochromatin Maintenance in Drosophila melanogaster
- 2015
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 11:9
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Tidskriftsartikel (refereegranskat)abstract
- RNA surveillance factors are involved in heterochromatin regulation in yeast and plants, but less is known about the possible roles of ribonucleases in the heterochromatin of animal cells. Here we show that RRP6, one of the catalytic subunits of the exosome, is necessary for silencing heterochromatic repeats in the genome of Drosophila melanogaster. We show that a fraction of RRP6 is associated with heterochromatin, and the analysis of the RRP6 interaction network revealed physical links between RRP6 and the heterochromatin factors HP1a, SU(VAR)3-9 and RPD3. Moreover, genome-wide studies of RRP6 occupancy in cells depleted of SU(VAR)3-9 demonstrated that SU(VAR)3-9 contributes to the tethering of RRP6 to a subset of heterochromatic loci. Depletion of the exosome ribonucleases RRP6 and DIS3 stabilizes heterochromatic transcripts derived from transposons and repetitive sequences, and renders the heterochromatin less compact, as shown by micrococcal nuclease and proximity-ligation assays. Such depletion also increases the amount of HP1a bound to heterochromatic transcripts. Taken together, our results suggest that SU(VAR)3-9 targets RRP6 to a subset of heterochromatic loci where RRP6 degrades chromatin-associated non-coding RNAs in a process that is necessary to maintain the packaging of the heterochromatin.
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| 6. |
- Filipović, Marko, 1984-
(författare)
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Characterisation of inputs and outputs of striatal medium spiny neurons in health and disease
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Striatal medium spiny neurons (MSNs) play a crucial role in various motor and cognitive functions. They are separated into those belonging to the direct pathway (dMSNs) and the indirect pathway (iMSNs) of the basal ganglia, depending on whether they express D1 or D2 type dopamine receptors, respectively. In this thesis I investigated the input processing of both MSN types, the characteristics of dMSN outputs, and the effect that aberrant iMSN activity has on the subthalamic nucleus-globus pallidus externa (STN-GPe) network.In order to verify a previous result from a computational study claiming that dMSNs should receive either more or stronger total input than iMSNs, I performed an analysis of in vivo whole-cell MSN recordings in healthy and dopamine (DA) depleted (6OHDA) anesthetized mice. To test this prediction, I compared subthreshold membrane potential fluctuations and spike-triggered average membrane potentials of the two MSN types. I found that dMSNs in healthy mice exhibited considerably larger fluctuations over a wide frequency range, as well as significantly faster depolarization towards the spiking threshold than iMSNs. However, these effects were not present in recordings from 6OHDA animals. Together, these findings strongly suggest that dMSNs do receive stronger total input than iMSNs in healthy condition.I also examined how different concentrations of dopamine affect neural trial-by-trial (or response) variability in a biophysically detailed compartmental model of a direct-pathway MSN. Some of the sources of trial-by-trial variability include synaptic noise, neural refractory period, and ongoing neural activity. The focus of this study was on the effects of two particular properties of the synaptic input: correlations of synaptic input rates, and the balance between excitatory and inhibitory inputs (E-I balance). The model demonstrates that dopamine is in general a significant diminisher of trial-by-trial variability, but that its efficacy depends on the properties of synaptic input. Moreover, input rate correlations and changes in the E-I balance by themselves also proved to have a marked impact on the response variability.Finally, I investigated the beta-band phase properties of the STN-GPe network, known for its exaggerated beta-band oscillations during Parkinson’s disease (PD). The current state-of-the-art computational model of the network can replicate both transient and persistent beta oscillations, but fails to capture the beta-band phase alignment between the two nuclei as seen in human recordings. This was particularly evident during simulations of the PD condition, where STN or GPe were receiving additional stimulation in order to induce pathological levels of beta-band activity. Here I show that by manipulating the percentage of the neurons in either population that receives stimulation it is possible to increase STN-GPe phase difference heterogeneity. Furthermore, a similar effect can be achieved by adjusting synaptic transmission delays between the two populations. Quantifying the difference between human recordings and network simulations, I provide the set of parameters for which the model produces the greatest correspondence with experimental results.
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| 7. |
- Filipovic, Marko, et al.
