Potential Biomarkers for Physical Exercise-Induced Brain Health

Physical exercise has long been recognized as an effective and economic strategy to promote brain health in humans. The cellular and structural changes in the brains of exercised animals, including enhancements of neurogenesis and synaptogenesis, dendritic remodeling, and synaptic plasticity, have been considered as the key biological alterations accounting for exercise-elicited benefits to brain health. However, what transduces body movements into the above-mentioned changes remains largely unknown. Emerging theories indicate that physical activity triggers the release of various factors into the circulation from skeletal muscle (neurotrophins, myokines, and cytokines) and/or adipose tissue (adipokines). In this chapter, we review several of these molecules that are potentially implicated in this process, including neurotrophic factors (BDNF, IGF-1, and VEGF), adipokines (adiponectin and irisin), and myokines/cytokines (IL-15). The relationship, either causal or concomitant, between levels of these molecules (particularly in the blood) and brain function after exercise may help to identify biomarkers that can serve as objective indicators to evaluate exercise therapy on diseased or ageing brain. In addition, unmasking biomarkers may be instrumental in elucidating the mechanisms mediating exercise-induced brain health, thereby contributing to novel drug discovery for treatments to maintain brain health

Fragile-X Syndrome Is Associated With NMDA Receptor Hypofunction and Reduced Dendritic Complexity in Mature Dentate Granule Cells

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. It is caused by the overexpansion of cytosine-guanine-guanine (CGG) trinucleotide in Fmr1 gene, resulting in complete loss of the fragile X mental retardation protein (FMRP). Previous studies using Fmr1 knockout (Fmr1 KO) mice have suggested that a N-methyl-D-aspartate receptors (NMDAR) hypofunction in the hippocampal dentate gyrus may partly contribute to cognitive impairments in FXS. Since activation of NMDAR plays an important role in dendritic arborization during neuronal development, we examined whether deficits in NMDAR function are associated with alterations in dendritic complexity in the hippocampal dentate region. The dentate granule cell layer (GCL) presents active postnatal neurogenesis, and consists of a heterogenous neuronal population with gradient ages from the superficial to its deep layer. Here, we show that neurons with multiple primary dendrites that reside in the outer GCL of Fmr1 KO mice display significantly smaller NMDAR excitatory post-synaptic currents (EPSCs) and a higher α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to NMDA ratio in comparison to their wild-type counterparts. These deficits were associated with a significant decrease in dendritic complexity, with both dendritic length and number of intersections being significantly reduced. In contrast, although neurons with a single primary dendrite resided in the inner GCL of Fmr1 KO mice had a trend toward a reduction in NMDAR EPSCs and a higher AMPA/NMDA ratio, no alterations were found in dendritic complexity at this developmental stage. Our data indicate that the loss of FMRP causes NMDAR deficits and reduced dendritic complexity in granule neurons with multiple primary dendrites which are thought to be more mature in the GCL

Effects of Maternal Voluntary Wheel Running During Pregnancy on Adult Hippocampal Neurogenesis, Temporal Order Memory, and Depression-Like Behavior in Adult Female and Male Offspring

Research suggests that maternal exercise in pregnancy may have beneficial effects on the brain function of offspring. This study sought to determine if voluntary wheel running during pregnancy improves depression-like behavior, temporal order memory, and hippocampal neurogenesis in both female and male offspring mice. Pregnant mice were allowed to run voluntarily by introducing running wheels into the housing cages throughout the gestational period. Male and female mice offspring at the age of 8- to 9-week-old were then tested on the temporal order task and forced swim test, then euthanized for immunostaining for examining adult hippocampal cell proliferation and neuronal differentiation. Results showed that both male and female pups had reduced depression-like behavior, while only male offspring demonstrated improvement in temporal order memory. Immunostaining revealed that male offspring showed an increase in the number of immature neurons in the ventral hippocampus, whereas female offspring showed enhanced cell proliferation in the dorsal hippocampus. These findings indicate that maternal voluntary wheel running benefits both female and male offspring on reducing depression-like behavior, but with gender effect on promoting hippocampal cell proliferation, neuronal differentiation, and temporal order memory

