Resolving Behavioral Output via Chemogenetic Designer Receptors Exclusively Activated by Designer Drugs

Abstract

Designer receptors exclusively activated by designer drugs (DREADDs) have proven to be highly effective neuromodulatory tools for the investigation of neural circuits underlying behavioral outputs. They exhibit a number of advantages: they rely on cell-specific manipulations through canonical intracellular signaling pathways, they are easy and cost-effective to implement in a laboratory setting, and they are easily scalable for single-region or full-brain manipulations. On the other hand, DREADDs rely on ligand-G-protein-coupled receptor interactions, leading to coarse temporal dynamics. In this review we will provide a brief overview of DREADDs, their implementation, and the advantages and disadvantages of their use in animal systems. We also will provide numerous examples of their use across a broad variety of biomedical research fields.

Mesopontine cholinergic inputs to midbrain dopamine neurons drive stress-induced depressive-like behaviors

“…To selectively activate LDTg cholinergic terminals in the VTA, guides were placed bilaterally above the VTA of LDTg ChAT-hM3 mice to locally infuse CNO. Local CNO infusion has been recently used for remote control of terminals activity 50 , 51 . LDTg ChAT-hM3 mice were submitted to SubSD as described above.…”

Chronic Chemogenetic Manipulation of Ventral Pallidum Targeted Neurons in Rats Fed an Obesogenic Diet

“…Our attempted translational intervention using chronic manipulation of the VP used the same DREADD receptors and CNO ligand that were used in previous acute VP DREADD manipulations that altered VP activity, changed food seeking and eating behavior [16][17][18]. It is possible that chronic activation caused unexpected changes in DREADD receptor function, CNO (or its clozapine metabolite) efficacy at the DREADD receptors over long periods of administration, CNO metabolism, and/or receptor/intracellular signaling adaptations to chronic agonist activity [46,47].…”

“…Among these, perhaps the most promising is a chemogenetic approach using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) [15]. DREADDs offer a naturalistic means of changing neuronal activity through endogenous intracellular signaling mechanisms and a relative non-invasiveness of delivering receptor ligands systemically once brain expression of the DREADD receptor has occurred [16][17][18]. As a result it has emerged as a highly attractive method for chronic brain manipulation with translational potential.…”

“…In most prior studies, acute chemogenetic manipulation produces a limited time window of effect (hours) and is tested on a behavior, such as an eating bout, that can be assessed acutely [16][17][18]. In contrast, treatment of chronic brain-based disorders (e.g., obesity and psychiatric illnesses) will likely require ongoing modulation on the order of months to years.…”

Optogenetic approaches for dissecting neuromodulation and GPCR signaling in neural circuits

“…Like optogenetic tools, chemogenetic tools enhance the spatial resolution of GPCR signaling; Chemogenetic tools are also more easily adaptable for behavioral applications (Table 2). For a more extensive review on these tools see Refs [87–89]. The most widely used chemogenetic tools are modified GPCRs (see below).…”