(författare)
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Direct pathway neurons in mouse dorsolateral striatum in vivo receive stronger synaptic input than indirect pathway neurons
- 2019
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Ingår i: Journal of Neurophysiology. - : AMER PHYSIOLOGICAL SOC. - 0022-3077 .- 1522-1598. ; 122:6, s. 2294-2303
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Tidskriftsartikel (refereegranskat)abstract
- Striatal projection neurons, the medium spiny neurons (MSNs), play a crucial role in various motor and cognitive functions. MSNs express either D1- or D2-type dopamine receptors and initiate the direct-pathway (dMSNs) or indirect pathways (iMSNs) of the basal ganglia, respectively. dMSNs have been shown to receive more inhibition than iMSNs from intrastriatal sources. Based on these findings, computational modeling of the suiatal network has predicted that under healthy conditions dMSNs should receive more total input than iMSNs. To test this prediction, we analyzed in vivo whole cell recordings from dMSNs and iMSNs in healthy and dopamine-depleted (60HDA) anaesthetized mice. By comparing their membrane potential fluctuations, we found that dMSNs exhibited considerably larger membrane potential fluctuations over a wide frequency range. Furthermore, by comparing the spike-triggered average membrane potentials. we found that dMSNs depolarized toward the spike threshold significantly faster than iMSNs did. Together, these findings (in particular the STA analysis) corroborate the theoretical prediction that direct-pathway MSNs receive stronger total input than indirect-pathway neurons. Finally, we found that dopamine-depleted mice exhibited no difference between the membrane potential fluctuations of dMSNs and iMSNs. These data provide new insights into the question of how the lack of dopamine may lead to behavioral deficits associated with Parkinson's disease. NEW & NOTEWORTHY The direct and indirect pathways of the basal ganglia originate from the D1- and D2-type dopamine receptor expressing medium spiny neurons (dMSNs and iMSNs). Theoretical results have predicted that dMSNs should receive stronger synaptic input than iMSNs. Using in vivo intracellular membrane potential data, we provide evidence that dMSNs indeed receive stronger input than iMSNs, as has been predicted by the computational model.
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| 8. |
- Forsberg, David, et al.
(författare)
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CO2-evoked release of PGE2 modulates sighs and inspiration as demonstrated in brainstem organotypic culture.
- 2016
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Ingår i: eLife. - 2050-084X. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation-induced release of prostaglandin E2 (PGE2) changes breathing patterns and the response to CO2 levels. This may have fatal consequences in newborn babies and result in sudden infant death. To elucidate the underlying mechanisms, we present a novel breathing brainstem organotypic culture that generates rhythmic neural network and motor activity for 3 weeks. We show that increased CO2 elicits a gap junction-dependent release of PGE2. This alters neural network activity in the preBötzinger rhythm-generating complex and in the chemosensitive brainstem respiratory regions, thereby increasing sigh frequency and the depth of inspiration. We used mice lacking eicosanoid prostanoid 3 receptors (EP3R), breathing brainstem organotypic slices and optogenetic inhibition of EP3R(+/+) cells to demonstrate that the EP3R is important for the ventilatory response to hypercapnia. Our study identifies a novel pathway linking the inflammatory and respiratory systems, with implications for inspiration and sighs throughout life, and the ability to autoresuscitate when breathing fails.
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| 9. |
- Hjorth, J. J. Johannes, et al.
(författare)
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The microcircuits of striatum in silico
- 2020
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 117:17, s. 9554-9565
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Tidskriftsartikel (refereegranskat)abstract
- The basal ganglia play an important role in decision making and selection of action primarily based on input from cortex, thalamus, and the dopamine system. Their main input structure, striatum, is central to this process. It consists of two types of projection neurons, together representing 95% of the neurons, and 5% of interneurons, among which are the cholinergic, fast-spiking, and low threshold-spiking subtypes. The membrane properties, somadendritic shape, and intrastriatal and extrastriatal synaptic interactions of these neurons are quite well described in the mouse, and therefore they can be simulated in sufficient detail to capture their intrinsic properties, as well as the connectivity. We focus on simulation at the striatal cellular/microcircuit level, in which the molecular/subcellular and systems levels meet. We present a nearly full-scale model of the mouse striatum using available data on synaptic connectivity, cellular morphology, and electrophysiological properties to create a microcircuit mimicking the real network. A striatal volume is populated with reconstructed neuronal morphologies with appropriate cell densities, and then we connect neurons together based on appositions between neurites as possible synapses and constrain them further with available connectivity data. Moreover, we simulate a subset of the striatum involving 10,000 neurons, with input from cortex, thalamus, and the dopamine system, as a proof of principle. Simulation at this biological scale should serve as an invaluable tool to understand the mode of operation of this complex structure. This platform will be updated with new data and expanded to simulate the entire striatum.