Hippocampal PACAP signaling activation triggers a rapid antidepressant response

Background The development of ketamine-like rapid antidepressants holds promise for enhancing the therapeutic efcacy of depression, but the underlying cellular and molecular mechanisms remain unclear. Implicated in depres‑ sion regulation, the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is investigated here to examine its role in mediating the rapid antidepressant response. Methods The onset of antidepressant response was assessed through depression-related behavioral paradigms. The signaling mechanism of PACAP in the hippocampal dentate gyrus (DG) was evaluated by utilizing site-directed gene knockdown, pharmacological interventions, or optogenetic manipulations. Overall, 446 mice were used for behavioral and molecular signaling testing. Mice were divided into control or experimental groups randomly in each experiment, and the experimental manipulations included: chronic paroxetine treatments (4, 9, 14 d) or a single treatment of keta‑ mine; social defeat or lipopolysaccharides-injection induced depression models; diferent doses of PACAP (0.4, 2, 4 ng/ site; microinjected into the hippocampal DG); pharmacological intra-DG interventions (CALM and PACAP6-38); intraDG viral-mediated PACAP RNAi; and opotogenetics using channelrhodopsins 2 (ChR2) or endoplasmic natronomonas halorhodopsine 3.0 (eNpHR3.0). Behavioral paradigms included novelty suppressed feeding test, tail suspension test, forced swimming test, and sucrose preference test. Western blotting, ELISA, or quantitative real-time PCR (RT-PCR) analysis were used to detect the expressions of proteins/peptides or genes in the hippocampus. Results Chronic administration of the slow-onset antidepressant paroxetine resulted in an increase in hippocam‑ pal PACAP expression, and intra-DG blockade of PACAP attenuated the onset of the antidepressant response. The levels of hippocampal PACAP expression were reduced in both two distinct depression animal models and intra-DG knockdown of PACAP induced depression-like behaviors. Conversely, a single infusion of PACAP into the DG region produced a rapid and sustained antidepressant response in both normal and chronically stressed mice. Optoge‑ netic intra-DG excitation of PACAP-expressing neurons instantly elicited antidepressant responses, while optoge‑ netic inhibition induced depression-like behaviors. The longer optogenetic excitation/inhibition elicited the more sustained antidepressant/depression-like responses. Intra-DG PACAP infusion immediately facilitated the signaling for rapid antidepressant response by inhibiting calcium/calmodulin-dependent protein kinase II (CaMKII)-eukaryotic elongation factor 2 (eEF2) and activating the mammalian target of rapamycin (mTOR). Pre-activation of CaMKII signaling within the DG blunted PACAP-induced rapid antidepressant response as well as eEF2-mTOR-brain-derivedneurotrophic factor (BDNF) signaling. Finally, acute ketamine treatment upregulated hippocampal PACAP expression, whereas intra-DG blockade of PACAP signaling attenuated ketamine’s rapid antidepressant response. Conclusions Activation of hippocampal PACAP signaling induces a rapid antidepressant response through the regu‑ lation of CaMKII inhibition-governed eEF2-mTOR-BDNF signaling

Adiponectin Mediates Running-Restored Hippocampal Neurogenesis in Streptozotocin-Induced Type 1 Diabetes in Mice

Streptozotocin (STZ)-induced diabetes impairs learning and memory performance and reduces adult hippocampal neurogenesis. Physical exercise brings beneficial effects. We have previously shown that adiponectin, an adipocyte-secreted hormone critically involved in the pathology of diabetes, is a key mediator for exercise-enhanced adult hippocampal neurogenesis. Here, we tested whether adiponectin is required for exercise to restore adult hippocampal neurogenesis in an animal model of diabetes. The findings showed that a single injection of 195 mg/kg STZ-induced diabetes significantly increased serum levels of corticosterone and reduced hippocampal adiponectin levels in adult mice. STZ injection also significantly reduced the number of Ki67 and doublecortin (DCX) positive cells and the ratio of co-labeling of DCX and bromodeoxyuridine (BrdU) in the hippocampal dentate region, indicating a decrease in adult hippocampal neurogenesis. Two-week voluntary wheel running significantly restored hippocampal neurogenesis in the diabetic wild-type mice, but not adiponectin knockout mice, indicating that adiponectin is critical for physical exercise to restore hippocampal adult neurogenesis in mice with diabetes. The results suggest that increasing adiponectin levels could be a therapeutic approach to restore hippocampal neurogenesis impairment in individuals with diabetes

Measurements of fiducial and differential cross sections for Higgs boson production in the diphoton decay channel at s√=8 TeV with ATLAS

Measurements of fiducial and differential cross sections are presented for Higgs boson production in proton-proton collisions at a centre-of-mass energy of s√=8 TeV. The analysis is performed in the H → γγ decay channel using 20.3 fb−1 of data recorded by the ATLAS experiment at the CERN Large Hadron Collider. The signal is extracted using a fit to the diphoton invariant mass spectrum assuming that the width of the resonance is much smaller than the experimental resolution. The signal yields are corrected for the effects of detector inefficiency and resolution. The pp → H → γγ fiducial cross section is measured to be 43.2 ±9.4(stat.) − 2.9 + 3.2 (syst.) ±1.2(lumi)fb for a Higgs boson of mass 125.4GeV decaying to two isolated photons that have transverse momentum greater than 35% and 25% of the diphoton invariant mass and each with absolute pseudorapidity less than 2.37. Four additional fiducial cross sections and two cross-section limits are presented in phase space regions that test the theoretical modelling of different Higgs boson production mechanisms, or are sensitive to physics beyond the Standard Model. Differential cross sections are also presented, as a function of variables related to the diphoton kinematics and the jet activity produced in the Higgs boson events. The observed spectra are statistically limited but broadly in line with the theoretical expectations

