Modulation Of Electrical Activity Research Articles

Intrapallidal injection of botulinum toxin A recovers gait deficits in a parkinsonian rodent model.

Modulation of electrical activity in the subthalamic nucleus has been therapeutically effective in Parkinson's disease. Pharmacological manipulation of glutamate release from subthalamic neurons could also favourably alter basal ganglia activity to improve motor symptoms. This study investigates the efficacy of selective suppression of hyperactive glutamatergic input from the subthalamic nucleus to the globus pallidus internal segment by botulinum toxin A (BoNT-A) in a parkinsonian model. Unilateral 6-hydroxydopamine lesioned parkinsonian rodents and controls received microinfusions of BoNT-A or vehicle into the ipsilateral internal globus pallidus (n=8 per group). Changes in gait were measured by the CatWalk apparatus, along with assessment of apomorphine-induced rotational behaviour prior to and following BoNT-A injection. Immunofluorescent staining for markers of glutamatergic, GABAergic and total terminals was performed at the internal globus pallidus. Administration of a single dose of BoNT-A (0.5ng) significantly improved the rotational asymmetry and gait abnormalities. Ameliorations in speed, body speed variation, cadence and walking pattern were comparable to pre-lesioned animals, and persisted up to 1month following BoNT-A injection. These changes are associated to BoNT-A's ability to selectively target glutamatergic terminals. Blockade of subthalamic hyperactivity by BoNT-A leads to sufficient reorganization in the basal ganglia needed to generate a consistent rhythmic pattern of walking. This suggests the potential use of intracerebral BoNT-A to produce effective neuromodulation in the parkinsonian brain, as well as expansion into other neurodegenerative disorders linked to excitotoxity.

Transcriptome landmarks of the functional maturity of rat beta-cells, from lactation to adulthood.

Research on the postnatal development of pancreatic beta-cells has become an important subject in recent years. Understanding the mechanisms that govern beta-cell postnatal maturation could bring new opportunities to therapeutic approaches for diabetes. The weaning period consists of a critical postnatal window for structural and physiologic maturation of rat beta-cells. To investigate transcriptome changes involved in the maturation of beta-cells neighboring this period, we performed microarray analysis in fluorescence-activated cell-sorted (FACS) beta-cell-enriched populations. Our results showed a variety of gene sets including those involved in the integration of metabolism, modulation of electrical activity, and regulation of the cell cycle that play important roles in the maturation process. These observations were validated using reverse hemolytic plaque assay, electrophysiological recordings, and flow cytometry analysis. Moreover, we suggest some unexplored pathways such as sphingolipid metabolism, insulin-vesicle trafficking, regulation of transcription/transduction by miRNA-30, trafficking proteins, and cell cycle proteins that could play important roles in the process mentioned above for further investigation.

Brain Electrical Activity and Peculiarities of the Self-Stimulation Reaction in Pubertate Rats with Addiction to Inhalation of Organic Solvent Vapors

In chronic experiments on 20 mongrel male rats of pubertate age (3 months), we studied the electrical activity of the structures of the limbico-neocortical system and reactions of self-stimulation of the positive emotiogenic zones in the ventralateral hypothalamus under conditions of addiction to vapors of an organic solvent, No. 646. It is shown that the state of addiction to inhalant vapors results in modifications of behavioral reactions, modulation of electrical activity in the neocortex, hippocampus, and medial olfactory region with increases in the powers of some spectral components, and intensification of the reaction of self-stimulation of the positive emotiogenic zones in the ventralateral hypothalamus.

Modulation of electrical activity and ionic currents of isolated neurons by orexin A

The changes in intracellular potential of resting (PR) and potential of action (PA) of the identified neurons of pedal and visceral ganglia of the CNS mollusk Planorbarius corneus registered by means of intracellular electrodes, and ionic currents of isolated neurons under fixed potential after administration of orexin A in concentrations 1, 10, 100 and 1000 µg/ml were studied by the method of fixation of membrane potential in isolated neurons of the Lymnaea stagnalis mollusk. Dibazol in concentrations of 1 and 10 µM effected slightly on the ionic currents. High concentrations of dibazol (100 and 1000 µM) inhibited all currents in dose dependent manner with maximal effect on potassium currents amplitude. ЕС50 were 7.4 мМ for INa, 4.0 мМ for ICa, 83.9 µM for IKs,1 (one group of neurons) and 2.9 мМ for IKs,2 (the another group of neurons). The voltage-amper membrane characteristics shift was not registered, but the kinetics of currents development was changed. Dibazol was more effective in inhibition of ionic currents compared to its structural analogs.

