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OCD and Optogenetics: Lighting the brain up to shut a behavior down

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People who suffer from obsessive compulsive disorder (OCD) can’t help some of their actions. They suffer from severely intrusive thoughts and anxiety, which they know are not right. And they feel a compulsion to do rituals to get rid of them. Maybe it’s repetitive hand washing. Maybe it’s checking that the stove is off exactly 7 times each night. Whatever it is, the symptoms can cause severely interfere with their daily lives.

What causes these compulsive, repetitive behaviors? We’re not sure, but today’s paper suggests a role of the circuit between the striatum and the orbitofrontal cortex, areas associated with impulsivity and repetitive behaviors. And it could be that increasing activity within certain parts of this circuit might help shut down some repetitive behaviors, giving us important insight into how repetitive behaviors work.

(Figure 1A)

Burguiere et al. “Optogenetic Stimulation of Lateral Orbitofronto-Striatal Pathway Suppresses Compulsive Behaviors” Science, 2013.

I should begin by noting that Ed also covered this paper over at Not Exactly Rocket Science, along with another paper about making compulsive behaviors. It’s a really cool look at the two papers and you should definitely check it out! Me, I’m interested in the circuit involved here, and why stimulating one part may end up inhibiting behavior.

The authors of this study started with a model of obsessive behavior, the SAPAP3 knockout mouse, which I actually wrote a bit about recently. This mouse has a knockout of a special protein associated with synapses. Without it, mice display obsessive (well, repetitive, we can’t really ask the mouse if they are obsessing) grooming behavior, grooming their faces so much that they will cause lesions to form. The authors wanted to look at what caused this behavior, and what could potentially stop it.

They started by training the mice to respond to a cue.

(Figure 1B, a schematic of the training)

First they would hear a tone, then a bit later they would get a drop of water on their foreheads. This is irritating to mice, normal and knockout alike, and they will start grooming their faces. As you train the mice up, at first they will start grooming when they hear the tone in anticipation of the water droplet, with more grooming when the water droplet appears. But as training goes on, normal mice will stop grooming in response to the tone, they will learn they can wait until the water droplet actually happens. In contrast, the SAPAP3 knockout mice will continue grooming in response to the tone.

(Figure 1D)

What you can see above is the frequency of grooming in the mice, where black is the wildtype and red is the knockout mouse. You can see at the beginning of training (top graph), both types of mice groomed to get rid of the water droplet. In the middle of training (middle graph), all mice groomed in response to the tone and to the water droplet. But by the end of training (bottom graph), only the SAPAP3 knockout mice were still grooming in response to the tone, the normal mice were saving their grooming for the water droplet. This is a model of compulsive behavior, where the SAPAP3 animals are unable to stop responding to the tone, even those the tone itself isn’t the water droplet.

What was the neurophysiology underlying this behavior? The scientists looked at the neuronal firing rates in the normal and the SAPAP3 knockout mice in the both the striatum and the orbitofrontal cortex, both areas important in impulsivity and inhibiting responses, looking to see where the two sets of animals might be different.

(Figure 2A and 2E)

What you can see above is the firing rate of neurons in these two areas, the top in the orbitofrontal cortex and the bottom in the striatum. While the orbitofrontal cortex firing rats were about the same, in the striatum, the SAPAP3 knockout mice showed increased firing rates, especially apparently as the training continued on. The SAPAP3 animals were showing a lack of “tuning” when they learned the task, remaining just as responsive to the tone no matter how long they were trained.

So why this lack of tuning? In this circuit, the signals are coming from the orbitofrontal cortex to the striatum. Neurons in the orbitofrontal cortex can inhibit the medium spiny neurons in the striatum, causing the decrease in firing rate in the wildtype mice. Maybe the SAPAP3 knockouts were suffering from a lack of inhibition, where their medium spiny neurons remained active, and their behavior failed to change.

