scholarly journals Global and local excitation and inhibition shape the dynamics of the cortico-striatal-thalamo-cortical pathway

2017 ◽  
Author(s):  
Anca R Radulescu ◽  
Joanna Herron ◽  
Caitlin Kennedy ◽  
Annalisa Scimemi
Keyword(s):  
Network Dynamics ◽  
Relative Strength ◽  
Medium Spiny Neurons ◽  
Linear Modeling ◽  
Obsessive Compulsive ◽  
D2 Dopamine Receptors ◽  
Compulsive Disorder ◽  
Spiny Neurons ◽  
Strength Of Excitation ◽  
Global And Local

The cortico-striatal-thalamo-cortical (CSTC) pathway is a brain circuit that controls movement execution, habit formation and reward. Hyperactivity in the CSTC pathway is involved in obsessive compulsive disorder, a neuropsychiatric disorder characterized by the execution of repetitive involuntary movements. The striatum shapes the activity of the CSTC pathway through the coordinated activation of two classes of medium spiny neurons (MSNs) expressing D1 or D2 dopamine receptors. The exact mechanisms by which balanced excitation/inhibition of these cells controls the network dynamics of the CSTC pathway remain unclear. Here we use non-linear modeling of neuronal activity and bifurcation theory to investigate how global and local changes in excitation/inhibition of MSNs regulate the activity of the CSTC pathway. Our findings indicate that a global and proportionate increase in excitation/inhibition pushes the system to states of generalized hyper-activity throughout the entire CSTC pathway. Certain disproportionate changes in global excitation/inhibition trigger network oscillations. Local changes in the excitation/inhibition of MSNs generate specific oscillatory behaviors in MSNs and in the CSTC pathway. These findings indicate that subtle changes in the relative strength of excitation/inhibition of MSNs can powerfully control the network dynamics of the CSTC pathway in ways that are not easily predicted by its synaptic connections.

scholarly journals Microglial NFκB-TNFα hyperactivation induces obsessive–compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia

2017 ◽  
Vol 114 (19) ◽  
pp. 5029-5034 ◽  
Author(s):  
Grietje Krabbe ◽  
S. Sakura Minami ◽  
Jon I. Etchegaray ◽  
Praveen Taneja ◽  
Biljana Djukic ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Frontotemporal Dementia ◽  
Knockout Mice ◽  
Nuclear Factor Κb ◽  
Medium Spiny Neurons ◽  
Obsessive Compulsive ◽  
Compulsive Disorder ◽  
Spiny Neurons ◽  
Increased Risk ◽  
Excessive Grooming

Frontotemporal dementia (FTD) is the second most common dementia before 65 years of age. Haploinsufficiency in the progranulin (GRN) gene accounts for 10% of all cases of familial FTD. GRN mutation carriers have an increased risk of autoimmune disorders, accompanied by elevated levels of tissue necrosis factor (TNF) α. We examined behavioral alterations related to obsessive–compulsive disorder (OCD) and the role of TNFα and related signaling pathways in FTD patients with GRN mutations and in mice lacking progranulin (PGRN). We found that patients and mice with GRN mutations displayed OCD and self-grooming (an OCD-like behavior in mice), respectively. Furthermore, medium spiny neurons in the nucleus accumbens, an area implicated in development of OCD, display hyperexcitability in PGRN knockout mice. Reducing levels of TNFα in PGRN knockout mice abolished excessive self-grooming and the associated hyperexcitability of medium spiny neurons of the nucleus accumbens. In the brain, PGRN is highly expressed in microglia, which are a major source of TNFα. We therefore deleted PGRN specifically in microglia and found that it was sufficient to induce excessive grooming. Importantly, excessive grooming in these mice was prevented by inactivating nuclear factor κB (NF-κB) in microglia/myeloid cells. Our findings suggest that PGRN deficiency leads to excessive NF-κB activation in microglia and elevated TNFα signaling, which in turn lead to hyperexcitability of medium spiny neurons and OCD-like behavior.

