Adeno-associated virus delivered Cre recombinase as a versatile strategy for modeling focal neuronal lesions

Lesion studies remain central to neuroscience, offering key insights into brain-behavior relationships. Excitotoxic agents, though widely used, often produce inconsistent, non-specific, and ethically complex outcomes. In contrast, optogenetics and chemogenetics enable precise, reversible manipulations but pose technical and interpretational challenges, including cost and non-physiological activation. There remains a need for robust, controlled, and ethical lesion methods. Here, we present Cre recombinase expression as a reproducible alternative to excitotoxic lesions in mice. Using high titration adeno-associated viral (AAV) vectors, we show that Cre expression induces focal neurodegeneration across brain regions, affecting both excitatory and inhibitory neurons. This effect is independent of viral serotype or fluorescent tags and is not visible with standard staining but is revealed by neuronal markers. The resulting neuronal loss is followed by glial remodeling and significant behavioral alterations. AAV-mediated Cre expression thus provides a powerful, genetically targeted lesion model that bridges classical and modern approaches to circuit manipulation.