Milk Ejection Burst-Like Electrical Activity Evoked in Supraoptic Oxytocin Neurons in Slices From Lactating Rats

2004 ◽  
Vol 91 (5) ◽  
pp. 2312-2321 ◽  
Author(s):  
Yu-Feng Wang ◽  
Glenn I. Hatton
Keyword(s):  
Membrane Potential ◽  
Firing Rate ◽  
Membrane Conductance ◽  
Peak Level ◽  
Sudden Increase ◽  
Milk Ejection ◽  
Peak Rate ◽  
Vasopressin Neurons

To examine the mechanisms underlying milk-ejection bursts of oxytocin (OT) neurons during suckling, both in vivo and in vitro studies were performed on supraoptic OT neurons from lactating rats. The bursts were first recorded extracellularly in anesthetized rats. Burst-related electrical parameters were essentially the same as previous reports except for a trend toward transient decreases in basal firing rates immediately preceding the burst. From putative OT neurons in slices with extracellular recordings, bursts that closely mimicked the in vivo bursts were elicited by phenylephrine, an α1-adrenoceptor agonist, in a low-Ca2+ medium. Moreover, in whole cell patch-clamp recordings, the in vitro bursts were recorded from immunocytochemically identified OT neurons. After a transient decrease in the basal firing rate, the in vitro bursts started with a sudden increase in the firing rate, quickly reaching a peak level, then gradually decaying, and ended with a postburst inhibition. A brief depolarization of the membrane potential and an increase in membrane conductance appeared after the onset of the burst. Spikes during a burst were characterized by a significant increase in the duration and decrease in the amplitude around the peak rate firing. These bursts were significantly different from short-lasting burst firing of vasopressin neurons in membrane potential changes, time to reach peak firing rate, spike amplitude and duration during peak rate firing. Our extensive analysis of these results suggests that the in vitro burst is a useful model for further study of mechanisms underlying milk-ejection bursts of OT neurons in vivo.

Autofeedback effects of progressively rising oxytocin concentrations on supraoptic oxytocin neuronal activity in slices from lactating rats

2006 ◽  
Vol 290 (5) ◽  
pp. R1191-R1198 ◽  
Author(s):  
Yu-Feng Wang ◽  
Todd A. Ponzio ◽  
Glenn I. Hatton
Keyword(s):  
Firing Rate ◽  
Peak Level ◽  
Milk Ejection ◽  
Whole Cell Patch Clamp ◽  
Glutamate Receptor Antagonists ◽  
Potential Spike ◽  
High Concentrations ◽  
Milk Ejection Reflex ◽  
Vasopressin Neurons ◽  
Dose Dependent

Suckling stimuli induce somatodendritic oxytocin (OT) release from supraoptic nucleus (SON) neurons, which raises intranuclear OT concentrations and contributes to the effectiveness of the milk-ejection reflex. To clarify how such changes in OT concentrations modulate the activity of OT neurons, we examined OT effects using whole cell patch-clamp recordings from SON neurons in slices from lactating rats. Progressive increases from extremely low OT concentrations (0.1–10 fM) to high concentrations (0.1–10 nM) induced excitation and subsequent spike frequency reduction (SFR) in OT neurons. Significant effects of OT on firing rates were observed starting at 1 fM, reached peak level from 1 fM to 1 pM before SFR occurred in most neurons. The buildup of OT concentrations progressively promoted depolarization of membrane potential, spike broadening, decreases in spike amplitude, and increases in the rise time of spike afterhyperpolarizations, which were unrelated to firing rate. However, intermittent application of OT (1 fM, 1 pM, and 1 nM, each for 5 min) evoked dose-dependent excitation but not the SFR. Application of 1 pM OT for 40 min simulated the effects of progressively increasing OT concentrations. Vasopressin neurons were also activated by OT but did not show SFR. Consistent with presynaptic loci of OT action, ionotropic glutamate receptor antagonists reduced OT effects on firing rate, whereas bicuculline did not change the excitatory effects. These results suggest that the specific autoregulatory effects of OT, and perhaps other neuropeptides as well, are time and concentration dependent.

scholarly journals Review of T-2307, an Investigational Agent That Causes Collapse of Fungal Mitochondrial Membrane Potential