scholarly journals Transcriptomic analysis of dystonia-associated genes reveals functional convergence within specific cell types and shared neurobiology with psychiatric disorders

2020 ◽  
Author(s):  
Niccolò E. Mencacci ◽  
Regina Reynolds ◽  
Sonia Garcia Ruiz ◽  
Jana Vandrovcova ◽  
Paola Forabosco ◽  
...  
Keyword(s):  
White Matter ◽  
Psychiatric Disorders ◽  
Obsessive Compulsive Disorder ◽  
Dopaminergic Neurons ◽  
Medium Spiny Neurons ◽  
Obsessive Compulsive ◽  
Compulsive Disorder ◽  
Functional Relationships ◽  
Spiny Neurons ◽  
Cellular Specificity

AbstractDystonia is a neurological disorder characterized by sustained or intermittent muscle contractions causing abnormal movements and postures, often occurring in absence of any structural brain abnormality. Psychiatric comorbidities, including anxiety, depression, obsessive-compulsive disorder and schizophrenia, are frequent in dystonia patients. While mutations in a fast-growing number of genes have been linked to Mendelian forms of dystonia, the cellular, anatomical, and molecular basis remains unknown for most genetic forms of dystonia, as does its genetic and biological relationship to neuropsychiatric disorders. Here we applied an unbiased systems-biology approach to explore the cellular specificity of all currently known dystonia-associated genes, predict their functional relationships, and test whether dystonia and neuropsychiatric disorders share a genetic relationship. To determine the cellular specificity of dystonia-associated genes in the brain, single-nuclear transcriptomic data derived from mouse brain was used together with expression-weighted cell-type enrichment. To identify functional relationships amongst dystonia-associated genes, we determined the enrichment of these genes in co-expression networks constructed from ten human brain regions. Stratified linkage-disequilibrium score regression was used to test whether co-expression modules enriched for dystonia-associated genes significantly contribute to the heritability of anxiety, major depressive disorder, obsessive-compulsive disorder, schizophrenia, and Parkinson’s disease. Dystonia-associated genes were significantly enriched in adult nigral dopaminergic neurons and striatal medium spiny neurons. Furthermore, four of the 220 gene co-expression modules tested were significantly enriched for the dystonia-associated genes. The identified modules were derived from the substantia nigra, putamen, frontal cortex, and white matter, and were all significantly enriched for genes associated with synaptic function. Finally, we demonstrated significant enrichments of the heritability of depression, obsessive-compulsive disorder and schizophrenia, but not anxiety and Parkinson’s disease, within the putamen and white matter modules. In conclusion, multiple dystonia-associated genes interact and contribute to pathogenesis likely through dysregulation of synaptic signalling in striatal medium spiny neurons, adult nigral dopaminergic neurons and frontal cortical neurons. Furthermore, the enrichment of the heritability of psychiatric disorders in the co-expression modules enriched for dystonia-associated genes indicates that psychiatric symptoms associated with dystonia are likely to be intrinsic to its pathophysiology.

scholarly journals Dystonia genes functionally converge in specific neurons and share neurobiology with psychiatric disorders

Brain ◽  
2020 ◽  
Vol 143 (9) ◽  
pp. 2771-2787 ◽  
Author(s):  
Niccolò E Mencacci ◽  
Regina Reynolds ◽  
Sonia Garcia Ruiz ◽  
Jana Vandrovcova ◽  
Paola Forabosco ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Obsessive Compulsive Disorder ◽  
Dopaminergic Neurons ◽  
Medium Spiny Neurons ◽  
Obsessive Compulsive ◽  
Major Depressive ◽  
Compulsive Disorder ◽  
Functional Relationships ◽  
Spiny Neurons ◽  
Cellular Specificity

