Chronic Activation of Corticotropin-Releasing Factor Type 2 Receptors Reveals a Key Role for 5-HT1A Receptor Responsiveness in Mediating Behavioral and Serotonergic Responses to Stressful Challenge

BackgroundThe corticotropin-releasing factor type 2 receptor (CRFR2) is suggested to play an important role in aiding recovery from acute stress, but any chronic effects of CRFR2 activation are unknown. CRFR2 in the midbrain raphé nuclei modulate serotonergic activity of this key source of serotonin (5-HT) forebrain innervation.MethodsTransgenic mice overexpressing the highly specific CRFR2 ligand urocortin 3 (UCN3OE) were analyzed for stress-related behaviors and hypothalamic-pituitary-adrenal axis responses. Responses to 5-HT receptor agonist challenge were assessed by local cerebral glucose utilization, while 5-HT and 5-hydroxyindoleacetic acid content were quantified in limbic brain regions.ResultsMice overexpressing urocortin 3 exhibited increased stress-related behaviors under basal conditions and impaired retention of spatial memory compared with control mice. Following acute stress, unlike control mice, they exhibited no further increase in these stress-related behaviors and showed an attenuated adrenocorticotropic hormone response. 5-HT and 5-hydroxyindoleacetic acid content of limbic nuclei were differentially regulated by stress in UCN3OE mice as compared with control mice. Responses to 5-HT type 1A receptor challenge were significantly and specifically reduced in UCN3OE mice. The distribution pattern of local cerebral glucose utilization and 5-HT type 1A receptor messenger RNA expression levels suggested this effect was mediated in the raphé nuclei.ConclusionsChronic activation of CRFR2 promotes an anxiety-like state, yet with attenuated behavioral and hypothalamic-pituitary-adrenal axis responses to stress. This is reminiscent of stress-related atypical psychiatric syndromes such as posttraumatic stress disorder, chronic fatigue, and chronic pain states. This new understanding indicates CRFR2 antagonism as a potential novel therapeutic target for such disorders

Increased anxiety in corticotropin-releasing factor type 2 receptor-null mice requires recent acute stress exposure and is associated with dysregulated serotonergic activity in limbic brain areas

BACKGROUND: Corticotropin-releasing factor type 2 receptors (CRFR2) are suggested to facilitate successful recovery from stress to maintain mental health. They are abundant in the midbrain raphe nuclei, where they regulate serotonergic neuronal activity and have been demonstrated to mediate behavioural consequences of stress. Here, we describe behavioural and serotonergic responses consistent with maladaptive recovery from stressful challenge in CRFR2-null mice. RESULTS: CRFR2-null mice showed similar anxiety levels to control mice before and immediately after acute restraint stress, and also after cessation of chronic stress. However, they showed increased anxiety by 24 hours after restraint, whether or not they had been chronically stressed. Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) contents were quantified and the level of 5-HIAA in the caudal dorsal raphe nucleus (DRN) was increased under basal conditions in CRFR2-null mice, indicating increased 5-HT turnover. Twenty-four hours following restraint, 5-HIAA was decreased only in CRFR2-null mice, suggesting that they had not fully recovered from the challenge. In efferent limbic structures, CRFR2-null mice showed lower levels of basal 5-HT in the lateral septum and subiculum, and again showed a differential response to restraint stress from controls. Local cerebral glucose utilization (LCMRglu) revealed decreased neuronal activity in the DRN of CRFR2-null mice under basal conditions. Following 5-HT receptor agonist challenge, LCMRglu responses indicated that 5-HT(1A) receptor responses in the DRN were attenuated in CRFR2-null mice. However, postsynaptic 5-HT receptor responses in forebrain regions were intact. CONCLUSIONS: These results suggest that CRFR2 are required for proper functionality of 5-HT(1A) receptors in the raphe nuclei, and are key to successful recovery from stress. This disrupted serotonergic function in CRFR2-null mice likely contributes to their stress-sensitive phenotype. The 5-HT content in lateral septum and subiculum was notably altered. These areas are important for anxiety, and are also implicated in reward and the pathophysiology of addiction. The role of CRFR2 in stress-related psychopathologies deserves further consideration