2021 ◽  
Vol 7 (2) ◽  
pp. 130
Author(s):  
Nathan P. Wiederhold
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Candida Species ◽  
Mammalian Cells ◽  
Mitochondrial Membrane ◽  
Fungal Infections ◽  
Published Data ◽  
Candida Auris

Invasive infections caused by Candida that are resistant to clinically available antifungals are of increasing concern. Increasing rates of fluconazole resistance in non-albicans Candida species have been documented in multiple countries on several continents. This situation has been further exacerbated over the last several years by Candida auris, as isolates of this emerging pathogen that are often resistant to multiple antifungals. T-2307 is an aromatic diamidine currently in development for the treatment of invasive fungal infections. This agent has been shown to selectively cause the collapse of the mitochondrial membrane potential in yeasts when compared to mammalian cells. In vitro activity has been demonstrated against Candida species, including C. albicans, C. glabrata, and C. auris strains, which are resistant to azole and echinocandin antifungals. Activity has also been reported against Cryptococcus species, and this has translated into in vivo efficacy in experimental models of invasive candidiasis and cryptococcosis. However, little is known regarding the clinical efficacy and safety of this agent, as published data from studies involving humans are not currently available.

scholarly journals Imaging the transmembrane and transendothelial sodium gradients in gliomas

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Muhammad H. Khan ◽  
John J. Walsh ◽  
Jelena M. Mihailović ◽  
Sandeep K. Mishra ◽  
Daniel Coman ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Magnetic Resonance ◽  
Cell Membrane ◽  
Normal Tissue ◽  
Magnetic Resonance Spectroscopic Imaging ◽  
Biological Factors ◽  
High Sodium ◽  
Intracellular Milieu

AbstractUnder normal conditions, high sodium (Na+) in extracellular (Na+e) and blood (Na+b) compartments and low Na+ in intracellular milieu (Na+i) produce strong transmembrane (ΔNa+mem) and weak transendothelial (ΔNa+end) gradients respectively, and these manifest the cell membrane potential (Vm) as well as blood–brain barrier (BBB) integrity. We developed a sodium (23Na) magnetic resonance spectroscopic imaging (MRSI) method using an intravenously-administered paramagnetic polyanionic agent to measure ΔNa+mem and ΔNa+end. In vitro 23Na-MRSI established that the 23Na signal is intensely shifted by the agent compared to other biological factors (e.g., pH and temperature). In vivo 23Na-MRSI showed Na+i remained unshifted and Na+b was more shifted than Na+e, and these together revealed weakened ΔNa+mem and enhanced ΔNa+end in rat gliomas (vs. normal tissue). Compared to normal tissue, RG2 and U87 tumors maintained weakened ΔNa+mem (i.e., depolarized Vm) implying an aggressive state for proliferation, whereas RG2 tumors displayed elevated ∆Na+end suggesting altered BBB integrity. We anticipate that 23Na-MRSI will allow biomedical explorations of perturbed Na+ homeostasis in vivo.

Serotonin has different effects on two classes of Betz cells from the cat

1994 ◽  
Vol 72 (4) ◽  
pp. 1925-1937 ◽  
Author(s):  
W. J. Spain
Keyword(s):  
Firing Rate ◽  
Potassium Conductance ◽  
Membrane Conductance ◽  
Constant Current ◽  
Repetitive Firing ◽  
Calcium Dependent ◽  
Constant Current Stimulation ◽  
Ionic Mechanisms ◽  
Betz Cells

1. Intracellular recording from cat Betz cells in vitro revealed a strong correlation between the dominant effect of serotonin (5-HT) and the Betz cell subtype in which it occurred. In large Betz cells that show posthyperpolarization excitation (termed PHE cells), 5-HT evoked a long-lasting membrane depolarization, whereas 5-HT evoked an initial hyperpolarization of variable duration in smaller Betz cells that show posthyperpolorization inhibition (termed PHI cells). 2. Voltage-clamp studies revealed that 5-HT caused a depolarizing shift of activation of the cation current Ih, which resulted in the depolarization in PHE cells, whereas the hyperpolarization in PHI cells is caused by an increase in a resting potassium conductance. 3. The effect of 5-HT on firing properties during constant current stimulation also differed consistently in the two types of Betz cells. In PHE cells the initial firing rate increased after 5-HT application, but the steady firing was unaffected. The depolarizing shift of Ih activation caused the increase of initial firing rate. 4. In PHI cells 5-HT caused a decrease in spike frequency adaptation. The decrease in adaptation was caused by a combination of two conductance changes. First, 5-HT caused a slow afterdepolarization in PHI cells that could trigger repetitive firing in the absence of further stimulation. The sADP depended on calcium entry through voltage-gated channels and was associated with a decrease in membrane conductance. Second, 5-HT caused reduction of a slow calcium-dependent potassium current that normally contributes to slow adaptation. 5. In conclusion, the effect of 5-HT on excitability differs systematically in Betz cell subtypes in part because they have different dominant ionic mechanisms that are modulated. If we assume that PHE cells and PHI cells represent fast and slow pyramidal tract (PT) neurons respectively, 5-HT will cause early recruitment of fast PT cells and delay recruitment of slow PT cells during low levels of synaptic excitation.

