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Molecular biomarkers, like gene transcripts or enzyme activities, are potentially powerful tools for early warning assessment of pollution. However, a thorough understanding of response and baseline variation is required to distinguish actual effects from pollution. Here, we assess the freshwater mussel Anodonta anatina as a biomarker model species for freshwater ecosystems, by testing responses of six transcriptional (cat, gst, hsp70, hsp90, mt, and sod) and two biochemical (AChE and GST) biomarkers to environmentally relevant Cu water concentrations. Mussels (n = 20), collected from a stream free from point source pollution, were exposed in the laboratory, for 96 h, to Cu treatments (< 0.2 mu g/L, 0.77 +/- 0.87 mu g/L, and 6.3 +/- 5.4 mu g/L). Gills and digestive glands were extracted and analyzed for transcriptional and biochemical responses. Biological and statistical effect sizes from Cu treatments were in general small (mean log(2) fold-change <= 0.80 and Cohen's f <= 0.69, respectively), and no significant treatment effects were observed. In contrast, four out of eight biomarkers (cat, gst, hsp70, and GST) showed a significant sex:tissue interaction, and additionally one (sod) showed significant overall effects from sex. Specifically, three markers in gills (cat, mt, GST) and one in digestive gland (AChE) displayed significant sex differences, independent of treatment. Results suggest that sex or tissue effects might obscure low-magnitude biomarker responses and potential early warnings. Thus, variation in biomarker baselines and response patterns needs to be further addressed for the future use of A. anatina as a biomarker model species., CC BY 4.0Environmental Science and Pollution Research. ISSN: 0944-1344 (Print) 1614-7499 (Online)

Molecular biomarkers, like gene transcripts or enzyme activities, are potentially powerful tools for early warning assessment of pollution. However, a thorough understanding of response and baseline variation is required to distinguish actual effects from pollution. Here, we assess the freshwater mussel Anodonta anatina as a biomarker model species for freshwater ecosystems, by testing responses of six transcriptional (cat, gst, hsp70, hsp90, mt, and sod) and two biochemical (AChE and GST) biomarkers to environmentally relevant Cu water concentrations. Mussels (n = 20), collected from a stream free from point source pollution, were exposed in the laboratory, for 96 h, to Cu treatments (< 0.2 mu g/L, 0.77 +/- 0.87 mu g/L, and 6.3 +/- 5.4 mu g/L). Gills and digestive glands were extracted and analyzed for transcriptional and biochemical responses. Biological and statistical effect sizes from Cu treatments were in general small (mean log(2) fold-change <= 0.80 and Cohen's f <= 0.69, respectively), and no significant treatment effects were observed. In contrast, four out of eight biomarkers (cat, gst, hsp70, and GST) showed a significant sex:tissue interaction, and additionally one (sod) showed significant overall effects from sex. Specifically, three markers in gills (cat, mt, GST) and one in digestive gland (AChE) displayed significant sex differences, independent of treatment. Results suggest that sex or tissue effects might obscure low-magnitude biomarker responses and potential early warnings. Thus, variation in biomarker baselines and response patterns needs to be further addressed for the future use of A. anatina as a biomarker model species., CC BY 4.0Environmental Science and Pollution Research. ISSN: 0944-1344 (Print) 1614-7499 (Online)

Despite the huge importance of spoken language production in everyday life, little is known about the manner and extent to which the motor aspects of speech production evolve with advancing age, as well as the nature of the underlying senescence mechanisms. In this cross-sectional group study, we examined the relationship between age and speech production performance using a nonlexical speech production task in which spoken syllable frequency and phonological complexity were systematically varied to test hypotheses about underlying mechanisms. A nonprobabilistic sample of 60 cognitively healthy adults (18-83 years) produced meaningless nonwords aloud as quickly and accurately as possible. Error rate, vocal reaction time (RT), vocal RT variability, vocal response duration, and vocal response duration variability were used as dependent variables to characterize speech production performance. The results showed an overall increase in error rate, which occurred mainly in the final syllable position (coda). There was also an increase in vocal response duration and in duration variability with age, which was moderated by phonological complexity and syllable frequency. Finally, we also found an age-related change in the relationship between vocal RT and vocal response duration. Together, these findings were interpreted as reflecting an age-related decline in the planning and execution of speech movements in cognitively healthy adults.

Molecular biomarkers, like gene transcripts or enzyme activities, are potentially powerful tools for early warning assessment of pollution. However, a thorough understanding of response and baseline variation is required to distinguish actual effects from pollution. Here, we assess the freshwater mussel Anodonta anatina as a biomarker model species for freshwater ecosystems, by testing responses of six transcriptional (cat, gst, hsp70, hsp90, mt, and sod) and two biochemical (AChE and GST) biomarkers to environmentally relevant Cu water concentrations. Mussels (n = 20), collected from a stream free from point source pollution, were exposed in the laboratory, for 96 h, to Cu treatments (< 0.2 mu g/L, 0.77 +/- 0.87 mu g/L, and 6.3 +/- 5.4 mu g/L). Gills and digestive glands were extracted and analyzed for transcriptional and biochemical responses. Biological and statistical effect sizes from Cu treatments were in general small (mean log(2) fold-change <= 0.80 and Cohen's f <= 0.69, respectively), and no significant treatment effects were observed. In contrast, four out of eight biomarkers (cat, gst, hsp70, and GST) showed a significant sex:tissue interaction, and additionally one (sod) showed significant overall effects from sex. Specifically, three markers in gills (cat, mt, GST) and one in digestive gland (AChE) displayed significant sex differences, independent of treatment. Results suggest that sex or tissue effects might obscure low-magnitude biomarker responses and potential early warnings. Thus, variation in biomarker baselines and response patterns needs to be further addressed for the future use of A. anatina as a biomarker model species., CC BY 4.0Environmental Science and Pollution Research. ISSN: 0944-1344 (Print) 1614-7499 (Online)

