Astrocytic contribution to neurodegenerative diseases is attracting attention as a potential target for drug discovery and therapeutics. Intracellular Ca²⁺ signaling in astrocytes is affected by bioactive substances from damaged brain cells including neurons. This can trigger theenhancement and/or attenuation of Ca²⁺-dependent processes in astrocytes, which lead to an alteration of gene expression profiles and secretion of neuroprotective and neurotoxic molecules. Thus, analysis of astrocytic Ca²⁺ activities may provide clues to regulatingneurodegenerative diseases. However, it remains elusive how the pathological conditions affect astrocytic Ca²⁺ activities. Therefore, we are trying to establish a new method to analyze astrocytic Ca²⁺ activities in neurodegenerative diseases. We applied drug-induced or geneticmanipulation-induced neurodegenerative disease models to transgenic mouse linesexpressing a Ca²⁺ sensor protein or a Ca²⁺ signal-suppressing enzyme in astrocytes. Using macroscopic in vivo Ca²⁺ imaging and optical clearing method-assisted volumetric immunohistochemical analysis, we found correlations between astrocytic Ca²⁺ activities and neurodegenerative phenotypes. These results and further analysis may contribute to the development of therapeutic strategies for neurodegenerative diseases.