The use of chemogenetics in behavioural neuroscience: receptor variants, targeting approaches and caveats

Abstract

The last decade has seen major advances in neuroscience tools allowing us to selectively modulate cellular pathways in freely moving animals. Chemogenetic approaches such as designer receptors exclusively activated by designer drugs (DREADDs) permit the remote control of neuronal function by systemic drug administration. These approaches have dramatically advanced our understanding of the neural control of behaviour. Here, we review the different techniques and genetic approaches available for the restriction of chemogenetic receptors to defined neuronal populations. We highlight the use of a dual virus approach to target specific circuitries and the effectiveness of different routes of administration of designer drugs. Finally, we discuss the potential caveats associated with DREADDs including off-target effects of designer drugs, the effects of chronic chemogenetic receptor activation and the issue of collateral projections associated with DREADD activation and inhibition.

Figure 1

Interrogation of neuronal circuitry using chemogenetics: local intracranial administration of the activating ligand. Intracranial injection of DREADD ligands can be used to selectively manipulate neuronal circuits and behavioural output. In this sagittal rat brain schematic, an AAV‐encoding non‐conditional DREADD is injected into the NAcs, and intracranial guide cannulas are implanted above the VTA. Intracranial infusion of the DREADD ligand into VTA will change the activity of DREADD‐expressing terminals in VTA.

Figure 2

Interrogation of neuronal circuitry using chemogenetics: dual viral vector approach. A dual‐virus approach may be used to manipulate neurons defined by their anatomical projections. In this sagittal rat brain schematic, an AAV‐encoding Cre‐dependent DREADD is injected into the NAcs, and a retrograde vector‐encoding Cre is injected into the VTA. With this arrangement, Cre expression can be expected in the inputs to VTA, such as NAc, prefrontal cortex (PFC) and lateral hypothalamus (LH). However, chemogenetic receptor expression will be confined to NAc → VTA neurons. Systemic injection of the DREADD ligand will affect the activity of NAc → VTA neurons. However, this manipulation will also affect collateral projections of NAc → VTA neurons, such as to LH, if they exist.