| 1. |
- 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
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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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| 2. |
- Hjorth, J. J. Johannes, et al.
(författare)
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The microcircuits of striatum in silico
- 2020
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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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| 3. |
- Håkansson, Stellan, et al.
(författare)
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Real-time PCR-assay in the delivery suite for determination of group B streptococcal colonization in a setting with risk-based antibiotic prophylaxis
- 2014
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Ingår i: Journal of Maternal-Fetal & Neonatal Medicine. - : Informa UK Limited. - 1476-7058 .- 1476-4954. ; 27:4, s. 328-332
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Intrapartum antibiotic prophylaxis (IAP) reduces the incidence of neonatal early onset group B streptococcal infections. The present study investigated if an automated PCR-assay, used bedside by the labor ward personnel was manageable and could decrease the use of IAP in a setting with a risk-based IAP strategy. Methods: The study comprises two phases. Phase 1 was a multicenter, randomized, controlled trial. Women with selected risk-factors were allocated either to PCR-IAP (prophylaxis given if positive or indeterminate) or IAP. A vaginal/rectal swab and superficial swabs from the neonate for conventional culture were also obtained. Phase 2 was non-randomized, assessing an improved version of the assay. Results: Phase 1 included 112 women in the PCR-IAP group and 117 in the IAP group. Excluding indeterminate results, the assay showed a sensitivity of 89% and a specificity of 90%. In 44 % of the PCR assays the result was indeterminate. The use of IAP was lower in the PCR group (53 versus 92%). Phase 2 included 94 women. The proportion of indeterminate results was reduced (15%). The GBS colonization rate was 31%. Conclusion: The PCR assay, in the hands of labor ward personnel, can be useful for selection of women to which IAP should be offered.
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| 4. |
- Tokarska, Anna
(författare)
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Diversity of striatal interneurons : connectivity and functions
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Multisensory integration of cortical and thalamic inputs by the striatal network, and its modulation by local acetylcholine and midbrain dopamine, are crucial components of movement control and striatal function. A flexible decision-making process, quick and smooth movement initiation, as well as proper habit-formation would not be possible without properly functioning striatal circuits. The efficient computation of the striatal network strongly relies on the local neural circuitry, provided by inhibitory projecting neurons and local GABAergic and cholinergic interneurons. Despite a growing body of research tackling the diversity of striatal GABAergic interneurons, and cell-type focused functional interrogations, many aspects of the striatal microcircuits remain unknown. A central goal of this thesis was to investigate this diversity of striatal interneurons and its functional implications in the striatal network. In particular, we wanted to unravel the patterns of connectivity between GABAergic and cholinergic interneurons, characterize the neuronal population linking those two systems, and how this interconnected network is modulated by dopamine. In Paper I, we focus on cholinergic and GABAergic interplay and its local modulation by midbrain dopamine. The balance between those systems is crucial for reward-related behaviors, formation of habits, and salience coding. Synchronized pauses in the activity of cholinergic cells, which are accompanied by dopamine bursts in response to reward-related stimuli, are a complex phenomenon and their underlying mechanism is still unknown. This paper investigates the connectivity of cholinergic cells with other striatal interneurons and proposes a local circuit that could contribute to their observed synchronicity, along with a characterization of its dopaminergic modulation. Paper II focuses on a population of striatal interneurons marked by the alpha-2 subunit of the nicotinic acetylcholine receptor (Chrna2). This novel marker, characterized previously for neurons in the cortex and hippocampus, could potentially link the cholinergic and GABAergic systems in the striatum. In this paper, we provide a classification system for this heterogeneous population. Using multineuron patch- clamp recordings combined with optogenetic stimulation and immunohistochemistry, we describe the diverse electrical, morphological and molecular properties of striatal Chrna2 interneurons as well as their synaptic connectivity. In Paper III, the data obtained from electrophysiological recordings were used to build an in silico model of the striatal network at the cellular level. The project was a multidisciplinary collaborative effort between computational and experimental neuroscientists, providing an expandable platform capable of simulating not only the local connectivity of different striatal interneurons and projection cells, but also the cortical and thalamic inputs and their modulation by dopamine. Altogether, the studies included in this thesis provide detailed, single-cell resolution data on novel aspects of the local striatal connectivity, focusing on characterization of striatal GABAergic interneurons and their modulation by the cholinergic and dopaminergic systems. The studies presented here will, hopefully, shed new light on the functional organization of the striatal neural circuitry.
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