Molecular biomarkers, like gene transcripts or enzyme activities, are potentially powerful tools for early warning assessment of pollution. However, a thorough understanding of response and baseline variation is required to distinguish actual effects from pollution. Here, we assess the freshwater mussel Anodonta anatina as a biomarker model species for freshwater ecosystems, by testing responses of six transcriptional (cat, gst, hsp70, hsp90, mt, and sod) and two biochemical (AChE and GST) biomarkers to environmentally relevant Cu water concentrations. Mussels (n = 20), collected from a stream free from point source pollution, were exposed in the laboratory, for 96 h, to Cu treatments (< 0.2 mu g/L, 0.77 +/- 0.87 mu g/L, and 6.3 +/- 5.4 mu g/L). Gills and digestive glands were extracted and analyzed for transcriptional and biochemical responses. Biological and statistical effect sizes from Cu treatments were in general small (mean log(2) fold-change <= 0.80 and Cohen's f <= 0.69, respectively), and no significant treatment effects were observed. In contrast, four out of eight biomarkers (cat, gst, hsp70, and GST) showed a significant sex:tissue interaction, and additionally one (sod) showed significant overall effects from sex. Specifically, three markers in gills (cat, mt, GST) and one in digestive gland (AChE) displayed significant sex differences, independent of treatment. Results suggest that sex or tissue effects might obscure low-magnitude biomarker responses and potential early warnings. Thus, variation in biomarker baselines and response patterns needs to be further addressed for the future use of A. anatina as a biomarker model species., CC BY 4.0Environmental Science and Pollution Research. ISSN: 0944-1344 (Print) 1614-7499 (Online)

Molecular biomarkers, like gene transcripts or enzyme activities, are potentially powerful tools for early warning assessment of pollution. However, a thorough understanding of response and baseline variation is required to distinguish actual effects from pollution. Here, we assess the freshwater mussel Anodonta anatina as a biomarker model species for freshwater ecosystems, by testing responses of six transcriptional (cat, gst, hsp70, hsp90, mt, and sod) and two biochemical (AChE and GST) biomarkers to environmentally relevant Cu water concentrations. Mussels (n = 20), collected from a stream free from point source pollution, were exposed in the laboratory, for 96 h, to Cu treatments (< 0.2 mu g/L, 0.77 +/- 0.87 mu g/L, and 6.3 +/- 5.4 mu g/L). Gills and digestive glands were extracted and analyzed for transcriptional and biochemical responses. Biological and statistical effect sizes from Cu treatments were in general small (mean log(2) fold-change <= 0.80 and Cohen's f <= 0.69, respectively), and no significant treatment effects were observed. In contrast, four out of eight biomarkers (cat, gst, hsp70, and GST) showed a significant sex:tissue interaction, and additionally one (sod) showed significant overall effects from sex. Specifically, three markers in gills (cat, mt, GST) and one in digestive gland (AChE) displayed significant sex differences, independent of treatment. Results suggest that sex or tissue effects might obscure low-magnitude biomarker responses and potential early warnings. Thus, variation in biomarker baselines and response patterns needs to be further addressed for the future use of A. anatina as a biomarker model species., CC BY 4.0Environmental Science and Pollution Research. ISSN: 0944-1344 (Print) 1614-7499 (Online)

