Rodent models of post-stroke depression: A comparative analysis of photothrombosis and endothelin-1 models

Reliable, repeatable and clinically translatable animal models are required to uncover pathological mechanisms underlying post-stroke depression (PSD) and develop targeted therapeutics. Traditional ischemic stroke models are limited by high mortality and large, variable infarcts that confound affective assessment, while PSD clinically presents as secondary affective dysfunction occurring in stroke survivors after cerebral infarction. Therefore, ideal preclinical PSD models must achieve controllable focal brain lesions and recapitulate persistent depressive-like phenotypes. In recent years, photothrombosis (PT) and endothelin-1 (ET-1)-induced focal ischemia have become the most widely adopted rodent PSD paradigms, as they enable precise localized brain injury and recapitulate core behavioral and molecular characteristics of PSD. This review systematically compares PT and ET-1 models from multiple dimensions including surgical protocols, behavioral phenotypes, histopathological traits, and neurobiological mechanisms, and further summarizes standardized neurobehavioral and molecular detection assays. Direct comparative analysis reveals divergent strengths and drawbacks of the two models: the PT approach generates highly repeatable cortical infarcts and stable depressive-like behaviors but is limited to superficial brain tissues and lacks a well-defined ischemic penumbra; conversely, the ET-1 model allows stereotactic lesioning of subcortical nuclei, yet it yields inconsistent affective deficits and generally requires combined chronic stress to induce robust PSD-like phenotypes. Based on these findings, we propose two core principles for rational model selection: the primary determinant is whether the research focuses on cortical or subcortical neural circuits, and co-administration of chronic stress substantially improves the reliability and persistence of depressive phenotypes, although its necessity is contingent on species, strain, lesion site, and behavioral endpoint. Balancing lesion localization accuracy and behavioral stability during model choice will provide solid experimental support for subsequent PSD mechanistic research and preclinical drug screening.