scholarly journals The Whisking Rhythm Generator: A Novel Mammalian Network for the Generation of Movement

2007 ◽  
Vol 97 (3) ◽  
pp. 2148-2158 ◽  
Author(s):  
Nathan P. Cramer ◽  
Ying Li ◽  
Asaf Keller
Keyword(s):  
Firing Rate ◽  
Serotonin Receptor ◽  
Central Pattern Generators ◽  
Rhythm Generator ◽  
Low Concentrations ◽  
Rhythmic Firing ◽  
Pattern Generators ◽  
Cortical Inputs

Using the rat vibrissa system, we provide evidence for a novel mechanism for the generation of movement. Like other central pattern generators (CPGs) that underlie many movements, the rhythm generator for whisking can operate without cortical inputs or sensory feedback. However, unlike conventional mammalian CPGs, vibrissa motoneurons (vMNs) actively participate in the rhythmogenesis by converting tonic serotonergic inputs into the patterned motor output responsible for movement of the vibrissae. We find that, in vitro, a serotonin receptor agonist, α-Me-5HT, facilitates a persistent inward current (PIC) and evokes rhythmic firing in vMNs. Within each motoneuron, increasing the concentration of α-Me-5HT significantly increases the both the magnitude of the PIC and the motoneuron's firing rate. Riluzole, which selectively suppresses the Na+ component of PICs at low concentrations, causes a reduction in both of these phenomena. The magnitude of this reduction is directly correlated with the concentration of riluzole. The joint effects of riluzole on PIC magnitude and firing rate in vMNs suggest that the two are causally related. In vivo we find that the tonic activity of putative serotonergic premotoneurons is positively correlated with the frequency of whisking evoked by cortical stimulation. Taken together, these results support the hypothesized novel mammalian mechanism for movement generation in the vibrissa motor system where vMNs actively participate in the rhythmogenesis in response to tonic drive from serotonergic premotoneurons.

Temporal constraints in associative synaptic plasticity in hippocampus and neocortex

1995 ◽  
Vol 73 (9) ◽  
pp. 1295-1311 ◽  
Author(s):  
Dominique Debanne ◽  
Daniel E. Shulz ◽  
Yves Frégnac
Keyword(s):  
Visual Cortex ◽  
Membrane Potential ◽  
Temporal Frequency ◽  
Postsynaptic Membrane ◽  
Synaptic Potentiation ◽  
Test Input ◽  
Homosynaptic Depression ◽  
Postsynaptic Cell

We present comparative experimental evidence for the induction of synaptic potentiation and depression in organotypic cultures of hippocampus and in visual cortex in vitro and in vivo. The effects of associative pairings on the efficacy of synaptic transmission are analyzed as a function of the temporal delay between presynaptic activity and post-synaptic changes imposed in membrane potential. Synchronous association at a low temporal frequency (<0.5 Hz) between presynaptic input and postsynaptic depolarization resulted in homosynaptic potentiation of functionally identified postsynaptic potentials in the three types of preparation. Synchronous pairing of afferent activity with hyperpolarization of the postsynaptic cell resulted in homosynaptic depression in visual cortex in vivo and in vitro. An associative form of depression was induced in hippocampus when the test input was followed repeatedly with a fixed-delay postsynaptic depolarization imposed either by intracellular current injection or synaptically. The latter process might play a significant role in heterosynaptic plasticity in visual cortex in vivo and in vitro, if it is assumed that associative depression still operates in visual cortex a few seconds after the initial surge of calcium in the postsynaptic cell. We conclude that the precise timing between presynaptic activity and polarization changes in postsynaptic membrane potential up- and down-regulates the efficacy of active pathways.Key words: synaptic potentiation, synaptic depression, asynchrony, covariance, supervised learning.