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, Striatala medium spiny neuroner (MSNs) spelar en stor roll för olika motoriska och kognitiva funktioner. Beroende på huruvida dessa neuroner uttrycker dopaminreceptorer av D1- eller D2-typ, klassificeras de som tillhörande den direkta (dMSN) respektive den indirekta (iMSN) vägen genom basala ganglierna. I denna avhandling undersöker jag hur inputet från kortex till de två typerna av MSNs processas och jag karakteriserar aktiviteten från dMSNs, samt undersöker även vilken effekt avvikande iMSN aktivitet ger upphov till i det basala ganglienätverk som består av den subthalamiska kärnan (STN) och globus pallidus externa (GPe).För att verifiera resultaten från en tidigare modelleringsstudie, som predicerat att dMSNs erhåller fler eller får starkare inputs från kortex jämfört med iMSNs, analyserade jag in vivo data från MSN ’wholecell’ registreringar gjorda i nedsövda möss som antingen tillhört en kontroll-grupp (friska möss) eller en grupp där dopamin (DA) reducerats m.h.a. 6OHDA. För att testa modellprediktionen jämförde jag subtröskliga membranpotentialfluktuationer och spik-triggade medelvärdesbildade membranpotentialer från de två typerna av MSNs. Jag upptäckte att dMSNs från kontrollgruppen uppvisade avsevärt större fluktuationer över ett brett frekvensintervall och också hade en snabbare depolarisering mot spiktröskeln jämfört med iMSNs. Dessa effekter syntes dock inte i experimentella data från de djur som behandlats med 6OHDA. Sammantaget tyder dessa observationer på att dMSNs i friska möss får starkare kortexinput än iMSNs.Jag använde även en biofysikaliskt detaljerad kompartmentmodell av en dMSN för att undersöka hur olika dopaminkoncentrationer påverkar responsvariabiliteten vid upprepade försök. Synaptiskt brus, neuronens refraktärperiod såväl som den pågående nätverksaktiviteten kan utgöra orsaker till responsvariabiliteten. I den här studien fokuserade vi på effekten av två egenskaper hos syn, “Striatal Medium Spiny Neurons“ (MSNs) spielen eine essentielle Rolle in verschiedensten Motor-und kognitiven Funktionen. Sie werden unterschieden in solche, die dem direkten (dMSNs) und dem indirekten (iMSNs) Signalweg der Basalganglien zugeordnet werden, abhängig davon ob sie D1- oder D2-typ Dopaminrezeptoren exprimieren. In dieser Arbeit untersuche ich die Eingangsverarbeitung beider MSN-Typen, die Charakteristiken von dMSN-Ausgängen, sowieden Effekt, den anomale iMSN-Aktivität auf das “Subthalamischer Nucleus-Globus Pallidus Externa” (STN-GPe)-Netzwerk hat.Um die Ergebnisse einer vorangehenden rechnergestützten (computational) Studie zu verifizieren, die den Anspruch erhebt, dass dMSNs entweder mehr, oder stärkeren Eingang als iMSNs bekommen sollten, habe ich in-vivo Ganzzellen-MSN-Messdaten in gesunden und Dopamin (DA)-abgereicherten (6OHDA) anästhesierten Mäusen analysiert. Um diese Vorhersage zu prüfen, habe ich Schwankungen des Membranpotentials unterhalb der Feuerschwelle und Spike-induzierte mittlere Membranpotentiale jener beiden MSN-Typen verglichen. Ich fand heraus, dass in gesunden Mäusen sMSNs deutlich größere Schwankungen über eine große Frequenzspanne, sowie eine signifikant schnellere Depolarisation hin zur Feuerschwelle zeigen als iMSNs dies tun. In Messdaten von 6OHDA-Versuchstieren hingegen waren diese Effekte nicht zu beobachten. Diese beiden Befunden zusammengenommen legen nahe, dass in gesundem Zustand dMSNs stärkeren Gesamteingang erhalten als iMSNs.Zudem habe ich untersucht inwiefern verschiedene Dopaminkonzentrationen neurale “trial-by-trial”-variabilität bzw. Antwort-Variabilität in einem biophysikalisch detaillierten Kompartiment-Modell von dMSNs beeinflussen. Quellen von trial-by-trial-Variabilität sind unter anderem synaptisches Rauschen, neurale Refraktionszeit und fortlaufende neurale Aktivität. Der Schwerpunkt dieser Studie lag auf dem Effekt zweier bestimmter Eigenschaften von synaptischem Eingang: Zum einen Korrela, This is a joint PhD programme between KTH Stockholm and University of Freiburg, Germany.QC20191126