Abstract Dystonia is a neurological disorder characterized by sustained or intermittent muscle contractions causing abnormal movements and postures, often occurring in absence of any structural brain abnormality. Psychiatric comorbidities, including anxiety, depression, obsessive-compulsive disorder and schizophrenia, are frequent in patients with dystonia. While mutations in a fast-growing number of genes have been linked to Mendelian forms of dystonia, the cellular, anatomical, and molecular basis remains unknown for most genetic forms of dystonia, as does its genetic and biological relationship to neuropsychiatric disorders. Here we applied an unbiased systems-biology approach to explore the cellular specificity of all currently known dystonia-associated genes, predict their functional relationships, and test whether dystonia and neuropsychiatric disorders share a genetic relationship. To determine the cellular specificity of dystonia-associated genes in the brain, single-nuclear transcriptomic data derived from mouse brain was used together with expression-weighted cell-type enrichment. To identify functional relationships among dystonia-associated genes, we determined the enrichment of these genes in co-expression networks constructed from 10 human brain regions. Stratified linkage-disequilibrium score regression was used to test whether co-expression modules enriched for dystonia-associated genes significantly contribute to the heritability of anxiety, major depressive disorder, obsessive-compulsive disorder, schizophrenia, and Parkinson’s disease. Dystonia-associated genes were significantly enriched in adult nigral dopaminergic neurons and striatal medium spiny neurons. Furthermore, 4 of 220 gene co-expression modules tested were significantly enriched for the dystonia-associated genes. The identified modules were derived from the substantia nigra, putamen, frontal cortex, and white matter, and were all significantly enriched for genes associated with synaptic function. Finally, we demonstrate significant enrichments of the heritability of major depressive disorder, obsessive-compulsive disorder and schizophrenia within the putamen and white matter modules, and a significant enrichment of the heritability of Parkinson’s disease within the substantia nigra module. In conclusion, multiple dystonia-associated genes interact and contribute to pathogenesis likely through dysregulation of synaptic signalling in striatal medium spiny neurons, adult nigral dopaminergic neurons and frontal cortical neurons. Furthermore, the enrichment of the heritability of psychiatric disorders in the co-expression modules enriched for dystonia-associated genes indicates that psychiatric symptoms associated with dystonia are likely to be intrinsic to its pathophysiology.

Dopamine facilitates dendritic spine formation by cultured striatal medium spiny neurons through both D1 and D2 dopamine receptors

2013 ◽  
Vol 67 ◽  
pp. 432-443 ◽  
Author(s):  
Caroline Fasano ◽  
Marie-Josée Bourque ◽  
Gabriel Lapointe ◽  
Damiana Leo ◽  
Dominic Thibault ◽  
...  
Keyword(s):  
Dopamine Receptors ◽  
Dendritic Spine ◽  
Medium Spiny Neurons ◽  
D2 Dopamine Receptors ◽  
Spine Formation ◽  
Spiny Neurons

scholarly journals Multi-level assessment of obsessive-compulsive disorder (OCD) reveals relations between neural and neurochemical levels

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Kathrin Viol ◽  
Günter Schiepek ◽  
Martin Kronbichler ◽  
Arnulf Hartl ◽  
Carina Grafetstätter ◽  
...  
Keyword(s):  
Symptom Severity ◽  
Anterior Cingulate ◽  
Linear Modeling ◽  
Obsessive Compulsive ◽  
Time Intervals ◽  
Immunological Parameters ◽  
Compulsive Disorder ◽  
Before And After ◽  
Treatment Changes ◽  
Open Question

Abstract Background While considerable progress has been made in exploring the psychological, the neural, and the neurochemical dimensions of OCD separately, their interplay is still an open question, especially their changes during psychotherapy. Methods Seventeen patients were assessed at these three levels by psychological questionnaires, fMRI, and venipuncture before and after inpatient psychotherapy. Seventeen controls were scanned at comparable time intervals. First, pre/post treatment changes were investigated for all three levels separately: symptom severity, whole-brain and regional activity, and the concentrations of cortisol, serotonin, dopamine, brain-derived neurotrophic factor (BDNF), and immunological parameters (IL-6, IL-10, TNFα). Second, stepwise linear modeling was used to find relations between the variables of the levels. Results The obsessive-compulsive, depressive, and overall symptom severity was significantly reduced after psychotherapy. At the neural level, the activity in the anterior cingulate cortex (ACC), in frontal regions, in the precuneus, and in the putamen had significantly decreased. No significant changes were found on the neurochemical level. When connecting the levels, a highly significant model was found that explains the decrease in neural activity of the putamen by increases of the concentrations of cortisol, IL-6, and dopamine. Conclusion Multivariate approaches offer insight on the influences that the different levels of the psychiatric disorder OCD have on each other. More research and adapted models are needed.

