Optogenetic Stimulation of Lateral Orbitofronto-Striatal Pathway Suppresses Compulsive Behaviors

  • Type:#article
  • Year read:
  • Subject: OCD
  • Bibtex: @burguiere2013
  • Bibliography: Burguière, E., Monteiro, P., Feng, G., & Graybiel, A. M. (2013). Optogenetic Stimulation of Lateral Orbitofronto-Striatal Pathway Suppresses Compulsive Behaviors. Science, 340(6137), 1243–1246. http://doi.org/10.1126/science.1232380

Why and when I was reading this

Key takeaways

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Summary of paper

They compared mice with Sapap3 deletion, which makes them develop compulsive behaviors more easily, to a control group of mice with the gene intact.

They hypothesize that the excessive grooming in Sapap3 deletion mice is a result of reduced response inhibition from the lateral orbitofrontal cortex (lOFC). To test this, they stimulated Sapap3 deletion mice in the lOFC and striatum and found that this normalized their behavioral responses to conditioned stimuli.

Main results

Knockout-mice continue to respond once a stimulus (tone) is conditioned, even if it no longer is associated with an unconditioned stimulus (water drop on forehead).

The Sapap3 mutant mice thus expressed an acquired maladaptive behavior characterized by defective inhibition of their conditioned responses to the originally neutral tone stimuli.

Stimulation of lOFC and striatum normalized responses in Sapap3 mutant mice. In other words, their ability to inhibit responses was restored.

The abnormal stimulus-evoked compulsive behavior in the Sapap3 mutants thus could have resulted from a deficit of behavioral inhibition that was restored by optogenetically stimulating the lOFC-striatal pathway.

They should not respond with grooming to the tone here. With stimulation, they stop responding to the tone and wait for the water drop before grooming.

Author conclusions

Our findings demonstrate that selective stimulation of the lOFC-striatal pathway can restore a behavioral inhibition signal in an animal model expressing pathological repetitive behaviors and can prevent overexpression of both conditioned and spontaneous repetitive grooming.

Validity criteria of animal models

Predictive validity

Performance in the test predicts performance in the condition/situation being modelled

They have a clear link between stimulation of the lOFC and striatal areas and improved response inhibition. Off/On/Off inhibition before, during, and after stimulation.

Face validity

Phenomenological similarity (etiology, biochemistry, symptomatology and treatment)

This is hard to tell here since we do not have knockout-humans. The line is blurred between CSTC-deficits and normal functioning. It is interesting that they stimulate the same areas that have been implicated in repetitive behavior in humans.

Construct validity

Theoretical rationale, demonstration of construct validity requires two things:

  1. Corresponding constructs are being studied in animals and humans. This presupposes that both the model and the disorder have been sufficiently studied to make an unambigious interpretation of the cognitive changes involved.
  2. A change in the construct is central to the disorder. This means that we must first understand mental disorders in people.

(1) This maps nicely to human studies emphasizing the over-reliance on habit learning in OCD. Compulsions become less responsive to outcomes once they are habits, similar to how the mice continue to respond to the tone even without water drops.

(2) Well, not known as far as I know. The role of response inhibition may be important but other constructs contribute to OCD as well.