Cardiac cushions modulate action potential phenotype during heart development

The extracellular matrix plays an important role in cardiac function. Its role in the generation and modulation of electrical activity in the early stages of heart development has not been studied extensively. Our study demonstrates that the extracellular matrix in cardiac cushions can alter the action potential phenotype by direct contact with cardiomyocytes from different regions of the heart. We also demonstrate that fibronectin, an important and abundant component of the cardiac extracellular matrix, partially mimics the effects of the cushion tissue in altering the changes in action potential. Fibronectin increases I(Ca) (2+) and acutely increases cytosolic calcium. These findings suggest that the composition of the cardiac extracellular matrix during development plays an important role in defining patterns of electrical activity in the developing heart.

PATHOPHYSIOLOGY

PATHOPHYSIOLOGY

2APB- and JTV519(K201)-sensitive micro Ca 2+ waves in arrhythmogenic Purkinje cells that survive in infarcted canine heart

Objectives/background Studies from several laboratories have implicated intracellular Ca 2+ dynamics in the modulation of electrical activity. We have reported that abnormal Ca 2+ wave activity is the underlying cause of afterdepolarization-induced electrical activity in subendocardial Purkinje cells that survive in the 48-hour infarcted canine heart. These cells form the focus of arrhythmias at this time postcoronary artery occlusion. Methods We studied the effects of agonists and antagonists on the abnormal Ca 2+ release activity of Purkinje cell aggregates dispersed from the subendocardium 48 hours postcoronary artery occlusion (IZPCs). Studies were completed using epifluorescent microscopy of Fluo-3 loaded Purkinje cells. Results Similar to our previous report, highly frequent traveling micro Ca 2+ transients(μCaiTs) and cell-wide Ca 2+waves were seen in IZPCs in the absence of any drug. Isoproterenol (ISO) increased μCaiTs and cell-wide Ca 2+waves in Purkinje cells dispersed from the normal heart (NZPCs). In IZPCs, ISO increased cell-wide wave frequency but had no effect on the already highly frequent micro Ca 2+ wave transient activity, suggesting that ISO lowers the threshold of cell-wide generators responding to micro Ca 2+ transients. Drugs that block inward sodium or calcium currents (verapamil, tetrodotoxin) had no effect on Ca 2+activity in Purkinje cells. Antagonists of intracellular Ca 2+release channels [ryanodine, JTV519(K201)] greatly suppressed spontaneous Ca 2+ release events in IZPCs. 2APB, an agent that blocks IP 3 receptors, greatly reduced the frequency of Ca 2+events in IZPCs. Conclusions In arrhythmogenic Purkinje cells that survive in the infarcted heart, agents that block or inhibit intracellular Ca 2+release channel activity reduced Ca 2+waves and could be antiarrhythmic.

Modulation of electrical activity by 5-hydroxytryptamine in crayfish neurosecretory cells.

The effect of 5-hydroxytryptamine (5-HT) was tested in a population of X organ neurosecretory cells in the eyestalk of the crayfish Procambarus clarkii. Tests were conducted both in situ and on isolated neurones kept in culture. The application of 5-HT induced action potentials in silent cells. In spontaneously active neurones, 5-HT increased the firing rate and either induced firing or enhanced bursting activity. The effect of 5-HT was dose-dependent within the range 1-100 micromol l-1 in cells of the intact organ. The effect persisted for 20-30 min after 5-HT had been removed from the bathing solution. Successive applications of 5-HT onto the same neurone reduced responsiveness, suggesting that desensitization had occurred. The effects of 5-HT were blocked by prior incubation with the 5-HT antagonist methysergide. In X organ cells whose axons and branches in the neuropile had been severed, 5-HT induced a depolarisation associated with a slow inward current. In X organ neurones isolated from the eyestalk and kept in culture, 5-HT was capable of evoking bursts of action potentials and elicited a slow inward current. This effect was also blocked by methysergide (10(-4 )mol l-1). These results suggest a direct modulatory effect of 5-HT on the pattern of electrical activity in the X organ cells.

T-type calcium channels facilitate insulin secretion by enhancing general excitability in the insulin-secreting beta-cell line, INS-1.

