This Week in Neuroblunders: Optogenetics Edition

Recent technological developments in neuroscience have enabled rapid advances in our knowledge of how neural circuits function in awake behaving animals. Highly targeted and reversible manipulations using light (optogenetics) or drugs have allowed scientists to demonstrate that activating a tiny population of neurons can evoke specific memories or induce insatiable feeding.

But this week we learned these popular and precise brain stimulation and inactivation methods may produce spurious links to behavior!! And that “controlling neurons with light or drugs may affect the brain in more ways than expected”! Who knew that rapid and reversible manipulations of a specific cell population might actually affect (gasp) more than the targeted circuit, suggesting that neural circuits do not operate in isolation??

Apparently, a lot of people already knew this.

Here's the dire Nature News report:

...stimulating one part of the brain to induce certain behaviours might cause other, unrelated parts to fire simultaneously, and so make it seem as if these circuits are also involved in the behaviour.

According to Ölveczky, the experiments suggest that although techniques such as optogenetics may show that a circuit can perform a function, they do not necessarily show that it normally performs that function. “I don’t want to say other studies have been wrong, but there is a danger to overinterpreting,” he says.

But the paper in question (Otchy et al., 2015) was not primarily about that problem. The major theme is shown in the figure above — the difference between acute manipulations using a drug (muscimol) to transiently inactivate a circuit versus the chronic effects of permanent damage (which show remarkable recovery).¹ In the songbird example, acute inactivation of the nucleus interface (Nif) vocal control area (and its “off-target” attachments) warped singing, but the “chronic” lesion did not.²

In an accompanying commentary, Dr. Thomas C. Südhof asked:

How should we interpret these experiments? Two opposing hypotheses come to mind. First, that acute manipulations are unreliable and should be discarded in favour of chronic manipulations. Second, that acute manipulations elicit results that truly reflect normal circuit functions, and the lack of changes after chronic manipulations is caused by compensatory plasticity. 

But not so fast! said Südhof (2015), who then stated the obvious. “Many chronic manipulations of neural circuits (both permanent genetic changes and physical lesions) do actually produce major behavioural changes.” [as if no one had ever heard of H.M. or Phineas Gage or Leborgne before now.]

The acute/chronic conundrum is nothing new in the world of human neurology. But centuries of crudely observing accidents of nature, with no control over which brain regions are damaged, and no delineation of precise neural mechanisms for behavior, don't count for much in our store of knowledge about acute vs. chronic manipulations of neural circuits.

Let's take a look at a few examples anyway.

In his 1876 Lecture on the Prognosis of Cerebral Hæmorrhage, Dr. Julius Althaus discussed recovery of function:

Do patients ever completely recover from an attack of cerebral hæmorrhage?
This question used formerly to be unhesitatingly answered in the affirmative.
. . .

The extent to which recovery of function may take place depends—

1. Upon the quantity of blood which has been effused.  ...

2. Upon the portion of the brain into which the effusion has taken place. Sensation is more easily re-established than motion; and hæmorrhage into the thalamus opticus seems to give better prospects of recovery than when the blood tears up the corpus striatum.  ...

[etc.]

In his 1913 textbook of neurology (Organic and Functional Nervous Diseases), Dr. Moses Allen Starr discussed aspects of paralysis from cortical disease, and the uniqueness of motor representations across individuals: “Every artisan, every musician, every dancer, has a peculiar individual store of motor memories. Some individuals possess a greater variety of them than others. Hence the motor zone on the cortex is of different extent in different persons, each newly acquired set of movements increasing its area.”

In 1983, we could read about Behavioral abnormalities after right hemisphere stroke and then Recovery of behavioral abnormalities after right hemisphere stroke.

More recently, there's been an emphasis on connectome-based approaches for quantifying the effects of focal brain injuries on large-scale network interactions, and how this might predict neuropsychological outcomes. So the trend in human neuroscience is to acknowledge the impact of chronic lesions on distant brain regions, rather than the current contention [in animals, of course] that “acute manipulations are probably more susceptible to off-target effects than are chronic lesions.”

But I digress...

Based on two Nature commentaries about the Otchy et al. paper, I was expecting “ah ha, gotcha, optogenetics is a fatally flawed technique.” This Hold Your Horses narrative fits nicely into a recap of neurogaffes in high places. One of the experiments did indeed use an optogenetic manipulation, but the issue wasn't specific to that method.

Ultimately, the neuroblunder for me wasn't the Experimental mismatch in neural circuits (or a failure of optogenetics per se), it was the mismatch between the-problem-as-hyped and a lack of historical context for said problem.


Footnotes

¹ Here's a figure from the other experiment, which involved acute vs. chronic inactivation of motor cortex in rats. Basically, the tiny injection of muscimol impaired lever-pressing behavior (acutely), but the large lesion did not (chronically). Panel H shows a similar deleterious effect using optogenetic stimulation.

Modified from Fig. 1 (Otchy et al., 2015).

I can't stress this point enough – a human with a comparably sized lesion in primary motor cortex would not [likely] show that much spontaneous recovery of function in 5-10 days. Yes, of course there's plasticity in the central nervous system of adult humans, but I think Otchy et al. (2015) overstate the case here:

As in our experimental animals, patients with lesions to motor-related brain areas have motor deficits that resolve in the days and weeks following the injury. Aspects of this recovery are thought to be independent of rehabilitation, suggesting spontaneous processes at work.

² It isn't exactly true that the lesions had no effect on song: “A fraction of the initial post-lesion vocalizations were severely degraded and did not resemble pre-lesion song.”


References

Althaus J (1876). A Lecture on the Prognosis of Cerebral Haemorrhage. British medical journal, 2 (812), 101-4. PMID: 20748269

Otchy, T., Wolff, S., Rhee, J., Pehlevan, C., Kawai, R., Kempf, A., Gobes, S., & Ölveczky, B. (2015). Acute off-target effects of neural circuit manipulations. Nature DOI: 10.1038/nature16442

Reardon, S. (2015). Brain-manipulation studies may produce spurious links to behaviour. Nature DOI: 10.1038/nature.2015.19003

Südhof, T. (2015). Reproducibility: Experimental mismatch in neural circuits. Nature DOI: 10.1038/nature16323