Sometimes the good guys win

Sep 30 2014 Published by under Neuroscience, NIH

I've mentioned a time or two that I think the DREADD approach is infinitely more useful than optogenetics for anything that matters.

So congrats to the team for this new award.

DREADD2.0: AN ENHANCED CHEMOGENETIC TOOLKIT

DESCRIPTION (provided by applicant): The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has the ambitious goal of elucidating how neuronal ensembles interactively encode higher brain processes. To accomplish this goal, new and improved methods for both recording and manipulating neuronal activity will be needed. In this application, we focus on technologies for manipulating neuronal activity. The major significance of this application is that we will provide an enhanced chemogenetic toolbox that allows non-invasive, multiplexed spatiotemporal control of neuronal activity in domains ranging from single synapses to ensembles of neurons. To achieve this, we will provide: Chemical actuators with improved pharmacokinetics and pharmacodyamics suited for use with current DREADDs in eukaryotes ranging from Drosophila to primates (Specific Aim #1) Photo-caged CNO and other chemical actuators to provide millisecond-scale control (Specific Aim #1) Novel DREADDs and 'split-DREADDs' targeted to distinct neuronal pathways to enable multiplexed interrogation of neuronal circuits (Specific Aims #2 and 3) Chemogenetic platforms with minimized desensitization and down-regulation (Specific Aim #3)

I am excited to see where this leads.

More awards under The BRAIN Initiative.

27 responses so far

  • dr24hours says:

    How am I supposed to argue when you blog stuff I don't understand?

  • Beaker says:

    It's interesting to see how many of the projects funded under the Brain Initiative involve "tool-making," which has traditionally been an approach that NIH does not fund through the R01 mechanism.

    I am not saying tool-making is a bad thing, but this is clearly a shift in approach for the NIH, who typically want to see that you have the optimized tools in hand already and you are now proposing to use your great new tools to address important questions related to human health.

  • BRAIN RFAs specifically solicited tool-making proposals.

  • dr_mho says:

    They'd be great if they actually worked. For most folks (including us) that have tried to combine the DREADDs with physiology to monitor how much cellular activity is modulated, the answer is not much at all.

  • drugmonkey says:

    Yeah...that was kind of the explicit point, was it not, Beaker? The mantra was "we can't get these funded and they would be so awesomely helpful".

  • Beaker says:

    @DM and CPP: Well yea, I can see that it was rather explicit in the RFAs. Since HHMI-Janelia and Allen Brain are partners in the Brain Initiative, I thought that perhaps the Dream Team would have recommended that the bulk of the tool-making be carried out via non-NIH mechanisms. Obviously I was wrong. Is the DARPA part also tool-making?

  • E-roock says:

    The scientific vision of the brain initiative is in phases. The first (5 yr) phase is specifically tech & tool development. They are also looking for ways to enhance data handling, management, and standards for data sharing sharing of very large data sets (Big Data). The health relevant stuff will be later. http://www.braininitiative.nih.gov/2025/index.htm

  • E-roock says:

    Side comment. This is a very exciting time to be in fields related to neuro & behavior. I have a feeling the next decade will be transformative and hard to predict what will come of it. But I think (hope) us youngins will have something to brag about in 25-50 years about the work that's getting it's start now.

  • drugmonkey says:

    They'd be great if they actually worked. For most folks (including us) that have tried to combine the DREADDs with physiology to monitor how much cellular activity is modulated, the answer is not much at all.

    Science is hard.

  • poke says:

    Meh. Neither dreadds or opto crap is even close to physiological and all those ground breaking behavioral results people are reporting don't mean what they think.

    I look forward to being part of the generation of scientists that has to purge the literature of thousands of ill-posed, poorly conceived experiments linking behavior and "circuit function."

    Great glam fodder though, so enjoy it while it lasts...

  • E-roock says:

    I attended a job talk last year wherein optogenetics was the main method. I was impressed with what the tech was able to do, however, it was criticized by the more experienced folks in the room because Candidate framed this tool as generating models of the disorder, which we can then test treatments for. Whereas it lacks face validity regarding etiopathogenesis because the optowhatsit is not cause if the human disorder. Probably the candidate would have sold the case better at a dept with a different mission. My dept is clinical focused and we had someone involved int the BRAIN initiative speak to us about the vision, mission, opportunities, but our main question at the end was, "what's there for us (clinicians) to do?" and the answer seemed to be to wait but find a date early in the night because after the tool building phase, there will be big multi institute projects, probably involving NGOs. But it kinda baffles me because I can't quite envision what Industry can do to profit this neuro stuff ... or it scares me.

