| 1. |
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| 2. |
- Björkstrand, Johannes, et al.
(författare)
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Decrease in amygdala activity during repeated exposure to spider images predicts avoidance behavior in spider fearful individuals.
- 2020
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Spider phobia is characterized by exaggerated fear of situations where spiders could be present, resulting in avoidance of such situations and compromised quality of life. An important component in psychological treatment of spider phobia is exposure to phobic situations that reduces avoidance behaviors. At the neural level, amygdala responses to phobic material are elevated, but normalizes following exposure treatment. To what extent amygdala activity decreases during a session of repeated phobic stimulation, and whether activity decrease is related to subsequent avoidance is not well studied. We hypothesized reduced amygdala activity during the course of repeated exposure to spider pictures, and that the degree of reduction would predict subsequent avoidance of spider pictures. To test our hypothesis, functional magnetic resonance imaging was performed in 45 individuals with spider fear during repeated exposure to spider pictures. Results showed that repeated exposure to spider stimuli attenuated amygdala reactivity and individual differences in activity reductions predicted subsequent avoidance behavior to spider pictures in an incentive-conflict task, with larger attenuations predicting less avoidance. At 6-month follow up, initial reductions in amygdala activation still predicted avoidance. This result demonstrates that reduction in amygdala responses is related to clinically meaningful outcomes in human anxiety, and suggests that within-session reductions in amygdala responses could be an important mechanism explaining the clinical effects of exposure therapy.
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| 3. |
- Björkstrand, Johannes, et al.
(författare)
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Disrupting Reconsolidation Attenuates Long-Term Fear Memory in the Human Amygdala and Facilitates Approach Behavior
- 2016
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Ingår i: Current Biology. - : Elsevier BV. - 0960-9822 .- 1879-0445. ; 26:19, s. 2690-95
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Tidskriftsartikel (refereegranskat)abstract
- Memories become labile and malleable to modification when recalled [1]. Fear-conditioning experiments in both rodents and humans indicate that amygdala-localized short-term fear memories can be attenuated by disruption of their reconsolidation with extinction training soon after memory activation [2-7]. However, this may not be true for natural long-term fears. Studies in rodents indicate that although it is possible to disrupt the reconsolidation of older memories [8-11], they appear to be more resistant [1, 3, 9, 12, 13]. In humans, 1-week-old conditioned fear memories have been attenuated by behaviorally induced disruption of reconsolidation [14], but it remains to be seen whether this is possible for naturally occurring long-term fears and whether the underlying neural mechanisms are similar to those found in experimental fear-conditioning paradigms. Using functional brain imaging in individuals with a lifelong fear of spiders, we show that fear memory activation followed by repeated exposure to feared cues after 10 min, which disrupts reconsolidation, attenuates activity in the basolateral amygdala at re-exposure 24 hr later. In contrast, repeated exposure 6 hr after fear memory activation, which allows for reconsolidation, did not attenuate amygdala activity. Disrupted, but not undisrupted, reconsolidation facilitated approach behavior to feared cues, and approach behavior was inversely related to amygdala activity during re-exposure. We conclude that memory activation immediately preceding exposure attenuates the neural and behavioral expression of decades-old fear memories and that, similar to experimentally induced fear memories, the basolateral amygdala is crucially involved in this process.
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| 4. |
- Björkstrand, Johannes, et al.
(författare)
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Think twice, it's all right : Long lasting effects of disrupted reconsolidation on brain and behavior in human long-term fear
- 2017
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Ingår i: Behavioural Brain Research. - : Elsevier BV. - 0166-4328 .- 1872-7549. ; 324, s. 125-129
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Tidskriftsartikel (refereegranskat)abstract
- Memories can be modified when recalled. Experimental fear conditioning studies support that amygdala-localized fear memories are attenuated when reconsolidation is disrupted through extinction training immediately following memory activation. Recently, using functional brain imaging in individuals with lifelong spider fears, we demonstrated that fear memory activation followed by repeated exposure to feared cues after 10 min, thereby disrupting reconsolidation, attenuated activity in the amygdala during later re-exposure, and also facilitated approach behavior to feared cues. In contrast, repeated exposure 6 h after fear memory activation, allowing for reconsolidation, did not attenuate amygdala activity and resulted in less approach behavior as compared to the group that received disrupted reconsolidation. We here evaluated if these effects are stable after 6 months and found that amygdala activity was further reduced in both groups, with a tendency towards greater reductions in the 10 min than the 6 h group. Hence, disrupted reconsolidation results in long lasting attenuation of amygdala activity. The behavioral effect, with more approach towards previously feared cues, in the 10 min than the 6 h group also persisted. Thus, the brain effect of disrupted reconsolidation is stable over 6 months and the behavioral effect also remained. We therefore conclude that disrupted reconsolidation result in a long-lasting diminished fear memory representation in the amygdala which may have clinical importance.
