DREADDs vs OPTO: does it matter to the neuron?

I get this question a lot and certainly there are a number of distinctions one can make with regard to these two technologies (Table 1).

TABLE 1. COMPARISON OF CHEMO- AND OPTOGENETIC PLATFORMS

IDEAL CRITERIA	OPTOGENETIC	CHEMOGENETIC
Non-invasive	No: Inherently invasive	Yes: chemical actuators may be administered via drinking water
Does not require specialized equipment	No: Multi-channel programmable light source optic fibers, implantable light source.	Yes:  routine laboratory equipment; chemical actuators commercially available
Capable of multiplexing	Yes: remarkable spectral diversity	Yes: at least theoretically
Neuronal subdomain-specific modulation	Yes/No: via excitation of opsins in axonal fibers; back-propagating action potentials reported.	Yes: via local injections and subdomain specific targeting
Intervention inert	No:  photon source creates heat (though can be minimized with more sensitive opsins); problematic for long-term stimulation; bacterial proteins antigenic	Yes/No: CNO is inert in rodents but not in primates; DREADDs are minimally-modified human proteins; improved chemical actuators useful for primates proposed (Chen et al, 2015)
Precise spatio-temporal control	Yes: optogenetics provides millisecond-scale control	Yes/No:  compounds with enhanced pharmacokinetic properties and photocaged compounds possible
Scalable to large brains/many neurons	No: attenuated light at target due to absorption, scattering and distance-dependent decay	Yes
Stimulation/inhibition is ‘physiologic’	No:  artificially synchronized patterns of excitation/inhibition induced	Yes: DREADDs use conserved and canonical GPCR signaling pathways
Non-desensitized	Yes	Yes/No: current DREADDs likely undergo desensitization; DREADDs not desensitized by canonical mechanisms would be useful

As can be seen, both technological approaches have inherent advantages and disadvantages and there is no 'one-size-fits-all' approach for circuit deconstruction and behavioral manipulation.  My advice is to use the technology which is best for your particular application. 

The other thing to realize is that to date there appear to be few significant differences comparing opto- and chemogenetic technologies with respect to the ultimate outcome of behavior.  Thus in Table 2 I've summarized several recent papers targeting distinct neuronal groups where opto- and/or chemogenetic approaches were used along with ablation in some cases.  In all of these particular instances the ultimate behavioral effects were certainly identical with respect to the magnitude and vector of the response but obviously not with respect to the duration.

1.  Krashes, M., et al.. J Clin Invest 121, 1424-1428 (2011).

2.  Aponte, Y., Atasoy, D. & Sternson, S.M. Nature neuroscience 14, 351-355 (2011).

3.  Zhan, C., et al. The Journal of neuroscience : the official journal of the Society for Neuroscience 33, 3624-3632 (2013).

4.  Pei, H., Sutton, A.K., Burnett, K.H., Fuller, P.M. & Olson, D.P. Mol Metab 3, 209-215 (2014).

5.  Cai, H., Haubensak, W., Anthony, T.E. & Anderson, D.J.. Nature neuroscience 17, 1240-1248 (2014).

6.  Carter, M.E., Soden, M.E., Zweifel, L.S. & Palmiter, R.D. Nature 503, 111-114 (2013).

7.  Sasaki, K., et al.. PloS one 6, e20360 (2011).

8.  Tsunematsu, T., et al.. The Journal of Neuroscience 31, 10529-10539 (2011).