Measurement of the production of a W boson in association with a charm quark in pp collisions at √s = 7 TeV with the ATLAS detector

The production of a W boson in association with a single charm quark is studied using 4.6 fb−1 of pp collision data at s√ = 7 TeV collected with the ATLAS detector at the Large Hadron Collider. In events in which a W boson decays to an electron or muon, the charm quark is tagged either by its semileptonic decay to a muon or by the presence of a charmed meson. The integrated and differential cross sections as a function of the pseudorapidity of the lepton from the W-boson decay are measured. Results are compared to the predictions of next-to-leading-order QCD calculations obtained from various parton distribution function parameterisations. The ratio of the strange-to-down sea-quark distributions is determined to be 0.96+0.26−0.30 at Q 2 = 1.9 GeV2, which supports the hypothesis of an SU(3)-symmetric composition of the light-quark sea. Additionally, the cross-section ratio σ(W + +c¯¯)/σ(W − + c) is compared to the predictions obtained using parton distribution function parameterisations with different assumptions about the s−s¯¯¯ quark asymmetry

Measurement of χ c1 and χ c2 production with s√ = 7 TeV pp collisions at ATLAS

The prompt and non-prompt production cross-sections for the χ c1 and χ c2 charmonium states are measured in pp collisions at s√ = 7 TeV with the ATLAS detector at the LHC using 4.5 fb−1 of integrated luminosity. The χ c states are reconstructed through the radiative decay χ c → J/ψγ (with J/ψ → μ + μ −) where photons are reconstructed from γ → e + e − conversions. The production rate of the χ c2 state relative to the χ c1 state is measured for prompt and non-prompt χ c as a function of J/ψ transverse momentum. The prompt χ c cross-sections are combined with existing measurements of prompt J/ψ production to derive the fraction of prompt J/ψ produced in feed-down from χ c decays. The fractions of χ c1 and χ c2 produced in b-hadron decays are also measured

Search for squarks and gluinos in events with isolated leptons, jets and missing transverse momentum at s√=8 TeV with the ATLAS detector

The results of a search for supersymmetry in final states containing at least one isolated lepton (electron or muon), jets and large missing transverse momentum with the ATLAS detector at the Large Hadron Collider are reported. The search is based on proton-proton collision data at a centre-of-mass energy s√=8 TeV collected in 2012, corresponding to an integrated luminosity of 20 fb−1. No significant excess above the Standard Model expectation is observed. Limits are set on supersymmetric particle masses for various supersymmetric models. Depending on the model, the search excludes gluino masses up to 1.32 TeV and squark masses up to 840 GeV. Limits are also set on the parameters of a minimal universal extra dimension model, excluding a compactification radius of 1/R c = 950 GeV for a cut-off scale times radius (ΛR c) of approximately 30

Search for squarks and gluinos with the ATLAS detector in final states with jets and missing transverse momentum using √s=8 TeV proton-proton collision data

A search for squarks and gluinos in final states containing high-p T jets, missing transverse momentum and no electrons or muons is presented. The data were recorded in 2012 by the ATLAS experiment in s√=8 TeV proton-proton collisions at the Large Hadron Collider, with a total integrated luminosity of 20.3 fb−1. Results are interpreted in a variety of simplified and specific supersymmetry-breaking models assuming that R-parity is conserved and that the lightest neutralino is the lightest supersymmetric particle. An exclusion limit at the 95% confidence level on the mass of the gluino is set at 1330 GeV for a simplified model incorporating only a gluino and the lightest neutralino. For a simplified model involving the strong production of first- and second-generation squarks, squark masses below 850 GeV (440 GeV) are excluded for a massless lightest neutralino, assuming mass degenerate (single light-flavour) squarks. In mSUGRA/CMSSM models with tan β = 30, A 0 = −2m 0 and μ > 0, squarks and gluinos of equal mass are excluded for masses below 1700 GeV. Additional limits are set for non-universal Higgs mass models with gaugino mediation and for simplified models involving the pair production of gluinos, each decaying to a top squark and a top quark, with the top squark decaying to a charm quark and a neutralino. These limits extend the region of supersymmetric parameter space excluded by previous searches with the ATLAS detector