Role of brain-derived neurotrophic factor in the circadian regulation of the suprachiasmatic pacemaker by light.
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The central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus mediates the generation of mammalian circadian rhythms, including an oscillation in pacemaker sensitivity to photic signals conveyed by the retinohypothalamic tract. Because brain-derived neurotrophic factor (BDNF) has been implicated in the functional regulation of neural input to other targets of visual pathways, the present study examined whether changes in BDNF expression or blockade of its action in the SCN affect circadian pacemaker responses to light. In rats receiving infusion of exogenous BDNF into the SCN, the free-running rhythm of activity in constant darkness was characterized by large phase advances in response to light exposure during the midsubjective day, when the circadian pacemaker is normally insensitive to photic perturbation. In contrast, SCN infusion of BDNF did not potentiate either phase-delaying or phase-advancing effects of light on the rat activity rhythm during the subjective night. In heterozygous BDNF mutant mice, deficits and damped rhythmicity in SCN levels of this neurotrophin were accompanied by marked decreases in the amplitude of light-induced phase shifts during the subjective night. In agreement with the effects of decreased BDNF expression, SCN infusion of the tyrosine kinase inhibitor K252a blocked or strongly inhibited both the phase-delaying and -advancing effects of light during the subjective night. Collectively, these findings suggest that BDNF-mediated signaling may play an important role in the circadian regulation of SCN pacemaker sensitivity to light. (+info)
The role of the hyperpolarization-activated current in modulating rhythmic activity in the isolated respiratory network of mice.
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We examined the role of the hyperpolarization-activated current (I(h)) in the generation of the respiratory rhythm using a spontaneously active brainstem slice of mice. This preparation contains the hypoglossus (XII) nucleus, which is activated in-phase with inspiration and the pre-Botzinger complex (PBC), the presumed site for respiratory rhythm generation. Voltage-clamp recordings (n = 90) indicate that cesium (Cs) (5 mM) blocked 77.2% of the I(h) current, and ZD 7288 (100 microM) blocked 85.8% of the I(h) current. This blockade increased the respiratory frequency by 161% in Cs and by 150% in ZD 7288 and increased the amplitude of integrated population activity in the XII by 97% in Cs and by 162% in ZD 7288, but not in the PBC (Cs, by 19%; ZD 7288, by -4.56%). All inspiratory PBC neurons (n = 44) recorded in current clamp within the active network revealed a significantly decreased frequency of action potentials during the interburst interval and an earlier onset of inspiratory bursts after I(h) current blockade. However, hyperpolarizing current pulses evoked only in a small proportion of inspiratory neurons (0% of type I; 29% of type II neurons) a depolarizing sag. Most of the neurons expressing an I(h) current (86%) were pacemaker neurons, which continued to generate rhythmic bursts after inactivating the respiratory network pharmacologically with CNQX alone or with CNQX, AP-5, strychnine, bicuculline, and carbenoxolone. Cs and ZD 7288 increased the frequency of pacemaker bursts and decreased the frequency of action potentials between pacemaker bursts. Our findings suggest that the I(h) current plays an important role in modulating respiratory frequency, which is presumably mediated by pacemaker neurons. (+info)
Modeling of spontaneous activity in developing spinal cord using activity-dependent depression in an excitatory network.
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Spontaneous episodic activity is a general feature of developing neural networks. In the chick spinal cord, the activity comprises episodes of rhythmic discharge (duration 5-90 sec; cycle rate 0.1-2 Hz) that recur every 2-30 min. The activity does not depend on specialized connectivity or intrinsic bursting neurons and is generated by a network of functionally excitatory connections. Here, we develop an idealized, qualitative model of a homogeneous, excitatory recurrent network that could account for the multiple time-scale spontaneous activity in the embryonic chick spinal cord. We show that cycling can arise from the interplay between excitatory connectivity and fast synaptic depression. The slow episodic behavior is attributable to a slow activity-dependent network depression that is modeled either as a modulation of cellular excitability or as synaptic depression. Although the two descriptions share many features, the model with a slow synaptic depression accounts better for the experimental observations during blockade of excitatory synapses. (+info)
Slowly inactivating sodium current (I(NaP)) underlies single-spike activity in rat subthalamic neurons.
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One-half of the subthalamic nucleus (STN) neurons switch from single-spike activity to burst-firing mode according to membrane potential. In an earlier study, the ionic mechanisms of the bursting mode were studied but the ionic currents underlying single-spike activity were not determined. The single-spike mode of activity of STN neurons recorded from acute slices in the current clamp mode is TTX-sensitive but is not abolished by antagonists of ionotropic glutamatergic and GABAergic receptors, blockers of calcium currents (2 mM cobalt or 40 microM nickel), or intracellular Ca(2+) ions chelators. Tonic activity is characterized by a pacemaker depolarization that spontaneously brings the membrane from the peak of the afterspike hyperpolarization (AHP) to firing threshold (from -57.1 +/- 0.5 mV to -42.2 +/- 0.3 mV). Voltage-clamp recordings suggest that the Ni(2+)-sensitive, T-type Ca(2+) current does not play a significant role in single-spike activity because it is totally inactivated at potentials more depolarized than -60 mV. In contrast, the TTX-sensitive, I(NaP) that activated at -54.4 +/- 0.6 mV fulfills the conditions for underlying pacemaker depolarization because it is activated below spike threshold and is not fully inactivated in the pacemaker range. In some cases, the depolarization required to reach the threshold for I(NaP) activation is mediated by hyperpolarization-activated cation current (I(h)). This was directly confirmed by the cesium-induced shift from single-spike to burst-firing mode which was observed in some STN neurons. Therefore, a fraction of I(h) which is tonically activated at rest, exerts a depolarizing influence and enables membrane potential to reach the threshold for I(NaP) activation, thus favoring the single-spike mode. The combined action of I(NaP) and I(h) is responsible for the dual mode of discharge of STN neurons. (+info)
Serotonin-induced spike narrowing in a locomotor pattern generator permits increases in cycle frequency during accelerations.
