Publications
Wakefulness Is Governed by GABA and Histamine Cotransmission.
, , , , , , , Susan Parker, , , , ,
ABSTRACT: Histaminergic neurons in the tuberomammilary nucleus (TMN) of the hypothalamus form a widely projecting, wake-active network that sustains arousal. Yet most histaminergic neurons contain GABA. Selective siRNA knockdown of the vesicular GABA transporter (vgat, SLC32A1) in histaminergic neurons produced hyperactive mice with an exceptional amount of sustained wakefulness. Ablation of the vgat gene throughout the TMN further sharpened this phenotype. Optogenetic stimulation in the caudate-putamen and neocortex of "histaminergic" axonal projections from the TMN evoked tonic (extrasynaptic) GABAA receptor Cl(-) currents onto medium spiny neurons and pyramidal neurons. These currents were abolished following vgat gene removal from the TMN area. Thus wake-active histaminergic neurons generate a paracrine GABAergic signal that serves to provide a brake on overactivation from histamine, but could also increase the precision of neocortical processing. The long range of histamine-GABA axonal projections suggests that extrasynaptic inhibition will be coordinated over large neocortical and striatal areas.
Neuron 06/2015; DOI:10.1016/j.neuron.2015.06.003 · 15.98 Impact Factor
An in-vacuo optical levitation trap for high-intensity laser interaction experiments with isolated microtargets
ABSTRACT: We report on the design, construction, and characterisation of a new class of in-vacuo optical levitation trap optimised for use in high-intensity, high-energy laser interaction experiments. The system uses a focused, vertically propagating continuous wave laser beam to capture and manipulate micro-targets by photon momentum transfer at much longer working distances than commonly used by optical tweezer systems. A high speed (10 kHz) optical imaging and signal acquisition system was implemented for tracking the levitated droplets position and dynamic behaviour under atmospheric and vacuum conditions, with ±5 um spatial resolution. Optical trapping of 10 ± 4 um oil droplets in vacuum was demonstrated, over timescales of >1 h at extended distances of c.40 mm from the final focusing optic. The stability of the levitated droplet was such that it would stay in alignment with a c. 7 um irradiating beam focal spot for up to 5 min without the need for re-adjustment. The performance of the trap was assessed in a series of high-intensity (1017 W cm2) laser experiments that measured the X-ray source size and inferred free-electron temperature of a single isolated droplet target, along with a measurement of the emitted radio-frequency pulse. These initial tests demonstrated the use of optically levitated microdroplets as a robust target platform for further high-intensity laser interaction and point source studies.
The Review of scientific instruments 03/2015; 86(3):033502. DOI:10.1063/1.4908285 · 1.58 Impact Factor
Altered Activity in the Central Medial Thalamus Precedes Changes in the Neocortex during Transitions into Both Sleep and Propofol Anesthesia
ABSTRACT: How general anesthetics cause loss of consciousness is unknown. Some evidence points toward effects on the neocortex causing "Âtop-down" inhibition, whereas other findings suggest that these drugs act via subcortical mechanisms, possibly selectively stimulating networks promoting natural sleep. To determine whether some neuronal circuits are affected before others, we used Morlet wavelet analysis to obtain high temporal resolution in the time-varying power spectra of local field potentials recorded simultaneously in discrete brain regions at natural sleep onset and during anesthetic-induced loss of righting reflex in rats. Although we observed changes in the local field potentials that were anesthetic-specific, there were some common changes in high-frequency (20-Â40 Hz) oscillations (reductions in frequency and increases in power) that could be detected at, or before, sleep onset and anesthetic-induced loss of righting reflex. For propofol and natural sleep, these changes occur first in the thalamus before changes could be detected in the neocortex. With dexmedetomidine, the changes occurred simultaneously in the thalamus and neocortex. In addition, the phase relationships between the low-frequency (1-Â4 Hz) oscillations in thalamic nuclei and neocortical areas are essentially the same for natural sleep and following dexmedetomidine administration, but a sudden change in phase, attributable to an effect in the central medial thalamus, occurs at the point of dexmedetomidine loss of righting reflex. Our data are consistent with the central medial thalamus acting as a key hub through which general anesthesia and natural sleep are initiated.
The Journal of Neuroscience : 10/2014; 34(40):13326. DOI:10.1523/JNEUROSCI.1519-14.2014 · 6.75 Impact Factor
PATENTS
Wakefulness Is Governed by GABA and Histamine Cotransmission.
