Optogenetics and Chemogenetics

Abstract

Optogenetics and chemogenetics provide the ability to modulate neurons in a type- and region-specific manner. These powerful techniques are useful to test hypotheses regarding the neural circuit mechanisms of general anesthetic end points such as hypnosis and analgesia. With both techniques, a genetic strategy is used to target expression of light-sensitive ion channels (opsins) or designer receptors exclusively activated by designer drugs in specific neurons. Optogenetics provides precise temporal control of neuronal firing with light pulses, whereas chemogenetics provides the ability to modulate neuronal firing for several hours with the single administration of a designer drug. This chapter provides an overview of neuronal targeting and experimental strategies and highlights the important advantages and disadvantages of each technique.

Keywords: Anesthetic mechanisms; Chemogenetics; DREADDs; Neural circuits; Neurophysiology; Optogenetics.

Fig. 1

Flowchart showing the typical sequence of events for performing optogenetics or chemogenetics experiments.

Fig. 2

Illumination of neurons that express channelrhodopsin2 (ChR2) with blue light (470 nm) allows Na⁺ ions to enter the cell, causing depolarization. Illumination of neurons that express halorhodopsin (NpHR) with yellow-orange light (589 nm) causes Cl⁻ ions to be pumped into the cell, inducing hyperpolarization.

Fig. 3

Human muscarinic (hM)-based DREADDs are activated by clozapine-N-oxide (CNO), whereas kappa opioid receptor (KOR)-based DREADDs are activated by Salvinorin B (SalB). CNO causes burst firing of neurons that express hM3Dq, and inhibition of neurons that express hM4Di. SalB inhibits neurons that express KORD, allowing for bidirectional chemogenetics in neurons that express both hM3Dq and KORD.