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| 10. |
- Krishnamurthy, Pradeep, et al.
(författare)
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Long-range recruitment of Martinotti cells causes surround suppression and promotes saliency in an attractor network model
- 2015
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Ingår i: Frontiers in Neural Circuits. - : Frontiers Media SA. - 1662-5110. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Although the importance of long-range connections for cortical information processing has been acknowledged for a long time, most studies focused on the long-range interactions between excitatory cortical neurons. Inhibitory interneurons play an important role in cortical computation and have thus far been studied mainly with respect to their local synaptic interactions within the cortical microcircuitry. A recent study showed that long-range excitatory connections onto Martinotti cells (MC) mediate surround suppression. Here we have extended our previously reported attractor network of pyramidal cells (PC) and MC by introducing long-range connections targeting MC. We have demonstrated how the network with Martinotti cell-mediated long-range inhibition gives rise to surround suppression and also promotes saliency of locations at which simple non-uniformities in the stimulus field are introduced. Furthermore, our analysis suggests that the presynaptic dynamics of MC is only ancillary to its orientation tuning property in enabling the network with saliency detection. Lastly, we have also implemented a disinhibitory pathway mediated by another interneuron type (VIP interneurons), which inhibits MC and abolishes surround suppression.
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| 11. |
- Lindroos, Robert, et al.
(författare)
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Basal Ganglia Neuromodulation Over Multiple Temporal and Structural Scales-Simulations of Direct Pathway MSNs Investigate the Fast Onset of Dopaminergic Effects and Predict the Role of Kv4.2
- 2018
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Ingår i: Frontiers in Neural Circuits. - : Frontiers Media S.A.. - 1662-5110. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- The basal ganglia are involved in the motivational and habitual control of motor and cognitive behaviors. Striatum, the largest basal ganglia input stage, integrates cortical and thalamic inputs in functionally segregated cortico-basal ganglia-thalamic loops, and in addition the basal ganglia output nuclei control targets in the brainstem. Striatal function depends on the balance between the direct pathway medium spiny neurons (D1-MSNs) that express D1 dopamine receptors and the indirect pathway MSNs that express D2 dopamine receptors. The striatal microstructure is also divided into striosomes and matrix compartments, based on the differential expression of several proteins. Dopaminergic afferents from the midbrain and local cholinergic interneurons play crucial roles for basal ganglia function, and striatal signaling via the striosomes in turn regulates the midbrain dopaminergic system directly and via the lateral habenula. Consequently, abnormal functions of the basal ganglia neuromodulatory system underlie many neurological and psychiatric disorders. Neuromodulation acts on multiple structural levels, ranging from the subcellular level to behavior, both in health and disease. For example, neuromodulation affects membrane excitability and controls synaptic plasticity and thus learning in the basal ganglia. However, it is not clear on what time scales these different effects are implemented. Phosphorylation of ion channels and the resulting membrane effects are typically studied over minutes while it has been shown that neuromodulation can affect behavior within a few hundred milliseconds. So how do these seemingly contradictory effects fit together? Here we first briefly review neuromodulation of the basal ganglia, with a focus on dopamine. We furthermore use biophysically detailed multi-compartmental models to integrate experimental data regarding dopaminergic effects on individual membrane conductances with the aim to explain the resulting cellular level dopaminergic effects. In particular we predict dopaminergic effects on Kv4.2 in D1-MSNs. Finally, we also explore dynamical aspects of the onset of neuromodulation effects in multi-scale computational models combining biochemical signaling cascades and multi-compartmental neuron models.
