The Experts below are selected from a list of 327 Experts worldwide ranked by ideXlab platform
Philippe Boulinguez - One of the best experts on this subject based on the ideXlab platform.
-
Clonidine modulates the activity of the subthalamic-supplementary motor loop: evidence from a pharmacological study combining deep brain stimulation and electroencephalography recordings in Parkinsonian patients
Journal of Neurochemistry, 2018Co-Authors: Charlotte Spay, Marion Albares, Guillaume Lio, Stephane Thobois, Emmanuel Broussolle, Brian Lau, Benedicte Ballanger, Philippe BoulinguezAbstract:Clonidine is an anti-hypertensive medication which acts as an alpha-adrenergic receptor agonist. As the Noradrenergic System is likely to support cognitive functions including attention and executive control, other clinical uses of clonidine have recently gained popularity for the treatment of neuropsychiatric disorders like attention-deficit hyperactivity disorder or Tourette syndrome, but the mechanism of action is still unclear. Here, we test the hypothesis that the Noradrenergic System regulates the activity of subthalamo-motor cortical loops, and that this influence can be modulated by clonidine. We used pharmacological manipulation of clonidine in a placebo-controlled study in combination with subthalamic nucleus-deep brain stimulation (STN-DBS) in 16 Parkinson's disease patients performing a reaction time task requiring to refrain from reacting (proactive inhibition). We recorded electroencephalographical activity of the whole cortex, and applied spectral analyses directly at the source level after advanced blind source separation. We found only one cortical source localized to the supplementary motor area (SMA) that supported an interaction of pharmacological and subthalamic stimulation. Under placebo, STN-DBS reduced proactive alpha power in the SMA, a marker of local inhibitory activity. This effect was associated with the speeding-up of movement initiation. Clonidine substantially increased proactive alpha power from the SMA source, and canceled out the benefits of STN-DBS on movement initiation. These results provide the first direct neural evidence in humans that the tonic inhibitory activity of the subthalamocortical loops underlying the control of movement initiation is coupled to the Noradrenergic System, and that this activity can be targeted by pharmacological agents acting on alpha-adrenergic receptors.
Irena Nalepa - One of the best experts on this subject based on the ideXlab platform.
-
Kreiner G: Inactivation of glucocorticoid receptor in Noradrenergic System influences anxiety- and depressivelike behavior in mice
2016Co-Authors: Piotr Chmielarz, Justyna Kuśmierczyk, Rosanna Parlato, Gunther Schutz, Irena NalepaAbstract:The aim of this study was to investigate whether conditional inactivation of the glucocorticoid receptors (GRs) in Noradrenergic neurons affects animal behavior in mice. Selective ablation of GRs in the Noradrenergic System was achieved using the Cre/loxP approach. We crossed transgenic mice expressing the Cre recombinase under the dopamine beta-hydroxylase (DBH) promoter with animals harboring the floxed GR gene. The resulting GRDBHCre mutant mice exhibited no alterations in terms of normal cage behavior, weight gain, spatial memory or spontaneous locomotor activity, regardless of gender. To assess depressive- and anxiety-like behaviors we performed the Tail Suspension Test and the Light-Dark Box Test. While male mutant animals did not show any alternations in both tests, female GRDBHCre mutants displayed depressive- and anxiety-like behavior. Additionally, male GRDBHCre mice were exposed to chronic restraint stress but still exhibited immobility times and anxiety statuses similar to those of non-stressed animals while stressed control mice clearly revealed depressive- and anxiety-like phenotype. Thus, in males the effects of the mutation were precipitated only after chronic restraint stress procedure. Our data reveal
-
selective ablation of glucocorticoid receptors in the Noradrenergic System affects evening corticosterone levels in a sex dependent manner
Pharmacological Reports, 2015Co-Authors: Piotr Chmielarz, Grzegorz Kreiner, Irena NalepaAbstract:Abstract Background The hypothalamic–pituitary–adrenal (HPA) axis, which is involved in the release of corticosterone in response to stress, exhibits large circadian variations in its activity that can also be regulated by the Noradrenergic System, thereby contributing to the pathophysiology of depression. We have recently shown that mice in which glucocorticoid receptors (GR) are selectively ablated in the Noradrenergic System (GR DBHCre mice) exhibit sex-dependent phenotype alterations, manifested as increased anxiety- and depressive-like behaviors in female but not male mutants. Methods In this study, we investigated the regulation of circadian HPA axis activity in GR DBHCre transgenic mice by measuring plasma corticosterone levels. Results We found that evening plasma corticosterone increase was profoundly higher in females than males, and this diversification was further augmented in mutant GR DBHCre mice. Conclusions Our results provide evidence of the involvement of the Noradrenergic System in the regulation of the sexually dimorphic circadian activity of the HPA axis.
