It all started with ketamine. To some, vets mainly, it’s a horse tranquilliser. To others, a party drug. To those with severe clinical depression, a potential, literal, life-saver. A dose of ketamine can rapidly dull the symptoms of depression, providing immediate relief for those crippled by the darkest thoughts. And while ketamine does not work for everyone, it seems to work in many people who are untouched by standard anti-depressant drugs.
Ketamine could then be our best lead in the hunt for depression. For if we search for where ketamine affects the brain, and for how it affects the brain, we will get vital clues to the cause of depression. And so to a long-lasting effective treatment. Two studies just published in Nature used precisely this trick, and spectacularly uncovered not just compelling evidence of the tiny brain region to target, but exactly what goes wrong in it to create depression — that some neurons are, literally, depressed.
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.
(W)hen 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?
The two studies in Nature from Hailan Hu and team answered both questions. Let’s start, as they did, with probable cause: if we stick ketamine into the habenula, does it alleviate depression? Yes. Depressed rats recover. In a bunch of tests, injecting ketamine into the habenula restores a rat’s élan: exploring, reacting, enjoying the taste of sweet sweet sucrose.
Right, so ketamine can work its magic from within the habenula. But we want evidence that it has any effect on the habenula itself. For, surely, if that over-active bursting of the habenula in some way causes depression then ketamine should clobber the bursts? Remarkably, it does. Ketamine reduces the number of bursting neurons, right down to the same number found in healthy brains. We now have a big wodge of evidence for a probable cause of depression: habenula neurons burst fire when they should not, and stopping this bursting with ketamine stops depression (in tiny rodents).