Optogenetic/Chemical-genetic Tools

Optogenetics: It is an interdisciplinary technology which combines genetic and optical technologies to manipulate neuronal activity in brain of living or free moving animals. Optogenetics offers millisecond-level temporal precision and single-cell level spatial precision. It was selected as the ‘method of the year’ in 2010 by Nature Methods and recognized as one of the breakthroughs of the past decade by Science. Optogenetic tools and applications in neurobiology hold promise for treating various neurological and psychiatric disorders such as Parkinson's disease, Alzheimer's disease, spinal cord injuries, schizophrenia, etc.

Chemical genetics: It involves the artificial modification of large molecules (proteins, nucleic acids, etc.) to respond specifically to certain synthesized small-molecule compounds. Similar to optogenetics, chemogenetics offers real-time, precise, and reversible control. It is widely used in signal transduction research, drug screening, and other areas. The most commonly used chemogenetic system is DREADDs (designer receptors exclusively activated by designer drugs), which involves different engineered G protein-coupled receptors (GPCRs) coupled with various effectors such as Gq, Gi, Gs, and Golf. 

The most widely used components of the Gq-DREADD system are hM3Dq proteins, which are engineered from the human muscarinic acetylcholine receptor (mAchRs) subtype M3 (also known as hM3). When combined with CNO, these modified proteins couple with Gq G protein to induce GPCR cascades, ultimately affecting intracellular calcium signaling. In neurons, hM3Dq activation leads to cellular depolarization and increased excitability, making it commonly used to promote neuronal firing activity. Similarly, researchers have engineered the Gi-hM4Di, derived from the M4 subtype of mAchRs, to exert inhibitory effects on neurons by activating G-protein inwardly rectifying potassium channels (GIRK).