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Untangling Cortico-Striatal Circuitry and its Role in Health and Disease - A computational investigation
KTH, Skolan för elektroteknik och datavetenskap (EECS), Beräkningsvetenskap och beräkningsteknik (CST).
2018 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

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

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

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

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

sted, utgiver, år, opplag, sider
Stockholm: KTH Royal Institute of Technology, 2018. , s. 88
Serie
TRITA-EECS-AVL ; 2018:9
Emneord [en]
cortico-striatal circuits, levodopa-induced dyskinesia, Parkinson’s disease, effective connectivity, cross-frequency coupling, corticostriatal network, network oscillations, GABAergic transmission. basal ganglia, striatum, cortex, fast spiking interneurons, medium spiny neurons, neuronal avalanches
HSV kategori
Identifikatorer
URN: urn:nbn:se:kth:diva-222467ISBN: 978-91-7729-676-8 (tryckt)OAI: oai:DiVA.org:kth-222467DiVA, id: diva2:1181680
Disputas
2018-03-05, F3, Lindstedtsvägen 26, KTH Campus, Stockholm, 13:15 (engelsk)
Opponent
Veileder
Merknad

QC 20180209

Tilgjengelig fra: 2018-02-09 Laget: 2018-02-09 Sist oppdatert: 2018-06-12bibliografisk kontrollert
Delarbeid
1. Untangling cortico-striatal connectivity and cross-frequency coupling in L-DOPA-induced dyskinesia
Åpne denne publikasjonen i ny fane eller vindu >>Untangling cortico-striatal connectivity and cross-frequency coupling in L-DOPA-induced dyskinesia
Vise andre…
2016 (engelsk)Inngår i: Frontiers in Systems Neuroscience, ISSN 1662-5137, E-ISSN 1662-5137, Vol. 10, nr 26, s. 1-12Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

We simultaneously recorded local field potentials in the primary motor cortex and sensorimotor striatum in awake, freely behaving, 6-OHDA lesioned hemi-parkinsonian rats in order to study the features directly related to pathological states such as parkinsonian state and levodopa-induced dyskinesia. We analysed the spectral characteristics of the obtained signals and observed that during dyskinesia the most prominent feature was a relative power increase in the high gamma frequency range at around 80 Hz, while for the parkinsonian state it was in the beta frequency range. Here we show that during both pathological states effective connectivity in terms of Granger causality is bidirectional with an accent on the striatal influence on the cortex. In the case of dyskinesia, we also found a high increase in effective connectivity at 80 Hz. In order to further understand the 80- Hz phenomenon, we performed cross-frequency analysis and observed characteristic patterns in the case of dyskinesia but not in the case of the parkinsonian state or the healthy state. We noted a large decrease in the modulation of the amplitude at 80 Hz by the phase of low frequency oscillations (up to ~10 Hz) across both structures in the case of dyskinesia. This may suggest a lack of coupling between the low frequency activity of the recorded network and the group of neurons active at ~80 Hz.

sted, utgiver, år, opplag, sider
Frontiers, 2016
Emneord
Cortico-striatal circuits, Levodopa-induced dyskinesia, Parkinson’s disease, effective connectivity, Cross-frequency coupling
HSV kategori
Identifikatorer
urn:nbn:se:kth:diva-184005 (URN)10.3389/fnsys.2016.00026 (DOI)000372965400001 ()2-s2.0-84964898882 (Scopus ID)
Eksternt samarbeid:
Forskningsfinansiär
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Research Council
Merknad

QC 20160419

Tilgjengelig fra: 2016-03-22 Laget: 2016-03-22 Sist oppdatert: 2018-02-09bibliografisk kontrollert
2. Behavior Discrimination Using a Discrete Wavelet Based Approach for Feature Extraction on Local Field Potentials in the Cortex and Striatum
Åpne denne publikasjonen i ny fane eller vindu >>Behavior Discrimination Using a Discrete Wavelet Based Approach for Feature Extraction on Local Field Potentials in the Cortex and Striatum
Vise andre…
2015 (engelsk)Inngår i: 7th International IEEE/EMBS Conference on Neural Engineering (NER), IEEE conference proceedings, 2015, Vol. 7, s. 964-967Konferansepaper, Publicerat paper (Fagfellevurdert)
Abstract [en]

