Rationale, Relevance, and Limits of Stress-Induced Psychopathology in Rodents as Models for Psychiatry Research: An Introductory Overview

Abstract

Emotional and cognitive information processing represent higher-order brain functions. They require coordinated interaction of specialized brain areas via a complex spatial and temporal equilibrium among neuronal cell-autonomous, circuitry, and network mechanisms. The delicate balance can be corrupted by stressful experiences, increasing the risk of developing psychopathologies in vulnerable individuals. Neuropsychiatric disorders affect twenty percent of the western world population, but therapies are still not effective for some patients. Elusive knowledge of molecular pathomechanisms and scarcity of objective biomarkers in humans present complex challenges, while the adoption of rodent models helps to improve our understanding of disease correlate and aids the search for novel pharmacological targets. Stress administration represents a strategy to induce, trace, and modify molecular and behavioral endophenotypes of mood disorders in animals. However, a mouse or rat model will only display one or a few endophenotypes of a specific human psychopathology, which cannot be in any case recapitulated as a whole. To override this issue, shared criteria have been adopted to deconstruct neuropsychiatric disorders, i.e., depression, into specific behavioral aspects, and inherent neurobiological substrates, also recognizable in lower mammals. In this work, we provide a rationale for rodent models of stress administration. In particular, comparing each rodent model with a real-life human traumatic experience, we intend to suggest an introductive guide to better comprehend and interpret these paradigms.

Encore: Behavioural animal models of stress, depression and mood disorders

“…In 2017, an estimated 971 million individuals worldwide suffered from mental disorders with depressive disorders accounting for 27% and anxiety disorders accounting for 29% of the estimated prevalence ( James et al, 2018 ). These disorders are accompanied by alterations in individuals’ perception of social reality, adaptive ability, and executive functioning ( Ferreri et al, 2011 ; Millan et al, 2012 ; Weightman et al, 2014 ; Solé et al, 2017 ; Italia et al, 2020 ). Currently, there are no obvious traceable structural and molecular correlates that uniquely map to specific disorders ( Nestler and Hyman, 2010 ).…”

“…As cognitive and emotional symptoms cannot be definitively established in animals, bluntly asserting particular symptomatology to animals represents an unjustified intellectual leap ( Geyer and Markou, 1995 ; Nestler and Hyman, 2010 ). This is the reason behind the recent subtle change in the field’s terminology, with a shift toward the use of more hypothetical language when describing an animal model ( Nestler and Hyman, 2010 ; Italia et al, 2020 ). Neuropsychiatric models can be developed through (1) a combination of plausible risk factors or (2) the establishment of a reasonable degree of neural and behavioural pathologies that correspond to the human disease.…”

“…Since neuropsychiatric disorders can be highly heterogeneous in their causes and symptoms, neuropsychiatry requires basic research to provide greater insight into the formation of the disease in order to develop more objective diagnostic procedures in humans ( López-León et al, 2008 ; Bosker et al, 2011 ; Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013 ; Wray et al, 2018 ). Animal models are unlikely to ever mirror the full extent of human neuropsychiatric disorders, and even those symptoms that can be ascertained with some confidence might not have a direct equivalence with human symptoms ( Nestler and Hyman, 2010 ; Italia et al, 2020 ). Instead of serving as defining features of the disease, symptoms can better serve as an identifying principle for genomic and molecular studies ( Manchia et al, 2013 ; Gade et al, 2015 ; Ohi et al, 2015 ; Papassotiropoulos and de Quervain, 2015 ).…”

“…Mice models share many biochemical and physiological pathways with humans ( Rossant and McKerlie, 2001 ). Mice and humans share evolutionary conserved stress-coping mechanisms, and they express genes with similar functions ( Mouse Genome Sequencing Consortium, 2002 ; Italia et al, 2020 ). Important traits such as disease susceptibility are inherited in a similar manner ( Rossant and McKerlie, 2001 ).…”

The environmental enrichment model revisited: A translatable paradigm to study the stress of our modern lifestyle

“…In humans, stress represents a major vulnerability factor for developing different neuropsychiatric disorders such as depression, anxiety and schizophrenia. Consequently, different preclinical stress models have been developed for studying biobehavioural factors underlying psychopathology (Italia et al., 2020). For these models to be considered reliable and informative, multiple methodological, empirical, and theoretical criteria should be fulfilled to ensure that the obtained results represent to some extent the behavioural and physiological processes occurring in humans (Belzung & Lemoine, 2011; Willner, 2017a).…”