scholarly journals Optogenetic activation of striatal D1/D2 medium spiny neurons differentially engages downstream connected areas beyond the basal ganglia

2021 ◽  
Author(s):  
Christina Grimm ◽  
Stefan Frässle ◽  
Céline Steger ◽  
Lukas von Ziegler ◽  
Oliver Sturman ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Functional Organization ◽  
Effective Connectivity ◽  
Activity Patterns ◽  
Computational Modelling ◽  
Medium Spiny Neurons ◽  
D2 Dopamine Receptors ◽  
Functional Relationships ◽  
Spiny Neurons ◽  
Thalamocortical Network

AbstractThe basal ganglia (BG) are a group of subcortical nuclei responsible for motor control, motor learning and executive function. Central to BG function are striatal medium spiny neurons (MSNs) expressing D1 and D2 dopamine receptors. D1 and D2 MSNs are typically considered functional antagonists that facilitate voluntary movements and inhibit competing motor patterns, respectively. While their opposite role is well documented for certain sensorimotor loops of the BG-thalamocortical network, it is unclear whether MSNs maintain a uniform functional role across the striatum and which influence they exert on brain areas outside the BG. Here, we addressed these questions by combining optogenetic activation of D1 and D2 MSNs in the mouse ventrolateral caudoputamen (vl CPu) with whole-brain functional MRI (fMRI) recordings. Neuronal excitation of either cell population in the vl CPu evoked distinct activity patterns in key regions of the BG-thalamocortical network including the pallidum, thalamus and motor cortex. Importantly, we report that striatal D1 and D2 MSN stimulation differentially engaged cerebellar and prefrontal regions. We characterised these long-range interactions by computational modelling of effective connectivity and confirmed that changes in D1 / D2 output drive functional relationships between regions within and beyond the BG. These results suggest a more complex functional organization of MSNs across the striatum than previously anticipated and provide evidence for the existence of an interconnected fronto - BG - cerebellar network modulated by striatal D1 and D2 MSNs.Graphical Abstract

scholarly journals Local Visual Processing in High Obsessive Compulsive Disorder (OCD) Scorers.

2021 ◽  
Author(s):  
◽  
Lisa Mae McLean
Keyword(s):  
Obsessive Compulsive Disorder ◽  
Visual Processing ◽  
Reaction Times ◽  
Obsessive Compulsive ◽  
Local Bias ◽  
Compulsive Disorder ◽  
Local Advantage ◽  
Memory Stage ◽  
Global And Local ◽  
Relevant Level

<p>Reaction times for big and small letters (global and local levels) were compared and examined to see whether differences would occur between a low scoring and high scoring Obsessive-  Compulsive Disorder (OCD) group. OCD patients have been shown to notice and pay more attention to small details (local bias) compared to most other populations (Shapiro, 1965; Yovel et al. 2006; Caberea et al., 2001). Although there is research supporting a local bias in OCD patients, it is unclear whether the bias occurs in the early stages of visual processing or in a later memory stage (Moritz & Wendt, 2006; Hermans et al, 2008). The study specifically examined a potential local bias for high OCD scorers in the early visual stage by manipulating perceptual and attentional mechanisms in two hierarchical letter tasks (Navon, 1977; Miller, 1981a, Plaisted et al. 1999). In Experiment 1, participants were told which level (the big or small letter) to respond to, results showed that high OCD scorers responded faster to local letters, showing support for a local processing advantage. Conversely, the low OCD group responded quicker to the global level. The finding of a local advantage in Experiment 1 suggests that the local advantage may be due to perceptual mechanisms as attention was already directed to the relevant level. However, in Experiment 2 where attention was not directed and the image quality was manipulated, local and global advantage effects were not replicated for the high and low OCD groups respectively. This showed that attentional and perceptual mechanisms did not make one level easier to process over the other. Therefore, it is possible that any local bias for OCD patients occurs in a later processing stage.</p>

scholarly journals Local Visual Processing in High Obsessive Compulsive Disorder (OCD) Scorers.

