Autonomic control of the cerebral circulation during normal and impaired peripheral circulatory control.
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OBJECTIVE: To determine whether oscillations in the cerebrovascular circulation undergo autonomic modulation in the same way as cardiovascular oscillations. DESIGN: Cardiovascular and cerebrovascular oscillations were monitored at rest and during sympathetic stimulation (head up tilt). The association with and transmission of the oscillations in the sympathetic (low frequency, LF) and respiratory (high frequency, HF) bands was assessed. SUBJECTS: 13 healthy volunteers, 10 subjects with vasovagal syncope, and 12 patients with complicated non-insulin dependent diabetes mellitus. MAIN OUTCOME MEASURES: Power spectrum analysis of cerebral blood flow velocity, arterial blood pressure, and heart rate. Coherence analysis was used to study the association between each pair of oscillations. Phase analysis showed the delay of the oscillations in the cardiovascular signals with respect to the cerebrovascular signals. RESULTS: The power in the sympathetic (LF) components in all the oscillations increased during head up tilt (p < 0.01) in the controls and in the subjects with vasovagal syncope, but not in patients with diabetes. Significant coherence (> 0.5) in the LF band was present between cerebrovascular and cardiovascular oscillations in most of the controls and in subjects with vasovagal syncope, but not in the diabetic patients (< 50% of the patients). In the LF band, cerebrovascular oscillations preceded the cardiovascular oscillations (p < 0.05) at rest in all groups: the phase shifts were reduced (p < 0.05) during head up tilt for all cardiovascular signals in healthy and syncopal subjects, but only for heart rate in diabetic patients. CONCLUSIONS: The cerebrovascular resistance vessels are subject to autonomic modulation; low frequency oscillations in cerebral blood flow velocity precede the resulting fluctuations in other cardiovascular signals. Autonomic neuropathy and microvascular stiffness in diabetic patients reduces this modulation. (+info)
A role for the proteasome in the light response of the timeless clock protein.
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The cyclic expression of the period (PER) and timeless (TIM) proteins is critical for the molecular circadian feedback loop in Drosophila. The entrainment by light of the circadian clock is mediated by a reduction in TIM levels. To elucidate the mechanism of this process, the sensitivity of TIM regulation by light was tested in an in vitro assay with inhibitors of candidate proteolytic pathways. The data suggested that TIM is degraded through a ubiquitin-proteasome mechanism. In addition, in cultures from third-instar larvae, TIM degradation was blocked specifically by inhibitors of proteasome activity. Degradation appeared to be preceded by tyrosine phosphorylation. Finally, TIM was ubiquitinated in response to light in cultured cells. (+info)
Dynamic behavior and autonomic regulation of ectopic atrial pacemakers.
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BACKGROUND: Heart rate (HR) variability reflects the neural regulation of normal pacemaker tissue, but the autonomic nervous regulation of abnormal atrial foci originating outside the sinus node has not been well characterized. We compared the HR variability of tachycardias originating from the ectopic foci and the sinus node. METHODS AND RESULTS: R-R-interval variability was analyzed from 24-hour Holter recordings in 12 patients with incessant ectopic atrial tachycardia (average HR 107+/-14 bpm), 12 subjects with sinus tachycardia (average HR 106+/-9 bpm), and 24 age- and sex-matched subjects with normal sinus rhythm (average HR 72+/-8 bpm). Time- and frequency-domain HR variability measures, along with approximate entropy, short- and long-term correlation properties of R-R intervals (exponents alpha(1) and alpha(2)), and power-law scaling (exponent beta), were analyzed. Time- and frequency-domain measures of HR variability did not differ between subjects with ectopic and sinus tachycardia. Fractal scaling exponents and approximate entropy were similar in sinus tachycardia and normal sinus rhythm, but the short-term scaling exponent alpha(1) was significantly lower in ectopic atrial tachycardia (0.71+/-0.16) than in sinus tachycardia (1.16+/-0.13; P<0.001) or normal sinus rhythm (1.19+/-0.11; P<0.001). Abrupt prolongations in R-R intervals due to exit blocks from the ectopic foci or instability in beat-to-beat R-R dynamics were the major reasons for altered short-term HR behavior during ectopic tachycardias. CONCLUSIONS: HR variability obtained by time- and frequency-domain methods does not differ between ectopic and sinus tachycardias, which suggests that abnormal atrial foci are under similar long-term autonomic regulation as normal pacemaker tissue. Short-term R-R-interval dynamics are altered toward more random behavior in ectopic tachycardia, which may result from a specific autonomic disturbance or an intrinsic abnormality of ectopic atrial pacemakers. (+info)
Mauthner cell-initiated electromotor behavior is mediated via NMDA and metabotropic glutamatergic receptors on medullary pacemaker neurons in a gymnotid fish.