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During serotonin-induced swim acceleration in the pteropod mollusk Clione limacina, interneurons of the central pattern generator (CPG) exhibit significant action potential narrowing. Spike narrowing is apparently necessary for increases in cycle frequency during swim acceleration because, in the absence of narrowing, the combined duration of the spike and the inhibitory postsynaptic potential (IPSP) of a single cycle is greater than the available cycle duration. Spike narrowing could negatively influence synaptic efficacy in all interneuron connections, including reciprocal inhibitory connections between the two groups of antagonistic CPG interneurons as well as the interneuron-to-motoneuron connections. Thus compensatory mechanisms must exist to produce the overall excitatory behavioral change of swim acceleration. Such mechanisms include 1) a baseline depolarization of interneurons, which brings them closer to spike threshold, 2) enhancement of their postinhibitory rebound, and 3) direct modulation of swim motoneurons and muscles, all through inputs from serotonergic modulatory neurons. (+info)
Intracellular Ca2+ release contributes to automaticity in cat atrial pacemaker cells.
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1. The cellular mechanisms governing cardiac atrial pacemaker activity are not clear. In the present study we used perforated patch voltage clamp and confocal fluorescence microscopy to study the contribution of intracellular Ca2+ release to automaticity of pacemaker cells isolated from cat right atrium. 2. In spontaneously beating pacemaker cells, an increase in subsarcolemmal intracellular Ca2+ concentration occurred concomitantly with the last third of diastolic depolarization due to local release of Ca2+ from the sarcoplasmic reticulum (SR), i.e. Ca2+ sparks. Nickel (Ni2+; 25-50 microM), a blocker of low voltage-activated T-type Ca2+ current ((ICa,T), decreased diastolic depolarization, prolonged pacemaker cycle length and suppressed diastolic Ca2+ release. 3. Voltage clamp analysis indicated that the diastolic Ca2+ release was voltage dependent and triggered at about -60 mV. Ni2+ suppressed low voltage-activated Ca2+ release. Moreover, low voltage-activated Ca2+ release was paralleled by a slow inward current presumably due to stimulation of Na+-Ca2+ exchange (INa-Ca). Low voltage-activated Ca2+ release was found in both sino-atrial node and latent atrial pacemaker cells but not in working atrial myocytes. 4. These findings suggest that low voltage-activated ICa,T triggers subsarcolemmal Ca2+ sparks, which in turn stimulate INa-Ca to depolarize the pacemaker potential to threshold. This novel mechanism indicates a pivotal role for ICa,T and subsarcolemmal intracellular Ca2+ release in normal atrial pacemaker activity and may contribute to the development of ectopic atrial arrhythmias. (+info)
Clock and induction model for somitogenesis.
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After many years of research, somitogenesis is still one of the major unresolved problems in developmental biology. Recent experimental findings show a novel type of pattern formation in which a signal sweeps along the presomitic mesoderm and narrows simultaneously as a new somite is formed. The signal then residues in the posterior half of the new somite, and another wave begins to sweep up from the caudal end. This behaviour is not easily explained by the existing theoretical models. We present a new model for somitogenesis that can account for this behaviour and is consistent with previous experimental observations. (+info)
Ectopic expression of the neuropeptide pigment-dispersing factor alters behavioral rhythms in Drosophila melanogaster.
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To study the function of the neuropeptide pigment-dispersing factor (PDF) in the circadian system of Drosophila, we misexpressed the pdf gene from the grasshopper Romalea in the CNS of Drosophila and investigated the effect of this on behavioral rhythmicity. pdf was either ectopically expressed in different numbers of neurons in the brain or the thoracical nervous system or overexpressed in the pacemaker neurons alone. We found severe alterations in the activity and eclosion rhythm of several but not all lines with ectopic pdf expression. Only ectopic pdf expression in neurons that projected into the dorsal central brain severely influenced activity rhythms. Therefore, we conclude that PDF acts as a neuromodulator in the dorsal central brain that is involved in the rhythmic control of behavior. Overexpression of pdf in the pacemaker neurons alone or in the other neurons that express the clock genes period (per) and timeless (tim) did not disturb the activity rhythm. Such flies still showed a rhythm in PDF accumulation in the central brain terminals. This rhythm was absent in the terminals of neurons that expressed PDF ectopically. Probably, PDF is rhythmically processed, transported, or secreted in neurons expressing per and tim, and additional PDF expression in these cells does not influence this rhythmic process. In neurons lacking per and tim, PDF appears to be continuously processed, leading to a constant PDF secretion at their nerve terminals. This may lead to conflicting signals in the rhythmic output pathway and result in a severely altered rhythmic behavior. (+info)