To look at this, the authors turned to optogenetics. They created mice with a gene for channelrhodopsin, targeted only to the cells in the orbitofrontal cortex of the SAPAP3 mice. The channelrhodopsin is a channel that responds to light, opening and allowing in ions, allowing the neuron in which it is placed to fire. So you can put a channelrhodopsin in a specific type of cell, activate it with a light, and make the cell fire, just when you want it to.

(Figure 3E)

What you can see above is a measure of firing rates in the striatum of the SAPAP3 knockout mouse, where the light to activate the channelrhodopsin in the orbitofrontal cortex is either on (purple) or off (black). You can see that when you use light to ACTIVATE the orbitofrontal cortex, you get a DECREASE in neuron firing in the striatum. Increasing the orbitofrontal activity inhibits the striatal activity. So if you have a striatum that is too active (as the SAPAP3 knockout mice do), you might be able to decrease that activity to normal levels.

But does it normalize the behavior?

(Figure 4B)

Yes, it DOES. When the author stimulated the orbitofrontal cortex as the SAPAP3 mice were trained, the animals learned to groom only to the water droplet, and not to the tone (blue line), whereas, when the laser was off (red line), the animals were grooming to both. Turning on a certain set of neurons helped to turn off a set of behaviors.

While these studies can’t immediately tell us what is wrong in people with OCD (after all, these mice do overgroom, but they don’t technically have OCD, there are a model), it does provide an interesting look at what might be going on in the brain during compulsive behaviors. And the more we understand, the more targets we end up with to try and fight the illness.

Burguiere et al. “Optogenetic Stimulation of Lateral Orbitofronto-Striatal Pathway Suppresses Compulsive Behaviors” Science, 2013.

Scicurious About the Author: Scicurious is a PhD in Physiology, and is currently a postdoc in biomedical research. She loves the brain. And so should you. Follow on Twitter @Scicurious.

The views expressed are those of the author and are not necessarily those of Scientific American.

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  1. 1. ironjustice 11:48 am 06/17/2013

    OCD is considered by some to be the cause of hoarding. A shock , such as a family members death or physical trauma can lead to hoarding , OCD. They have also shown they can lead to hyperviscous blood , which can lead to extravasated blood , due to the ‘pooling’ of the blood , ischemia , lack of blood flow. Iron is in the spilled blood is called hemosiderin.
    “Hemosiderin deposition in the brain”
    “He complained of impulsive sexual and aggressive thoughts that were intrusive, repetitive and distressing. He also complained of compulsive behaviors and rituals, such as hoarding, arranging, ordering, preoccupations with symmetry, exactness, rewriting and
    doubting. Interrupting the patient while carrying out his rituals lead to violence. The patient had moderate insight of his illness.”

    Link to this
  2. 2. doc_becca 2:05 pm 06/17/2013

    I’m confused as to why, if the firing rates in OFC were comparable between WT and SAPAP3 mice, they thought that OFC neurons were the source of inhibition loss in the striatum. If that were the case, wouldn’t you expect to see lower OFC activity in SAPAP3 mice? Why not just express halorhodopsin in the striatum and shut things down directly?

    Link to this
  3. 3. scicurious 2:14 pm 06/17/2013

    A good question, I was also surprised they didn’t see lower firing rates in the OFC. Their hypothesis is that the firing in the OFC is similar, but the response in the striatum is the one that’s limited. I didn’t cover it above, but they found fewer parvalbumin interneurons in striatum of the knockouts than in the control. It would seem like the source of the issue was then the striatum, and they DID do light stimulation there as well (with channelrhodopsin in the striatum on the medium spiny neurons, increasing the inhibition), and got similar effects. But the ones they got when they simulated the OFC were much more drastic. I’m not sure why that is, though. They hypothesize that the OFC is signaling to fast spiking interneurons in the striatum, which then inhibit the MSNs. Still yeah, they should have seen an even bigger effect with direct striatal stimulation, they don’t have the space to discuss why the results turned out this way, though.

    Link to this

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