Chronic 2-Fold Elevation of Endogenous GDNF Levels Is Safe and Enhances Motor and Dopaminergic Function in Aged Mice

Glial cell line-derived neurotrophic factor (GDNF) supports function and survival of dopamine neurons that degenerate in Parkinson's disease (PD). Ectopic delivery of GDNF in clinical trials to treat PD is safe but lacks significant therapeutic effect. In pre-clinical models, ectopic GDNF is effective but causes adverse effects, including downregulation of tyrosine hydroxylase, only a transient boost in dopamine metabolism, aberrant neuronal sprouting, and hyperactivity. Hindering development of GDNF mimetic increased signaling via GDNF receptor RET by activating mutations results in cancer. Safe and effective mode of action must be defined first in animal models to develop successful GDNF-based therapies. Previously we showed that about a 2-fold increase in endogenous GDNF expression is safe and results in increased motor and dopaminergic function and protection in a PD model in young animals. Recently, similar results were reported using a novel Gdnf mRNA-targeting strategy. Next, it is important to establish the safety of a long-term increase in endogenous GDNF expression. We report behavioral, dopamine system, and cancer analysis of five cohorts of aged mice with a 2-fold increase in endogenous GDNF. We found a sustained increase in dopamine levels, improvement in motor learning, and no side effects or cancer. These results support the rationale for further development of endogenous GDNF-based treatments and GDNF mimetic.Peer reviewe

Elevated endogenous GDNF induces altered dopamine signalling in mice and correlates with clinical severity in schizophrenia

Presynaptic increase in striatal dopamine is the primary dopaminergic abnormality in schizophrenia, but the underlying mechanisms are not understood. Here, we hypothesized that increased expression of endogenous GDNF could induce dopaminergic abnormalities that resemble those seen in schizophrenia. To test the impact of GDNF elevation, without inducing adverse effects caused by ectopic overexpression, we developed a novel in vivo approach to conditionally increase endogenous GDNF expression. We found that a 2-3-fold increase in endogenous GDNF in the brain was sufficient to induce molecular, cellular, and functional changes in dopamine signalling in the striatum and prefrontal cortex, including increased striatal presynaptic dopamine levels and reduction of dopamine in prefrontal cortex. Mechanistically, we identified adenosine A2a receptor (A(2A)R), a G-protein coupled receptor that modulates dopaminergic signalling, as a possible mediator of GDNF-driven dopaminergic abnormalities. We further showed that pharmacological inhibition of A(2A)R with istradefylline partially normalised striatal GDNF and striatal and cortical dopamine levels in mice. Lastly, we found that GDNF levels are increased in the cerebrospinal fluid of first episode psychosis patients, and in post-mortem striatum of schizophrenia patients. Our results reveal a possible contributor for increased striatal dopamine signalling in a subgroup of schizophrenia patients and suggest that GDNF-A(2A)R crosstalk may regulate dopamine function in a therapeutically targetable manner.</p

Increasing the Astrophysical Reach of the Advanced Virgo Detector via the Application of Squeezed Vacuum States of Light

Current interferometric gravitational-wave detectors are limited by quantum noise over a wide range of their measurement bandwidth. One method to overcome the quantum limit is the injection of squeezed vacuum states of light into the interferometer’s dark port. Here, we report on the successful application of this quantum technology to improve the shot noise limited sensitivity of the Advanced Virgo gravitational-wave detector. A sensitivity enhancement of up to 3.2±0.1  dB beyond the shot noise limit is achieved. This nonclassical improvement corresponds to a 5%–8% increase of the binary neutron star horizon. The squeezing injection was fully automated and over the first 5 months of the third joint LIGO-Virgo observation run O3 squeezing was applied for more than 99% of the science time. During this period several gravitational-wave candidates have been recorded

Quantum Backaction on kg-Scale Mirrors: Observation of Radiation Pressure Noise in the Advanced Virgo Detector

The quantum radiation pressure and the quantum shot noise in laser-interferometric gravitational wave detectors constitute a macroscopic manifestation of the Heisenberg inequality. If quantum shot noise can be easily observed, the observation of quantum radiation pressure noise has been elusive, so far, due to the technical noise competing with quantum effects. Here, we discuss the evidence of quantum radiation pressure noise in the Advanced Virgo gravitational wave detector. In our experiment, we inject squeezed vacuum states of light into the interferometer in order to manipulate the quantum backaction on the 42 kg mirrors and observe the corresponding quantum noise driven displacement at frequencies between 30 and 70 Hz. The experimental data, obtained in various interferometer configurations, is tested against the Advanced Virgo detector quantum noise model which confirmed the measured magnitude of quantum radiation pressure noise

Calibration of advanced Virgo and reconstruction of the detector strain h( t) during the observing run O3

