Understanding the brain a little better

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Psychosis is triggered in the striatum , a small curved tissue deep in the brain that helps control how we move, feel, and make decisions. Densely packed neurons extend their spiny branches out of the striatum, like ribbon cables. Dopamine causes these neurons to send signals to other parts of the brain. This interface is where a rush of dopamine is believed to overwhelm the mind.

About 95% of the neurons connecting the striatum to the rest of the brain are SPNs, each with a D1 or D2 receptor. When dopamine attaches to D1, those neurons become more excited; when it sticks to D2, they beco Phone Number List me less excited. The entire system is interconnected, making it difficult to determine exactly causes and effects. But Parker believes that by controlling individual cells, scientists can reverse engineer enough of the circuit to learn how to deliver drugs as effectively as possible.

The first step of their experiment was to mimic excess dopamine in mice by giving them amphetamines . "If you inject them with amphetamines, they run more. If you inject them with antipsychotics first, they run less. That's the current state of the art," explains Parker.

Next, to find out exactly which neurons the amphetamines interacted with, his team implanted tiny endoscopes in each mouse's brain and set up tiny two-gram microscopes to look through them. Parker learned this type of in vivo imaging during his time as a Pfizer employee at Stanford University, where he was researching alongside Mark Schnitzer, a biophysicist who pioneered the use of this method to study neurons more generally. . Endoscopes are invasive, but not so bothersome that they hinder experiments.

Because D1 and D2 neurons are genetically different, the scientists were able to study each one separately. To distinguish them, they designed fluorescent molecules that marked only cells with a specific genetic sequence. They then recorded how the neurons reacted after the amphetamine injections: D1 SPNs became more excitable , or sensitive , and D2 less so . This was consistent with textbook theory, Parker says, "but no one had proven it yet."



Then things got weird
Each of the mice had already been injected with one of four drugs: haloperidol , a first-generation drug from the 1950s known for its motor side effects; olanzapine , a second generation drug; clozapine , very powerful and given when others do not work; and MP-10 , a candidate Pfizer had developed that appeared effective in animals, but which failed during clinical trials in 2019 when it exacerbated psychosis in humans.

Most neuroscientists would bet that the three effective drugs should ignite some action in the D2 SPNs, and might do nothing in the D1 SPNs. Indeed, haloperidol and olanzapine counteracted the effect of amphetamine on D2, as expected. But clozapine didn't. And the big surprise was that the control of D1 neurons seemed to be the factor that mattered most. All three effective drugs normalized action on D1, and MP-10 did not. In fact, MP-10 had leveled the activity in D2, but actually worsened the abnormal activity in D1 . "It exacerbated the hyperactivity," Parker notes.