-
disruption of glucocorticoid receptors in the Noradrenergic System leads to bdnf up regulation and altered serotonergic transmission associated with a depressive like phenotype in female grdbhcre mice
Pharmacology Biochemistry and Behavior, 2015Co-Authors: Piotr Chmielarz, Grzegorz Kreiner, Wladyslawa A Daniel, Marta Kot, Agnieszka Zelekmolik, M Kowalska, M Baginska, Irena NalepaAbstract:Recently, we have demonstrated that conditional inactivation of glucocorticoid receptors (GRs) in the Noradrenergic System, may evoke depressive-like behavior in female but not male mutant mice (GR(DBHCre) mice). The aim of the current study was to dissect how selective ablation of glucocorticoid signaling in the Noradrenergic System influences the previously reported depressive-like phenotype and whether it might be linked to neurotrophic alterations or secondary changes in the serotonergic System. We demonstrated that selective depletion of GRs enhances brain derived neurotrophic factor (BDNF) expression in female but not male GR(DBHCre) mice on both the mRNA and protein levels. The possible impact of the mutation on brain Noradrenergic and serotonergic Systems was addressed by investigating the tissue neurotransmitter levels under basal conditions and after acute restraint stress. The findings indicated a stress-provoked differential response in tissue noradrenaline content in the GR(DBHCre) female but not male mutant mice. An analogous gender-specific effect was identified in the diminished content of 5-hydroxyindoleacetic acid, the main metabolite of serotonin, in the prefrontal cortex, which suggests down-regulation of this monoamine System in female GR(DBHCre) mice. The lack of GR also resulted in an up-regulation of alpha2-adrenergic receptor (α2-AR) density in the female but not male mutants in the locus coeruleus. We have also confirmed the utility of the investigated model in pharmacological studies, which demonstrates that the depressive-like phenotype of GR(DBHCre) female mice can be reversed by antidepressant treatment with desipramine or fluoxetine, with the latter drug evoking more pronounced effects. Overall, our study validates the use of female GR(DBHCre) mice as an interesting and novel genetic tool for the investigation of the cross-connected mechanisms of depression that is not only based on behavioral phenotypes.
-
inactivation of glucocorticoid receptor in Noradrenergic System influences anxiety and depressive like behavior in mice
PLOS ONE, 2013Co-Authors: Piotr Chmielarz, Irena Nalepa, Justyna Kuśmierczyk, Rosanna Parlato, Gunther Schutz, Grzegorz KreinerAbstract:The aim of this study was to investigate whether conditional inactivation of the glucocorticoid receptors (GRs) in Noradrenergic neurons affects animal behavior in mice. Selective ablation of GRs in the Noradrenergic System was achieved using the Cre/loxP approach. We crossed transgenic mice expressing the Cre recombinase under the dopamine beta-hydroxylase (DBH) promoter with animals harboring the floxed GR gene. The resulting GRDBHCre mutant mice exhibited no alterations in terms of normal cage behavior, weight gain, spatial memory or spontaneous locomotor activity, regardless of gender. To assess depressive- and anxiety-like behaviors we performed the Tail Suspension Test and the Light-Dark Box Test. While male mutant animals did not show any alternations in both tests, female GRDBHCre mutants displayed depressive- and anxiety-like behavior. Additionally, male GRDBHCre mice were exposed to chronic restraint stress but still exhibited immobility times and anxiety statuses similar to those of non-stressed animals while stressed control mice clearly revealed depressive- and anxiety-like phenotype. Thus, in males the effects of the mutation were precipitated only after chronic restraint stress procedure. Our data reveal a possible gender-dependent role of GRs in the Noradrenergic System in anxiety- and depressive-like behavior in mice.