Observation of two new Ξb−\Xi_b^- baryon resonances

Two structures are observed close to the kinematic threshold in the $\Xi_b^0 \pi^-$ mass spectrum in a sample of proton-proton collision data, corresponding to an integrated luminosity of 3.0 fb$^{-1}$ recorded by the LHCb experiment. In the quark model, two baryonic resonances with quark content $bds$ are expected in this mass region: the spin-parity $J^P = \frac{1}{2}^+$ and $J^P=\frac{3}{2}^+$ states, denoted $\Xi_b^{\prime -}$ and $\Xi_b^{*-}$. Interpreting the structures as these resonances, we measure the mass differences and the width of the heavier state to be $m(\Xi_b^{\prime -}) - m(\Xi_b^0) - m(\pi^{-}) = 3.653 \pm 0.018 \pm 0.006$ MeV$/c^2$, $m(\Xi_b^{*-}) - m(\Xi_b^0) - m(\pi^{-}) = 23.96 \pm 0.12 \pm 0.06$ MeV$/c^2$, $\Gamma(\Xi_b^{*-}) = 1.65 \pm 0.31 \pm 0.10$ MeV, where the first and second uncertainties are statistical and systematic, respectively. The width of the lighter state is consistent with zero, and we place an upper limit of $\Gamma(\Xi_b^{\prime -}) < 0.08$ MeV at 95% confidence level. Relative production rates of these states are also reported.Comment: 17 pages, 2 figure

Observation of associated production of a ZZ boson with a DD meson in the~forward region

A search for associated production of a $Z$ boson with an open charm meson is presented using a data sample, corresponding to an integrated luminosity of $1.0\,\mathrm{fb}^{-`}$ of proton--proton collisions at a centre-of-mass energy of 7\,TeV, collected by the LHCb experiment. %% Seven candidate events for associated production of a $Z$ boson with a $D^0$ meson and four candidate events for a $Z$ boson with a $D^+$ meson are observed with a combined significance of 5.1standard deviations. The production cross-sections in the forward region are measured to be $$\sigma_{Z\rightarrow\mu^+\mu^-\!,D^0} = 2.50\pm1.12\pm0.22pb$$ $$\sigma_{Z\rightarrow\mu^+\mu^-\!,D^+} = 0.44\pm0.23\pm0.03pb,$$ where the first uncertainty is statistical and the second systematic.Comment: 18 pages, 2 figure

Measurements of the B+B^+, B0B^0, Bs0B_s^0 meson and Λb0\Lambda_b^0 baryon lifetimes

Measurements of $b$-hadron lifetimes are reported using $pp$ collision data, corresponding to an integrated luminosity of 1.0fb$^{-1}$, collected by the LHCb detector at a centre-of-mass energy of $7$Tev. Using the exclusive decays $B^+\to J/\psi K^+$, $B^0\to J/\psi K^*(892)^0$, $B^0\to J/\psi K^0_{\rm S}$, $\Lambda_b^0\to J/\psi \Lambda$ and $B^0_s\to J/\psi \phi$ the average decay times in these modes are measured to be $\tau_{B^+\to J/\psi K^+}$ = $1.637 \pm$ 0.004 $\pm$ 0.003 ps, $\tau_{B^0\to J/\psi K^*(892)^0}$ = $1.524 \pm$ 0.006 $\pm$ 0.004 ps, $\tau_{B^0\to J/\psi K^0_{\rm S}}$ = $1.499 \pm$ 0.013 $\pm$ 0.005 ps, $\tau_{\Lambda_b^0\to J/\psi \Lambda}$ = $1.415 \pm$ 0.027 $\pm$ 0.006 ps and $\tau_{B^0_s\to J/\psi \phi}$ = $1.480 \pm$ 0.011 $\pm$ 0.005 ps, where the first uncertainty is statistical and the second is systematic. These represent the most precise lifetime measurements in these decay modes. In addition, ratios of these lifetimes, and the ratio of the decay-width difference, $\Delta\Gamma_d$, to the average width, $\Gamma_d$, in the $B^0$ system, $\Delta \Gamma_d/\Gamma_d = -0.044 \pm 0.025 \pm 0.011$, are reported. All quantities are found to be consistent with Standard Model expectations.Comment: 28 pages, 4 figures. Updated reference

Precision measurement of CPCP violation in Bs0→J/ψK+K−B_s^0 \to J/\psi K^+K^- decays

