Opioid receptor antagonists increase hyperalgesia in humans and animals, which indicates that endogenous activation of opioid receptors provides relief from acute pain; however, the mechanisms of ...long-term opioid inhibition of pathological pain have remained elusive. We found that tissue injury produced μ-opioid receptor (MOR) constitutive activity (MORCA) that repressed spinal nociceptive signaling for months. Pharmacological blockade during the posthyperalgesia state with MOR inverse agonists reinstated central pain sensitization and precipitated hallmarks of opioid withdrawal (including adenosine 3',5'-monophosphate overshoot and hyperalgesia) that required N-methyl-D-aspartate receptor activation of adenylyl cyclase type 1. Thus, MOR CA initiates both analgesic signaling and a compensatory opponent process that generates endogenous opioid dependence. Tonic MOR CA suppression of withdrawal hyperalgesia may prevent the transition from acute to chronic pain.
Chronic wasting disease (CWD) is a highly contagious, fatal neurodegenerative disease caused by infectious prions (PrP
) affecting wild and captive cervids. Although experimental feeding studies have ...demonstrated prions in feces of crows (Corvus brachyrhynchos), coyotes (Canis latrans), and cougars (Puma concolor), the role of scavengers and predators in CWD epidemiology remains poorly understood. Here we applied the real-time quaking-induced conversion (RT-QuIC) assay to detect PrP
in feces from cervid consumers, to advance surveillance approaches, which could be used to improve disease research and adaptive management of CWD. We assessed recovery and detection of PrP
by experimental spiking of PrP
into carnivore feces from 9 species sourced from CWD-free populations or captive facilities. We then applied this technique to detect PrP
from feces of predators and scavengers in free-ranging populations. Our results demonstrate that spiked PrP
is detectable from feces of free-ranging mammalian and avian carnivores using RT-QuIC. Results show that PrP
acquired in natural settings is detectable in feces from free-ranging carnivores, and that PrP
rates of detection in carnivore feces reflect relative prevalence estimates observed in the corresponding cervid populations. This study adapts an important diagnostic tool for CWD, allowing investigation of the epidemiology of CWD at the community-level.
Aims. WISE provides an infrared all-sky survey that aims at completing our knowledge on the possibly dramatically increasing number of brown dwarfs with lower temperatures. We search for the nearest ...representatives of the coolest brown dwarfs, which will be very interesting for detailed follow-up observations, once they have been discovered. Methods. We used the preliminary data release from WISE, then selected bright candidates with colours typical of late-T dwarfs, and tried to match them with faint 2MASS and SDSS objects, to determine their proper motions, and to follow them up spectroscopically. Results. We have identified two new ultracool brown dwarfs with large proper motions, WISE J0254+0223 (2.5 arcsec/yr) and WISE J1741+2553 (1.5 arcsec/yr). With their w1 − w2 ~ 3.0 and J − w2 ~ 4.0 colour indices, we expect both to have spectral types of ~T8-T10 and absolute magnitude of Mw2 ~ 14. We confirm WISE J1741+2553 as a T9-T10 dwarf from near-infrared spectroscopy with LBT/LUCIFER1. From their bright WISE w2 magnitudes of 12.7 and 12.3, we estimate distances of 5.5\hbox{$^{+2.3}_{-1.6}$}+2.3-1.6 pc and 4.6\hbox{$^{+1.2}_{-1.0}$}+1.2-1.0 pc and tangential velocities of ~65 km s-1 and ~34 km s-1 that indicate Galactic thick and thin disk membership, respectively.
Context. Although many new brown dwarf (BD) neighbours have recently been discovered thanks to new sky surveys in the mid- and near-infrared (MIR, NIR), their numbers are still more than five times ...lower than those of stars in the same volume. Aims. Our aim is to detect and classify new BDs to eventually complete their census in the immediate solar neighbourhood. Methods. We combined multi-epoch data from sky surveys at different wavelengths to detect BD neighbours of the Sun by their high proper motion (HPM). We concentrated on relatively bright MIR (w2 < 13.5) BD candidates from the Wide-field Infrared Survey Explorer (WISE) expected to be so close to the Sun that they may also be seen in older NIR (Two Micron All Sky Survey – 2MASS –; DEep Near-Infrared Survey – DENIS) or even red optical (Sloan Digital Sky Survey (SDSS) i- and z-band, SuperCOSMOS Sky Surveys (SSS) I-band) surveys. With low-resolution NIR spectroscopy we classified the new BDs and estimated their distances and velocities. Results. We have discovered the HPM (μ ~ 470 mas/yr) T7.5 dwarf, WISE J0521+1025, which is at d = 5.0 ± 1.3 pc from the Sun the nearest known T dwarf in the northern sky, and two early T dwarfs, WISE J0457−0207 (T2) and WISE J2030+0749 (T1.5), with proper motions of ~120 and ~670 mas/yr and distances of 12.5 ± 3.1 pc and 10.5 ± 2.6 pc, respectively. The last one was independently discovered and also classified as a T1.5 dwarf by Mace and coworkers. All three show thin disc kinematics. They may have been overlooked in the past owing to overlapping images and because of problems with matching objects between different surveys and measuring their proper motions.
