Translational new approaches for investigating mood disorders in rodents and what they may reveal about the underlying neurobiology of major depressive disorder

Mood disorders represent one of society's most costly and challenging health burdens. The drug treatments used today were initially discovered serendipitously in the 1950s. Animal models were then developed based on the ability of these drugs to alter specific behaviours. These models have played a major role in the development of the second generation of antidepressants. However, their use has been heavily criticized, particularly in relation to whether they recapitulate similar underlying biology to the psychiatric disorder they are proposed to represent. This article considers our work in the field of affective bias and the development of a translational research programme to try to develop and validate better animal models. We discuss whether the new data that have arisen from these studies support an alternative perspective on the underlying neurobiological processes that lead to major depressive disorder (MDD). Specifically, this article will consider whether a neuropsychological mechanism involving affective biases plays a causal role in the development of MDD and its associated emotional and behavioural symptoms. These animal studies also raise the possibility that neuropsychological mechanisms involving affective biases are a precursor to, rather than a consequence of, the neurotrophic changes linked to MDD. This article is part of a discussion meeting issue ‘Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists’.</jats:p

Pavlovian influences on learning differ between rats and mice in a counter-balanced Go/NoGo judgement bias task

Judgement bias tests of animal affect and hence welfare assume that the animal's responses to ambiguous stimuli, which may herald positive or negative outcomes, are under instrumental control and reflect 'optimism' or 'pessimism' about what will happen. However, Pavlovian control favours responses (e.g. approach or withdrawal) according to the valence associated with a stimulus, rather than the anticipated response outcomes. Typically, positive contexts promote action and approach whilst negative contexts promote inhibition or withdrawal. The prevalence of Go-for-reward (Go-pos) and NoGo-to-avoid-punishment (NoGo-neg) judgement bias tasks reflects this Pavlovian influence. A Pavlovian increase or decrease in activity or vigour has also been argued to accompany positive or negative affective states, and this may interfere with instrumental Go or NoGo decisions under ambiguity based on anticipated decision outcomes. One approach to these issues is to develop counter-balanced Go-pos/NoGo-neg and Go-neg/NoGo-pos tasks. Here we implement such tasks in Sprague Dawley rats and C57BL/6J mice using food and air-puff as decision outcomes. We find striking species/strain differences with rats achieving criterion performance on the Go-pos/NoGo-neg task but failing to learn the Go-neg/NoGo-pos task, in line with predictions, whilst mice do exactly the opposite. Pavlovian predispositions may thus differ between species, for example reflecting foraging and predation ecology and/or baseline activity rates. Learning failures are restricted to cues predicting a negative outcome; use of a more powerful air-puff stimulus may thus allow implementation of a fully counter-balanced task. Rats and mice achieve criterion faster than in comparable automated tasks and also show the expected generalisation of responses across ambiguous tones. A fully counter-balanced task thus offers a potentially rapidly implemented and automated method for assessing animal welfare, identifying welfare problems and areas for welfare improvement and 3Rs Refinement, and assessing the effectiveness of refinements

Four Models of Protecting Citizenship and Social rights in Europe: conclusions to the special issue Rethinking the European Social Market Economy

This article offers a synthesis of and conclusion to the contributions included in the Special Issue‘Rethinking the European Social Market Economy’. Based on different understandings of citizen-ship in the European Union and the roles of the EU and its member states in providing social pro-tection arrangements, it develops a typology of four models of the EU’s role in social protection. Itthen discusses the contributions to this Special Issue in light of this typology and draws a numberof overarching conclusions

Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation

Rationale Asthma phenotyping requires novel biomarker discovery. Objectives To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs). Methods An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED. Results In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-β and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation. Conclusions The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA. © 2022 European Respiratory Society. All rights reserved