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| 5. |
- Carannante, Ilaria, et al.
(författare)
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The impact of Parkinson’s disease on striatal network connectivity and cortico-striatal drive : an in-silico study
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 6. |
- Costache, Madalina Elena, et al.
(författare)
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Higher- and lower-order personality traits and cluster subtypes in social anxiety disorder
- 2020
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 15:4
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Tidskriftsartikel (refereegranskat)abstract
- Social anxiety disorder (SAD) can come in different forms, presenting problems for diagnostic classification. Here, we examined personality traits in a large sample of patients (N = 265) diagnosed with SAD in comparison to healthy controls (N = 164) by use of the Revised NEO Personality Inventory (NEO-PI-R) and Karolinska Scales of Personality (KSP). In addition, we identified subtypes of SAD based on cluster analysis of the NEO-PI-R Big Five personality dimensions. Significant group differences in personality traits between patients and controls were noted on all Big Five dimensions except agreeableness. Group differences were further noted on most lower-order facets of NEO-PI-R, and nearly all KSP variables. A logistic regression analysis showed, however, that only neuroticism and extraversion remained significant independent predictors of patient/control group when controlling for the effects of the other Big Five dimensions. Also, only neuroticism and extraversion yielded large effect sizes when SAD patients were compared to Swedish normative data for the NEO-PI-R. A two-step cluster analysis resulted in three separate clusters labelled Prototypical (33%), Introvert-Conscientious (29%), and Instable-Open (38%) SAD. Individuals in the Prototypical cluster deviated most on the Big Five dimensions and they were at the most severe end in profile analyses of social anxiety, self-rated fear during public speaking, trait anxiety, and anxiety-related KSP variables. While additional studies are needed to determine if personality subtypes in SAD differ in etiological and treatment-related factors, the present results demonstrate considerable personality heterogeneity in socially anxious individuals, further underscoring that SAD is a multidimensional disorder.
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| 7. |
- Djurfeldt, Mikael, 1967-, et al.
(författare)
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Run-Time Interoperability Between Neuronal Network Simulators Based on the MUSIC Framework
- 2010
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Ingår i: Neuroinformatics. - : Springer Science and Business Media LLC. - 1539-2791 .- 1559-0089. ; 8:1, s. 43-60
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Tidskriftsartikel (refereegranskat)abstract
- MUSIC is an API allowing large scale neuron simulators using MPI internally to exchange data during runtime. We provide experiences from the adaptation of two neuronal network simulators of different kinds, NEST and MOOSE, to this API. A multi-simulation of a cortico-striatal network model involving both simulators is performed, demonstrating how MUSIC can promote inter-operability between models written for different simulators and how these can be re-used to build a larger model system. We conclude that MUSIC fulfills the design goals of being portable and simple to adapt to existing simulators. In addition, since the MUSIC API enforces independence between the applications, the multi-simulationcould be built from pluggable component modules without adaptation of the components to each other in terms of simulation time-step or topology of connections between the modules.
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| 8. |
- Frost Nylén, Johanna, et al.
(författare)
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The roles of surround inhibition for the intrinsic function of the striatum, analyzed in silico
- 2023
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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. ; 120:45
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Tidskriftsartikel (refereegranskat)abstract
- The basal ganglia are important for action initiation, selection, and motor learning. The input level, the striatum, receives input preferentially from the cortex and thalamus and is to 95% composed of striatal projection neurons (SPNs) with sparse GABAergic collaterals targeting distal dendrites of neighboring SPNs, in a distance-dependent manner. The remaining 5% are GABAergic and cholinergic interneurons. Our aim here is to investigate the role of surround inhibition for the intrinsic function of the striatum. Large-scale striatal networks of 20 to 40 thousand neurons were simulated with detailed multicompartmental models of different cell types, corresponding to the size of a module of the dorsolateral striatum, like the forelimb area (mouse). The effect of surround inhibition on dendritic computation and network activity was investigated, while groups of SPNs were activated. The SPN-induced surround inhibition in distal dendrites shunted effectively the corticostriatal EPSPs. The size of dendritic plateau-like potentials within the specific dendritic segment was both reduced and enhanced by inhibition, due to the hyperpolarized membrane potential of SPNs and the reversal-potential of GABA. On a population level, the competition between two subpopulations of SPNs was found to depend on the distance between the two units, the size of each unit, the activity level in each subgroup and the dopaminergic modulation of the dSPNs and iSPNs. The SPNs provided the dominating source of inhibition within the striatum, while the fast-spiking interneuron mainly had an initial effect due to short-term synaptic plasticity as shown in with ablation of the synaptic interaction.