  • dsks says:

    As Lloyd Bridges famously opined in Airplane!, "Looks like I picked the wrong week to quit neuroscience."

    🙁

  • Grumble says:

    DM: "I think the DREADD approach is infinitely more useful than optogenetics for anything that matters. "

    Care to explain further? If you need precise temporal control, DREADDs are useless. (At least until the folks who got the grant you linked to make their caged CNO - but using it will be a lot clunkier than optogenetics.)

  • drugmonkey says:

    How do we treat people with either of these Grumble? Which is even remotely likely to be useful? Hint: not the one that requires lasers in the brain.

  • Jessica Tollkuhn says:

    I think lowering the threshold for a neuron to fire in it's own way is more physiologically relevant than driving it (and everything connected to it) at whatever intensity is necessary to generate the phenotype you want to see.

  • becca says:

    HUMPH. You just don't want me to ever get lasers for my brain. You big meanie.

  • rxnm says:

    "I think lowering the threshold for a neuron to fire in it's own way is more physiologically relevant than driving it (and everything connected to it) at whatever intensity is necessary to generate the phenotype you want to see."

    bless you

  • Comradde PhysioProffe says:

    What I'd like to see is an optowhatsus paper in which the authors first measure the actual firing patterns of a population of neurons during a behavioral state, and then use optowhatsus to induce that specific firing pattern, confirmed by measuring the optowhatsus-induced firing pattern. This is a lot more meaningful than hammering the fucke out of a population with optowhatsus. Anybody able to point me to such a paper?

  • Grumble says:

    Treatment isn't everything. In fact, if you think that the major promise of either chemo- or opt0-genetics is in their translational potential, then you grossly misunderstand what they are really useful for.

    It's also kind of odd that the grant you linked to specifies, as one of its aims, development of a caged CNO. Using such a thing in vivo would require... you got it, lasers in the brain.

  • neuropop says:

    @CPP

    How about this?
    Nature. 2013 Jun 20;498(7454):363-6. doi: 10.1038/nature12176. Epub 2013 May 26.
    Distinct behavioural and network correlates of two interneuron types in prefrontal cortex.
    Kvitsiani D1, Ranade S, Hangya B, Taniguchi H, Huang JZ, Kepecs A.

    Not exactly what you suggest, but a creative use of optogenetics - namely to assist in classification/identification of particular populations during behavior without stimulation.

  • Comradde PhysioProffe says:

    That's got zero to do with what I am asking for.

  • neuropop says:

    @CPP - but it's a start. If you don't know which of your optowhatsus neurons are firing and when, you learn precious little by blasting away. In the cortex or hippocampus, it is hard to tell from spikes alone what kind of neuron was firing when. The use of optowhatsus to first identify and mark the particular population paves the way to then do the experiment you suggest.

  • The experiment I am asking for gets at the heart of the optowhatsus catechism, which is that behavioral outputs induced by optowhatsal manipulation of neuronal activity tell us something meaningful about the relationship between the endogenous activity of the manipulated neurons and that behavior. In your example, it is purely coincidental that optowhatsus was part of the methodology used to make those determinations vis a vis the experiment I am asking for.

    Remember, optowhatsus is being sold as revolutionary not because it provides clever ways of identifying neuron types in complex circuits, but because it answers the question "how the brain works": how does endogenous neuronal activity in intact circuits drive behavior? The fact that it is useful for other things to help "pave the way" has fuckeall to do with this main claim.

  • neuropop says:

    @CPP. Agreed. Until that happens, optowhatsus remains a sophisticated cudgel compared to micro stimulation.

  • drugmonkey says:

    Filling in "how the brain actually works" in the wake of vertically ascending science is for the riff raff to fill in, CPP. Why are you concerned?

  • Learn to read dumasse. I have not taken a position on whether I am "concerned" with "how the brain works". I am simply restating what others claim as the end game of the optowhatsus "revolution".

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