Dopamine Increases the Gain of the Input-Output Response of Rat Prefrontal Pyramidal Neurons

Dopaminergic modulation of prefrontal cortical activity is known to affect cognitive functions like working memory. Little consensus on the role of dopamine modulation has been achieved, however, in part because quantities directly relating to the neuronal substrate of working memory are difficult to measure. Here we show that dopamine increases the gain of the frequency-current relationship of layer 5 pyramidal neurons in vitro in response to noisy input currents. The gain increase could be attributed to a reduction of the slow afterhyperpolarization by dopamine. Dopamine also increases neuronal excitability by shifting the input-output functions to lower inputs. The modulation of these response properties is mainly mediated by D1 receptors. Integrate-and-fire neurons were fitted to the experimentally recorded input-output functions and recurrently connected in a model network. The gain increase induced by dopamine application facilitated and stabilized persistent activity in this network. The results support the hypothesis that catecholamines increase the neuronal gain and suggest that dopamine improves working memory via gain modulation.

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Background Activity Regulates Excitability of Rat Hippocampal CA1 Pyramidal Neurons by Adaptation of a K+ Conductance

Journal of Neurophysiology ◽

10.1152/jn.00220.2005 ◽

2006 ◽

Vol 95 (3) ◽

pp. 2007-2012 ◽

Cited By ~ 11

Author(s):

Ingrid van Welie ◽

Johannes A. van Hooft ◽

Wytse J. Wadman

Keyword(s):

Neuronal Excitability ◽

Pyramidal Neurons ◽

Dynamic Range ◽

Background Activity ◽

Hippocampal Slices ◽

Synaptic Activity ◽

Input Output ◽

Ca1 Pyramidal Neurons

In the in vivo brain background synaptic activity has a strong modulatory influence on neuronal excitability. Here we report that in rat hippocampal slices, blockade of endogenous in vitro background activity results in an increased excitability of CA1 pyramidal neurons within tens of minutes. The increase in excitability constitutes a leftward shift in the input–output relationship of pyramidal neurons, indicating a reduced threshold for the induction of action potentials. The increase in excitability results from an adaptive decrease in a sustained K+ conductance, as recorded from somatic cell–attached patches. After 20 min of blockade of background activity, the mean sustained K+ current amplitude in somatic patches was reduced to 46 ± 9% of that in time-matched control patches. Blockade of background activity did not affect fast Na+ conductance. Together, these results suggests that the reduction in K+ conductance serves as an adaptive mechanism to increase the excitability of CA1 pyramidal neurons in response to changes in background activity such that the dynamic range of the input–output relationship is effectively maintained.

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STEROID HORMONE METABOLISM IN RESPONSIVE TISSUES IN VITRO

Acta Endocrinologica ◽

10.1530/acta.0.068s279 ◽

1971 ◽

Vol 68 (1_Suppl) ◽

pp. S279-S294 ◽

Cited By ~ 12

Author(s):

Paul Robel

Keyword(s):

Steroid Hormone ◽

Physiological Activity ◽

Physiological State ◽

Target Cells ◽

Target Tissue ◽

Hormone Metabolism ◽

Metabolizing Enzymes ◽

Relationship Of

ABSTRACT Of the information available on steroid hormone metabolism in responsive tissues, only that relating hormone metabolism to physiological activity is reviewed, i. e. metabolite activity in isolated in vitro systems, binding of metabolites to target tissue receptors, specific steroid hormone metabolizing enzymes and relationship of hormone metabolism to target organ physiological state. Further, evidence is presented in the androgen field, demonstrating 5α-reduced metabolites, formed inside the target cells, as active compounds. This has led to a consideration of testosterone as a »prehormone«. The possibility that similar events take place in tissues responding to progesterone is discussed. Finally, the role of hormone metabolism in the regulation of hormone availability and/or renewal in target cells is discussed. In this context, reference is made to the potential role of plasma binding proteins and cytosol receptors.

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The scattered puzzle effect: implantation disorders in chronic endometritis

GYNECOLOGY ◽

10.26442/20795696.2020.6.200493 ◽

2020 ◽

Vol 22 (6) ◽

pp. 93-100

Author(s):

Victor E. Radzinsky ◽

Mekan R. Orazov ◽

Liliia R. Toktar ◽

Liudmila M. Mihaleva ◽

Pavel A. Semenov ◽

...