scholarly journals Meloxicam, a Selective COX-2 Inhibitor, Mediates Hypoxia-Inducible Factor- (HIF-) 1α Signaling in Hepatocellular Carcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Yinghong Zhou ◽  
Xiaofeng Dong ◽  
Peng Xiu ◽  
Xin Wang ◽  
Jianrong Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Transcriptional Activation ◽  
Mitochondrial Membrane ◽  
Hypoxia Inducible Factor ◽  
Luciferase Assay ◽  
Cox 2

Hepatocellular carcinoma (HCC) is regarded as a leading cause of cancer-related deaths, and its progression is associated with hypoxia and the induction of hypoxia-inducible factor (HIF). Meloxicam, a selective cyclooxygenase-2 (COX-2) inhibitor, induces cell death in various malignancies. However, the underlying mechanism remains to be elucidated in HCC, especially under hypoxic conditions. The alteration of COX-2 and HIF-1α oncogenicity was evaluated in HCC specimens by tissue microarray. Cell viability, angiogenesis assays, and xenografted nude mice were used to evaluate the effects of meloxicam, along with flow cytometry to detect the cell cycle, apoptosis, and mitochondrial membrane potential (ΔΨm) of HCC. qRT-PCR, Western blotting, immunofluorescence, immunohistochemistry, luciferase assay, and RNAi were carried out to determine the HIF-1α signaling affected by meloxicam. In this study, we showed that meloxicam exerts antiproliferative and antiangiogenesis efficacy in vitro and in vivo and causes disruption of mitochondrial membrane potential (ΔΨm), thus leading to caspase-dependent apoptosis under hypoxic environments. Exposure to meloxicam significantly reduced HIF-1α transcriptional activation and expression through sequestering it in the cytoplasm and accelerating degradation via increasing the von Hippel-Lindau tumor suppressor protein (pVHL) in HCC. These data demonstrated that inhibition of HIF-1α by meloxicam could suppress angiogenesis and enhance apoptosis of HCC cells. This discovery highlights that COX-2 specific inhibitors may be a promising therapy in the treatment of HCC.

NO inhibits supraoptic oxytocin and vasopressin neurons via activation of GABAergic synaptic inputs

2001 ◽  
Vol 280 (6) ◽  
pp. R1815-R1822 ◽  
Author(s):  
Javier E. Stern ◽  
Mike Ludwig
Keyword(s):  
Neuronal Excitability ◽  
Cell Types ◽  
Synaptic Activity ◽  
No Donor ◽  
Whole Cell Patch Clamp ◽  
Electrophysiological Recordings ◽  
Neuronal Types ◽  
Vasopressin Neurons

To study modulatory actions of nitric oxide (NO) on GABAergic synaptic activity in hypothalamic magnocellular neurons in the supraoptic nucleus (SON), in vitro and in vivo electrophysiological recordings were obtained from identified oxytocin and vasopressin neurons. Whole cell patch-clamp recordings were obtained in vitro from immunochemically identified oxytocin and vasopressin neurons. GABAergic synaptic activity was assessed in vitro by measuring GABAA miniature inhibitory postsynaptic currents (mIPSCs). The NO donor and precursor sodium nitroprusside (SNP) and l-arginine, respectively, increased the frequency and amplitude of GABAA mIPSCs in both cell types ( P ≤ 0.001). Retrodialysis of SNP (50 mM) onto the SON in vivo inhibited the activity of both neuronal types ( P ≤ 0.002), an effect that was reduced by retrodialysis of the GABAA-receptor antagonist bicuculline (2 mM, P≤ 0.001). Neurons activated by intravenous infusion of 2 M NaCl were still strongly inhibited by SNP. These results suggest that NO inhibition of neuronal excitability in oxytocin and vasopressin neurons involves pre- and postsynaptic potentiation of GABAergic synaptic activity in the SON.