Charlotte Spay - One of the best experts on this subject based on the ideXlab platform.
-
Clonidine modulates the activity of the subthalamic-supplementary motor loop: evidence from a pharmacological study combining deep brain stimulation and electroencephalography recordings in Parkinsonian patients
Journal of Neurochemistry, 2018Co-Authors: Charlotte Spay, Marion Albares, Guillaume Lio, Stephane Thobois, Emmanuel Broussolle, Brian Lau, Benedicte Ballanger, Philippe BoulinguezAbstract:Clonidine is an anti-hypertensive medication which acts as an alpha-adrenergic receptor agonist. As the Noradrenergic System is likely to support cognitive functions including attention and executive control, other clinical uses of clonidine have recently gained popularity for the treatment of neuropsychiatric disorders like attention-deficit hyperactivity disorder or Tourette syndrome, but the mechanism of action is still unclear. Here, we test the hypothesis that the Noradrenergic System regulates the activity of subthalamo-motor cortical loops, and that this influence can be modulated by clonidine. We used pharmacological manipulation of clonidine in a placebo-controlled study in combination with subthalamic nucleus-deep brain stimulation (STN-DBS) in 16 Parkinson's disease patients performing a reaction time task requiring to refrain from reacting (proactive inhibition). We recorded electroencephalographical activity of the whole cortex, and applied spectral analyses directly at the source level after advanced blind source separation. We found only one cortical source localized to the supplementary motor area (SMA) that supported an interaction of pharmacological and subthalamic stimulation. Under placebo, STN-DBS reduced proactive alpha power in the SMA, a marker of local inhibitory activity. This effect was associated with the speeding-up of movement initiation. Clonidine substantially increased proactive alpha power from the SMA source, and canceled out the benefits of STN-DBS on movement initiation. These results provide the first direct neural evidence in humans that the tonic inhibitory activity of the subthalamocortical loops underlying the control of movement initiation is coupled to the Noradrenergic System, and that this activity can be targeted by pharmacological agents acting on alpha-adrenergic receptors.
Jonathan M Wastling - One of the best experts on this subject based on the ideXlab platform.
-
downregulation of the central Noradrenergic System by toxoplasma gondii infection
Infection and Immunity, 2019Co-Authors: Isra Alsaady, Ellen Tedford, Mohammad Alsaad, Greg C Bristow, Shivali Kohli, Matthew J Murray, Matthew B Reeves, M S Vijayabaskar, Steven J Clapcote, Jonathan M WastlingAbstract:Toxoplasma gondii is associated with physiological effects in the host. Dysregulation of catecholamines in the central nervous System has previously been observed in chronically infected animals. In the study described here, the Noradrenergic System was found to be suppressed with decreased levels of norepinephrine (NE) in brains of infected animals and in infected human and rat neural cells in vitro The mechanism responsible for the NE suppression was found to be downregulation of dopamine β-hydroxylase (DBH) gene expression, encoding the enzyme that synthesizes norepinephrine from dopamine, with downregulation observed in vitro and in infected brain tissue, particularly in the dorsal locus coeruleus/pons region. The downregulation was sex specific, with males expressing reduced DBH mRNA levels whereas females were unchanged. Rather, DBH expression correlated with estrogen receptor in the female rat brains for this estrogen-regulated gene. DBH silencing was not a general response of neurons to infection, as human cytomegalovirus did not downregulate DBH expression. The Noradrenergic-linked behaviors of sociability and arousal were altered in chronically infected animals, with a high correlation between DBH expression and infection intensity. A decrease in DBH expression in Noradrenergic neurons can elevate dopamine levels, which provides a possible explanation for mixed observations of changes in this neurotransmitter with infection. Decreased NE is consistent with the loss of coordination and motor impairments associated with toxoplasmosis. Further, the altered norepinephrine synthesis observed here may, in part, explain behavioral effects of infection and associations with mental illness.
