µ-opioid receptor-mediated downregulation of midline thalamic pathways to basal and central amygdala.

Brain µ-opioid receptors (MOR) mediate reward and help coping with pain, social rejection, anxiety and depression. The dorsal midline thalamus (dMT) integrates visceral/emotional signals and biases behavior towards aversive or defensive states through projections to the amygdala. While a dense MOR expression in the dMT has been described, the exact cellular and synaptic mechanisms of µ-opioidergic modulation in the dMT-amygdala circuitry remain unresolved. Here, we hypothesized that MORs are important negative modulators of dMT-amygdala excitatory networks. Using retrograde tracers and targeted channelrhodopsin expression in combination with patch-clamp electrophysiology, we found that projections of dMT neurons onto both basal amygdala principal neurons (BA PN) and central amygdala (CeL) neurons are attenuated by stimulation of somatic or synaptic MORs. Importantly, dMT efferents to the amygdala drive feedforward excitation of centromedial amygdala neurons (CeM), which is dampened by MOR activation. This downregulation of excitatory activity in dMT-amygdala networks puts the µ-opioid system in a position to ameliorate aversive or defensive behavioral states associated with stress, withdrawal, physical pain or social rejection.

Cannabinoid CB1 receptors in distinct circuits of the extended amygdala determine fear responsiveness to unpredictable threat.

The brain circuits underlying behavioral fear have been extensively studied over the last decades. Although the vast majority of experimental studies assess fear as a transient state of apprehension in response to a discrete threat, such phasic states of fear can shift to a sustained anxious apprehension, particularly in face of diffuse cues with unpredictable environmental contingencies. Unpredictability, in turn, is considered an important variable contributing to anxiety disorders. The networks of the extended amygdala have been suggested keys to the control of phasic and sustained states of fear, although the underlying synaptic pathways and mechanisms remain poorly understood. Here, we show that the endocannabinoid system acting in synaptic circuits of the extended amygdala can explain the fear response profile during exposure to unpredictable threat. Using fear training with predictable or unpredictable cues in mice, combined with local and cell-type-specific deficiency and rescue of cannabinoid type 1 (CB1) receptors, we found that presynaptic CB1 receptors on distinct amygdala projections to bed nucleus of the stria terminalis (BNST) are both necessary and sufficient for the shift from phasic to sustained fear in response to an unpredictable threat. These results thereby identify the causal role of a defined protein in a distinct brain pathway for the temporal development of a sustained state of anxious apprehension during unpredictability of environmental influences, reminiscent of anxiety symptoms in humans.

Heterosynaptic long-term potentiation at interneuron-principal neuron synapses in the amygdala requires nitric oxide signalling.

Long-lasting changes of synaptic efficacy are thought to be a prerequisite for memory formation and maintenance. In the basolateral complex of the amygdala (BLA), one of the main regions for fear and extinction learning of the brain, various forms of long-term potentiation (LTP) have been described for excitatory glutamatergic synapses. In contrast, little is known about the mechanisms of LTP at inhibitory GABAergic synapses. Here we provide evidence that (1) LTP at inhibitory GABAergic synapses (LTP(i)) between inhibitory interneurons and principal neurons (PNs) can be induced by theta-burst stimulation (TBS), (2) this LTP(i) is prevented by AMPA- or NMDA-receptor antagonists, and (3) this LTP(i) is abolished by the NO synthase (NOS) inhibitor L-NAME or the NO scavenger PTIO, and thus is critically dependent on nitric oxide (NO) signalling. These findings are corroborated by immunocytochemical stainings for neuronal (n) NOS, which revealed the existence of nNOS-positive neurons and fibres in the BLA. We conclude that LTP of GABAergic synaptic transmission to PNs is induced by activation of AMPA and NMDA receptors at glutamatergic synapses and subsequent retrograde NO signalling to enhance GABAergic transmission. This form of LTP at GABAergic synapses comprises a novel form of heterosynaptic plasticity within the BLA, apt to shape conditioned fear responses.

Defect formation in hafnium dioxide thin films.