Linkage between behavioral states and neural activity is one of the most important challenges in neuroscience. The network activity patterns in the awake resting state and in the actively behaving state in rodents are not well understood, and a better tool for differentiating these states can provide insights on healthy brain functions and its alteration with disease. Therefore, we simultaneously recorded local field potentials (LFPs) bilaterally in motor cortex and striatum, and measured locomotion from healthy, freely behaving rats. Here we analyze spectral characteristics of the obtained signals and present an algorithm for automatic discrimination of the awake resting and the behavioral states. We used the Support Vector Machine (SVM) classifier and utilized features obtained by applying discrete wavelet transform (DWT) on LFPs, which arose as a solution with high accuracy.

sted, utgiver, år, opplag, sider
IEEE conference proceedings, 2015
HSV kategori
Identifikatorer
urn:nbn:se:kth:diva-168488 (URN)10.1109/NER.2015.7146786 (DOI)000377414600242 ()2-s2.0-84940386288 (Scopus ID)
Konferanse
7th Annual International IEEE EMBS Conference on Neural Engineering
Merknad

QC 20150623

Tilgjengelig fra: 2015-06-04 Laget: 2015-06-04 Sist oppdatert: 2018-02-09bibliografisk kontrollert
3. Interplay between periodic stimulation and GABAergic inhibition in striatal network oscillations
Åpne denne publikasjonen i ny fane eller vindu >>Interplay between periodic stimulation and GABAergic inhibition in striatal network oscillations
2017 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 4, s. 1-17Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Network oscillations are ubiquitous across many brain regions. In the basal ganglia, oscillations are also present at many levels and a wide range of characteristic frequencies have been reported to occur during both health and disease. The striatum, the main input nucleus of the basal ganglia, receives massive glutamatergic inputs from the cortex and is highly susceptible to external oscillations. However, there is limited knowledge about the exact nature of this routing process and therefore, it is of key importance to understand how time-dependent, external stimuli propagate through the striatal circuitry. Using a network model of the striatum and corticostriatal projections, we try to elucidate the importance of specific GABAergic neurons and their interactions in shaping striatal oscillatory activity. Here, we propose that fast-spiking interneurons can perform an important role in transferring cortical oscillations to the striatum especially to those medium spiny neurons that are not directly driven by the cortical oscillations. We show how the activity levels of different populations, the strengths of different inhibitory synapses, degree of outgoing projections of striatal cells, ongoing activity and synchronicity of inputs can influence network activity. These results suggest that the propagation of oscillatory inputs into the medium spiny neuron population is most efficient, if conveyed via the fast-spiking interneurons. Therefore, pharmaceuticals that target fast-spiking interneurons may provide a novel treatment for regaining the spectral characteristics of striatal activity that correspond to the healthy state.

Emneord
striatum, fast-spiking interneurons, network oscillations, medium spiny neurons, GABAergic transmission, corticostriatal interactions
HSV kategori
Forskningsprogram
Datalogi
Identifikatorer
urn:nbn:se:kth:diva-205220 (URN)10.1371/journal.pone.0175135 (DOI)000399371900097 ()2-s2.0-85017146743 (Scopus ID)
Merknad

QC 20170411

Tilgjengelig fra: 2017-04-10 Laget: 2017-04-10 Sist oppdatert: 2018-02-09bibliografisk kontrollert
4. Interactions in the Striatal Network with Different Oscillation Frequencies
Åpne denne publikasjonen i ny fane eller vindu >>Interactions in the Striatal Network with Different Oscillation Frequencies
2017 (engelsk)Inngår i: Artificial Neural Networks and Machine Learning – ICANN. Lecture Notes in Computer Science, Springer, 2017, Vol. 10613, s. 129-136Konferansepaper, Publicerat paper (Fagfellevurdert)
Abstract [en]

Simultaneous oscillations in different frequency bands are implicated in the striatum, and understanding their interactions will bring us one step closer to restoring the spectral characteristics of striatal activity that correspond to the healthy state. We constructed a computational model of the striatum in order to investigate how different, simultaneously present, and externally induced oscillations propagate through striatal circuitry and which stimulation parameters have a significant contribution. Our results show that features of these oscillations and their interactions can be influenced via amplitude, input frequencies, and the phase offset between different external inputs. Our findings provide further untangling of the oscillatory activity that can be seen within the striatal network.

sted, utgiver, år, opplag, sider
Springer, 2017
Emneord
Corticostriatal network, Network oscillations, GABAergic transmission, Basal ganglia, Cortex
HSV kategori
Identifikatorer
urn:nbn:se:kth:diva-217110 (URN)10.1007/978-3-319-68600-4_16 (DOI)2-s2.0-85034229782 (Scopus ID)978-3-319-68599-1 (ISBN)
Konferanse
Artificial Neural Networks and Machine Learning – ICANN 2017.
Merknad