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, Striatala medium spiny neuroner (MSNs) spelar en stor roll för olika motoriska och kognitiva funktioner. Beroende på huruvida dessa neuroner uttrycker dopaminreceptorer av D1- eller D2-typ, klassificeras de som tillhörande den direkta (dMSN) respektive den indirekta (iMSN) vägen genom basala ganglierna. I denna avhandling undersöker jag hur inputet från kortex till de två typerna av MSNs processas och jag karakteriserar aktiviteten från dMSNs, samt undersöker även vilken effekt avvikande iMSN aktivitet ger upphov till i det basala ganglienätverk som består av den subthalamiska kärnan (STN) och globus pallidus externa (GPe).För att verifiera resultaten från en tidigare modelleringsstudie, som predicerat att dMSNs erhåller fler eller får starkare inputs från kortex jämfört med iMSNs, analyserade jag in vivo data från MSN ’wholecell’ registreringar gjorda i nedsövda möss som antingen tillhört en kontroll-grupp (friska möss) eller en grupp där dopamin (DA) reducerats m.h.a. 6OHDA. För att testa modellprediktionen jämförde jag subtröskliga membranpotentialfluktuationer och spik-triggade medelvärdesbildade membranpotentialer från de två typerna av MSNs. Jag upptäckte att dMSNs från kontrollgruppen uppvisade avsevärt större fluktuationer över ett brett frekvensintervall och också hade en snabbare depolarisering mot spiktröskeln jämfört med iMSNs. Dessa effekter syntes dock inte i experimentella data från de djur som behandlats med 6OHDA. Sammantaget tyder dessa observationer på att dMSNs i friska möss får starkare kortexinput än iMSNs.Jag använde även en biofysikaliskt detaljerad kompartmentmodell av en dMSN för att undersöka hur olika dopaminkoncentrationer påverkar responsvariabiliteten vid upprepade försök. Synaptiskt brus, neuronens refraktärperiod såväl som den pågående nätverksaktiviteten kan utgöra orsaker till responsvariabiliteten. I den här studien fokuserade vi på effekten av två egenskaper hos syn, “Striatal Medium Spiny Neurons“ (MSNs) spielen eine essentielle Rolle in verschiedensten Motor-und kognitiven Funktionen. Sie werden unterschieden in solche, die dem direkten (dMSNs) und dem indirekten (iMSNs) Signalweg der Basalganglien zugeordnet werden, abhängig davon ob sie D1- oder D2-typ Dopaminrezeptoren exprimieren. In dieser Arbeit untersuche ich die Eingangsverarbeitung beider MSN-Typen, die Charakteristiken von dMSN-Ausgängen, sowieden Effekt, den anomale iMSN-Aktivität auf das “Subthalamischer Nucleus-Globus Pallidus Externa” (STN-GPe)-Netzwerk hat.Um die Ergebnisse einer vorangehenden rechnergestützten (computational) Studie zu verifizieren, die den Anspruch erhebt, dass dMSNs entweder mehr, oder stärkeren Eingang als iMSNs bekommen sollten, habe ich in-vivo Ganzzellen-MSN-Messdaten in gesunden und Dopamin (DA)-abgereicherten (6OHDA) anästhesierten Mäusen analysiert. Um diese Vorhersage zu prüfen, habe ich Schwankungen des Membranpotentials unterhalb der Feuerschwelle und Spike-induzierte mittlere Membranpotentiale jener beiden MSN-Typen verglichen. Ich fand heraus, dass in gesunden Mäusen sMSNs deutlich größere Schwankungen über eine große Frequenzspanne, sowie eine signifikant schnellere Depolarisation hin zur Feuerschwelle zeigen als iMSNs dies tun. In Messdaten von 6OHDA-Versuchstieren hingegen waren diese Effekte nicht zu beobachten. Diese beiden Befunden zusammengenommen legen nahe, dass in gesundem Zustand dMSNs stärkeren Gesamteingang erhalten als iMSNs.Zudem habe ich untersucht inwiefern verschiedene Dopaminkonzentrationen neurale “trial-by-trial”-variabilität bzw. Antwort-Variabilität in einem biophysikalisch detaillierten Kompartiment-Modell von dMSNs beeinflussen. Quellen von trial-by-trial-Variabilität sind unter anderem synaptisches Rauschen, neurale Refraktionszeit und fortlaufende neurale Aktivität. Der Schwerpunkt dieser Studie lag auf dem Effekt zweier bestimmter Eigenschaften von synaptischem Eingang: Zum einen Korrela, This is a joint PhD programme between KTH Stockholm and University of Freiburg, Germany.QC20191126

© Copyright © 2019 Andrillon, Windt, Silk, Drummond, Bellgrove and Tsuchiya. Sleep has been classically described as an all-or-nothing global phenomenon. However, recent research strongly suggests that this view requires tempering. Invasive and non-invasive recordings in animals and humans show that neural activity typically associated with sleep can locally occur during wakefulness. Although local sleep is defined neuronally, it has been associated with impaired performance during cognitive tasks. Comparatively, the phenomenology of local sleep (i.e., what it feels like when your brain is partially asleep) has been less explored. Taking into account the literature on the neuronal and behavioral profile of local sleep intrusions in wakefulness, we propose that occurrences of local sleep could represent the neural mechanism underlying many attentional lapses. In particular, we argue that a unique physiological event such as local sleep could account for a diversity of behavioral outcomes from sluggish to impulsive responses. We further propose that local sleep intrusions could impact individuals’ subjective experience. Specifically, we propose that the timing and anatomical sources of local sleep intrusions could be responsible for both the behavioral consequences and subjective content of attentional lapses and may underlie the difference between subjective experiences such as mind wandering and mind blanking. Our framework aims to build a parallel between spontaneous experiences in sleep and wakefulness by integrating evidence across neuronal, behavioral and experiential levels. We use the example of attention deficit hyperactivity disorder (ADHD) to illustrate how local sleep could explain complex cognitive profiles which include inattention, impulsivity, mind-wandering and mind-blanking.