2021 ◽  
Author(s):  
◽  
Lisa Mae McLean
Keyword(s):  
Obsessive Compulsive Disorder ◽  
Visual Processing ◽  
Reaction Times ◽  
Obsessive Compulsive ◽  
Local Bias ◽  
Compulsive Disorder ◽  
Local Advantage ◽  
Memory Stage ◽  
Global And Local ◽  
Relevant Level

<p>Reaction times for big and small letters (global and local levels) were compared and examined to see whether differences would occur between a low scoring and high scoring Obsessive-  Compulsive Disorder (OCD) group. OCD patients have been shown to notice and pay more attention to small details (local bias) compared to most other populations (Shapiro, 1965; Yovel et al. 2006; Caberea et al., 2001). Although there is research supporting a local bias in OCD patients, it is unclear whether the bias occurs in the early stages of visual processing or in a later memory stage (Moritz & Wendt, 2006; Hermans et al, 2008). The study specifically examined a potential local bias for high OCD scorers in the early visual stage by manipulating perceptual and attentional mechanisms in two hierarchical letter tasks (Navon, 1977; Miller, 1981a, Plaisted et al. 1999). In Experiment 1, participants were told which level (the big or small letter) to respond to, results showed that high OCD scorers responded faster to local letters, showing support for a local processing advantage. Conversely, the low OCD group responded quicker to the global level. The finding of a local advantage in Experiment 1 suggests that the local advantage may be due to perceptual mechanisms as attention was already directed to the relevant level. However, in Experiment 2 where attention was not directed and the image quality was manipulated, local and global advantage effects were not replicated for the high and low OCD groups respectively. This showed that attentional and perceptual mechanisms did not make one level easier to process over the other. Therefore, it is possible that any local bias for OCD patients occurs in a later processing stage.</p>

Muscarinic Enhancement of Persistent Sodium Current Synchronizes Striatal Medium Spiny Neurons

2009 ◽  
Vol 102 (2) ◽  
pp. 682-690 ◽  
Author(s):  
Luis Carrillo-Reid ◽  
Fatuel Tecuapetla ◽  
Nicolas Vautrelle ◽  
Adán Hernández ◽  
Ramiro Vergara ◽  
...  
Keyword(s):  
Sodium Current ◽  
Network Dynamics ◽  
Receptor Activation ◽  
Procedural Memory ◽  
Negative Slope ◽  
Medium Spiny Neurons ◽  
Persistent Sodium Current ◽  
Intrinsic Properties ◽  
Bistable Behavior ◽  
Spiny Neurons

Network dynamics denoted by synchronous firing of neuronal pools rely on synaptic interactions and intrinsic properties. In striatal medium spiny neurons, N-methyl-d-aspartate (NMDA) receptor activation endows neurons with nonlinear capabilities by inducing a negative-slope conductance region (NSCR) in the current–voltage relationship. Nonlinearities underlie associative learning, procedural memory, and the sequential organization of behavior in basal ganglia nuclei. The cholinergic system modulates the function of medium spiny projection neurons through the activation of muscarinic receptors, increasing the NMDA-induced NSCR. This enhancement is reflected as a change in the NMDA-induced network dynamics, making it more synchronous. Nevertheless, little is known about the contribution of intrinsic properties that promote this activity. To investigate the mechanisms underlying the cholinergic modulation of bistable behavior in the striatum, we used whole cell and calcium-imaging techniques. A persistent sodium current modulated by muscarinic receptor activation participated in the enhancement of the NSCR and the increased network synchrony. These experiments provide evidence that persistent sodium current generates bistable behavior in striatal neurons and contributes to the regulation of synchronous network activity. The neuromodulation of bistable properties could represent a cellular and network mechanism for cholinergic actions in the striatum.

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