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| 9. |
- Hjorth, Johannes, 1978-
(författare)
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Computer Modelling of Neuronal Interactions in the Striatum
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Large parts of the cortex and the thalamus project into the striatum,which serves as the input stage of the basal ganglia. Information isintegrated in the striatal neural network and then passed on, via themedium spiny (MS) projection neurons, to the output stages of thebasal ganglia. In addition to the MS neurons there are also severaltypes of interneurons in the striatum, such as the fast spiking (FS)interneurons. I focused my research on the FS neurons, which formstrong inhibitory synapses onto the MS neurons. These striatal FSneurons are sparsely connected by electrical synapses (gap junctions),which are commonly presumed to synchronise their activity.Computational modelling with the GENESIS simulator was used toinvestigate the effect of gap junctions on a network of synapticallydriven striatal FS neurons. The simulations predicted a reduction infiring frequency dependent on the correlation between synaptic inputsto the neighbouring neurons, but only a slight synchronisation. Thegap junction effects on modelled FS neurons showing sub-thresholdoscillations and stuttering behaviour confirm these results andfurther indicate that hyperpolarising inputs might regulate the onsetof stuttering.The interactions between MS and FS neurons were investigated byincluding a computer model of the MS neuron. The hypothesis was thatdistal GABAergic input would lower the amplitude of back propagatingaction potentials, thereby reducing the calcium influx in thedendrites. The model verified this and further predicted that proximalGABAergic input controls spike timing, but not the amplitude ofdendritic calcium influx after initiation.Connecting models of neurons written in different simulators intonetworks raised technical problems which were resolved by integratingthe simulators within the MUSIC framework. This thesis discusses theissues encountered by using this implementation and gives instructionsfor modifying MOOSE scripts to use MUSIC and provides guidelines forachieving compatibility between MUSIC and other simulators.This work sheds light on the interactions between striatal FS and MSneurons. The quantitative results presented could be used to developa large scale striatal network model in the future, which would beapplicable to both the healthy and pathological striatum.
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| 10. |
- Hjorth, Johannes, et al.
(författare)
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GABAergic control of backpropagating action potentials in striatal medium spiny neurons
- 2008
-
Konferensbidrag (refereegranskat)abstract
- Experiments have demonstrated the ability of action potentials to actively backpropagate in striatal medium spiny (MS) neurons, affecting the calcium levels in the dendrites[1-3]. Increased calcium levels trigger changes in plasticity[4,5], which is important for learning and other functions[6]. Studies in the hippocampus have shown that GABAergic input can modulate the backpropagation of action potentials from the soma to the distal dendrites[7]. The MS neurons receive both proximal feedforward GABAergic inhibition from fast spiking interneurons (FS), and distal feedback inhibition from other neighbouring MS neurons. In the present study the effect of these GABAergic inputs on the dendritic calcium dynamics is investigated.
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| 11. |
- Hjorth, Johannes, et al.
(författare)
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GABAergic control of dendritic calcium dynamics in striatal medium spiny neurons
- 2008
-
Ingår i: Frontiers in Neuroinformatics. - : Frontiers Media SA. - 1662-5196.
-
Konferensbidrag (refereegranskat)abstract
- Experiments have demonstrated the ability of action potentials to actively backpropagate in striatal medium spiny (MS) neurons, affecting the calcium levels in the dendrites [1, 2, 3]. Increased calcium levels trigger changes in plasticity [4, 5], which is important for learning and other functions [6]. Studies in the hippocampus have shown that GABAergic input can modulate the backpropagation of action potentials from the soma to the distal dendrites [7]. The MS neurons receive both proximal feedforward GABAergic inhibition from fast spiking interneurons (FS), and distal feedback inhibition from other neighbouring MS neurons. In the present study the effect of GABAergic inputs on the dendritic calcium dynamics is investigated.
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| 12. |
- Hjorth, Johannes, et al.
(författare)
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Gap Junctions between Striatal Fast-Spiking Interneurons Regulate Spiking Activity and Synchronization as a Function of Cortical Activity
- 2009
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Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 29:16, s. 5276-5286
-
Tidskriftsartikel (refereegranskat)abstract
- Striatal fast-spiking (FS) interneurons are interconnected by gap junctions into sparsely connected networks. As demonstrated for cortical FS interneurons, these gap junctions in the striatum may cause synchronized spiking, which would increase the influence that FS neurons have on spiking by the striatal medium spiny (MS) neurons. Dysfunction of the basal ganglia is characterized by changes in synchrony or periodicity, thus gap junctions between FS interneurons may modulate synchrony and thereby influence behavior such as reward learning and motor control. To explore the roles of gap junctions on activity and spike synchronization in a striatal FS population, we built a network model of FS interneurons. Each FS connects to 30-40% of its neighbors, as found experimentally, and each FS interneuron in the network is activated by simulated corticostriatal synaptic inputs. Our simulations show that the proportion of synchronous spikes in FS networks with gap junctions increases with increased conductance of the electrical synapse; however, the synchronization effects are moderate for experimentally estimated conductances. Instead, the main tendency is that the presence of gap junctions reduces the total number of spikes generated in response to synaptic inputs in the network. The reduction in spike firing is due to shunting through the gap junctions; which is minimized or absent when the neurons receive coincident inputs. Together these findings suggest that a population of electrically coupled FS interneurons may function collectively as input detectors that are especially sensitive to synchronized synaptic inputs received from the cortex.