Keyword(s):

Uterine Cavity ◽

Special Role ◽

Inadequate Response ◽

Chronic Endometritis ◽

Vitro Fertilization ◽

Endometrial Cells ◽

Adverse Pregnancy ◽

Relationship Of

Chronic endometritis (CE) is defined as a state of inflammation localized in the endometrium, accompanied by edema, dissociated maturation of epithelial cells and fibroblasts, increased stromal density and the presence of plasma cell infiltrate in it. The connection between chronic inflammation in the endometrium and infertility deserves special attention. Inadequate response of immunocompetent endometrial cells, including impaired synthesis of proinflammatory cytokines, dysreceptiveness, disorders of proliferation and differentiation processes are the main links in the formation of infertility in patients with CE. Despite the fact that the presence of a normocenosis of the uterine cavity today is not in doubt this is a physiological norm, persistent bacterial infection of the endometrium is still called the main etiopathogenetic factor of CE and, therefore, the main point of application of therapeutic agents. Nevertheless, a number of works have emphasized the special role of not bacterial, but viral etiology of endometritis, especially in the context of infertility developing against this background. It seems that the role of viral endometrial infection in adverse pregnancy outcomes and in vitro fertilization programs is underestimated. Further research is needed to clarify the relationship of viral infection as a trigger of implantation failure in infertile women with CE.

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TNF-α and myocardial depression in endotoxemic rats: temporal discordance of an obligatory relationship

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.275.2.r502 ◽

1998 ◽

Vol 275 (2) ◽

pp. R502-R508 ◽

Cited By ~ 13

Author(s):

Xianzhong Meng ◽

Lihua Ao ◽

Daniel R. Meldrum ◽

Brian S. Cain ◽

Brian D. Shames ◽

...

Keyword(s):

Temporal Relationship ◽

Contractile Function ◽

Myocardial Depression ◽

Tnf Α ◽

Myocardial Contractile ◽

Factor Α ◽

Relationship Of

Exogenous tumor necrosis factor-α (TNF-α) induces delayed myocardial depression in vivo but promotes rapid myocardial depression in vitro. The temporal relationship between endogenous TNF-α and endotoxemic myocardial depression is unclear, and the role of TNF-α in this myocardial disorder remains controversial. Using a rat model of endotoxemia not complicated by shock, we sought to determine 1) the temporal relationship of changes in circulating and myocardial TNF-α with myocardial depression, 2) the influences of protein synthesis inhibition or immunosuppression on TNF-α production and myocardial depression, and 3) the influence of neutralization of TNF-α on myocardial depression. Rats were treated with lipopolysaccharide (LPS, 0.5 mg/kg ip). Circulating and myocardial TNF-α increased at 1 and 2 h, whereas myocardial contractility was depressed at 4 and 6 h. Pretreatment with cycloheximide or dexamethasone abolished the increase in circulating and myocardial TNF-α and preserved myocardial contractile function. Similarly, treatment with TNF binding protein immediately after LPS prevented myocardial depression. We conclude that endogenous TNF-α mediates delayed myocardial depression in endotoxemic rats and that inhibition of TNF-α production or neutralization of TNF-α preserves myocardial contractile function in endotoxemia.

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Neuromodulation by a Cytokine: Interferon-β Differentially Augments Neocortical Neuronal Activity and Excitability

Journal of Neurophysiology ◽

10.1152/jn.01224.2003 ◽

2005 ◽

Vol 93 (2) ◽

pp. 843-852 ◽

Cited By ~ 21

Author(s):

Gergana Hadjilambreva ◽

Eilhard Mix ◽

Arndt Rolfs ◽

Jana Müller ◽

Ulf Strauss

Keyword(s):

Neuronal Excitability ◽

Pyramidal Neurons ◽

Membrane Resistance ◽

Interferon Β ◽

Action Potential Firing ◽

Somatosensory Neurons ◽

Potential Firing ◽

Intracellular Process ◽

Neuronal Functions

The immunomodulatory cytokine interferon-β (IFN-β) is used in the treatment of autoimmune diseases such as multiple sclerosis. However, the effect of IFN-β on neuronal functions is currently unknown. Intracellular recordings were conducted on somatosensory neurons of neocortical layers 2/3 and 5 exposed to IFN-β. The excitability of neurons was increased by IFN-β (10–10,000 U/ml) in two kinetically distinct, putatively independent manners. First IFN-β reversibly influenced the subthreshold membrane response by raising the membrane resistance RM 2.5-fold and the membrane time constant τ 1.7-fold dose-dependently. The effect required permanent exposure to IFN-β and was reduced in magnitude if the extracellular K+ was lowered. However, the membrane response to IFN-β in the subthreshold range was prevented by ZD7288 (a specific blocker of Ih) but not by Ni2+, carbachol, or bicuculline, pointing to a dependence on an intact Ih. Second, IFN-β enhanced the rate of action potential firing. This effect was observed to develop for >1 h when the cell was exposed to IFN-β for 5 min or >5 min and showed no reversibility (≤210 min). Current-discharge ( F-I) curves revealed a shift (prevented by bicuculline) as well as an increase in slope (prevented by carbachol and Ni2+). Layer specificity was not observed with any of the described effects. In conclusion, IFN-β influences the neuronal excitability in neocortical pyramidal neurons in vitro, especially under conditions of slightly increased extracellular K+. Our blocker experiments indicate that changes in various ionic conductances with different voltage dependencies cause different IFN-β influences on sub- and suprathreshold behavior, suggesting a more general intracellular process induced by IFN-β.

