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.

Keywords: animal models; construct validity; face validity; neuropsychiatric disorders; predictive validity; stress; stress-induced psychopathology.

Figure 1

Primary and secondary autonomic nervous system (ANS) and the hypothalamus-pituitary-adrenal (HPA) axis response to stress. In the table, the molecular mediators and the main effects of primary and secondary responses to stress of ANS and HPA axis are reported. In both systems, the primary response promotes fight-or-flight reaction to properly face the perceived stress. Conversely, different secondary response mechanisms are adopted: ANS actively promotes rest and digest response through the activation of PSNS, whereas HPA axis secondary response consists of negative feedback mechanisms guaranteeing the recovery of resting conditions-inherent axis responsivity. SNS (Sympathetic nervous system); PSNS (Parasympathetic nervous system); PVN (Paraventricular nucleus); CRH (Corticotropin releasing hormone); ACTH (Adrenocorticotropic hormone); GRs (Glucocorticoid receptors); MRs (Mineralocorticoid receptors); CNS (Central nervous system); ECS (Endocannabinoid system).

Figure 2

Summary of mentioned stress paradigms. The table shows the main features of mentioned stress paradigms in terms of stress category; human traumatic experience mimicked, proximity to human emotion, and pathological conditions. PTSD (Post-traumatic stress disorder).