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| 12. |
- Nagaraja, Chetan, 1983-
(författare)
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Functional Imaging of Spinal Locomotor Networks
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Movement is necessary for the survival of most animals. The spinal cord contains neuronal networks that are capable of motor coordination and of producing different movements. In particular, a very reduced neuronal network in the spinal cord can produce simple rhythmic outputs even in the absence of descending or sensory inputs. This basic circuit was discovered by Thomas Graham Brown (reported in 1911) and is termed central pattern generator. For over a century a large number of studies have been carried out in order to identify the neuronal components that are part of these networks.In project 1 we focused on Renshaw cells, which are a population of spinal interneurons expressing the alpha-2 subunit of the nicotinic acetylcholine receptors (Chrna2). Renshaw cells are the only identified central targets for motor neuron inputs, and in turn they mediate inhibition of the motor neurons. We analyzed the activity pattern of Renshaw cells on a cell-population level in neonates when the circuit is still developing. At segment 1 of the lumbar spinal cord, Renshaw cells show significantly greater activity response to functional sensory and motor inputs from rostral compared to the caudal segments. Contrarily, the suppression of the monosynaptic stretch reflex was more pronounced when caudal roots were stimulated. Our data underline the importance of sensory input during motor circuit development and help to understand the functional organization of Renshaw cell connectivity.Several neurons that play distinct roles in locomotor central pattern generation have been identified with the help of genetics. For instance, the V0 population of spinal interneurons are identified by the expression of transcription factor developing brain homeobox 1 (Dbx1). V0 neurons are necessary for producing an alternating rhythm at all locomotor speeds. In project 2 we have looked at a population of dorsally derived ventrally projecting interneurons that express the transcription factor doublesex and mab-3 related transcription factor 3 (Dmrt3). On a behavioral level Dmrt3 neurons are involved in regulating coordination across different locomotor speeds. On a microcircuit level, we have shown that individual Dmrt3 neurons show distinct frequencies of oscillations for a constant locomotor rhythm. In addition, removal of inhibitory neurotransmission from Dmrt3 neurons results in uncoupling of rhythm in motor neurons.In project 3 the activity patterns in populations of flexor related motor neurons are characterized during fictive locomotion in neonatal mice. An interesting and intriguing finding in project 3 is the presence of multiple rhythmicities in motor neurons. Multiple rhythmicities are seen even when the locomotor output shows a constant frequency.
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| 13. |
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| 14. |
- Papathanou, Maria, 1984-, et al.
(författare)
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Targeting VGLUT2 in Mature Dopamine Neurons Decreases Mesoaccumbal Glutamatergic Transmission and Identifies a Role for Glutamate Co-release in Synaptic Plasticity by Increasing Baseline AMPA/NMDA Ratio
- 2018
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Ingår i: Frontiers in Neural Circuits. - : Frontiers Media SA. - 1662-5110. ; 12, s. 1-20
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Tidskriftsartikel (refereegranskat)abstract
- Expression of the Vglut2/Slc17a6 gene encoding the Vesicular glutamate transporter 2 (VGLUT2) in midbrain dopamine (DA) neurons enables these neurons to co-release glutamate in the nucleus accumbens (NAc), a feature of putative importance to drug addiction. For example, it has been shown that conditional deletion of Vglut2 gene expression within developing DA neurons in mice causes altered locomotor sensitization to addictive drugs, such as amphetamine and cocaine, in adulthood. Alterations in DA neurotransmission in the mesoaccumbal pathway has been proposed to contribute to these behavioral alterations but the underlying molecular mechanism remains largely elusive. Repeated exposure to cocaine is known to cause lasting adaptations of excitatory synaptic transmission onto medium spiny neurons (MSNs) in the NAc, but the putative contribution of VGLUT2-mediated glutamate co-release from the mesoaccumbal projection has never been investigated. In this study, we implemented a tamoxifen-inducible Cre-LoxP strategy to selectively probe VGLUT2 in mature DA neurons of adult mice. Optogenetics-coupled patch clamp analysis in the NAc demonstrated a significant reduction of glutamatergic neurotransmission, whilst behavioral analysis revealed a normal locomotor sensitization to amphetamine and cocaine. When investigating if the reduced level of glutamate co-release from DA neurons caused a detectable post-synaptic effect on MSNs, patch clamp analysis identified an enhanced baseline AMPA/NMDA ratio in DA receptor subtype 1 (DRD1)-expressing accumbal MSNs which occluded the effect of cocaine on synaptic transmission. We conclude that VGLUT2 in mature DA neurons actively contributes to glutamatergic neurotransmission in the NAc, a finding which for the first time highlights VGLUT2-mediated glutamate co-release in the complex mechanisms of synaptic plasticity in drug addiction.
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| 15. |
- Planert, Henrike, et al.
