The hunt for depression is a tricky case for any neural detective. Your brain has 86 billion neurons. Where to start looking for suspects? Well, let’s think about that for a second. We want somewhere in the brain that can control how you feel things are going — that things are sometimes better than expected, and worth enjoying. And somewhere in the brain that has something to do with serotonin, because the long-standing treatment for clinical depression are “SSRIs”, drugs that make more serotonin available by stopping it from being mopped up.

Enter the lateral habenula. Rolls off the tongue, doesn’t it? But it fits the suspect’s profile. It connects to both serotonin and dopamine releasing neurons. When dopamine neurons burst with activity, that’s a signal we just got something better than expected (serotonin neurons might signal a similar thing). And when the lateral habenula releases a burst of activity, it stops the dopamine and serotonin neurons from bursting. Stops them from telling the brain — hey, that was unexpected.

Now, usually, this is for the common good. The lateral habenula sends the signal that what just happened was, in fact, expected. So you, little dopamine neuron, and you, precious serotonin neuron, do not need to burst — everything is as it is should be. With this signal from the habenula, your brain knows the world is predictable, and can go about its business; if every little thing was signalled as being surprising, you’d spend all day giggling and kicking things to see what they did. You’d be a three year old.

But when we look in the brains of depressed mice, we see their lateral habenula is bursting more than usual. Much more. The “nothing surprising” signal is being sent far too much, and at the wrong time. The dopamine and serotonin neurons cannot frolic and play. The brain is robbed of some key signals that life is worth pursuing.

We suspect the lateral habenula based on this strong circumstantial evidence, that it connects to the right things and its signals go haywire in depressed mice. Now to get a conviction we need more than circumstantial evidence. We need probable cause: does ketamine stop the bursting and remove depression? And we need motive: what drives the habenula to increase its bursting?