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| 13. |
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| 14. |
- Hjorth, Johannes, 1978-
(författare)
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Information processing in the Striatum : a computational study
- 2006
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The basal ganglia form an important structure centrally placed in the brain. They receive input from motor, associative and limbic areas, and produce output mainly to the thalamus and the brain stem. The basal ganglia have been implied in cognitive and motor functions. One way to understand the basal ganglia is to take a look at the diseases that affect them. Both Parkinson's disease and Huntington's disease with their motor problems are results of malfunctioning basal ganglia. There are also indications that these diseases affect cognitive functions. Drug addiction is another example that involves this structure, which is also important for motivation and selection of behaviour. In this licentiate thesis I am laying the groundwork for a detailed model of the striatum, which is the input stage of the basal ganglia. The striatum receives glutamatergic input from the cortex and thalamus, as well as dopaminergic input from substantia nigra. The majority of the neurons in the striatum are medium spiny (MS) projection neurons that project mainly to globus pallidus but also to other neurons in the striatum and to both dopamine producing and GABAergic neurons in substantia nigra. In addition to the MS neurons there are fast spiking (FS) interneurons that are in a position to regulate the firing of the MS neurons. These FS neurons are few, but connected into large networks through electrical synapses that could synchronise their effect. By forming strong inhibitory synapses on the MS neurons the FS neurons have a powerful influence on the striatal output. The inhibitory output of the basal ganglia on the thalamus is believed to keep prepared motor commands on hold, but once one of them is disinhibited, then the selected motor command is executed. This disinhibition is initiated in the striatum by the MS neurons. Both MS and FS neurons are active during so called up-states, which are periods of elevated cortical input to striatum. Here I have studied the FS neurons and their ability to detect such up-states. This is important because FS neurons can delay spikes in MS neurons and the time between up-state onset and the first spike in the MS neurons is correlated with the amount of calcium entering the MS neuron, which in turn might have implications for plasticity and learning of new behaviours. The effect of different combinations of electrical couplings between two FS neurons has been tested, where the location, number and strength of these gap junctions have been varied. I studied both the ability of the FS neurons to fire action potentials during the up-state, and the synchronisation between neighbouring FS neurons due to electrical coupling. I found that both proximal and distal gap junctions synchronised the firing, but the distal gap junctions did not have the same temporal precision. The ability of the FS neurons to detect an up-state was affected by whether the neighbouring FS neuron also received up-state input or not. This effect was more pronounced for distal gap junctions than proximal ones, due to a stronger shunting effect of distal gap junctions when the dendrites were synaptically activated. We have also performed initial stochastic simulations of the Ca2+-calmodulin-dependent protein kinase II (CaMKII). The purpose here is to build the knowledge as well as the tools necessary for biochemical simulations of intracellular processes that are important for plasticity in the MS neurons. The simulated biochemical pathways will then be integrated into an existing model of a full MS neuron. Another venue to explore is to build striatal network models consisting of MS and FS neurons and using experimental data of the striatal microcircuitry. With these different approaches we will improve our understanding of striatal information processing.
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| 15. |
- Hjorth, J. J. Johannes, et al.
(författare)
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Predicting Synaptic Connectivity for Large-Scale Microcircuit Simulations Using Snudda
- 2021
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Ingår i: Neuroinformatics. - : Springer Nature. - 1539-2791 .- 1559-0089. ; 19:4, s. 685-701
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Tidskriftsartikel (refereegranskat)abstract
- Simulation of large-scale networks of neurons is an important approach to understanding and interpreting experimental data from healthy and diseased brains. Owing to the rapid development of simulation software and the accumulation of quantitative data of different neuronal types, it is possible to predict both computational and dynamical properties of local microcircuits in a ‘bottom-up’ manner. Simulated data from these models can be compared with experiments and ‘top-down’ modelling approaches, successively bridging the scales. Here we describe an open source pipeline, using the software Snudda, for predicting microcircuit connectivity and for setting up simulations using the NEURON simulation environment in a reproducible way. We also illustrate how to further ‘curate’ data on single neuron morphologies acquired from public databases. This model building pipeline was used to set up a first version of a full-scale cellular level model of mouse dorsal striatum. Model components from that work are here used to illustrate the different steps that are needed when modelling subcortical nuclei, such as the basal ganglia.