(författare)
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Dynamics of Synaptic Transmission between Fast-Spiking Interneurons and Striatal Projection Neurons of the Direct and Indirect Pathways
- 2010
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Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 30:9, s. 3499-3507
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Tidskriftsartikel (refereegranskat)abstract
- The intrastriatal microcircuit is a predominantly inhibitory GABAergic network comprised of a majority of projection neurons [medium spiny neurons (MSNs)] and a minority of interneurons. The connectivity within this microcircuit is divided into two main categories: lateral connectivity between MSNs, and inhibition mediated by interneurons, in particular fast spiking (FS) cells. To understand the operation of striatum, it is essential to have a good description of the dynamic properties of these respective pathways and how they affect different types of striatal projection neurons. We recorded from neuronal pairs, triplets, and quadruplets in slices of rat and mouse striatum and analyzed the dynamics of synaptic transmission between MSNs and FS cells. Retrograde fluorescent labeling and transgenic EGFP (enhanced green fluorescent protein) mice were used to distinguish between MSNs of the direct (striatonigral) and indirect (striatopallidal) pathways. Presynaptic neurons were stimulated with trains of action potentials, and activity-dependent depression and facilitation of synaptic efficacy was recorded from postsynaptic neurons. We found that FS cells provide a strong and homogeneously depressing inhibition of both striatonigral and striatopallidal MSN types. Moreover, individual FS cells are connected to MSNs of both types. In contrast, both MSN types receive sparse and variable, depressing and facilitating synaptic transmission from nearby MSNs. The connection probability was higher for pairs with presynaptic striatopallidal MSNs; however, the variability in synaptic dynamics did not depend on the types of interconnected MSNs. The differences between the two inhibitory pathways were clear in both species and at different developmental stages. Our findings show that the two intrastriatal inhibitory pathways have fundamentally different dynamic properties that are, however, similarly applied to both direct and indirect striatal projections.
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| 16. |
- Silberberg, Gilad, et al.
(författare)
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Deregulation of the A-to-I RNA editing mechanism in psychiatric disorders
- 2012
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:2, s. 311-321
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia and bipolar disorder (BPD) are common neurodevelopmental disorders, characterized by various life-crippling symptoms and high suicide rates. Multiple studies support a strong genetic involvement in the etiology of these disorders, although patterns of inheritance are variable and complex. Adenosine-to-inosine RNA editing is a cellular mechanism, which has been implicated in mental disorders and suicide. To examine the involvement of altered RNA editing in these disorders, we: (i) quantified the mRNA levels of the adenosine deaminase acting on RNA (ADAR) editing enzymes by real-time quantitative polymerase chain reaction, and (ii) measured the editing levels in transcripts of several neuroreceptors using 454 high-throughput sequencing, in dorsolateral-prefrontal cortices of schizophrenics, BPD patients and controls. Increased expression of specific ADAR2 variants with diminished catalytic activity was observed in schizophrenia. Our results also indicate that the I/V editing site in the glutamate receptor, ionotropic kainate 2 (GRIK2) transcript is under-edited in BPD (type I) patients (45.8 versus 53.9%, P= 0.023). GRIK2 has been implicated in mood disorders, and editing of its I/V site can modulate Ca(+2) permeability of the channel, consistent with numerous observations of elevated intracellular Ca(+2) levels in BPD patients. Our findings may therefore, at least partly, explain a molecular mechanism underlying the disorder. In addition, an intriguing correlation was found between editing events on separate exons of GRIK2. Finally, multiple novel editing sites were detected near previously known sites, albeit most with very low editing rates. This supports the hypothesis raised previously regarding the existence of wide-spread low-level 'background' editing as a mechanism that enhances adaptation and evolvability.
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| 17. |
- Silberberg, Gilad, et al.
(författare)
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The edited transcriptome : novel high throughput approaches to detect nucleotide deamination
- 2011
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Ingår i: Current Opinion in Genetics and Development. - : Elsevier BV. - 0959-437X .- 1879-0380. ; 21:4, s. 401-406
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Forskningsöversikt (refereegranskat)abstract
- RNA editing is emerging as a wide-spread phenomenon both in coding and non-coding RNA regions. While the mechanisms underlying many of these post-transcriptional modifications have not been elucidated, RNA editing by nucleotide deamination has been known for over two decades as a mechanism to generate base substitutions. With the recently growing use of high throughput sequencing technologies, knowledge about the frequency and diversity of RNA nucleotide substitutions has vastly increased. In this review we will highlight recent findings within this field, and illustrate how novel technologies have made it possible to detect and measure the efficiency of editing in an unprecedented accuracy and robustness. Future prospects for the detection of important transcriptome variations will also be discussed.
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| 18. |
- Wallis, Karin, et al.