The present study addresses the function of T-type voltage-gated calcium channels in insulin-secreting cells. We used whole-cell voltage and current recordings, capacitance measurements, and RIA techniques to determine the contribution of T-type calcium channels in modulation of electrical activity and in stimulus-secretion coupling in a rat insulin secreting cell line, INS-1. By employing a double pulse protocol in the current-clamp mode, we found that activation of T-type calcium channels provided a low threshold depolarizing potential that decreased the latency of onset of action potentials and furthermore increased the frequency of action potentials, both of which are abolished by administration of nickel chloride (NiCl2), a selective T-type calcium channel blocker. Moreover application of high frequency stimulation, as compared with low frequency stimulation, caused a greater change in membrane capacitance (deltaCm), suggesting higher insulin secretion. We demonstrated that glucose stimulated insulin secretion in INS-1 is reduced dose dependently by NiCl2. We conclude that T-type calcium channels facilitate insulin secretion by enhancing the general excitability of these cells. In light of the pathological effects of both hypo and hyperinsulinemia, the T-type calcium channel may be a therapeutic target.

Electrotonic modulation of electrical activity in rabbit atrioventricular node myocytes.

Electrotonic effects of electrically coupling atrioventricular (AV) nodal cells to each other and to real and passive models of atrial and ventricular cells were studied using a technique that does not require functional gap junctions. Membrane potential was measured in each cell using suction pipettes. Mutual entrainment of two spontaneously firing AV nodal cells was achieved with a junctional resistance (Rj) of 500 M omega, which corresponds to only 39 junctional channels, assuming a single-channel conductance of 50 pS. Coupling of AV nodal and atrial cells at Rj of 50 M omega caused hyperpolarization of the nodal cell, decreasing its action potential duration and either slowing or blocking diastolic depolarization in the AV node myocyte. Opposite changes occurred in the atrial action potential. When AV nodal and ventricular cells were coupled at Rj of 50 M omega, nodal diastolic potential was markedly hyperpolarized and diastolic depolarization was completely blocked with little change in ventricular diastolic potential. However, coupling did elicit marked changes in the action potential duration of both cells, with prolongation in the nodal cell and shortening in the ventricular cell. Nodal maximum upstroke velocity was increased by both atrial and ventricular coupling, as expected from the hyperpolarization that occurred. With an Rj of 50 M omega, spontaneous firing was blocked in all single AV nodal pacemaker cells during coupling to a real or passive model of an atrial or ventricular cell. These results demonstrate that action potential formation and waveform in a single AV nodal cell is significantly affected by electrical coupling to other myocytes.

Acute Estradiol Modulation of Electrical Activity of the LHRH Pulse Generator in the Ovariectomized Rat: Restoration by Naloxone

Whether estrogen has the brain as a site of its negative feedback action was investigated by checking the acute effect of estradiol-17 beta (E2) on the electrical activity of the luteinizing hormone-releasing hormone (LHRH) pulse generator in ovariectomized rats fitted with chronically implanted electrode arrays in the medial basal hypothalamus. Before subcutaneous E2 implantation, the hypothalamic multiunit activity (MUA) exhibited, at an average frequency of 2.43/h, characteristic increases (volleys), each of which was associated with the initiation of an LH pulse. Within 2 h after E2 implantation, the frequency of MUA volleys was reduced significantly, probably associated with decreases in the frequency of LH pulses. The decrease in the amplitude of LH pulses occurred later than 2 h, but this effect was considered not to be mediated by the brain since the duration of MUA volleys was not changed. Since the mean serum LH concentration started to decrease within 2 h after E2 implantation, it was concluded that the acute inhibitory E2 effect on LH release is mediated by the brain. On the day after E2 implantation, intravenous infusion of naloxone (2 mg/kg/h) promptly elicited intermittent MUA volleys each of which was associated with an LH pulse. This suggests that operation of the LHRH pulse generator in the ovariectomized condition is restrained by the action of E2 with the mediation of endogenous opioid peptide neurons.

Modulation of Electrical Activity and of Intracellular Calcium Oscillations of Smooth Muscle Cells by Calcium Antagonists, Agonists, and Vasopressin