-
downregulation of the central Noradrenergic System by toxoplasma gondii infection
bioRxiv, 2018Co-Authors: Isra Alsaady, Ellen Tedford, Mohammad Alsaad, Greg C Bristow, Shivali Kohli, Matthew J Murray, Matthew B Reeves, M S Vijayabaskar, Steven J Clapcote, Jonathan M WastlingAbstract:The parasitic protozoan Toxoplasma gondiibecomes encysted in brain and muscle tissue during chronic infection, a stage that was previously thought to be dormant but has been found to be active and associated with physiological effects in the host. Dysregulation of catecholamines in the CNS has previously been observed in chronically-infected animals. In the study described here, the Noradrenergic System was suppressed with decreased levels of norepinephrine in brains of infected animals and in infected neuronal cells in vitro. Expression of dopamine b-hydroxylase (DBH), essential for synthesis of norepinephrine from dopamine, was the most differentially-expressed gene in infections in vitroand was down-regulated in infected brain tissue, particularly in the prefrontal cortex and dorsal locus coeruleus/pons region. The down-regulated DBH expression in infected rat catecholaminergic and human neuronal cells corresponded with decreased norepinephrine and increased dopamine. As the DBH suppression was observed in vitro, this effect is not caused by neuroinflammation. Silencing of DBH expression was specific for T. gondiiinfection and was not observed with CMV infection. The Noradrenergic-linked behaviors of sociability and arousal were altered in chronically-infected animals, with a high correlation between DBH expression and infection intensity. These findings together provide a plausible mechanism to explain prior discrepancies in changes to CNS neurotransmitters levels with infection. The suppression of norepinephrine synthesis observed here may, in part, explain behavioural effects of infection, associations with mental illness, and neurological consequences of infection such as the loss of coordination and motor impairments associated with human toxoplasmosis.
Piotr Chmielarz - One of the best experts on this subject based on the ideXlab platform.
-
Kreiner G: Inactivation of glucocorticoid receptor in Noradrenergic System influences anxiety- and depressivelike behavior in mice
2016Co-Authors: Piotr Chmielarz, Justyna Kuśmierczyk, Rosanna Parlato, Gunther Schutz, Irena NalepaAbstract:The aim of this study was to investigate whether conditional inactivation of the glucocorticoid receptors (GRs) in Noradrenergic neurons affects animal behavior in mice. Selective ablation of GRs in the Noradrenergic System was achieved using the Cre/loxP approach. We crossed transgenic mice expressing the Cre recombinase under the dopamine beta-hydroxylase (DBH) promoter with animals harboring the floxed GR gene. The resulting GRDBHCre mutant mice exhibited no alterations in terms of normal cage behavior, weight gain, spatial memory or spontaneous locomotor activity, regardless of gender. To assess depressive- and anxiety-like behaviors we performed the Tail Suspension Test and the Light-Dark Box Test. While male mutant animals did not show any alternations in both tests, female GRDBHCre mutants displayed depressive- and anxiety-like behavior. Additionally, male GRDBHCre mice were exposed to chronic restraint stress but still exhibited immobility times and anxiety statuses similar to those of non-stressed animals while stressed control mice clearly revealed depressive- and anxiety-like phenotype. Thus, in males the effects of the mutation were precipitated only after chronic restraint stress procedure. Our data reveal
-
selective ablation of glucocorticoid receptors in the Noradrenergic System affects evening corticosterone levels in a sex dependent manner
Pharmacological Reports, 2015Co-Authors: Piotr Chmielarz, Grzegorz Kreiner, Irena NalepaAbstract:Abstract Background The hypothalamic–pituitary–adrenal (HPA) axis, which is involved in the release of corticosterone in response to stress, exhibits large circadian variations in its activity that can also be regulated by the Noradrenergic System, thereby contributing to the pathophysiology of depression. We have recently shown that mice in which glucocorticoid receptors (GR) are selectively ablated in the Noradrenergic System (GR DBHCre mice) exhibit sex-dependent phenotype alterations, manifested as increased anxiety- and depressive-like behaviors in female but not male mutants. Methods In this study, we investigated the regulation of circadian HPA axis activity in GR DBHCre transgenic mice by measuring plasma corticosterone levels. Results We found that evening plasma corticosterone increase was profoundly higher in females than males, and this diversification was further augmented in mutant GR DBHCre mice. Conclusions Our results provide evidence of the involvement of the Noradrenergic System in the regulation of the sexually dimorphic circadian activity of the HPA axis.
