Repeated Corcico-Striatal Stimulation Generates Persistent OCD-Like Behavior

  • Type:#article
  • Year read:#read2021
  • Subject: (in brackets, can also bracket keywords in text)
  • Bibtex: @ahmari2013
  • Bibliography: Ahmari, S. E., Spellman, T., Douglass, N. L., Kheirbek, M. A., Simpson, H. B., Deisseroth, K., et al. (2013). Repeated Cortico-Striatal Stimulation Generates Persistent OCD-Like Behavior. Science, 340(6137), 1234–1239.

Why and when I was reading this

I was doing a deep dive into animal models and OCD

Key takeaways

  • Progressive increase in grooming behavior after stimulation, not an instant effect but builds up over time
  • They increased Construct validity by making sure that the behavior was specific to OCD (grooming) and not anxiety in general (moving around)
  • Further specificity: grooming increased only after orbitofrontal cortex and ventro-medial striatum stimulation, not after infralimbic and prelimbic cortex stimulation

Summary of paper

They found that repeated cortico-striatal stimulation produced a progressive increase in grooming (11 mice in total, 6 active group and 5 control group). The behavior lasted for two weeks after stimulation had ended. It was reduced by fluoxetine. Key regions that were stimulated with optogenetics:

  • Orbitofrontal cortex (OFC)
  • Ventro-medial striatum (VMS)

Specifically, they targeted cells in OFC that project to VMS. The authors could demonstrate an increased activity in these neurons after injection.

Main results

They found that, over time, grooming behavior in the stimulated group increased. This was not seen immediately during stimulation but rather as a progressive increase that lasted up to two weeks after stimulation had ended.

No increase in anxiety behavior, the authors claim there was a specific effect on grooming behavior.

To ensure that increased grooming was not simply a consequence of increased locomotion, we planted fiber optics in the motor cortex and stimulated for five days. This stimulation led to increases in locomotion, but not in grooming.

Another specificity check: Same stimulation paradigm in infralimbic and prelimbic cortex. No effect on grooming behavior.

Author conclusions

Repeated hyperactivation of OFC-VMS projections generates a progressive increase in grooming… Acute stimulation of OFC-VMS pathway was not sufficient to produce OCD-relevant excessive grooming.

The activated cell-type was cortical glutamatergic projection neurons.

We speculate that brief episodes of light-induced activity lead to long-lasting changes that prime OFC-VMS synapses, decreasing the activation threshold during subsequent bouts of stimulation.

In turn, increased activity at OFC-VMS synapses may transmit information through the CSTC circuit and lead to multiple downstream events that ultimately reinforce repetitive behaviors, including (i) plasticity in downstream structures such as thalamus and prefrontal cortex, and (ii) increased motivational saliency mediated by the ventral tegmental area.

Validity criteria of animal models

Predictive validity

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

So and so… There was no direct effect of stimulation on grooming behavior. They did find that grooming behavior increased over time, something they attribute to OFC-VMS synapses being primed and reducing their activation threshold.

Face validity

Phenomenological similarity (etiology, biochemistry, symptomatology and treatment)

This is looking quite good. Excessive grooming in mice has similarities to compulsions in humans. Furthermore, they stimulate a specific brain region (OFC) that has been associated with OCD in humans. They also saw that fluoxetine had an effect on grooming, mirroring the effect of SSRI’s 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.

For number one they are pretty well off, there could always be more to know but in terms of psychopathology this is a well-defined construct. Number two is less clear though.