Genetically encoded sensors illuminate in vivo detection for neurotransmission: Development, application, and optimization strategies

Limitations in existing tools have hindered neuroscientists from achieving a deeper understanding of complex behaviors and diseases. The recent development and optimization of genetically encoded sensors offer a powerful solution for investigating intricate dynamics such as calcium influx, membrane potential, and the release of neurotransmitters and neuromodulators. In contrast, traditional methods are constrained by insufficient spatial and/or temporal resolution, low sensitivity, and stringent application conditions. Genetically encoded sensors have gained widespread popularity due to their advantageous features, which stem from their genetic encoding and optical imaging capabilities. These include broad applicability, tissue specificity, and non-invasive operation. When combined with advanced microscopic techniques, optogenetics, and machine learning approaches, these sensors have become versatile tools for studying neuronal circuits in intact living systems, providing millisecond-scale temporal resolution and spatial resolution ranging from nanometers to micrometers. In this review, we highlight the advantages of genetically encoded sensors over traditional methods in the study of neurotransmission. We also discuss their recent advancements, diverse applications, and optimization strategies.