Neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), are devastating age-associated brain disorders. Significant efforts have been made to uncover the molecular and cellular pathogenic mechanisms that underlie NDDs. However, our understanding of the neural circuit mechanisms that mediate NDDs and associated symptomatic features have been hindered by technological limitations. Our inability to identify and track individual neurons longitudinally in subcortical brain regions that are preferentially targeted in NDDs has left gaping holes in our knowledge of NDDs. Recent development and advancement of the miniature fluorescence microscope (miniscope) has opened up new avenues for examining spatially and temporally coordinated activity from hundreds of cells in deep brain structures in freely moving rodents. In the present mini-review, we examine the capabilities of current and future miniscope tools and discuss the innovative applications of miniscope imaging techniques that can push the boundaries of our understanding of neural circuit mechanisms of NDDs into new territories.