This review might interest you: "Remote Control of Neuronal Signaling, Rogan & Roth, Pharmacol Rev, 63:291–315, 2011"

I agree. Optogenetics have much better temporal control. However, light delivery is difficult. This might result in an insufficient number of affected cells to influence behaviour. The latter is evaded by the use of DREADDs. Every cell that expresses the DREADD will be affected making a 'negative' result in a behavioural test less likely to be attributed to insufficient neuronal effect. Although showing that the CNO-DREADD (de)activates all the neurons sufficiently can be challenge as well.

Hi Ewan,

I develop optogenetic recordings in the lab Im working in as a post doc. I dont have much experience with DREADD technique but as you said the major difference is the temporal resolution you can achieve with these 2 techniques. With light stimulation you have a really tight control of the electrical activity of the neurons, you can apply different stimulation frequency.... For me, the major drawback of DREADD is that you loose all this temporal resolution because you need time for the activation and for the inactivation. Another point is that light scattering and tissue penetration is not such a big issue now with the new technique developed recently (guide cannula, cutting edge cannula, optrodes...) for in vivo activation and recordings.

So I would say that the 2 technique are useful and are not mutually exclusive but depending on the kind of experiments you planned to perform you'll have to take into account these problems.

Hope it can help you a bit and if you have other questions feel free to contact me at this email adress for further discussions: [email protected].

Best,

Julien

For structures very well contained spatially, it is probably better to use optogenetics because you can affect efficiently a well defined portion of tissue and the unit recording will give you a direct and quick feedbak of the induced effect. For structures more diffuse or extended, let's imagine you need to inject your virus in multiple places to affect a bigger network, then the DREADDs would likely be more efficient in modulating a large volume of tissue.

Hi Ewan, you should also consider whether you want to manipulate the activity of transfected neurons or rather transmitter release in target regions of transfected neurons. The latter might be more difficult with DREADDs and would require local infusion of CNO (did anyone try this?). That said, DREADDs are great if you want to look at general and long-lasting effects. On-off effects are possible if you look at behaviour on seperate days. Experiments are minimally invasive and budget-friendly.

Many thanks for all the input, it is much appreciated!

After a look through online, I see that Brain Research have recently had an issue reviewing these technologies:

http://www.sciencedirect.com/science/journal/00068993/1511/supp/C

I hope that is of use to people following this question.

Thanks again!

Hi Ewan,

People here already brought up great points. I only would like to add a couple of side points:

Due to the significant difference in temporal resolution of DREADD and optogenetics, DREADD actually compares better to pharmacological perturbations e.g. Muscimol, and in that comparison DREADD wins because 1) it's way cheaper, faster, easier, and more controlled 2) doing histology afterwards give you exact knowledge of infected area -something you cannot have with Muscimol easily (you can use florescence Muscimol but the spread of drug is different from normal Muscimol)

However, DREADS has downsides such 1) imagine you have a valuable rat, trained on a difficult task and you want to manipulate multiple brain areas independently (e.g. unilateral vs. bilateral stimulation). You cannot do this using DREADD, because once injected with the ligand then any brain area injected with the AAV would be affected. and remember finding different ligands for different areas is currently non-exisiting.

2) I know some labs have been struggling to use DREADD in subcortical structures like striatum or hippocampus, many gave up completely. for some reasons, DREADD works fine in cortex but it is tricky to get it work for other parts of the brain.

My general advice is to adapt either of these methods (optogenetics, muscimol, or DREADD) given the exact questions you're having on the table. Either of them has its own merits and limitations. If you really care about temporal dynamics of a particular process, then you HAVE to use optogenetics. If not, then you can use a bigger hammer like musciomol or DREADD.

and btw, you may find this wiki page useful for DREADD:

http://pdspit3.mml.unc.edu/projects/dreadd/wiki/WikiStart

Having a cell on or off is a fairly rudimentary approach http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636996/.

It is highly important to know how electrical activity propagates inside the cell, probably you'll need both techniques to have a temporal and spatial control within every neuron.

Depends on optogenetics techniques stories are different. If you want to use optogenetic stimulation for stimulating cortical neurons or if you want to stimulate ChR2 expressing neurons projecting to cortical areas, best way is non-invasive stimulation without insertion of optical-fiber, I mean with two-phton system or .... for deeper structures you have to optimize place of fiber insertion and also size of fiber and intensity of stimulation. Also results depends on the method of ChR2 expression, transgenic animal is recommended but If you are using virus injection or inutero-electroparation, you need to optimize technique, however I recommend optogenetics because with 1 millisecond temporal resolution you can modulate network activity.

Dear Athena, I have been using Gi-coupled DREADDs for manipulations of subcortical neurons and it seems to work. For others it seems to work as well (J Neurosci. 2013 Jul 10;33(28):11668-76. Neuropsychopharmacology. 2013 Apr;38(5):854-62. Nat Neurosci. 2013 May;16(5):632-8.). Maybe it's a question of specifics of the behavioral task or serotype of the AAV? Best, Dimitri.

Dear Dimitri, Thanks a lot for the references.

Thanks Ewan, for the reference and initiating the discussion!

Dear Ewan, 

to use optogenetics instead of DREADD or viceversa depends from the behavioral experiment!

The optogenetic stimulation is time-dependent, while if you would like to record the behavior for a couple of hours the DREADD system is better. 

Best, 

Yes, in both cases is Cre-recombinase.

I met a problem from my boss and I can't find it from literatures now so I hope someone could help me. Does more light stimulation (duration or frequency) would produce stronger behavior? Does anyone tried longer time or higher frequency really enhance behavior in mouse? Neuron are all or none so I don't think it will enhance. However, I don't find any evidence. Thanks.

Well, more light will illuminate ore tissue. So, it might actually enhance the effect. Different duration and frequency can also have different effects. One issue with interpretation of negative effects of these kinds of experiments is always the question if it is because you have not (de)activated enough neurons or because that part of the brain is not essential for that behavior.

DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) and optogenetics are both advanced techniques used in neuroscience to manipulate neuronal activity, but they operate on different principles and have distinct advantages and limitations. Here's a comparative analysis:

In summary, the choice between DREADDs and optogenetics depends on the specific requirements of the experiment, such as the need for temporal precision, invasiveness, and the depth of the target neuronal population. Both techniques have significantly advanced our ability to understand and manipulate neuronal circuits, each with its own set of advantages and limitations.

Check out this protocol list; it might provide additional insights for resolving the issue.