Dissecting the Hippocampal Regulation of Approach-Avoidance Conflict: Integrative Perspectives From Optogenetics, Stress Response, and Epigenetics

Psychiatric disorders are multifactorial conditions without clear biomarkers, influenced by genetic, environmental, and developmental factors. Understanding these disorders requires identifying specific endophenotypes that help break down their complexity. Here, we undertake an in-depth analysis of one such endophenotype, namely imbalanced approach-avoidance conflict (AAC), reviewing its significant dependency on the hippocampus. Imbalanced AAC is a transdiagnostic endophenotype, being a feature of many psychiatric conditions in humans. However, it is predominantly examined in preclinical research through paradigms that subject rodents to conflict-laden scenarios. This review offers an original perspective by discussing the AAC through three distinct lights: optogenetic modulation of the AAC, which updates our understanding of the hippocampal contribution to behavioral inhibition; the impact of environmental stress, which exacerbates conflict and strengthens the stress-psychopathology axis; and inherent epigenetic aspects, which uncover crucial molecular underpinnings of environmental (mal) adaptation. By integrating these perspectives, in this review we aim to underline a cross-species causal nexus between heightened hippocampal activity and avoidance behavior. In addition, we suggest a rationale to explore epigenetic pharmacology as a potential strategy to tackle AAC-related psychopathology. This review assumes greater significance when viewed through the lens of advancing AAC-centric diagnostics in human subjects. Unlike traditional questionnaires, which struggle to accurately measure individual differences in AAC-related dimensions, new approaches using virtual reality and computer games show promise in better focusing the magnitude of AAC contribution to psychopathology

Preclinical and clinical evidence on the approach-avoidance conflict evaluation as an integrative tool for psychopathology

The approach-avoidance conflict (AAC), i.e. the competing tendencies to undertake goal-directed actions or to withdraw from everyday life challenges, stands at the basis of humans' existence defining behavioural and personality domains. Gray's Reinforcement Sensitivity Theory posits that a stable bias toward approach or avoidance represents a psychopathological trait associated with excessive sensitivity to reward or punishment. Optogenetic studies in rodents and imaging studies in humans associated with cross-species AAC paradigms granted new emphasis to the hippocampus as a hub of behavioural inhibition. For instance, recent functional neuroimaging studies show that functional brain activity in the human hippocampus correlates with threat perception and seems to underlie passive avoidance. Therefore, our commentary aims to (i) discuss the inhibitory role of the hippocampus in approach-related behaviours and (ii) promote the integration of functional neuroimaging with cross-species AAC paradigms as a means of diagnostic, therapeutic, follow up and prognosis refinement in psychiatric populations

A novel role for LSD1 splicing modulation in homeostatic adaptation to chronic stress

The stress response serves as a protective mechanism to address daily challenges, yet it's crucial for it to cease when the threat subsides, as prolonged stress engagement links to higher vulnerability to neuropsychiatric disorders. Lysine Specific Demethylase 1 (LSD1) is an epigenetic enzyme participating in the CoREST/HDAC2 corepressor complex regulating neuronal plasticity-related gene transcription. In the mammalian brain, LSD1 activity is modulated by its neurospecific splicing isoform neuroLSD1, lacking co-repressive activity as long as the ability to recruit corepressor partners. Numerous studies have compellingly demonstrated that when faced with potent environmental stimuli, LSD1/neuroLSD1 ratio is prompted toward LSD1 by splicing regulation, promoting an overall reduction of the stress-induced plasticity-related mechanisms of hippocampal glutamatergic neurons. In this project, we established an animal model of chronic psychosocial stress based on a modified version of the chronic Social Defeat Stress paradigm, which allowed us to cluster behaviorally resilient and susceptible animals. The behavioral-guided clustering of susceptible animals correlates to decreased LSD1 hippocampal levels, unraveling a mechanism of desensitization of the splicing modulation mechanism after sustained stress in a subset of susceptible animals. In parallel, molecular-guided clustering, based on LSD1 levels, shows that animals with higher LSD1 expression rank within resilient behavioral profile. Relevantly, data obtained from post-mortem human hippocampal of suicide samples feature decreased levels of LSD1. These data preliminarily support a role for LSD1 in the biology of environmental stress resiliency, a hot topic of neuropsychopharmacology

Planck intermediate results: LI. Features in the cosmic microwave background temperature power spectrum and shifts in cosmological parameters