-
disruption of glucocorticoid receptors in the Noradrenergic System leads to bdnf up regulation and altered serotonergic transmission associated with a depressive like phenotype in female grdbhcre mice
Pharmacology Biochemistry and Behavior, 2015Co-Authors: Piotr Chmielarz, Grzegorz Kreiner, Wladyslawa A Daniel, Marta Kot, Agnieszka Zelekmolik, M Kowalska, M Baginska, Irena NalepaAbstract:Recently, we have demonstrated that conditional inactivation of glucocorticoid receptors (GRs) in the Noradrenergic System, may evoke depressive-like behavior in female but not male mutant mice (GR(DBHCre) mice). The aim of the current study was to dissect how selective ablation of glucocorticoid signaling in the Noradrenergic System influences the previously reported depressive-like phenotype and whether it might be linked to neurotrophic alterations or secondary changes in the serotonergic System. We demonstrated that selective depletion of GRs enhances brain derived neurotrophic factor (BDNF) expression in female but not male GR(DBHCre) mice on both the mRNA and protein levels. The possible impact of the mutation on brain Noradrenergic and serotonergic Systems was addressed by investigating the tissue neurotransmitter levels under basal conditions and after acute restraint stress. The findings indicated a stress-provoked differential response in tissue noradrenaline content in the GR(DBHCre) female but not male mutant mice. An analogous gender-specific effect was identified in the diminished content of 5-hydroxyindoleacetic acid, the main metabolite of serotonin, in the prefrontal cortex, which suggests down-regulation of this monoamine System in female GR(DBHCre) mice. The lack of GR also resulted in an up-regulation of alpha2-adrenergic receptor (α2-AR) density in the female but not male mutants in the locus coeruleus. We have also confirmed the utility of the investigated model in pharmacological studies, which demonstrates that the depressive-like phenotype of GR(DBHCre) female mice can be reversed by antidepressant treatment with desipramine or fluoxetine, with the latter drug evoking more pronounced effects. Overall, our study validates the use of female GR(DBHCre) mice as an interesting and novel genetic tool for the investigation of the cross-connected mechanisms of depression that is not only based on behavioral phenotypes.
-
inactivation of glucocorticoid receptor in Noradrenergic System influences anxiety and depressive like behavior in mice
PLOS ONE, 2013Co-Authors: Piotr Chmielarz, Irena Nalepa, Justyna Kuśmierczyk, Rosanna Parlato, Gunther Schutz, Grzegorz KreinerAbstract:The aim of this study was to investigate whether conditional inactivation of the glucocorticoid receptors (GRs) in Noradrenergic neurons affects animal behavior in mice. Selective ablation of GRs in the Noradrenergic System was achieved using the Cre/loxP approach. We crossed transgenic mice expressing the Cre recombinase under the dopamine beta-hydroxylase (DBH) promoter with animals harboring the floxed GR gene. The resulting GRDBHCre mutant mice exhibited no alterations in terms of normal cage behavior, weight gain, spatial memory or spontaneous locomotor activity, regardless of gender. To assess depressive- and anxiety-like behaviors we performed the Tail Suspension Test and the Light-Dark Box Test. While male mutant animals did not show any alternations in both tests, female GRDBHCre mutants displayed depressive- and anxiety-like behavior. Additionally, male GRDBHCre mice were exposed to chronic restraint stress but still exhibited immobility times and anxiety statuses similar to those of non-stressed animals while stressed control mice clearly revealed depressive- and anxiety-like phenotype. Thus, in males the effects of the mutation were precipitated only after chronic restraint stress procedure. Our data reveal a possible gender-dependent role of GRs in the Noradrenergic System in anxiety- and depressive-like behavior in mice.