The A7r5 smooth muscle cell line, which originally was derived from fetal rat aorta, shows spontaneous calcium oscillations associated with electrical activity (frequency of 0.2-0.5 Hz). Organic calcium antagonists such as isradipine (10(-8) M) stopped the calcium oscillations whereas calcium agonists (e.g., Bay K 8644, 10(-8) M) increased the frequency and amplitude of calcium oscillations without changing the shape of the electrical spikes. The enantiomers of the dihydropyridine SDZ 202-791 known to have opposite activity with respect to L-type Ca2+ channels antagonized each other when tested for their effects on the calcium oscillations. The modulation of the activity of these cells by inorganic ions that affect Ca2+ and K+ channels was also investigated. The addition of barium chloride (10(-4) M) to the bathing solution increased the spiking rate whereas cadmium chloride (10(-6) M) abolished the spikes. The vasoconstrictor peptide vasopressin first induced a hyperpolarization associated with the cessation of spiking activity followed by a slow depolarization. The intracellular Ca2+ concentration ([Ca2+]i), measured with the calcium indicator fura-2, was increased transiently to a level about 10-fold above basal and then gained a new steady state at about twice the basal level. Vasopressin stimulated Ca2+ release from intracellular stores (via InsP3), resulting in membrane hyperpolarization through activation of Ca(2+)-activated K+ channels. The late and long-lasting [Ca2+]i elevation was due to Ca2+ influx through dihydropyridine-insensitive channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of Electrical Activity and of Intracellular Calcium Oscillations of Smooth Muscle Cells by Calcium Antagonists, Agonists, and Vasopressin

Modulation of Electrical Activity and of Intracellular Calcium Oscillations of Smooth Muscle Cells by Calcium Antagonists, Agonists, and Vasopressin

Nucleus accumbens and preoptic area stimulation: tuberoinfundibular single unit responses, modulation of electrical activity and gonadotrophin secretion.

Single unit activity was recorded from tuberoinfundibular neurones in urethane-anaesthetized pro-oestrous rats. Responses following single shock (0.2 Hz) stimulation of the preoptic area/anterior hypothalamus (PO/AH) or nucleus accumbens (ACB) were recorded and computed for 137 single units. More cells were shown, by antidromic activation, to project to ACB (4 of 77) than to PO/AH (1 of 60). Fewer units were responsive to stimulation of ACB (p less than 0.02), those that were responsive showing a longer latency to the onset of response compared to that following PO/AH stimulation. Significantly (p less than 0.02) more slowly firing cells were found in the group of animals tested with stimulation of PO/AH. Delivery of high frequency stimulation to PO/AH resulted in a 21/2 fold increase in plasma luteinizing hormone (LH) levels (p less than 0.05), whereas ACB-stimulated and control animals showed no increases in plasma LH concentrations. During delivery of the high frequency stimulation only one cell in the ACB group of animals was orthodromically affected (out of five tested). However, in the PO/AH group, five of the seven cells tested showed either excitation or inhibition during stimulation. The possibility that the functional connections demonstrated between ACB and the endocrine hypothalamus are involved in the expression of 'higher' brain functions, recognised during changing endocrine states, is discussed.

Modulation of electrical activity and cyclic nucleotide metabolism in molluscan nervous system by a peptide-containing nervous system extract

A peptide-containing extract (PE) from Helix nervous system modifies the endogenous bursting pattern of electrical activity in Helix neurone F-1. This effect is similar to that induced in neuron F-1 by certain phosphodiesterase inhibitors and cAMP derivatives. The PE, and the vertebrate peptide hormones vasopressin and oxytocin, also cause an accumulation of cAMP in Helix ganglia in vitro. The factor in the PE which causes the cAMP accumulation is destroyed by Pronase, is lost on dialysis, and is stable to boiling. In all these respects it is identical to the factor which causes the change in neuronal electrical activity. The PE also stimulates adenylate cyclase activity in a crude membrane fraction prepared from Helix ganglion homogenates. This stimulation is abolished by prior dialysis of the PE, or pretreatment of the PE with pepsin, but is not affected by boiling of the PE. Pepsin-treated PE has no effect on electrical activity in neuron F-1. The adenylate cyclase-stimulating activity of the PE, like the factor which modifies neurone F-1 electrical activity, elutes in the void volume of a Sephadex G-10 column. The included volume of this column contains a factor which inhibits PE modification of neuronal electrical activity, and also inhibits both basal and PE-stimulated adenylate cyclase activity. The data are consistent with the possibility that cAMP mediates the effects of the PE on electrical activity in molluscan neurones.

Modulation of electrical activity in Aplysia neurones by cholesterol.

VARIOUS hormones and drugs induce long-lasting alterations of electrical activity in certain neurones from the marine snail Aplysia californica1–5. Drugs and hormones were found to affect the lipid microviscosity of biological membranes6,7, so it is plausible that their effect on electrical activity is mediated by changes in membrane fluidity. We report here that by changing the cholesterol content of Aplysia neurones, which presumably increases its membrane microviscosity8, long term, though reversible, alterations in electrical activity are induced.