The six parameters of the standard ΛCDM model have best-fit values derived from the Planck temperature power spectrum that are shifted somewhat from the best-fit values derived from WMAP data. These shifts are driven by features in the Planck temperature power spectrum at angular scales that had never before been measured to cosmic-variance level precision. We have investigated these shifts to determine whether they are within the range of expectation and to understand their origin in the data. Taking our parameter set to be the optical depth of the reionized intergalactic medium, the baryon density ω b , the matter density ω m , the angular size of the sound horizon the spectral index of the primordial power spectrum, n s , and A s e -2τ (where A s is the amplitude of the primordial power spectrum), we have examined the change in best-fit values between a WMAP-like large angular-scale data set (with multipole moment 800, or splitting at a different multipole, yields similar results. We examined the 800 power spectrum data and find that the features there that drive these shifts are a set of oscillations across a broad range of angular scales. Although they partly appear similar to the effects of enhanced gravitational lensing, the shifts in ΛCDM parameters that arise in response to these features correspond to model spectrum changes that are predominantly due to non-lensing effects; the only exception is, which, at fixed A s e -2τ , affects the > 800 temperature power spectrum solely through the associated change in A s and the impact of that on the lensing potential power spectrum. We also ask, "what is it about the power spectrum at < 800 that leads to somewhat different best-fit parameters than come from the full range?" We find that if we discard the data at < 30, where there is a roughly 2σ downward fluctuation in power relative to the model that best fits the full range, the < 800 best-fit parameters shift significantly towards the < 2500 best-fit parameters. In contrast, including < 30, this previously noted "low-deficit" drives n s up and impacts parameters correlated with n s , such as ω m and H 0 . As expected, the < 30 data have a much greater impact on the < 800 best fit than on the < 2500 best fit. So although the shifts are not very significant, we find that they can be understood through the combined effects of an oscillatory-like set of high-residuals and the deficit in low-power, excursions consistent with sample variance that happen to map onto changes in cosmological parameters. Finally, we examine agreement between PlanckTT data and two other CMB data sets, namely the Planck lensing reconstruction and the TT power spectrum measured by the South Pole Telescope, again finding a lack of convincing evidence of any significant deviations in parameters, suggesting that current CMB data sets give an internally consistent picture of the ΛCDM model

Planck intermediate results. XLIX. Parity-violation constraints from polarization data

Parity-violating extensions of the standard electromagnetic theory cause in vacuo rotation of the plane of polarization of propagating photons. This effect, also known as cosmic birefringence, has an impact on the cosmic microwave background (CMB) anisotropy angular power spectra, producing non-vanishing T–B and E–B correlations that are otherwise null when parity is a symmetry. Here we present new constraints on an isotropic rotation, parametrized by the angle α, derived from Planck 2015 CMB polarization data. To increase the robustness of our analyses, we employ two complementary approaches, in harmonic space and in map space, the latter based on a peak stacking technique. The two approaches provide estimates for α that are in agreement within statistical uncertainties and are very stable against several consistency tests.Considering the T–B and E–B information jointly, we find from the harmonic analysis and from the stacking approach. These constraints are compatible with no parity violation and are dominated by the systematic uncertainty in the orientation of Planck’s polarization-sensitive bolometers

Planck intermediate results. XLVIII. Disentangling Galactic dust emission and cosmic infrared background anisotropies

Using the Planck 2015 data release (PR2) temperature maps, we separate Galactic thermal dust emission from cosmic infrared background (CIB) anisotropies. For this purpose, we implement a specifically tailored component-separation method, the so-called generalized needlet internal linear combination (GNILC) method, which uses spatial information (the angular powerspectra) to disentangle the Galactic dust emission and CIB anisotropies. We produce significantly improved all-sky maps of Planck thermal dust emission, with reduced CIB contamination, at 353, 545, and 857 GHz. By reducing the CIB contamination of the thermal dust maps, we provide more accurate estimates of the local dust temperature and dust spectral index over the sky with reduced dispersion, especially at high Galactic latitudes above b = ±20°. We find that the dust temperature is T = (19.4 ± 1.3) K and the dust spectral index is β = 1.6 ± 0.1 averaged over the whole sky, while T = (19.4 ± 1.5) K and β = 1.6 ± 0.2 on 21% of the sky at high latitudes. Moreover, subtracting the new CIB-removed thermal dust maps from the CMB-removed Planck maps gives access to the CIB anisotropies over 60% of the sky at Galactic latitudes |b| > 20°. Because they are a significant improvement over previous Planck products, the GNILC maps are recommended for thermal dust science. The new CIB maps can be regarded as indirect tracers of the dark matter and they are recommended for exploring cross-correlations with lensing and large-scale structure optical surveys. The reconstructed GNILC thermal dust and CIB maps are delivered as Planck products

Planck 2018 results. VIII. Gravitational lensing

We present measurements of the cosmic microwave background (CMB) lensing potential using the final Planck 2018 temperature and polarization data. We increase the significance of the detection of lensing in the polarization maps from 5σ to 9σ. Combined with temperature, lensing is detected at 40σ4. We present an extensive set of tests of the robustness of the lensing-potential power spectrum, and construct a minimum-variance estimator likelihood over lensing multipoles 8≤L≤400. We find good consistency between lensing constraints and the results from the Planck CMB power spectra within the ΛCDMΛCDM model. Combined with baryon density and other weak priors, the lensing analysis alone constrains σ8Ω0.25m=0.589±0.020 (1σ errors). Also combining with baryon acoustic oscillation (BAO) data, we find tight individual parameter constraints, σ8=0.811±0.019, H0=67.9+1.2−1.3kms−1Mpc−1, and Ωm=0.303+0.016−0.018. Combining with Planck CMB power spectrum data, we measure σ8 to better than 1% precision, finding σ8=0.811±0.006. We find consistency with the lensing results from the Dark Energy Survey, and give combined lensing-only parameter constraints that are tighter than joint results using galaxy clustering. Using Planck cosmic infrared background (CIB) maps we make a combined estimate of the lensing potential over 60% of the sky with considerably more small-scale signal. We demonstrate delensing of the Planck power spectra, detecting a maximum removal of 40% of the lensing-induced power in all spectra. The improvement in the sharpening of the acoustic peaks by including both CIB and the quadratic lensing reconstruction is detected at high significance (abridged)

