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We combined real-time calcium-based neural activity imaging with whole-cell patch-clamp recording techniques to map the spatial organization and analyze electrophysiological properties of respiratory neurons forming the circuit transmitting rhythmic drive from the pre-Bötzinger complex (pre-BötC) through premotoneurons to hypoglossal (XII) motoneurons. Inspiratory pre-BötC neurons, XII premotoneurons (preMNs), and XII motoneurons (MNs) were retrogradely labeled with Ca 2ϩ -sensitive dye in neonatal rat in vitro brainstem slices. PreMN cell bodies were arrayed dorsomedially to pre-BötC neurons with little spatial overlap; axonal projections to MNs were ipsilateral. Inspiratory MNs were distributed in dorsal and ventral subnuclei of XII. Voltage-clamp recordings revealed that two currents, persistent sodium current (NaP) and K ϩ -dominated leak current (Leak), primarily contribute to preMN/MN subthreshold current-voltage relationships. NaP or Leak conductance densities in preMNs and MNs were not significantly different. We quantified preMN and MN action potential time course and spike frequency-current ( f-I) relationships and found no significant differences in repetitive spiking dynamics, steady-state f-I gains, and afterpolarizing potentials. Rhythmic synaptic drive current densities were similar in preMNs and MNs. Our results indicate that, despite topographic and morphological differences, preMNs and MNs have some common intrinsic membrane, synaptic integration, and spiking properties that we postulate ensure fidelity of inspiratory drive transmission and conversion of synaptic drive into (pre)motor output. There also appears to be a common architectonic organization for some respiratory drive transmission circuits whereby many preMNs are spatially segregated from pre-BötC rhythm-generating neurons, which we hypothesize may facilitate downstream integration of convergent inputs for premotor pattern formation.

BACE1 is required for the release of ␤-amyloid (A␤) in vivo, and inhibition of BACE1 activity is targeted for reducing A␤ generation in Alzheimer's patients. To further our understanding of the safe use of BACE1 inhibitors in human patients, we aimed to study the physiological functions of BACE1 by characterizing BACE1-null mice. Here, we report the finding of spontaneous behavioral seizures in BACE1-null mice. Electroencephalographic recordings revealed abnormal spike-wave discharges in BACE1-null mice, and kainic acidinduced seizures also occurred more frequently in BACE1-null mice compared with their wild-type littermates. Biochemical and morphological studies showed that axonal and surface levels of Na v 1.2 were significantly elevated in BACE1-null mice, consistent with the increased fast sodium channel current recorded from BACE1-null hippocampal neurons. Patch-clamp recording also showed altered intrinsic firing properties of isolated BACE1-null hippocampal neurons. Furthermore, population spikes were significantly increased in BACE1-null brain slices, indicating hyperexcitability of BACE1-null neurons. Together, our results suggest that increased sodium channel activity contributes to the epileptic behaviors observed in BACE1-null mice. The knowledge from this study is crucial for the development of BACE1 inhibitors for Alzheimer's therapy and to the applicative study of epilepsy.

Pb xs ratio in suspended sediments to determine the time since the particles were tagged by precipitation-derived radionuclides (i.e. the age of the suspended sediment). In addition, an alternative model is presented to determine the fraction of the sediment that is 'newly tagged'. These two models are applied to three catchments -Old Woman Creek, Ohio; Weeks Bay, Alabama; and South Slough, Oregon -and yield similar findings at all three sites. Sediment ages increase from 0 in newly tagged material, to 50-80 days in rivers, to about 80-100 days in the estuaries, to about 200 days in the sediment traps, to about 300 days on surface bottom sediments. Alternatively, the percentage new sediment decreases from 100 per cent in newly tagged material, to about 35-50 per cent in rivers, to 25-35 per cent in the estuary, to less than 10 per cent in the sediment traps, to 1-4 per cent on the surface of the bottom sediments.

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Serotonin (5HT) is a powerful modulator of respiratory circuitry in vitro but its role in the development of breathing behavior in vivo is poorly understood. Here we show, using 5HT neurondeficient Pet-1 (Pet-1 −/− ) neonates, that serotonergic function is required for the normal timing of postnatal respiratory maturation. Plethysmographic recordings reveal that Pet-1 −/− mice are born with a depressed breathing frequency and a higher incidence of spontaneous and prolonged respiratory pauses relative to wild type littermates. The wild type breathing pattern stabilizes by postnatal day 4.5, while breathing remains depressed, highly irregular, and interrupted more frequently by respiratory pauses in Pet-1 −/− mice. Analysis of in vitro hypoglossal nerve discharge indicates that instabilities in the central respiratory rhythm generator contribute to the abnormal Pet-1 −/− breathing behavior. In addition, the breathing pattern in Pet-1 −/− neonates is susceptible to environmental conditions, and can be further destabilized by brief exposure to hypoxia. By postnatal day 9.5, however, breathing frequency in Pet-1 −/− animals is only slightly depressed compared to wild type, and prolonged respiratory pauses are rare, indicating that the abnormalities seen earlier in the Pet-1 −/− mice are transient. Our findings provide unexpected insight into the development of breathing behavior by demonstrating that defects in 5HT neuron development can extend and exacerbate the period of breathing instability that occurs immediately after birth during which respiratory homeostasis is vulnerable to environmental challenges.

Background:We have previously shown an increased incidence of intermittent hypoxemia (Ih) events in preterm infants with severe retinopathy of prematurity (ROP). animal models suggest that patterns of Ih events may play a role in ROP severity as well. We hypothesize that specific Ih event patterns are associated with ROP in preterm infants. Methods: Variability in Ih event duration, severity, and the time interval between Ih events (≤80%, ≥10 s, and ≤3 min) along with the frequency spectrum of the oxygen saturation (spO 2 ) waveform were assessed. results: severe ROP was associated with (i) an increased mean and sD of the duration of Ih event (P < 0.005), (ii) more variability (histogram entropy) of the time interval between Ih events (P < 0.005), (iii) a higher Ih nadir (P < 0.05), (iv) a time interval between Ih events of 1-20 min (P < 0.05), and (v) increased spectral power in the range of 0.002-0.008 hz (P < 0.05), corresponding to spO 2 waveform oscillations of 2-8 min in duration. spectral differences were detected as early as 14 d of life. conclusion: severe ROP was associated with more variable, longer, and less severe Ih events. Identification of specific spectral components in the spO 2 waveform may assist in early identification of infants at risk for severe ROP.