Hafnium dioxide thin films were deposited by reactive electron-beam evaporation at six different substrate temperatures on fused-silica substrates. During the depositions, the scattering of light caused by the growth of defects in the films was recorded with in situ total internal reflection microscopy. After deposition the films were analyzed by angle-resolved scatterometery, spectrophotometric measurement of film reflectance and transmittance, atomic force microscopy, and x-ray diffraction. We explore the effects of film defect formation on film optical properties and film surface topography using these data.

Influence of crystal structure on the light scatter of zirconium oxide films.

The relationship of light scatter by a thin film to thin-film morphology is examined. Light scatter by reactively evaporated ZrO(2) thin films is analyzed by using in situ total internal reflection microscopy and angle-resolved scatterometry. Film crystal structure is analyzed by transmission electron microscopy and x-ray diffraction. Relations between film crystal structure and film scatter are established by using this information. Surface topography is analyzed by the use of scanning force microscopy. Results of a spectrophotometric determination of the film refractive index are reported. The film scatter is found to be sensitive to the crystal phase of the film, which is a function of substrate deposition temperature. A simple method of separating bulk from surface scatter is described.

Float-polishing process and analysis of float-polished quartz.

A fluid-mechanical model is developed for the float-polishing process. In this model laminar flow between the sample and the lap results in pressure gradients at the grooves that support the sample on a fluid layer. The laminar fluid motion also produces supersmooth, damage-free surfaces. Quartz substrates for applications in high-stress environments were float polished, and their surfaces were analyzed by optical scatterometry, photoacoustic spectroscopy, and atomic force microscopy. The removal of 100 µm of material by a lapping-polishing process, with final float polishing, left low levels of subsurface damage, with a surface roughness of approximately 0.2-nm rms.

Subsurface damage identification in optically transparent materials using a nondestructive method.

Total internal reflection microscopy has been applied to image subsurface damage sites in conventionally polished fused-silica flats. This technique can differentiate between surface and subsurface features by changing the illuminating polarization. The method is nondestructive, and no surface preparation is required other than a thorough cleaning of the surface. The intensity distributions in the illuminated region of interest are discussed. The technique has been used successfully as an optical fabrication in-process diagnostic.

Correlation between substrate preparation technique and scatter observed from optical coatings.

We present experimental evidence of the dependence of coating scatter on a substrate preparation technique for fused silica substrates. Samples included conventionally polished, superpolished, andfloat-polished substrates. We used scatterometry and total internal reflection microscopy to investigate the effects of substrate preparation on the performance of zirconium oxide thin films. Results indicate that scatter from coatings dominates the scatter signature of the coated optic. They also demonstrate that substrate preparation can affect the level of scatter produced in optical coatings. In addition it is observed that the substrates with the lowest scatter do not necessarily result in the coatings with the lowest scatter.

Enhanced drug metabolism after sulfinpyrazone treatment in patients aged 50 to 60 years.

The induction of liver drug metabolism was investigated in five patients before and after the administration of 800 mg sulfinpyrazone daily for 4 weeks, by using antipyrine plasma-pharmacokinetics and by determining urinary excretion of 6-beta-OH-cortisol and serum gamma-glutamyl-transpeptidase (GGT) activity. Antipyrine half-life was shortened in all patients from a mean value of 12.3 +/- 3.9 h to 7.8 +/- 2.0 h and antipyrine clearance was increased from 39.0 +/- 16.0 ml/min to 57.6 +/- 13.7 ml/min. In contrast the volume of distribution of antipyrine was unaffected; the values being 38.0 +/- 8.6 liters and 37.4 +/- 5.7 liters, respectively. In all patients the excretion of 6-beta-OH-cortisol in the urine went up from 65.0 +/- 25.7 micrograms/24 h to 346.8 +/- 193.4 micrograms/24 h. The ratio 6-beta-OH-cortisol/free cortisol changed from 4.1 to 15.8. After 21 days of treatment the GGT increased from 17.4 +/- 4.9 units/liter to 32.6 +/- 12.5 units/liter The data presented confirm that sulfinpyrazone induces drug metabolism in patients of the older age group. Interactions between sulfinpyrazone and other drugs given simultaneously must be borne in mind.