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, Striatala medium spiny neuroner (MSNs) spelar en stor roll för olika motoriska och kognitiva funktioner. Beroende på huruvida dessa neuroner uttrycker dopaminreceptorer av D1- eller D2-typ, klassificeras de som tillhörande den direkta (dMSN) respektive den indirekta (iMSN) vägen genom basala ganglierna. I denna avhandling undersöker jag hur inputet från kortex till de två typerna av MSNs processas och jag karakteriserar aktiviteten från dMSNs, samt undersöker även vilken effekt avvikande iMSN aktivitet ger upphov till i det basala ganglienätverk som består av den subthalamiska kärnan (STN) och globus pallidus externa (GPe).För att verifiera resultaten från en tidigare modelleringsstudie, som predicerat att dMSNs erhåller fler eller får starkare inputs från kortex jämfört med iMSNs, analyserade jag in vivo data från MSN ’wholecell’ registreringar gjorda i nedsövda möss som antingen tillhört en kontroll-grupp (friska möss) eller en grupp där dopamin (DA) reducerats m.h.a. 6OHDA. För att testa modellprediktionen jämförde jag subtröskliga membranpotentialfluktuationer och spik-triggade medelvärdesbildade membranpotentialer från de två typerna av MSNs. Jag upptäckte att dMSNs från kontrollgruppen uppvisade avsevärt större fluktuationer över ett brett frekvensintervall och också hade en snabbare depolarisering mot spiktröskeln jämfört med iMSNs. Dessa effekter syntes dock inte i experimentella data från de djur som behandlats med 6OHDA. Sammantaget tyder dessa observationer på att dMSNs i friska möss får starkare kortexinput än iMSNs.Jag använde även en biofysikaliskt detaljerad kompartmentmodell av en dMSN för att undersöka hur olika dopaminkoncentrationer påverkar responsvariabiliteten vid upprepade försök. Synaptiskt brus, neuronens refraktärperiod såväl som den pågående nätverksaktiviteten kan utgöra orsaker till responsvariabiliteten. I den här studien fokuserade vi på effekten av två egenskaper hos syn, “Striatal Medium Spiny Neurons“ (MSNs) spielen eine essentielle Rolle in verschiedensten Motor-und kognitiven Funktionen. Sie werden unterschieden in solche, die dem direkten (dMSNs) und dem indirekten (iMSNs) Signalweg der Basalganglien zugeordnet werden, abhängig davon ob sie D1- oder D2-typ Dopaminrezeptoren exprimieren. In dieser Arbeit untersuche ich die Eingangsverarbeitung beider MSN-Typen, die Charakteristiken von dMSN-Ausgängen, sowieden Effekt, den anomale iMSN-Aktivität auf das “Subthalamischer Nucleus-Globus Pallidus Externa” (STN-GPe)-Netzwerk hat.Um die Ergebnisse einer vorangehenden rechnergestützten (computational) Studie zu verifizieren, die den Anspruch erhebt, dass dMSNs entweder mehr, oder stärkeren Eingang als iMSNs bekommen sollten, habe ich in-vivo Ganzzellen-MSN-Messdaten in gesunden und Dopamin (DA)-abgereicherten (6OHDA) anästhesierten Mäusen analysiert. Um diese Vorhersage zu prüfen, habe ich Schwankungen des Membranpotentials unterhalb der Feuerschwelle und Spike-induzierte mittlere Membranpotentiale jener beiden MSN-Typen verglichen. Ich fand heraus, dass in gesunden Mäusen sMSNs deutlich größere Schwankungen über eine große Frequenzspanne, sowie eine signifikant schnellere Depolarisation hin zur Feuerschwelle zeigen als iMSNs dies tun. In Messdaten von 6OHDA-Versuchstieren hingegen waren diese Effekte nicht zu beobachten. Diese beiden Befunden zusammengenommen legen nahe, dass in gesundem Zustand dMSNs stärkeren Gesamteingang erhalten als iMSNs.Zudem habe ich untersucht inwiefern verschiedene Dopaminkonzentrationen neurale “trial-by-trial”-variabilität bzw. Antwort-Variabilität in einem biophysikalisch detaillierten Kompartiment-Modell von dMSNs beeinflussen. Quellen von trial-by-trial-Variabilität sind unter anderem synaptisches Rauschen, neurale Refraktionszeit und fortlaufende neurale Aktivität. Der Schwerpunkt dieser Studie lag auf dem Effekt zweier bestimmter Eigenschaften von synaptischem Eingang: Zum einen Korrela, This is a joint PhD programme between KTH Stockholm and University of Freiburg, Germany.QC20191126