, , , , , , , Susan Parker, , , , ,
ABSTRACT: Histaminergic neurons in the tuberomammilary nucleus (TMN) of the hypothalamus form a widely projecting, wake-active network that sustains arousal. Yet most histaminergic neurons contain GABA. Selective siRNA knockdown of the vesicular GABA transporter (vgat, SLC32A1) in histaminergic neurons produced hyperactive mice with an exceptional amount of sustained wakefulness. Ablation of the vgat gene throughout the TMN further sharpened this phenotype. Optogenetic stimulation in the caudate-putamen and neocortex of "histaminergic" axonal projections from the TMN evoked tonic (extrasynaptic) GABAA receptor Cl(-) currents onto medium spiny neurons and pyramidal neurons. These currents were abolished following vgat gene removal from the TMN area. Thus wake-active histaminergic neurons generate a paracrine GABAergic signal that serves to provide a brake on overactivation from histamine, but could also increase the precision of neocortical processing. The long range of histamine-GABA axonal projections suggests that extrasynaptic inhibition will be coordinated over large neocortical and striatal areas.
Neuron 06/2015; DOI:10.1016/j.neuron.2015.06.003 ÃÂ÷ 15.98 Impact Factor
An in-vacuo optical levitation trap for high-intensity laser interaction experiments with isolated microtargets
ABSTRACT: We report on the design, construction, and characterisation of a new class of in-vacuo optical levitation trap optimised for use in high-intensity, high-energy laser interaction experiments. The system uses a focused, vertically propagating continuous wave laser beam to capture and manipulate micro-targets by photon momentum transfer at much longer working distances than commonly used by optical tweezer systems. A high speed (10 kHz) optical imaging and signal acquisition system was implemented for tracking the levitated droplets position and dynamic behaviour under atmospheric and vacuum conditions, with ÃÂñ5 ÃÂüm spatial resolution. Optical trapping of 10 ÃÂñ 4 ÃÂüm oil droplets in vacuum was demonstrated, over timescales of >1 h at extended distances of âÃÂü40 mm from the final focusing optic. The stability of the levitated droplet was such that it would stay in alignment with a âÃÂü7 ÃÂüm irradiating beam focal spot for up to 5 min without the need for re-adjustment. The performance of the trap was assessed in a series of high-intensity (10(17) W cm(-2)) laser experiments that measured the X-ray source size and inferred free-electron temperature of a single isolated droplet target, along with a measurement of the emitted radio-frequency pulse. These initial tests demonstrated the use of optically levitated microdroplets as a robust target platform for further high-intensity laser interaction and point source studies.
The Review of scientific instruments 03/2015; 86(3):033502. DOI:10.1063/1.4908285 ÃÂ÷ 1.58 Impact Factor
Altered Activity in the Central Medial Thalamus Precedes Changes in the Neocortex during Transitions into Both Sleep and Propofol Anesthesia
ABSTRACT: How general anesthetics cause loss of consciousness is unknown. Some evidence points toward effects on the neocortex causing âÃÂÃÂtop-downâÃÂàinhibition, whereas other findings suggest that these drugs act via subcortical mechanisms, possibly selectively stimulating networks promoting natural sleep. To determine whether some neuronal circuits are affected before others, we used Morlet wavelet analysis to obtain high temporal resolution in the time-varying power spectra of local field potentials recorded simultaneously in discrete brain regions at natural sleep onset and during anesthetic-induced loss of righting reflex in rats. Although we observed changes in the local field potentials that were anesthetic-specific, there were some common changes in high-frequency (20âÃÂÃÂ40 Hz) oscillations (reductions in frequency and increases in power) that could be detected at, or before, sleep onset and anesthetic-induced loss of righting reflex. For propofol and natural sleep, these changes occur first in the thalamus before changes could be detected in the neocortex. With dexmedetomidine, the changes occurred simultaneously in the thalamus and neocortex. In addition, the phase relationships between the low-frequency (1âÃÂÃÂ4 Hz) oscillations in thalamic nuclei and neocortical areas are essentially the same for natural sleep and following dexmedetomidine administration, but a sudden change in phase, attributable to an effect in the central medial thalamus, occurs at the point of dexmedetomidine loss of righting reflex. Our data are consistent with the central medial thalamus acting as a key hub through which general anesthesia and natural sleep are initiated.
The Journal of Neuroscience : 10/2014; 34(40):13326. DOI:10.1523/JNEUROSCI.1519-14.2014 ÃÂ÷ 6.75 Impact Factor