Thermalisation of sterile neutrinos in the early universe in the 3+1 scheme with full mixing matrix

In the framework of a 3+1 scheme with an additional inert state, we consider the thermalisation of sterile neutrinos in the early Universe taking into account the full 4×4 mixing matrix. The evolution of the neutrino energy distributions is found solving the momentum-dependent kinetic equations with full diagonal collision terms, as in previous analyses of flavour neutrino decoupling in the standard case. The degree of thermalisation of the sterile state is shown in terms of the effective number of neutrinos, Neff, and its dependence on the three additional mixing angles (θ_14, θ_24, θ_34) and on the squared mass difference Δm^2_41 is discussed. Our results are relevant for fixing the contribution of a fourth light neutrino species to the cosmological energy density, whose value is very well constrained by the final Planck analysis. For the preferred region of active-sterile mixing parameters from short-baseline neutrino experiments, we find that the fourth state is fully thermalised (Neff≃4)

Prone position in intubated, mechanically ventilated patients with COVID-19: a multi-centric study of more than 1000 patients

Background: Limited data are available on the use of prone position in intubated, invasively ventilated patients with Coronavirus disease-19 (COVID-19). Aim of this study is to investigate the use and effect of prone position in this population during the first 2020 pandemic wave. Methods: Retrospective, multicentre, national cohort study conducted between February 24 and June 14, 2020, in 24 Italian Intensive Care Units (ICU) on adult patients needing invasive mechanical ventilation for respiratory failure caused by COVID-19. Clinical data were collected on the day of ICU admission. Information regarding the use of prone position was collected daily. Follow-up for patient outcomes was performed on July 15, 2020. The respiratory effects of the first prone position were studied in a subset of 78 patients. Patients were classified as Oxygen Responders if the PaO2/FiO2 ratio increased ≥ 20&nbsp;mmHg during prone position and as Carbon Dioxide Responders if the ventilatory ratio was reduced during prone position. Results: Of 1057 included patients, mild, moderate and severe ARDS was present in 15, 50 and 35% of patients, respectively, and had a resulting mortality of 25, 33 and 41%. Prone position was applied in 61% of the patients. Patients placed prone had a more severe disease and died significantly more (45% vs. 33%, p &lt; 0.001). Overall, prone position induced a significant increase in PaO2/FiO2 ratio, while no change in respiratory system compliance or ventilatory ratio was observed. Seventy-eight % of the subset of 78 patients were Oxygen Responders. Non-Responders had a more severe respiratory failure and died more often in the ICU (65% vs. 38%, p = 0.047). Forty-seven % of patients were defined as Carbon Dioxide Responders. These patients were older and had more comorbidities; however, no difference in terms of ICU mortality was observed (51% vs. 37%, p = 0.189 for Carbon Dioxide Responders and Non-Responders, respectively). Conclusions: During the COVID-19 pandemic, prone position has been widely adopted to treat mechanically ventilated patients with respiratory failure. The majority of patients improved their oxygenation during prone position, most likely due to a better ventilation perfusion matching. Trial registration: clinicaltrials.gov number: NCT0438867

Planck intermediate results: XLVI. Reduction of large-scale systematic effects in HFI polarization maps and estimation of the reionization optical depth

© 2016 ESO. This paper describes the identification, modelling, and removal of previously unexplained systematic effects in the polarization data of the Planck High Frequency Instrument (HFI) on large angular scales, including new mapmaking and calibration procedures, new and more complete end-to-end simulations, and a set of robust internal consistency checks on the resulting maps. These maps, at 100, 143, 217, and 353 GHz, are early versions of those that will be released in final form later in 2016. The improvements allow us to determine the cosmic reionization optical depth τ using, for the first time, the low-multipole EE data from HFI, reducing significantly the central value and uncertainty, and hence the upper limit. Two different likelihood procedures are used to constrain τ from two estimators of the CMB E-and B-mode angular power spectra at 100 and 143 GHz, after debiasing the spectra from a small remaining systematic contamination. These all give fully consistent results. A further consistency test is performed using cross-correlations derived from the Low Frequency Instrument maps of the Planck 2015 data release and the new HFI data. For this purpose, end-to-end analyses of systematic effects from the two instruments are used to demonstrate the near independence of their dominant systematic error residuals. The tightest result comes from the HFI-based τ posterior distribution using the maximum likelihood power spectrum estimator from EE data only, giving a value 0.055 ± 0.009. In a companion paper these results are discussed in the context of the best-fit PlanckΛCDM cosmological model and recent models of reionization