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| 16. |
- 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
-
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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| 17. |
- Hjorth, Johannes, et al.
(författare)
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Synchronization Effects in Networks of Striatal Fast Spiking Interneurons - Role of Gap Junctions
- 2008
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Ingår i: ADVANCES IN COGNITIVE NEURODYNAMICS, PROCEEDINGS. - TOTOWA : HUMANA PRESS INC. - 9781402083860 ; , s. 63-66
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Konferensbidrag (refereegranskat)abstract
- Recent studies have found gap junctions between striatal fast spiking interneurons (FSN). Gap junctions between neocortical FSNs cause increased synchrony of firing in response to current injection, but the effect of gap junctions in response to synaptic input is unknown. To explore this issue, we built a network model of FSNs. Each FSN connects to 30-40% of its neighbours, as found experimentally, and each FSN in the network is activated by simulated up-state synaptic inputs. Simulation experiments show that the proportion of synchronous spikes in coupled FSNs increases with gap junction conductance. Proximal gap junctions increase the synchronization more than distal gap junctions. During up-states the synchronization effects in FSNs coupled pairwise with proximal gap junctions are small for experimentally estimated gap junction conductances; however, higher order correlations are significantly increased in larger FSN networks.
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| 18. |
- Hjorth, Johannes, et al.
(författare)
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The influence of stuttering properties for firing activity in pairs of electrically coupled striatal fast-spiking interneurons
- 2009
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Ingår i: Neuroinformatics 2009. Pilsen, Czech Republic, September 06 - 08, 2009. - : Frontiers Media SA.
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The striatum is the main input stage of the basal ganglia system, which is involved in executive functions of the forebrain – such as the planning and the selection of motor behavior. Feedforward inhibition of medium-sized spiny projection neurons in the striatum by fast-spiking interneurons is supposed to be an important determinant of controlling striatal output to later stages of the basal ganglia [1]. Striatal fast-spiking interneurons, which constitute approximately 1-2 % of all striatal neurons, show many similarities to cortical fast-spiking cells. In response to somatic current injection, for example, some of these neurons exhibit spike bursts with a variable number of action potentials (so called stuttering) [2-4]. Interestingly, the membrane potential between such stuttering episodes oscillates in the range of 20-100 Hz [3,5]. The first spike of each stuttering episode invariably occurs at a peak of the underlying subthreshold oscillation. In both cortex and striatum, fast-spiking cells have been shown to be inter-connected by gap junctions [6,7]. In vitro measurements as well as theoretical studies indicate that electrical coupling via gap junctions might be able to promote synchronous activity among these neurons [6,8].Here we use computational modeling to investigate how the presence of subthreshold oscillations and stuttering properties influence the synchronization of activity in pairs of electrically coupled fast-spiking neurons. We use the model of Golomb et al. [3], which we have extended with a dendritic tree in order to be able to simulate distal synaptic input. We show that gap junctions are able to synchronize both subthreshold membrane potential fluctuations as well as the stuttering periods in response to somatic current injection. In response to synaptic input, however, our model neuron rarely shows subthreshold oscillations, and the stuttering behavior changes to a firing pattern with single spikes or spike doublets. We furthermore investigate the effect of GABAergic (i.e. inhibitory) input to the model of the fast-spiking neuron and predict that inhibitory input is able to induce overlapping stuttering episodes in these cells. We finally discuss our results in the context of the feedforward inhibitory network which is likely to play an important role in striatal and basal ganglia function.
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| 19. |
- Hjorth, Johannes, et al.
(författare)
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The significance of gap junction location in striatal fast spiking interneurons
- 2007
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Ingår i: Neurocomputing. - : Elsevier BV. - 0925-2312 .- 1872-8286. ; 70:10-12, s. 1887-1891
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Tidskriftsartikel (refereegranskat)abstract
- Fast spiking (FS) interneurons in the striatunt are hypothesised to control spike timing in the numerous medium spiny (MS) projection neurons by inhibiting or delaying firing in the MS neurons. The FS neurons are connected to each other through electrical gap junctions. This might synchronise the FS neurons, leading to increased influence on target neurons. Here, we explore the possible difference between proximal and distal gap junction locations. Somatic and distal dendritic gap junctions with equal effective coupling coefficient, as defined for steady-state somatic inputs, showed significantly different effective coupling coefficient with transient inputs. However, the ability to synchronise spiking in pairwise coupled FS neurons, which received synaptic inputs as during striatal up-state periods, was as effective with distal gap junctions as with proximal ones. Proximal gap junctions, however, caused synchronisation within a more precise time window.
