Chemogenetics drives paradigm change in the investigation of behavioral circuits and neural mechanisms underlying drug action

Abstract

Recent developments in chemogenetic approaches to the investigation of brain function have ushered in a paradigm change in the strategy for drug and behavior research and clinical drug-based medications. As the nature of the drug action is based on humoral regulation, it is a challenge to identify the neuronal mechanisms responsible for the expression of certain targeted behavior induced by drug application. The development of chemogenetic approaches has allowed researchers to control neural activities in targeted neurons through a toolbox, including engineered G protein-coupled receptors or ligand-gated ion channels together with exogenously inert synthetic ligands. This review provides a brief overview of the chemogenetics toolbox with an emphasis on the DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) technique used in rodent models, which is applicable to the investigation of how specific neural circuits regulate behavioral processes. The use of chemogenetics has had a significant impact on basic neuroscience for a better understanding of the relationships between brain activity and the expression of behaviors with cell- and circuit-specific orders. Furthermore, chemogenetics is potentially a useful tool to deconstruct the neuropathological mechanisms of mental diseases and its regulation by drug, and provide us with transformative therapeutics with medication. We also review recent findings in the use of chemogenetic techniques to uncover functional circuit connections of serotonergic neurons in rodent models.

Keywords: Animal models; Behavioral pharmacology; Chemogenetics; DREADDs; Drug treatment; Neural circuits; Research strategies.

Figure 1.

DREADD delivery strategies. (A) Virally injected DREADD into the targeted region in wildtype mice. (B) Virally injected cre-dependent DREADD in combination with virally injected cre driver target in wildtype mice. (C) Virally injected cre-dependent DREADD in cre driver mice. (D) Virally injected cre-dependent DREADD into transgenic mice that can express exogenously (e.g., tamoxifen) inducible cre recombinase from promoter elements (e.g., Fos-TRAP2 mice (Allen et al., 2017)). (E) Virally injected cre driver target in DREADD floxed mice (e.g., hM3Dq-DREADD mice (Zhu et al., 2016)). (F) Breeding cre driver mice with DREADD floxed mice, then F1-hybrid offspring expresses cre-dependent DREADD. Abbreviations: AAV (Adeno-associated virus), DIO (Double-floxed inverted), and DREADD (Designer receptors exclusively activated by designer drugs).

Figure 2.

A schematic diagram of putative processing models in the differences of neuronal manipulation by drugs/ligands administration and the DREADD application. Drug administration induces humoral processes widely distributing drugs throughout the body via osmotic and circulation drive. Compounds of the drugs penetrate into the neurons and synaptic clefts and ultimately bind to several receptors in its affinity dependent manner. The locations of receptors include pre- and post-synapses and axonal tracts. Therefore, the total outputs of neural firing stimulated by drug administration will reflect combined effects of agonism and antagonism of drug stimulations, which would be read out as non-linear quantitative effects on the output of neuronal firing. On the other hand, the DREADDs application can archive cell- or circuit-specific manipulation of the simple output from the target neuronal node, which allows to investigate the neuron specific function on regulating particular behavior.

Figure 3.

A schematic of summarized research investigating serotonergic circuits in the raphe nuclei, using chemogenetic manipulation. Cell-region specific manipulation; designed to manipulate region-dependent (MRN: median raphe, DRN: dorsal raphe) cell-type (5-HT: serotonergic neuron) specific activities (A-D). Output projection-cell specific manipulation; designed to modulate serotonergic projecting neurons to targeted regions (NAc; nucleus accumbens, OFC; orbitofrontal cortex, and CeA; central amygdala)(E-I). Input projection-cell specific manipulation; designed to manipulate specific projecting neurons (DA; dopaminergic, and glutamate; glutamatergic) from afferent regions (LHb; the lateral habenula, PAG; the periaqueductal gray) to the DRN (serotonergic) neurons (J-L).