When certain memory becomes obsolete, effective suppression of the previously established memory is essential for animals to adapt to the changing environment. At the cellular level, reversal of ...synaptic potentiation may be important for neurons to acquire new information and to prevent synaptic saturation. Here, we investigated the function of Ca(2+)-stimulated cAMP signaling in the regulation of bidirectional synaptic plasticity and spatial memory formation in double knock-out mice (DKO) lacking both type 1 and 8 adenylyl cyclases (ACs). In anesthetized animals, the DKO mutants showed defective long-term potentiation (LTP) after a single high-frequency stimulation (HFS) or two spaced HFSs at 100 Hz. However, DKO mice showed normal LTP after a single HFS at 200 Hz or two compressed HFSs at 100 Hz. Interestingly, reversal of synaptic potentiation as well as de novo synaptic depression was impaired in DKO mice. In the Morris water maze, DKO mice showed defective acquisition and memory retention, although the deficits could be attenuated by overtraining or compressed trainings with a shorter intertrial interval. In the reversal platform test, DKO animals were impaired in both relearning and old memory suppression. Furthermore, the extinction of the old spatial memory was not efficient in DKO mice. These data demonstrate that Ca(2+)-stimulated AC activity is important not only for LTP and spatial memory formation but also for the suppression of both previously established synaptic potentiation and old spatial memory.
Quantal release of the principal excitatory neurotransmitter glutamate requires a mechanism for its transport into secretory vesicles. Within the brain, the complementary expression of vesicular ...glutamate transporters (VGLUTs) 1 and 2 accounts for the release of glutamate by all known excitatory neurons. We now report the identification of VGLUT3 and its expression by many cells generally considered to release a classical transmitter with properties very different from glutamate. Remarkably, subpopulations of inhibitory neurons as well as cholinergic interneurons, monoamine neurons, and glia express VGLUT3. The dendritic expression of VGLUT3 by particular neurons also indicates the potential for retrograde synaptic signaling. The distribution and subcellular location of VGLUT3 thus suggest novel modes of signaling by glutamate.
Consolidation of hippocampus-dependent memory is dependent on activation of the cAMP/Erk/MAPK (mitogen-activated protein kinase) signal transduction pathway in the hippocampus. Recently, we ...discovered that adenylyl cyclase and MAPK activities undergo a circadian oscillation in the hippocampus and that inhibition of this oscillation impairs contextual memory. This suggests the interesting possibility that the persistence of hippocampus-dependent memory depends upon the reactivation of MAPK in the hippocampus during the circadian cycle. A key unanswered question is whether the circadian oscillation of this signaling pathway is intrinsic to the hippocampus or is driven by the master circadian clock in the suprachiasmatic nucleus (SCN). To address this question, we ablated the SCN of mice by electrolytic lesion and examined hippocampus-dependent memory as well as adenylyl cyclase and MAPK activities. Electrolytic lesion of the SCN 2 d after training for contextual fear memory reduced contextual memory measured 2 weeks after training, indicating that maintenance of contextual memory depends on the SCN. Spatial memory was also compromised in SCN-lesioned mice. Furthermore, the diurnal oscillation of adenylyl cyclase and MAPK activities in the hippocampus was destroyed by lesioning of the SCN. These data suggest that hippocampus-dependent long-term memory is dependent on the SCN-controlled oscillation of the adenylyl cyclase/MAPK pathway in the hippocampus.
One of the most intriguing questions in neurobiology is how neurons and synapses encode the long-term changes in synaptic efficacy that underlie memory consolidation. A recent set of studies suggests ...that the ERK/mitogen-activated protein kinase (MAPK) plays a fundamental role in vertebrate and invertebrate memory consolidation. These findings suggest that the ERK/MAPK cascade should join the cAMP response element binding protein/cAMP response element (CREB/CRE) and cAMP/protein kinase A (PKA) pathways as evolutionarily conserved regulators of memory formation. Because the MAPK cascade was previously identified as a critical regulator of cell growth, its regulatory role in synaptic function in postmitotic neurons was unexpected. Nevertheless, a wide body of work now shows that the MAPK cascade is potently activated by synaptic activity and by increases in intracellular Ca super(2+) and cAMP. Here, we focus on recent exciting studies that indicate that the MAPK signaling cascade is critical for both memory consolidation and long-term neuronal plasticity. We also address the mechanisms for activity- and plasticity-mediated activation of MAPK in central nervous system (CNS) neurons and discuss evidence that activation of CREB by the ERK/MAPK cascade plays a pivotal role in some forms of neuronal plasticity.
Aims. Our aim is to detect and classify previously overlooked brown dwarfs in the solar neighbourhood. Methods. We performed a proper motion search among bright sources observed with the Wide-field ...Infrared Survey Explorer (WISE) that are also seen in the Two Micron All Sky Survey (2MASS). Our candidates appear according to their red J−Ks colours as nearby late-L dwarf candidates. Low-resolution near-infrared (NIR) classification spectroscopy in the HK band allowed us to get spectroscopic distance and tangential velocity estimates. Results. We have discovered a new L9.5 dwarf, WISEA J064750.85-154616.4, at a spectroscopic distance of about 14 pc and with a tangential velocity of about 11 km s-1, typical of the Galactic thin disc population. We have confirmed another recently found L/T transition object at about 10 pc, WISEA J140533.13+835030.7, which we classified as L8 (NIR).
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