(författare)
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Locomotor deficiencies and aberrant development of subtype-specific GABAergic interneuros caused by a unlignded thyroid hormopne receptor alpha-1
- 2008
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Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 28:8, s. 1904-1915
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Tidskriftsartikel (refereegranskat)abstract
- Thyroid hormone (TH) deficiency during development causes severe and permanent neuronal damage, but the primary insult at the tissue level has remained unsolved. We have defined locomotor deficiencies in mice caused by a mutant thyroid hormone receptor alpha 1 (TR alpha 1) with potent aporeceptor activity attributable to reduced affinity to TH. This allowed identification of distinct functions that required either maternal supply of TH during early embryonic development or sufficient innate levels of hormone during late fetal development. In both instances, continued exposure to high levels of TH after birth and throughout life was needed. The hormonal dependencies correlated with severely delayed appearance of parvalbumin-immunoreactive GABAergic interneurons and increased numbers of calretinin-immunoreactive cells in the neocortex. This resulted in reduced numbers of fast spiking interneurons and defects in cortical network activity. The identification of locomotor deficiencies caused by insufficient supply of TH during fetal/perinatal development and their correlation with subtype-specific interneurons suggest a previously unknown basis for the neuronal consequences of endemic cretinism and untreated congenital hypothyroidism, and specifies TR alpha 1 as the receptor isoform mediating these effects.
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| 19. |
- Wärnberg, Emil
(författare)
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On learning in mice and machines : continuous population codes in natural and artificial neural networks
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neural networks, whether artificial in a computer or natural in the brain, could represent information either using discrete symbols or continuous vector spaces. In this thesis, I explore how neural networks can represent continuous vector spaces, using both simulated neural networks and analysis of real neural population data recorded from mice. A special focus is on the networks of the basal ganglia circuit and on reinforcement learning, i.e., learning from rewards and punishments.The thesis includes four scientific papers: two theoretical/computational (Papers I and IV) and two with analysis of real data (Papers II and III).In Paper I, we explore methods for implementing continuous vector spaces in networks of spiking neurons using multidimensional attractors, and propose an explanation for why it is hard to escape the neural manifolds created by such attractors.In Paper II, we analyze experimental data from dorsomedial striatum collected using 1-photon calcium imaging of transgenic mice with celltype-specific markers for the striatal direct, indirect and patch pathways, as the mice were gathering rewards in a 2-choice task. In line with extensive previous results, our data analysis revealed a number of neural signatures of reinforcement learning, but no apparent difference between the pathways.In Paper III, we present a new software tool for tracking neurons across weeks of 1-photon calcium imaging, and employ it to follow patch-specific striatal projection neurons from the dorsomedial striatum across two weeks of daily recordings.In Paper IV, we propose a model for how the nigrostriatal dopaminergic projection could, in a biologically plausible way, convey a vector-valued error gradient to the dorsal striatum, as required for backpropagation.Based on the results of the papers and a review of existing literature, I argue that while the basal ganglia indeed make up a circuit for reinforcement learning as previously thought, this circuit represents reinforcement learning states, actions and policies using a continuous population code and not using discrete symbols.
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| 20. |
- Öberg Sysojev, Anton, et al.
(författare)
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Genome-wide investigation of persistence with methotrexate treatment in early rheumatoid arthritis
- 2024
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Ingår i: Rheumatology. - : Oxford University Press. - 1462-0324 .- 1462-0332. ; 63:5, s. 1221-1229
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To investigate the influence of genetic factors on persistence to treatment of early rheumatoid arthritis (RA) with methotrexate (MTX) monotherapy.Methods: We conducted a genome-wide association study (GWAS) in a sample of 3902 Swedish early RA patients initiating MTX in DMARD-monotherapy as their first ever DMARD. The outcome, short- and long-term persistence to this treatment, was defined as remaining on MTX at one and at three years, respectively, with no additional DMARDs added. As genetic predictors, we investigated individual SNPs, and a polygenic risk score (PRS) based on SNPs associated with RA risk. The SNP-based heritability of persistence was estimated overall and by RA serostatus.Results: No individual SNP reached genome-wide significance (p < 5e-8), neither for persistence at one nor at three years. The RA PRS was not significantly associated with persistence at one (RR = 0.98 (0.96-1.01)) nor three years (RR = 0.96 (0.93-1.00)). The heritability for persistence was estimated to be 0.45 (0.15-0.75) at one year and 0.14 (0-0.40) at three years. Results in seropositive RA were comparable to those in the analysis of RA overall, while heritability estimates and PRS RRs were attenuated towards the null in seronegative RA.Conclusions: Despite being the largest GWAS on an MTX treatment outcome to date, no genome-wide significant associations were detected. The modest heritability observed, coupled with the broad spread of suggestively associated loci, indicate that genetic influence is of polygenic nature. Nevertheless, persistence to MTX monotherapy was lower in patients with a greater genetic disposition, per the PRS, towards RA.
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