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Weakly electric fish generate meaningful electromotor behaviors by specific modulations of the discharge of their medullary pacemaker nucleus from which the rhythmic command for each electric organ discharge (EOD) arises. Certain electromotor behaviors seem to involve the activation of specific neurotransmitter receptors on particular target cells within the nucleus, i.e., on pacemaker or on relay cells. This paper deals with the neural basis of the electromotor behavior elicited by activation of Mauthner cells in Gymnotus carapo. This behavior consists of an abrupt and prolonged increase in the rate of the EOD. The effects of specific glutamate agonists and antagonists on basal EOD frequency and on EOD accelerations induced by Mauthner cell activation were assessed. Injections of both ionotropic (AMPA, kainate, and NMDA) and metabotropic (trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid) glutamate agonists induced increases in EOD rate that were maximal when performed close to the soma of pacemaker cells. In contrast, injections in the proximity of relay cells were ineffective. Therefore, pacemaker neurons are probably endowed with diverse glutamate receptor subtypes, whereas relay cells are probably not. The Mauthner cell-evoked electromotor behavior was suppressed by injections of AP-5 and (+/-)-amino-4-carboxy-methyl-phenylacetic acid, NMDA receptor and metabotropic glutamate receptor antagonists, respectively. Thus, this electromotor behavior relies on the activation of the NMDA and metabotropic glutamate receptor subtypes of pacemaker cells. Our study gives evidence for the synergistic effects of NMDA and metabotropic receptor activation and shows how a simple circuit can produce specific electromotor outputs. (+info)
Interlocked feedback loops within the Drosophila circadian oscillator.
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Drosophila Clock (dClk) is rhythmically expressed, with peaks in mRNA and protein (dCLK) abundance early in the morning. dClk mRNA cycling is shown here to be regulated by PERIOD-TIMELESS (PER-TIM)-mediated release of dCLK- and CYCLE (CYC)-dependent repression. Lack of both PER-TIM derepression and dCLK-CYC repression results in high levels of dClk mRNA, which implies that a separate dClk activator is present. These results demonstrate that the Drosophila circadian feedback loop is composed of two interlocked negative feedback loops: a per-tim loop, which is activated by dCLK-CYC and repressed by PER-TIM, and a dClk loop, which is repressed by dCLK-CYC and derepressed by PER-TIM. (+info)
Light-independent role of CRY1 and CRY2 in the mammalian circadian clock.
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Cryptochrome (CRY), a photoreceptor for the circadian clock in Drosophila, binds to the clock component TIM in a light-dependent fashion and blocks its function. In mammals, genetic evidence suggests a role for CRYs within the clock, distinct from hypothetical photoreceptor functions. Mammalian CRY1 and CRY2 are here shown to act as light-independent inhibitors of CLOCK-BMAL1, the activator driving Per1 transcription. CRY1 or CRY2 (or both) showed light-independent interactions with CLOCK and BMAL1, as well as with PER1, PER2, and TIM. Thus, mammalian CRYs act as light-independent components of the circadian clock and probably regulate Per1 transcriptional cycling by contacting both the activator and its feedback inhibitors. (+info)
Cardioventilatory coupling in atrial fibrillation.
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Cardioventilatory coupling is an entrainment phenomena, distinct from respiratory sinus arrhythmia, whereby heart and breathing rhythms show temporal coherence. Coupling is commonly observed during rest, sleep and anaesthesia. Five graphical methods, each with different underlying mechanistic assumptions, have been suggested for studying this entrainment relationship: (a) time relationship between inspiration and a preceding heart beat, (b) time relationship between inspiration and a following heart beat, (c) phase of the cardiac cycle at which inspiration occurs, (d) phases of the ventilatory cycle at which heart beats occur and (e) 'relative phases' over multiple ventilatory cycles at which heart beats occur. In eight elderly human subjects with atrial fibrillation, breathing spontaneously during general anaesthesia, we recorded heart period and ventilatory time series and compared each of the graphical methods used for demonstration of coupling. We observed cardioventilatory coupling in seven of eight subjects. In each of these seven subjects, coupling was best described, both qualitatively and quantitatively, in terms of the relationship between inspiration and a preceding heart beat. The variation of the interval between inspiration and a preceding heart beat was less than for any other phase or time relationship. These data support a model of cardioventilatory coupling in which a heart beat triggers the onset of inspiration, rather than modulation of cardiac timing by ventilation or a phase relationship between the two systems. (+info)
Anaesthetic/amnesic agents disrupt beta frequency oscillations associated with potentiation of excitatory synaptic potentials in the rat hippocampal slice.
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1. Anaesthetic agents produce disruption in cognitive function typified by reductions in sensory perception and memory formation. Oscillations within the EEG gamma and beta bands have been linked to sensory perception and memory and have been shown to be modified by anaesthetic agents. 2. Synchronous gamma oscillations generated by brief tetanic stimulation in two regions of hippocampal area CA1 in slices in vitro were seen to potentiate excitatory synaptic communication between the areas. This synaptic potentiation, was seen to contribute to a transition from gamma frequency (30 - 70 Hz) to beta frequency (12 - 30 Hz) oscillations. 3. Four drugs having anaesthetic/hypnotic and amnesic properties were tested on this synchronous gamma-induced beta oscillation. Thiopental 10 - 200 microM, Diazepam 0.05 - 1.0 microM, Morphine 10 - 200 microM, and Ketamine 10 - 200 microM were all added to the bathing medium. Each drug markedly disrupted the formation of beta oscillations in a manner consistent with their primary modes of action. Thiopental and morphine disrupted synchrony of gamma oscillations and prevented potentiation of recurrent excitatory potentials measured in stratum oriens (fEPSPs). Neither diazepam, nor ketamine produced such marked changes in synchrony at gamma frequencies or reduction in potentiation of fEPSPs. However, each disrupted expression of subsequent beta oscillation via changes in the magnitude of inhibitory network gamma oscillations and the duration and magnitude of tetanus-induced depolarization respectively. 4. The degree of disruption of fEPSP potentiation correlated quantitatively with the degree of disruption in synchrony between sites during gamma oscillations. The data indicate that synchronous gamma-induced beta oscillations represent a mode of expression of excitatory synaptic potentiation in the hippocampus, and that anaesthetic/amnesic agents can disrupt this process markedly. (+info)