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, Striatala medium spiny neuroner (MSNs) spelar en stor roll för olika motoriska och kognitiva funktioner. Beroende på huruvida dessa neuroner uttrycker dopaminreceptorer av D1- eller D2-typ, klassificeras de som tillhörande den direkta (dMSN) respektive den indirekta (iMSN) vägen genom basala ganglierna. I denna avhandling undersöker jag hur inputet från kortex till de två typerna av MSNs processas och jag karakteriserar aktiviteten från dMSNs, samt undersöker även vilken effekt avvikande iMSN aktivitet ger upphov till i det basala ganglienätverk som består av den subthalamiska kärnan (STN) och globus pallidus externa (GPe).För att verifiera resultaten från en tidigare modelleringsstudie, som predicerat att dMSNs erhåller fler eller får starkare inputs från kortex jämfört med iMSNs, analyserade jag in vivo data från MSN ’wholecell’ registreringar gjorda i nedsövda möss som antingen tillhört en kontroll-grupp (friska möss) eller en grupp där dopamin (DA) reducerats m.h.a. 6OHDA. För att testa modellprediktionen jämförde jag subtröskliga membranpotentialfluktuationer och spik-triggade medelvärdesbildade membranpotentialer från de två typerna av MSNs. Jag upptäckte att dMSNs från kontrollgruppen uppvisade avsevärt större fluktuationer över ett brett frekvensintervall och också hade en snabbare depolarisering mot spiktröskeln jämfört med iMSNs. Dessa effekter syntes dock inte i experimentella data från de djur som behandlats med 6OHDA. Sammantaget tyder dessa observationer på att dMSNs i friska möss får starkare kortexinput än iMSNs.Jag använde även en biofysikaliskt detaljerad kompartmentmodell av en dMSN för att undersöka hur olika dopaminkoncentrationer påverkar responsvariabiliteten vid upprepade försök. Synaptiskt brus, neuronens refraktärperiod såväl som den pågående nätverksaktiviteten kan utgöra orsaker till responsvariabiliteten. I den här studien fokuserade vi på effekten av två egenskaper hos syn, “Striatal Medium Spiny Neurons“ (MSNs) spielen eine essentielle Rolle in verschiedensten Motor-und kognitiven Funktionen. Sie werden unterschieden in solche, die dem direkten (dMSNs) und dem indirekten (iMSNs) Signalweg der Basalganglien zugeordnet werden, abhängig davon ob sie D1- oder D2-typ Dopaminrezeptoren exprimieren. In dieser Arbeit untersuche ich die Eingangsverarbeitung beider MSN-Typen, die Charakteristiken von dMSN-Ausgängen, sowieden Effekt, den anomale iMSN-Aktivität auf das “Subthalamischer Nucleus-Globus Pallidus Externa” (STN-GPe)-Netzwerk hat.Um die Ergebnisse einer vorangehenden rechnergestützten (computational) Studie zu verifizieren, die den Anspruch erhebt, dass dMSNs entweder mehr, oder stärkeren Eingang als iMSNs bekommen sollten, habe ich in-vivo Ganzzellen-MSN-Messdaten in gesunden und Dopamin (DA)-abgereicherten (6OHDA) anästhesierten Mäusen analysiert. Um diese Vorhersage zu prüfen, habe ich Schwankungen des Membranpotentials unterhalb der Feuerschwelle und Spike-induzierte mittlere Membranpotentiale jener beiden MSN-Typen verglichen. Ich fand heraus, dass in gesunden Mäusen sMSNs deutlich größere Schwankungen über eine große Frequenzspanne, sowie eine signifikant schnellere Depolarisation hin zur Feuerschwelle zeigen als iMSNs dies tun. In Messdaten von 6OHDA-Versuchstieren hingegen waren diese Effekte nicht zu beobachten. Diese beiden Befunden zusammengenommen legen nahe, dass in gesundem Zustand dMSNs stärkeren Gesamteingang erhalten als iMSNs.Zudem habe ich untersucht inwiefern verschiedene Dopaminkonzentrationen neurale “trial-by-trial”-variabilität bzw. Antwort-Variabilität in einem biophysikalisch detaillierten Kompartiment-Modell von dMSNs beeinflussen. Quellen von trial-by-trial-Variabilität sind unter anderem synaptisches Rauschen, neurale Refraktionszeit und fortlaufende neurale Aktivität. Der Schwerpunkt dieser Studie lag auf dem Effekt zweier bestimmter Eigenschaften von synaptischem Eingang: Zum einen Korrela, This is a joint PhD programme between KTH Stockholm and University of Freiburg, Germany.QC20191126