The three advanced Virgo and LIGO gravitational wave detectors participated to the third observing run (O3) between 1 April 2019 15:00 UTC and 27 March 2020 17:00 UTC, leading to several gravitational wave detections per month. This paper describes the advanced Virgo detector calibration and the reconstruction of the detector strain h(t) during O3, as well as the estimation of the associated uncertainties. For the first time, the photon calibration technique as been used as reference for Virgo calibration, which allowed to cross-calibrate the strain amplitude of the Virgo and LIGO detectors. The previous reference, so-called free swinging Michelson technique, has still been used but as an independent cross-check. h(t) reconstruction and noise subtraction were processed online, with good enough quality to prevent the need for offline reprocessing, except for the two last weeks of September 2019. The uncertainties for the reconstructed h(t) strain, estimated in this paper in a 20-2000 Hz frequency band, are frequency independent: 5% in amplitude, 35 mrad in phase and 10 μs in timing, with the exception of larger uncertainties around 50 Hz

Advanced Virgo Plus: Future Perspectives

While completing the commissioning phase to prepare the Virgo interferometer for the next joint Observation Run (O4), the Virgo collaboration is also finalizing the design of the next upgrades to the detector to be employed in the following Observation Run (O5). The major upgrade will concern decreasing the thermal noise limit, which will imply using very large test masses and increased laser beam size. But this will not be the only upgrade to be implemented in the break between the O4 and O5 observation runs to increase the Virgo detector strain sensitivity. The paper will cover the challenges linked to this upgrade and implications on the detector's reach and observational potential, reflecting the talk given at 12th Cosmic Ray International Seminar - CRIS 2022 held in September 2022 in Napoli

Virgo Detector Characterization and Data Quality during the O3 run

The Advanced Virgo detector has contributed with its data to the rapid growth of the number of detected gravitational-wave signals in the past few years, alongside the two LIGO instruments. First, during the last month of the Observation Run 2 (O2) in August 2017 (with, most notably, the compact binary mergers GW170814 and GW170817) and then during the full Observation Run 3 (O3): an 11 months data taking period, between April 2019 and March 2020, that led to the addition of about 80 events to the catalog of transient gravitational-wave sources maintained by LIGO, Virgo and KAGRA. These discoveries and the manifold exploitation of the detected waveforms require an accurate characterization of the quality of the data, such as continuous study and monitoring of the detector noise. These activities, collectively named {\em detector characterization} or {\em DetChar}, span the whole workflow of the Virgo data, from the instrument front-end to the final analysis. They are described in details in the following article, with a focus on the associated tools, the results achieved by the Virgo DetChar group during the O3 run and the main prospects for future data-taking periods with an improved detector.Comment: 86 pages, 33 figures. This paper has been divided into two articles which supercede it and have been posted to arXiv on October 2022. Please use these new preprints as references: arXiv:2210.15634 (tools and methods) and arXiv:2210.15633 (results from the O3 run

The Advanced Virgo+ status

The gravitational wave detector Advanced Virgo+ is currently in the commissioning phase in view of the fourth Observing Run (O4). The major upgrades with respect to the Advanced Virgo configuration are the implementation of an additional recycling cavity, the Signal Recycling cavity (SRC), at the output of the interferometer to broaden the sensitivity band and the Frequency Dependent Squeezing (FDS) to reduce quantum noise at all frequencies. The main difference of the Advanced Virgo + detector with respect to the LIGO detectors is the presence of marginally stable recycling cavities, with respect to the stable recycling cavities present in the LIGO detectors, which increases the difficulties in controlling the interferometer in presence of defects (both thermal and cold defects). This work will focus on the interferometer commissioning, highlighting the control challenges to maintain the detector in the working point which maximizes the sensitivity and the duty cycle for scientific data taking

Virgo Detector Characterization and Data Quality: results from the O3 run

The Advanced Virgo detector has contributed with its data to the rapid growth of the number of detected gravitational-wave (GW) signals in the past few years, alongside the two Advanced LIGO instruments. First during the last month of the Observation Run 2 (O2) in August 2017 (with, most notably, the compact binary mergers GW170814 and GW170817), and then during the full Observation Run 3 (O3): an 11-months data taking period, between April 2019 and March 2020, that led to the addition of about 80 events to the catalog of transient GW sources maintained by LIGO, Virgo and now KAGRA. These discoveries and the manifold exploitation of the detected waveforms require an accurate characterization of the quality of the data, such as continuous study and monitoring of the detector noise sources. These activities, collectively named {\em detector characterization and data quality} or {\em DetChar}, span the whole workflow of the Virgo data, from the instrument front-end hardware to the final analyses. They are described in details in the following article, with a focus on the results achieved by the Virgo DetChar group during the O3 run. Concurrently, a companion article describes the tools that have been used by the Virgo DetChar group to perform this work.Comment: 57 pages, 18 figures. To be submitted to Class. and Quantum Grav. This is the "Results" part of preprint arXiv:2205.01555 [gr-qc] which has been split into two companion articles: one about the tools and methods, the other about the analyses of the O3 Virgo dat