The time-dependent $CP$ asymmetry in $B_s^0 \to J/\psi K^+K^-$ decays is measured using $pp$ collision data, corresponding to an integrated luminosity of $3.0$fb$^{-1}$, collected with the LHCb detector at centre-of-mass energies of $7$ and $8$TeV. In a sample of 96 000 $B_s^0 \to J/\psi K^+K^-$ decays, the $CP$-violating phase $\phi_s$ is measured, as well as the decay widths $\Gamma_{L}$ and $\Gamma_{H}$ of the light and heavy mass eigenstates of the $B_s^0-\bar{B}_s^0$ system. The values obtained are $\phi_s = -0.058 \pm 0.049 \pm 0.006$ rad, $\Gamma_s \equiv (\Gamma_{L}+\Gamma_{H})/2 = 0.6603 \pm 0.0027 \pm 0.0015$ps$^{-1}$, and$\Delta\Gamma_s \equiv \Gamma_{L} - \Gamma_{H} = 0.0805 \pm 0.0091 \pm 0.0032$ps$^{-1}$, where the first uncertainty is statistical and the second systematic. These are the most precise single measurements of those quantities to date. A combined analysis with $B_s^{0} \to J/\psi \pi^+\pi^-$ decays gives $\phi_s = -0.010 \pm 0.039$rad. All measurements are in agreement with the Standard Model predictions. For the first time the phase $\phi_s$ is measured independently for each polarisation state of the $K^+K^-$ system and shows no evidence for polarisation dependence.Comment: 6 figure

Observation of J/ψpJ/\psi p resonances consistent with pentaquark states in Λb0→J/ψK−p{\Lambda_b^0\to J/\psi K^-p} decays

Observations of exotic structures in the $J/\psi p$ channel, that we refer to as pentaquark-charmonium states, in $\Lambda_b^0\to J/\psi K^- p$ decays are presented. The data sample corresponds to an integrated luminosity of 3/fb acquired with the LHCb detector from 7 and 8 TeV pp collisions. An amplitude analysis is performed on the three-body final-state that reproduces the two-body mass and angular distributions. To obtain a satisfactory fit of the structures seen in the $J/\psi p$ mass spectrum, it is necessary to include two Breit-Wigner amplitudes that each describe a resonant state. The significance of each of these resonances is more than 9 standard deviations. One has a mass of $4380\pm 8\pm 29$ MeV and a width of $205\pm 18\pm 86$ MeV, while the second is narrower, with a mass of $4449.8\pm 1.7\pm 2.5$ MeV and a width of $39\pm 5\pm 19$ MeV. The preferred $J^P$ assignments are of opposite parity, with one state having spin 3/2 and the other 5/2.Comment: 48 pages, 18 figures including the supplementary material, v2 after referee's comments, now 19 figure

Search for the rare decays B0→J/ψγB^{0}\to J/\psi \gamma and Bs0→J/ψγB^{0}_{s} \to J/\psi \gamma

A search for the rare decay of a $B^{0}$ or $B^{0}_{s}$ meson into the final state $J/\psi\gamma$ is performed, using data collected by the LHCb experiment in $pp$ collisions at $\sqrt{s}=7$ and $8$ TeV, corresponding to an integrated luminosity of 3 fb$^{-1}$. The observed number of signal candidates is consistent with a background-only hypothesis. Branching fraction values larger than $1.7\times 10^{-6}$ for the $B^{0}\to J/\psi\gamma$ decay mode are excluded at 90% confidence level. For the $B^{0}_{s}\to J/\psi\gamma$ decay mode, branching fraction values larger than $7.4\times 10^{-6}$ are excluded at 90% confidence level, this is the first branching fraction limit for this decay.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2015-044.htm

First observation and amplitude analysis of the B−→D+K−π−B^{-}\to D^{+}K^{-}\pi^{-} decay

The $B^{-}\to D^{+}K^{-}\pi^{-}$ decay is observed in a data sample corresponding to $3.0~\rm{fb}^{-1}$ of $pp$ collision data recorded by the LHCb experiment during 2011 and 2012. Its branching fraction is measured to be ${\cal B}(B^{-}\to D^{+}K^{-}\pi^{-}) = (7.31 \pm 0.19 \pm 0.22 \pm 0.39) \times 10^{-5}$ where the uncertainties are statistical, systematic and from the branching fraction of the normalisation channel $B^{-}\to D^{+}\pi^{-}\pi^{-}$, respectively. An amplitude analysis of the resonant structure of the $B^{-}\to D^{+}K^{-}\pi^{-}$ decay is used to measure the contributions from quasi-two-body $B^{-}\to D_{0}^{*}(2400)^{0}K^{-}$, $B^{-}\to D_{2}^{*}(2460)^{0}K^{-}$, and $B^{-}\to D_{J}^{*}(2760)^{0}K^{-}$ decays, as well as from nonresonant sources. The $D_{J}^{*}(2760)^{0}$ resonance is determined to have spin~1.Comment: 39 pages, 10 figures, submitted to Phys. Rev. D. Updated following erratum 10.1103/PhysRevD.93.11990