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| 20. |
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| 21. |
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| 22. |
- Hjorth, Olof, et al.
(författare)
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Serotonin and dopamine transporter availability in social anxiety disorder after combined treatment with escitalopram and cognitive-behavioral therapy
- 2022
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Selective serotonin reuptake inhibitors (SSRIs) and internet-based cognitive behavioral therapy (ICBT) are recommended treatments of social anxiety disorder (SAD), and often combined, but their effects on monoaminergic signaling are not well understood. In this multi-tracer positron emission tomography (PET) study, 24 patients with SAD were randomized to treatment with escitalopram+ICBT or placebo+ICBT under double-blind conditions. Before and after 9 weeks of treatment, patients were examined with positron emission tomography and the radioligands [11C]DASB and [11C]PE2I, probing the serotonin (SERT) and dopamine (DAT) transporter proteins respectively. Both treatment combinations resulted in significant improvement as measured by the Liebowitz Social Anxiety Scale (LSAS). At baseline, SERT-DAT co-expression was high and, in the putamen and thalamus, co-expression showed positive associations with symptom severity. SERT-DAT co-expression was also predictive of treatment success, but predictor-outcome associations differed in direction between the treatments. After treatment, average SERT occupancy in the SSRI + ICBT group was >80%, with positive associations between symptom improvement and occupancy in the nucleus accumbens, putamen and anterior cingulate cortex. Following placebo+ICBT, SERT binding increased in the raphe nuclei. DAT binding increased in both groups in limbic and striatal areas, but relations with symptom improvement differed, being negative for SSRI + ICBT and positive for placebo + ICBT. Thus, serotonin-dopamine transporter co-expression exerts influence on symptom severity and remission rate in the treatment of social anxiety disorder. However, the monoamine transporters are modulated in dissimilar ways when cognitive-behavioral treatment is given concomitantly with either SSRI-medication or pill placebo.
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| 23. |
- Jensen, Vivi Flou Hjorth, et al.
(författare)
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Importance of gestational hypoglycaemia for foetal malformations and skeletal development in rats
- 2020
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Ingår i: Reproductive Toxicology. - : Elsevier BV. - 0890-6238. ; 91, s. 14-26
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Tidskriftsartikel (refereegranskat)abstract
- The aim was to investigate embryo-foetal effects of continuous maternal insulin-induced hypoglycaemia extending throughout gestation or until gestation day (GD)17 (typical last day of dosing during pre-clinical evaluation) providing comparator data for safety assessment of longer-acting insulin analogues in non-diabetic rats. Pregnant rats received human insulin (HI)-infusion during gestation until either GD20 or GD17 (HI-GD20; HI-GD17). On GD20, foetal abnormalities and skeletal ossification/mineralisation were evaluated. HI-infusion induced continuous hypoglycaemia. Foetal skeletal and eye malformations (e.g. bent ribs, microphthalmia) were common in both groups. Foetal size and skeletal ossification/mineralisation decreased, particularly with infusion throughout gestation. Concluding, insulin-induced hypoglycaemia during gestation in non-diabetic rats is damaging to embryo-foetal growth and skeletal development, particularly after GD17. Three days without HI-infusion after GD17 allows for some developmental catch-up. Eye development is sensitive to HI-infusion before GD17. These results should serve as a benchmark during pre-clinical safety assessment of longer-acting insulin analogues tested in rats.
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| 24. |
- Klaus, A., et al.
(författare)
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Striatal fast-spiking interneurons : from firing patterns to postsynaptic impact
- 2011
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Ingår i: Frontiers in Systems Neuroscience. - : Frontiers Media SA. - 1662-5137. ; 5:July, s. 57-
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Tidskriftsartikel (refereegranskat)abstract
- In the striatal microcircuit, fast-spiking (FS) interneurons have an important role in mediating inhibition onto neighboring medium spiny (MS) projection neurons. In this study, we combined computational modeling with in vitro and in vivo electrophysiological measurements to investigate FS cells in terms of their discharge properties and their synaptic efficacies onto MS neurons. In vivo firing of striatal FS interneurons is characterized by a high firing variability. It is not known, however, if this variability results from the input that FS cells receive, or if it is promoted by the stuttering spike behavior of these neurons. Both our model and measurements in vitro show that FS neurons that exhibit random stuttering discharge in response to steady depolarization do not show the typical stuttering behavior when they receive fluctuating input. Importantly, our model predicts that electrically coupled FS cells show substantial spike synchronization only when they are in the stuttering regime. Therefore, together with the lack of synchronized firing of striatal FS interneurons that has been reported in vivo, these results suggest that neighboring FS neurons are not in the stuttering regime simultaneously and that in vivo FS firing variability is more likely determined by the input fluctuations. Furthermore, the variability in FS firing is translated to variability in the postsynaptic amplitudes in MS neurons due to the strong synaptic depression of the FS-to-MS synapse. Our results support the idea that these synapses operate over a wide range from strongly depressed to almost fully recovered. The strong inhibitory effects that FS cells can impose on their postsynaptic targets, and the fact that the FS-to-MS synapse model showed substantial depression over extended periods of time might indicate the importance of cooperative effects of multiple presynaptic FS interneurons and the precise orchestration of their activity.