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, Striatala medium spiny neuroner (MSNs) spelar en stor roll för olika motoriska och kognitiva funktioner. Beroende på huruvida dessa neuroner uttrycker dopaminreceptorer av D1- eller D2-typ, klassificeras de som tillhörande den direkta (dMSN) respektive den indirekta (iMSN) vägen genom basala ganglierna. I denna avhandling undersöker jag hur inputet från kortex till de två typerna av MSNs processas och jag karakteriserar aktiviteten från dMSNs, samt undersöker även vilken effekt avvikande iMSN aktivitet ger upphov till i det basala ganglienätverk som består av den subthalamiska kärnan (STN) och globus pallidus externa (GPe).För att verifiera resultaten från en tidigare modelleringsstudie, som predicerat att dMSNs erhåller fler eller får starkare inputs från kortex jämfört med iMSNs, analyserade jag in vivo data från MSN ’wholecell’ registreringar gjorda i nedsövda möss som antingen tillhört en kontroll-grupp (friska möss) eller en grupp där dopamin (DA) reducerats m.h.a. 6OHDA. För att testa modellprediktionen jämförde jag subtröskliga membranpotentialfluktuationer och spik-triggade medelvärdesbildade membranpotentialer från de två typerna av MSNs. Jag upptäckte att dMSNs från kontrollgruppen uppvisade avsevärt större fluktuationer över ett brett frekvensintervall och också hade en snabbare depolarisering mot spiktröskeln jämfört med iMSNs. Dessa effekter syntes dock inte i experimentella data från de djur som behandlats med 6OHDA. Sammantaget tyder dessa observationer på att dMSNs i friska möss får starkare kortexinput än iMSNs.Jag använde även en biofysikaliskt detaljerad kompartmentmodell av en dMSN för att undersöka hur olika dopaminkoncentrationer påverkar responsvariabiliteten vid upprepade försök. Synaptiskt brus, neuronens refraktärperiod såväl som den pågående nätverksaktiviteten kan utgöra orsaker till responsvariabiliteten. I den här studien fokuserade vi på effekten av två egenskaper hos syn, “Striatal Medium Spiny Neurons“ (MSNs) spielen eine essentielle Rolle in verschiedensten Motor-und kognitiven Funktionen. Sie werden unterschieden in solche, die dem direkten (dMSNs) und dem indirekten (iMSNs) Signalweg der Basalganglien zugeordnet werden, abhängig davon ob sie D1- oder D2-typ Dopaminrezeptoren exprimieren. In dieser Arbeit untersuche ich die Eingangsverarbeitung beider MSN-Typen, die Charakteristiken von dMSN-Ausgängen, sowieden Effekt, den anomale iMSN-Aktivität auf das “Subthalamischer Nucleus-Globus Pallidus Externa” (STN-GPe)-Netzwerk hat.Um die Ergebnisse einer vorangehenden rechnergestützten (computational) Studie zu verifizieren, die den Anspruch erhebt, dass dMSNs entweder mehr, oder stärkeren Eingang als iMSNs bekommen sollten, habe ich in-vivo Ganzzellen-MSN-Messdaten in gesunden und Dopamin (DA)-abgereicherten (6OHDA) anästhesierten Mäusen analysiert. Um diese Vorhersage zu prüfen, habe ich Schwankungen des Membranpotentials unterhalb der Feuerschwelle und Spike-induzierte mittlere Membranpotentiale jener beiden MSN-Typen verglichen. Ich fand heraus, dass in gesunden Mäusen sMSNs deutlich größere Schwankungen über eine große Frequenzspanne, sowie eine signifikant schnellere Depolarisation hin zur Feuerschwelle zeigen als iMSNs dies tun. In Messdaten von 6OHDA-Versuchstieren hingegen waren diese Effekte nicht zu beobachten. Diese beiden Befunden zusammengenommen legen nahe, dass in gesundem Zustand dMSNs stärkeren Gesamteingang erhalten als iMSNs.Zudem habe ich untersucht inwiefern verschiedene Dopaminkonzentrationen neurale “trial-by-trial”-variabilität bzw. Antwort-Variabilität in einem biophysikalisch detaillierten Kompartiment-Modell von dMSNs beeinflussen. Quellen von trial-by-trial-Variabilität sind unter anderem synaptisches Rauschen, neurale Refraktionszeit und fortlaufende neurale Aktivität. Der Schwerpunkt dieser Studie lag auf dem Effekt zweier bestimmter Eigenschaften von synaptischem Eingang: Zum einen Korrela, This is a joint PhD programme between KTH Stockholm and University of Freiburg, Germany.QC20191126

Despite the huge importance of spoken language production in everyday life, little is known about the manner and extent to which the motor aspects of speech production evolve with advancing age as well as the nature of the underlying senescence mechanisms. In this crosssectional group study, we examined the relationship between age and speech production performance using a non-lexical speech production task in which spoken syllable frequency and phonological complexity were systematically varied to test hypotheses about underlying mechanisms. A non-probabilistic sample of 60 cognitively healthy adults (18 - 83 years) produced meaningless nonwords aloud as quickly and accurately as possible. Error rate, vocal reaction time, vocal reaction time variability, vocal response duration and vocal response duration variability were used as dependent variables to characterize speech production performance. The results showed an overall increase in error rate, which occurred mainly in the final syllable position (coda). There was also an increase in vocal response duration and induration variability with age, which was moderated by phonological complexity and syllable frequency. Finally, we also found an age-related change in the relationship between vocal reaction time and vocal response duration. Together, these findings were interpreted as reflecting an age-related decline in the planning and execution of speech movements in cognitively healthy adults.

Improving bacterial nitrogen fixation in grain legumes is central to sustainable intensification of agriculture in sub-Saharan Africa. In the case of soyabean, two main approaches have been pursued: first, promiscuous varieties were developed to form effective symbiosis with locally abundant nitrogen fixing bacteria. Second, inoculation with elite bacterial strains is being promoted. Analyses of the success of these approaches in tropical smallholder systems are scarce. It is unclear how current promiscuous and non-promiscuous soyabean varieties perform in inoculated and uninoculated fields, and the extent of variation in inoculation response across regions and environmental conditions remains to be determined.We present an analysis of on-farm yields and inoculation responses across ten countries in Sub Saharan Africa, including both promiscuous and non-promiscuous varieties. By combining data from a core set of replicated on-farm trials with that from a large number of farmer-managed try-outs, we study the potential for inoculation to increase yields in both variety types and evaluate the magnitude and variability of response.Average yields were estimated to be 1343 and 1227. kg/ha with and without inoculation respectively. Inoculation response varied widely between trials and locations, with no clear spatial patterns at larger scales and without evidence that this variation could be explained by yield constraints or environmental conditions. On average, specific varieties had similar uninoculated yields, while responding more strongly to inoculation. Side-by side comparisons revealed that stronger responses were observed at sites where promiscuous varieties had superior uninoculated yields, suggesting the availability of compatible, effective bacteria as a yield limiting factor and as a determinant of the magnitude of inoculation response.