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Conditional Upregulation of KCC2 selectively enhances neuronal inhibition during seizures

10.1101/253831 ◽

2018 ◽

Cited By ~ 1

Author(s):

CS Goulton ◽

M Watanabe ◽

DL Cheung ◽

KW Wang ◽

T Oba ◽

...

Keyword(s):

Status Epilepticus ◽

Transgenic Mouse ◽

Brain Function ◽

Neuronal Excitability ◽

Hippocampal Slices ◽

Transport Function ◽

Neuronal Inhibition ◽

Proof Of Principle

Abstract/SummaryEfficacious neuronal inhibition is sustained by the neuronal K+Cl- co-transporter KCC2, and loss of KCC2 function through injury or mutation is associated with altered GABAergic signalling and neuronal seizures. Here we report a transgenic mouse with conditional KCC2 overexpression that results in increased membrane transport function. Increased KCC2 has little impact on behavioural and in vitro assays of neuronal excitability and GABAA receptor responses under resting conditions. In contrast, increased KCC2 imparts resistance to seizure-like neuronal activity in hippocampal slices and prevents the progression of mice into behavioural status epilepticus following multiple kainic acid doses. Our results demonstrate a transgenic mouse to facilitate investigations into the role of KCC2 in brain function, and provide a proof of principle that targeting KCC2 may be an effective way to selectively enhance neuronal inhibition to mitigate against diseases that involve an imbalance between excitation and inhibition.

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RGS7/Gβ5/R7BP complex regulates synaptic plasticity and memory by modulating hippocampal GABABR-GIRK signaling

eLife ◽

10.7554/elife.02053 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 41

Author(s):

Olga Ostrovskaya ◽

Keqiang Xie ◽

Ikuo Masuho ◽

Ana Fajardo-Serrano ◽

Rafael Lujan ◽

...

Keyword(s):

Synaptic Plasticity ◽

Neuronal Excitability ◽

Pyramidal Neurons ◽

Dynamic Range ◽

Gabab Receptor ◽

Girk Channels ◽

Hippocampal Pyramidal Neurons ◽

Inhibitory Neurotransmitter ◽

Membrane Anchoring

In the hippocampus, the inhibitory neurotransmitter GABA shapes the activity of the output pyramidal neurons and plays important role in cognition. Most of its inhibitory effects are mediated by signaling from GABAB receptor to the G protein-gated Inwardly-rectifying K+ (GIRK) channels. Here, we show that RGS7, in cooperation with its binding partner R7BP, regulates GABABR-GIRK signaling in hippocampal pyramidal neurons. Deletion of RGS7 in mice dramatically sensitizes GIRK responses to GABAB receptor stimulation and markedly slows channel deactivation kinetics. Enhanced activity of this signaling pathway leads to decreased neuronal excitability and selective disruption of inhibitory forms of synaptic plasticity. As a result, mice lacking RGS7 exhibit deficits in learning and memory. We further report that RGS7 is selectively modulated by its membrane anchoring subunit R7BP, which sets the dynamic range of GIRK responses. Together, these results demonstrate a novel role of RGS7 in hippocampal synaptic plasticity and memory formation.

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Role of miR-100-5p and CDC25A in breast carcinoma cells

PeerJ ◽

10.7717/peerj.12263 ◽

2022 ◽

Vol 9 ◽

pp. e12263

Author(s):

Xiaoping Li ◽

Yanli Ren ◽

Donghong Liu ◽

Xi Yu ◽

Keda Chen

Keyword(s):

Breast Carcinoma ◽

Carcinoma Cells ◽

Luciferase Assay ◽

Migration And Invasion ◽

Mrna Levels ◽

Breast Carcinoma Cells ◽

Cell Functions ◽

Relationship Of

Objective To inquiry about mechanism of miR-100-5p/CDC25A axis in breast carcinoma (BC), thus offering a new direction for BC targeted treatment. Methods qRT-PCR was employed to explore miR-100-5p and CDC25A mRNA levels. Western blot was employed for detecting protein expression of CDC25A. Targeting relationship of miR-100-5p and CDC25A was verified by dual-luciferase assay. In vitro experiments were used for assessment of cell functions. Results In BC tissue and cells, miR-100-5p was significantly lowly expressed (P < 0.05) while CDC25A was highly expressed. Besides, miR-100-5p downregulated CDC25A level. miR-100-5p had a marked influence on the prognosis of patients. The forced miR-100-5p expression hindered BC cell proliferation, migration and invasion, and facilitated cell apoptosis. Upregulated miR-100-5p weakened promotion of CDC25A on BC cell growth. Conclusion Together, these findings unveiled that CDC25A may be a key target of miR-100-5p that mediated progression of BC cells. Hence, miR-100-5p overexpression or CDC25A suppression may contribute to BC diagnosis.

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