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| 25. |
- Klaus, A., et al.
(författare)
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The influence of subthreshold membrane potential oscillations and GABAergic input on firing activity in striatal fast-spiking neurons
- 2009
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Ingår i: BMC Neuroscience. - 1471-2202. ; 10:Suppl.1, s. P244-
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Tidskriftsartikel (refereegranskat)abstract
- The striatum is the main input stage of the basal ganglia system, which is involved in executive functions of the forebrain, such as the planning and the selection of motor behavior. Feedforward inhibition of medium-sized spiny projection neurons in the striatum by fast-spiking interneurons is supposed to be an important determinant of controlling striatal output to later stages of the basal ganglia[1]. Striatal fast-spiking interneurons, which constitute approximately 1–2% of all striatal neurons, show many similarities to cortical fast-spiking cells. In response to somatic current injection, for example, some of these neurons exhibit spike bursts with a variable number of action potentials (so called stuttering)[2-4]. Interestingly, the membrane potential between such stuttering episodes oscillates in the range of 20–100 Hz[3,5]. The first spike of each stuttering episode invariably occurs at a peak of the underlying subthreshold oscillation. In both cortex and striatum, fast-spiking cells are inter-connected by gap junctions[6,7]. In vitro measurements as well as theoretical studies indicate that electrical coupling via gap junctions might be able to promote synchronous activity among these neurons[6,8]. Here we investigate the possible role of subthreshold oscillations on the synchronization of sub- and suprathreshold activity in a model of electrically coupled fast-spiking neurons. We use the model of Golomb et al.[3], which we extended with a dendritic tree so as to be able to simulate distal synaptic input. We show that gap junctions are able to synchronize subthreshold membrane potential fluctuations in response to somatic current injection. However, the oscillations are only prevalent in the subthreshold range and therefore require enough membrane potential depolarization[5]. In response to synaptic input, our model neuron only enters the subthreshold oscillatory regime with AMPA and NMDA synapses located at distal dendrites. Proximal synaptic input leads to more random fluctuations of the membrane potential, reflecting a smaller extent of dendritic filtering of the Poisson-distributed postsynaptic potentials. We furthermore investigate the effect of GABAergic (i.e. inhibitory) input to the model of the fast-spiking neuron and predict that inhibitory input is able to induce a stuttering episode in these cells. We finally discuss our results in the context of the feedforward inhibitory network, which is likely to play an important role in striatal and basal ganglia function.
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| 26. |
- Nadadhur, A. G., et al.
(författare)
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Multi-level characterization of balanced inhibitory-excitatory cortical neuron network derived from human pluripotent stem cells
- 2017
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 12:6
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Tidskriftsartikel (refereegranskat)abstract
- Generation of neuronal cultures from induced pluripotent stem cells (hiPSCs) serve the studies of human brain disorders. However we lack neuronal networks with balanced excitatory- inhibitory activities, which are suitable for single cell analysis. We generated low-density networks of hPSC-derived GABAergic and glutamatergic cortical neurons. We used two different co-culture models with astrocytes. We show that these cultures have balanced excitatory-inhibitory synaptic identities using confocal microscopy, electrophysiological recordings, calcium imaging and mRNA analysis. These simple and robust protocols offer the opportunity for single-cell to multi-level analysis of patient hiPSC-derived cortical excitatory- inhibitory networks; thereby creating advanced tools to study disease mechanisms underlying neurodevelopmental disorders.
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| 27. |
- Nylen, Johanna Frost, et al.