Adolescence is a period of learning, exploration, and continuous adaptation to fluctuating environments. Response variability during adolescence is an important, understudied, and developmentally appropriate behavior. The purpose of this study was to identify the association between performance on a dynamic risky decision making task and white matter microstructure in a sample of 48 adolescents (14-16 years). Individuals with the greatest response variability on the task obtained the widest range of experience with potential outcomes to risky choice. When compared with their more behaviorally consistent peers, adolescents with greater response variability rated real-world examples of risk taking behaviors as less risky via self-report. Tract-Based Spatial Statistics (TBSS) were used to examine fractional anisotropy (FA) and mean diffusivity (MD). Greater FA in long-range, late-maturing tracts was associated with higher response variability. Greater FA and lower MD were associated with lower riskiness ratings of real-world risky behaviors. Results suggest that response variability and lower perceived risk attitudes of real-world risk are supported by neural maturation in adolescents.

Adolescence is a period of learning, exploration, and continuous adaptation to fluctuating environments. Response variability during adolescence is an important, understudied, and developmentally appropriate behavior. The purpose of this study was to identify the association between performance on a dynamic risky decision making task and white matter microstructure in a sample of 48 adolescents (14-16 years). Individuals with the greatest response variability on the task obtained the widest range of experience with potential outcomes to risky choice. When compared with their more behaviorally consistent peers, adolescents with greater response variability rated real-world examples of risk taking behaviors as less risky via self-report. Tract-Based Spatial Statistics (TBSS) were used to examine fractional anisotropy (FA) and mean diffusivity (MD). Greater FA in long-range, late-maturing tracts was associated with higher response variability. Greater FA and lower MD were associated with lower riskiness ratings of real-world risky behaviors. Results suggest that response variability and lower perceived risk attitudes of real-world risk are supported by neural maturation in adolescents.

Recent findings have shown that listening to white noise can improve memory in people with ADHD or low levels of attention. The current study explored whether white noise can improve performance on a test of sustained attention. Participants (N=19) were divided into an attentive (N=10) and inattentive group (N=9) based on the inattention sub-section of the ASRS (Adult Self-Report ADHD Scale). Participants completed four blocks of a Three-Stimulus Oddball task. Participants completed the task under four conditions: in silence, while listening to continuous white noise, listening to a tone and listening to short bursts of white noise. It was found that the inattentive group performed worse in all four conditions compared to the attentive group by making more errors and having a higher variability in response times. There was no positive effect of listening to white noise or the tone for either group. The results of the study did not lend support towards the hypothesis that inattentive participants benefit from white noise on a test of sustained attention. It was suggested that future research should replicate the current experiment using more participants, more noise manipulations and by increasing motivation through including continuous feedback. It was also suggested that white noise should be tested in conjunction with working memory tasks and test of inhibition and interference handling since impairments in these processes are also implicated in the ADHD symptom profile.

Recent findings have shown that listening to white noise can improve memory in people with ADHD or low levels of attention. The current study explored whether white noise can improve performance on a test of sustained attention. Participants (N=19) were divided into an attentive (N=10) and inattentive group (N=9) based on the inattention sub-section of the ASRS (Adult Self-Report ADHD Scale). Participants completed four blocks of a Three-Stimulus Oddball task. Participants completed the task under four conditions: in silence, while listening to continuous white noise, listening to a tone and listening to short bursts of white noise. It was found that the inattentive group performed worse in all four conditions compared to the attentive group by making more errors and having a higher variability in response times. There was no positive effect of listening to white noise or the tone for either group. The results of the study did not lend support towards the hypothesis that inattentive participants benefit from white noise on a test of sustained attention. It was suggested that future research should replicate the current experiment using more participants, more noise manipulations and by increasing motivation through including continuous feedback. It was also suggested that white noise should be tested in conjunction with working memory tasks and test of inhibition and interference handling since impairments in these processes are also implicated in the ADHD symptom profile.

Attention deficit hyperactivity disorder (ADHD) and autism are two neurodevelopmental disorders associated with prominent executive dysfunction, which may be underpinned by disruption within fronto-striatal and fronto-parietal circuits. We probed executive function in these disorders using a sustained attention task with a validated brain-behaviour basis. Twenty-three children with ADHD, 21 children with high-functioning autism (HFA) and 18 control children were tested on the Sustained Attention to Response Task (SART). In a fixed sequence version of the task, children were required to withhold their response to a predictably occurring no-go target (3) in a 1-9 digit sequence; in the random version the sequence was unpredictable. The ADHD group showed clear deficits in response inhibition and sustained attention, through higher errors of commission and omission on both SART versions. The HFA group showed no sustained attention deficits, through a normal number of omission errors on both SART versions. The HFA group showed dissociation in response inhibition performance, as indexed by commission errors. On the Fixed SART, a normal number of errors was made, however when the stimuli were randomised, the HFA group made as many commission errors as the ADHD group. Greater slow-frequency variability in response time and a slowing in mean response time by the ADHD group suggested impaired arousal processes. The ADHD group showed greater fast-frequency variability in response time, indicative of impaired top-down control, relative to the HFA and control groups. These data imply involvement of fronto-parietal attentional networks and sub-cortical arousal systems in the pathology of ADHD and prefrontal cortex dysfunction in children with HFA. © 2007 Elsevier Ltd. All rights reserved.