QC 20171101

Tilgjengelig fra: 2017-10-31 Laget: 2017-10-31 Sist oppdatert: 2018-02-09bibliografisk kontrollert
5. Mapping of Cortical Avalanches to the Striatum
Åpne denne publikasjonen i ny fane eller vindu >>Mapping of Cortical Avalanches to the Striatum
2015 (engelsk)Inngår i: Advances in Cognitive Neurodynamics, Springer Netherlands, 2015, 4, s. 291-297Kapittel i bok, del av antologi (Fagfellevurdert)
Abstract [en]

Neuronal avalanches are found in the resting state activity of the mammaliancortex. Here we studied whether and how cortical avalanches are mappedonto the striatal circuitry, the first stage of the basal ganglia. We first demonstrate using organotypic cortex-striatum-substantia nigra cultures from rat that indeed striatal neurons respond to cortical avalanches originating in superficial layers. We simultaneously recorded spontaneous local field potentials (LFPs) in the cortical and striatal tissue using high-density microelectrode arrays. In the cortex, spontaneous neuronal avalanches were characterized by intermittent spatiotemporal activity clusters with a cluster size distribution that followed a power law with exponent 1.5. In the striatum, intermittent spatiotemporal activity was found to correlate with cortical avalanches. However, striatal negative LFP peaks (nLFPs) did not showavalanche signatures, but formed a cluster size distribution that had a much steeper drop-off, i.e., lacked large spatial clusters that are commonly expected for avalanche dynamics. The underlying de-correlation of striatal activity could have its origin in the striatum through local inhibition and/or could result from a particular mapping in the corticostriatal pathway. Here we show, using modeling, that highly convergent corticostriatal projections can map spatially extended cortical activity into spatially restricted striatal regimes.

sted, utgiver, år, opplag, sider
Springer Netherlands, 2015 Opplag: 4
Emneord
Neuronal avalanches, Striatum, Cortico-striatal network, Cortex, Basal ganglia
HSV kategori
Identifikatorer
urn:nbn:se:kth:diva-168104 (URN)10.1007/978-94-017-9548-7_41 (DOI)000380362800041 ()978-94-017-9547-0 (ISBN)
Merknad

QC 20150623

Tilgjengelig fra: 2015-05-27 Laget: 2015-05-27 Sist oppdatert: 2018-02-09bibliografisk kontrollert
6. Striatal processing of cortical neuronal avalanches – A computational investigation
Åpne denne publikasjonen i ny fane eller vindu >>Striatal processing of cortical neuronal avalanches – A computational investigation
2016 (engelsk)Inngår i: International Conference on Artificial Neural Networks. Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics), Springer, 2016, Vol. 9886, s. 72-79Konferansepaper, Publicerat paper (Fagfellevurdert)
Abstract [en]

In the cortex, spontaneous neuronal avalanches can be characterized by spatiotemporal activity clusters with a cluster size distribution that follows a power law with exponent –1.5. Recordings in the striatum revealed that striatal activity was also characterized by spatiotemporal clusters that followed a power law distribution albeit, with significantly steeper slope, i.e., they lacked the large spatial clusters that are commonly expected for avalanche dynamics. In this study, we used computational modeling to investigate the influence of intrastriatal inhibition and corticostriatal interplay as important factors to understand the experimental findings and overall information transmission among these circuits.

sted, utgiver, år, opplag, sider
Springer, 2016
Serie
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics), ISSN 0302-9743 ; 9886
Emneord
Corticostriatal network, Neuronal avalanches, Striatum, Basal ganglia, Cortex
HSV kategori
Forskningsprogram
Datalogi
Identifikatorer
urn:nbn:se:kth:diva-191313 (URN)10.1007/978-3-319-44778-0_9 (DOI)000389086300009 ()2-s2.0-84987956630 (Scopus ID)978-3-319-44778-0 (ISBN)978-3-319-44777-3 (ISBN)
Konferanse
25th International Conference on Artificial Neural Networks, ICANN 2016, Barcelona, Spain, 6 September 2016 through 9 September 2016
Merknad

QC 20160829

Tilgjengelig fra: 2016-08-28 Laget: 2016-08-28 Sist oppdatert: 2018-03-23bibliografisk kontrollert

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