(författare)
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Dopaminergic and Cholinergic Modulation of Large Scale Networks in silico Using Snudda
- 2021
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Ingår i: Frontiers in Neural Circuits. - : Frontiers Media SA. - 1662-5110. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Neuromodulation is present throughout the nervous system and serves a critical role for circuit function and dynamics. The computational investigations of neuromodulation in large scale networks require supportive software platforms. Snudda is a software for the creation and simulation of large scale networks of detailed microcircuits consisting of multicompartmental neuron models. We have developed an extension to Snudda to incorporate neuromodulation in large scale simulations. The extended Snudda framework implements neuromodulation at the level of single cells incorporated into large-scale microcircuits. We also developed Neuromodcell, a software for optimizing neuromodulation in detailed multicompartmental neuron models. The software adds parameters within the models modulating the conductances of ion channels and ionotropic receptors. Bath application of neuromodulators is simulated and models which reproduce the experimentally measured effects are selected. In Snudda, we developed an extension to accommodate large scale simulations of neuromodulation. The simulator has two modes of simulation - denoted replay and adaptive. In the replay mode, transient levels of neuromodulators can be defined as a time-varying function which modulates the receptors and ion channels within the network in a cell-type specific manner. In the adaptive mode, spiking neuromodulatory neurons are connected via integrative modulating mechanisms to ion channels and receptors. Both modes of simulating neuromodulation allow for simultaneous modulation by several neuromodulators that can interact dynamically with each other. Here, we used the Neuromodcell software to simulate dopaminergic and muscarinic modulation of neurons from the striatum. We also demonstrate how to simulate different neuromodulatory states with dopamine and acetylcholine using Snudda. All software is freely available on Github, including tutorials on Neuromodcell and Snudda-neuromodulation.
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| 28. |
- 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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| 29. |
- Sandström, Malin, et al.
(författare)
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The impact of the distribution of isoforms on CaMKII activation
- 2006
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Ingår i: Neurocomputing. - : Elsevier BV. - 0925-2312. ; 69:10-12, s. 1010-1013
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Tidskriftsartikel (refereegranskat)abstract
- We have developed a computational model of the regulation of alpha- and beta-CaMKII activity, in order to examine (i) the importance of neighbour subunit interactions and (ii) the effect the higher CaMCa4 affinity of beta-CaMKII has on the holoenzyme activity in different configurations with the same alpha: beta ratio. The model consists of a deterministic biochemical network coupled to stochastic activation of CaMKII The results suggest that CaMKII holoenzyme activity is non-linear and dependent on the holoenzyme configuration of isoforms. This is especially pronounced in situations with a high-dephosphorylation rate of CaMKII.
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| 30. |
- Wlad, Magdalena, et al.
(författare)
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Dorsal anterior cingulate cortex activity during cognitive challenge in social anxiety disorder
- 2023
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Ingår i: Behavioural Brain Research. - : Elsevier. - 0166-4328 .- 1872-7549. ; 442
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Tidskriftsartikel (refereegranskat)abstract
- Background: Social anxiety disorder (SAD) is associated with aberrant emotional information processing while little is known about non-emotional cognitive processing biases. The dorsal anterior cingulate cortex (dACC) has been implicated in SAD neuropathology and is activated both by emotional and non-affective cognitive challenges like the Multisource Interference Task (MSIT).Methods: Here, we used fMRI to compare dACC activity and test performance during MSIT in 69 SAD patients and 38 healthy controls. In addition to patient-control comparisons, we examined whether neural activity in the dACC correlated with social anxiety, trait anxiety or depression levels.Results: The MSIT activated the dACC as expected but with no differences in task performance or neural reactivity between SAD patients and controls. There were no significant correlations between dACC activity and social or trait anxiety symptom severity. In patients, there was a significant negative correlation between dACC activity and depressive symptoms.Conclusions: In absence of affective challenge, we found no disorder-related cognitive profile in SAD patients since neither MSIT task performance nor dACC neural activity deviated in patients relative to controls.
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| 31. |
- Zhang, Yichen, et al.
(författare)
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A GPU-based computational framework that bridges neuron simulation and artificial intelligence
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Biophysically detailed multi-compartment models are powerful tools to explore computational principles of the brain and also serve as a theoretical framework to generate algorithms for artificial intelligence (AI) systems. However, the expensive computational cost severely limits the applications in both the neuroscience and AI fields. The major bottleneck during simulating detailed compartment models is the ability of a simulator to solve large systems of linear equations. Here, we present a novel Dendritic Hierarchical Scheduling (DHS) method to markedly accelerate such a process. We theoretically prove that the DHS implementation is computationally optimal and accurate. This GPU-based method performs with 2-3 orders of magnitude higher speed than that of the classic serial Hines method in the conventional CPU platform. We build a DeepDendrite framework, which integrates the DHS method and the GPU computing engine of the NEURON simulator and demonstrate applications of DeepDendrite in neuroscience tasks. We investigate how spatial patterns of spine inputs affect neuronal excitability in a detailed human pyramidal neuron model with 25,000 spines. Furthermore, we provide a brief discussion on the potential of DeepDendrite for AI, specifically highlighting its ability to enable the efficient training of biophysically detailed models in typical image classification tasks.
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