Chemogenetics (DREADD) | Can We Remotely Control Brain Cells With a Designer Drug?

Chemogenetics is a cutting-edge technique in neuroscience that allows scientists to control the activity of specific cells, particularly neurons, using engineered molecules. The most common chemogenetic tool is called DREADD, which stands for Designer Receptor Exclusively Activated by a Designer Drug. The system functions like a custom-designed lock and key. First, scientists use genetic engineering to introduce a "designer receptor" (the lock) into a specific type of neuron in the brain. This receptor is a modified protein that does not respond to any natural molecules in the body; it is inert and does nothing on its own. The second component is the "designer drug" (the key), a synthetic chemical compound like Clozapine-N-oxide (CNO). When this drug is administered, it travels through the bloodstream to the brain and binds exclusively to the designer receptors. This binding event is what activates the receptor, flipping a switch that either turns the neuron on or off, depending on the type of DREADD used. This method provides precise control over defined cell populations, enabling researchers to establish direct causal links between the activity of a specific neural circuit and a particular behavior, such as memory formation or anxiety.

The significance of chemogenetics lies in its high degree of specificity and its non-invasive nature compared to other neuromodulation techniques. Before DREADDs, scientists relied on methods like electrical stimulation, which activate all cells in a given area, making it impossible to know which specific cells were responsible for an observed effect. DREADDs solve this by allowing for the genetic targeting of only one cell type. Furthermore, unlike a technique such as optogenetics which requires a surgically implanted fiber-optic cable to deliver light into the brain, chemogenetics is activated by a drug that can be administered systemically, such as through a simple injection. This makes it ideal for studying complex behaviors in freely moving subjects over extended periods, from hours to days. This capability has revolutionized our ability to map the intricate neural circuits that underlie both normal brain function and the dysfunction seen in psychiatric and neurological disorders.

Scientists deliver the genetic blueprint for the DREADD receptor into target cells using a modified, harmless virus as a delivery vehicle. This method is called viral-mediated gene transfer. The most commonly used viruses are adeno-associated viruses (AAVs). Researchers first remove the virus's own genetic material so it cannot replicate, making it safe. Then, they insert the DNA sequence that codes for the DREADD receptor. To ensure the receptor is only made in the desired cell type (e.g., only in dopamine neurons), they pair it with a specific genetic element called a promoter, which acts as an "on switch" that is only functional in that particular cell type.

There are two primary types of DREADDs that serve opposite functions. The first is hM3Dq, which is an excitatory, or activating, receptor. When the designer drug binds to hM3Dq, it initiates a signaling cascade inside the neuron that causes the cell to become more active and fire more electrical signals. The second is hM4Di, which is an inhibitory receptor. When activated by the same drug, it triggers a different internal pathway that suppresses the neuron's activity, making it less likely to fire. This powerful on/off capability allows researchers to determine not only what happens when a group of cells is activated, but also what happens when they are silenced, providing a complete picture of their role in the brain.

Chemogenetics and optogenetics are the two premier technologies for controlling neural activity, but they differ in their strengths and applications. The primary advantage of optogenetics is its temporal precision. It uses light-sensitive proteins to control neurons, and by flashing a light through a fiber-optic implant, scientists can turn cells on and off with millisecond-level accuracy. This is perfect for studying rapid processes like sensory perception. However, it requires an invasive, permanent implant. Chemogenetics, on the other hand, offers a less invasive approach. The activating drug can be delivered systemically, and its effects are sustained over a longer duration (minutes to hours). This makes chemogenetics better suited for studying the neural basis of more prolonged behavioral states, such as mood, motivation, or the effects of a disease over time. The choice between the two depends on the specific scientific question: optogenetics for temporal precision, and chemogenetics for long-lasting, less invasive modulation.