Possible Effects of Depolarizing GABAA Conductance on the Neuronal Input–Output Relationship: A Modeling Study

2005 ◽  
Vol 93 (6) ◽  
pp. 3504-3523 ◽  
Author(s):  
Kenji Morita ◽  
Kunichika Tsumoto ◽  
Kazuyuki Aihara
Keyword(s):  
Firing Rate ◽  
Cortical Neurons ◽  
Reversal Potential ◽  
Pyramidal Cells ◽  
Resting Potential ◽  
Input Output ◽  
Wide Range ◽  
The Relationship

Recent in vitro experiments revealed that the GABAA reversal potential is about 10 mV higher than the resting potential in mature mammalian neocortical pyramidal cells; thus GABAergic inputs could have facilitatory, rather than inhibitory, effects on action potential generation under certain conditions. However, how the relationship between excitatory input conductances and the output firing rate is modulated by such depolarizing GABAergic inputs under in vivo circumstances has not yet been understood. We examine herewith the input–output relationship in a simple conductance-based model of cortical neurons with the depolarized GABAA reversal potential, and show that a tonic depolarizing GABAergic conductance up to a certain amount does not change the relationship between a tonic glutamatergic driving conductance and the output firing rate, whereas a higher GABAergic conductance prevents spike generation. When the tonic glutamatergic and GABAergic conductances are replaced by in vivo–like highly fluctuating inputs, on the other hand, the effect of depolarizing GABAergic inputs on the input–output relationship critically depends on the degree of coincidence between glutamatergic input events and GABAergic ones. Although a wide range of depolarizing GABAergic inputs hardly changes the firing rate of a neuron driven by noncoincident glutamatergic inputs, a certain range of these inputs considerably decreases the firing rate if a large number of driving glutamatergic inputs are coincident with them. These results raise the possibility that the depolarized GABAA reversal potential is not a paradoxical mystery, but is instead a sophisticated device for discriminative firing rate modulation.

Synaptic and intrinsic responses of medical entorhinal cortical cells in normal and magnesium-free medium in vitro

1988 ◽  
Vol 59 (5) ◽  
pp. 1476-1496 ◽  
Author(s):  
R. S. Jones ◽  
U. Heinemann
Keyword(s):  
Entorhinal Cortex ◽  
Action Potentials ◽  
Membrane Conductance ◽  
Nmda Receptor Antagonist ◽  
Field Potentials ◽  
Cortical Cells ◽  
Medial Entorhinal Cortex ◽  
Membrane Hyperpolarization

1. Extracellular recordings were made from slices of hippocampus plus parahippocampal regions maintained in vitro. Field potentials, recorded in the entorhinal cortex after stimulation in the subiculum, resembled those observed in vivo. 2. Washout of magnesium from the slices resulted in paroxysmal events which resembled those occurring during sustained seizures in vivo. These events were greatest in amplitude and duration in layers IV/V of the medial entorhinal cortex and could occur both spontaneously and in response to subicular stimulation. Spontaneous seizure-like events were not prevented by severing the connections between the hippocampus and entorhinal cortex, but much smaller and shorter events occurring in the dentate gyrus were stopped by this manipulation. Both spontaneous and evoked paroxysmal events were blocked by perfusion with the N-methyl-D-aspartate (NMDA) receptor antagonist, DL-2-amino-5-phosphonovalerate (2-AP5). 3. Neurons in layers IV/V were characterized by intracellular recording. Injection of depolarizing current in most cells evoked a train of nondecrementing action potentials with only weak spike frequency accommodation and little or no posttrain after hyperpolarization. 4. A small number of cells displayed burst response when depolarized by positive current. The burst consisted of a slow depolarization with superimposed action potentials which decreased in amplitude and increased in duration during the discharge. The burst was terminated by a strong after hyperpolarization and thereafter, during prolonged current pulses a train of nondecrementing spikes occurred. The burst response remained if the cell was held at hyperpolarized levels but was inactivated by holding the cell at a depolarized level. 5. Depolarizing synaptic potentials could be evoked by stimulation in the subiculum. A delayed and prolonged depolarization clearly decremented with membrane hyperpolarization and, occasionally, increased with depolarization. 6. Washout of magnesium from the slices resulted in an enhancement of the late depolarization and a reversal of its voltage dependence. Eventually a single shock to the subiculum evoked a large all-or-none paroxysmal depolarization associated with a massive increase in membrane conductance. Similar events occurred spontaneously in all cells tested. The paroxysmal depolarizations, both spontaneous and evoked, were rapidly blocked by 2-AP5. 7. It is concluded that medial entorhinal cortical cells possess several intrinsic and synaptic properties which confer an extreme susceptibility to generation of sustained seizure activity.(ABSTRACT TRUNCATED AT 400 WORDS)

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