Combination method of macroscopic imaging with MRI and microscopic imaging with super resolution microscopy for brain microstructure analysis.

Identifying disease-relevant and therapy-related brain regions remains a major challenge in studies using animal models of psychiatric disorders. Conventional hypothesis-driven approaches often result in limited or subjective identification of brain regions. In this study, we propose an integrative method combining unbiased whole-brain structural magnetic resonance imaging (MRI) screening and detailed histological analysis. Our methodology uses structural MRI to systematically detect volumetric changes across the entire brain, enabling the identification of target regions without relying on predefined hypotheses. Once brain regions are identified, super-resolution microscopy (SRM) is employed to determine microstructural alterations at the cellular level, focusing on neurons and glial cells within those regions. To exemplify the utility of this method, we applied it to a mouse model treated with electroconvulsive therapy (ECT), an intervention which is known to increase hippocampal volume. Our demonstration highlights the potential of this approach to systematically search for brain regions of interest, providing valuable insights and guiding future studies toward a more focused exploration of key aspects of psychiatric disorder research, both in terms of pathophysiology and therapeutic action.