New neurons buffer the brains of mice against stress and depressive symptoms

For large swathes of the brain, the neurons we’re born with are the ones we’re stuck with. But a few small areas, such as the hippocampus, create new neurons throughout our lives, through a process known as neurogenesis. This production line may be important for learning and memory. But it has particularly piqued the interest of scientists because of the seductive but controversial idea that it could protect against depression, anxiety and other mood disorders.

Now, by studying mice, Jason Snyder from the National Institute of Mental Health has found some of the strongest evidence yet for a connection between neurogenesis and depression (or, at least, mouse behaviours that resemble depression). He found that the new neurons help to buffer the brains of mice against stress. Without them, the rodents become more susceptible to stress hormones and they behave in unusual ways that are reminiscent of depressive symptoms in humans.

Snyder brought the hippocampus’s production line to a screeching halt by targeting the cells that produce new neurons. He loaded these cells with a protein that sensitises them to a drug called valganciclovir, but only when they’re multiplying. With a dose of the drug, Snyder could stop the hippocampus from producing new neurons without harming any of the existing cells.

When Snyder stressed these mice by restraining them for half an hour, they produced higher levels of the stress hormone corticosterone. That’s par for the course. Normal mice show the same peak, but their brains soon damp down the flood of corticosterone. Not so for the mice that couldn’t produce new neurons – their high corticosterone levels still hadn’t recovered half an hour after they were freed. The levels of this hormone also rise and fall in a daily rhythm, and in this respect, Snyder’s altered mice were normal. Their problems only came to light when they were stressed.

Their behaviour also changed. Without the ability to create new neurons, the stressed mice were less likely to enter an unfamiliar area to retrieve a piece of food, even if they were very hungry. And when they were placed in a cylinder of water, they gave up swimming more quickly and floated motionless, a supposed sign of “behavioural despair”.  Again, the mice only behaved differently if they were stressed; under normal circumstances, they were indistinguishable from their peers.

Finally, Snyder looked for signs that the mice were no longer gaining pleasure from activities that were once enjoyable – this is one of the “hallmark symptoms” of depression. Snyder gave his mice a choice between sugary or plain water, depriving them of both, and then offering the thirsty mice the same choice. All of them preferred the sugary drink at first, but only those that could still produce new neurons retained their preference the second time round. Those with a disabled production line sipped equally from both drinks.

“I find this paper very important,” says Amelia Eisch, who studies neurogenesis at Southwestern Medical Centre. “It is the first time that adult-generated neurons have been firmly linked to the behavioural responses to stress.”

Snyder’s study arrives after an intense decade of research, which really kicked off when Rob Duman found that antidepressants stimulate neurogenesis in rats. Many other rodent experiments produced results in a similar vein. The presence of new neurons after long-term doses of antidepressants went hand in hand (or rather, paw in paw) with improvements in behaviour. All types of antidepressants, from drugs to rich environments to exercise, seem to give the neural production line a boost, while things that can lead to depression, such as stress, make it slow down. But there were exceptions; some groups found that neurogenesis had no influence on behaviour or the effectiveness of antidepressants.

Most of these studies did nothing more than find interesting correlations. None of them could show that increasing neurogenesis would actually alleviate the symptoms of depression, or that stopping it could lead to the condition in the first place. All of the things that affect the assembly of new neurons – stress, antidepressants, and so on – have a myriad of other effects on the brain.

To move beyond such correlations, scientists needed to actually manipulate neurogenesis to see what happens. Luca Santarelli did that in 2003 by hitting the hippocampus of mice with X-rays. The radiation stopped neurogenesis in its tracks, and it rendered the mice immune to the effects of two antidepressants.

But once again, inconsistent results turned up. For example, various groups have reduced neurogenesis by anywhere from 40 to 90 percent, without triggering any depressive symptoms. This might be because the animals in question weren’t stressed. According to Snyder’s study, getting rid of new neurons doesn’t do anything in itself. Their importance only becomes clear during times of hardship. At least in mice, these newborn neurons help to control the brain’s reaction to stress, altering the levels of individual hormones and affecting the behaviour of entire animals.

This chain of events loops back on itself because stress, and hormones like corticosterone, can also affect the neural production line in the hippocampus. By tamping down neurogenesis, stress in the present can make animals more responsive to stress in the future. Snyder writes, “This type of programming could be adaptive, predisposing animals to behave in ways best suited to the severity of their particular environments.” But if neurogenesis continues to be blocked, things go awry; animals fail to properly recover from stress, and depressive symptoms could kick in.

Could this lead to better treatments for depression? It’s too early to say. Just a few months ago, Amar Sahay from Columbia University found that increasing neurogenesis does not alleviate depressive behaviour in mice in the way that antidepressants can. Eisch says, “If less neurogenesis equals less stress buffering, we can’t say that more neurogenesis equals more stress buffering.” Nonetheless, Eisch hopes that the new data could eventually help to explain why some people and animals are vulnerable to stress, while others are resilient. And at the very least, it’s a step forward in terms of resolving some of the frustrating discrepancies in the field.

For more on this topic: Snyder has been describing his work on his own blog Functional Neurogenesison his own blog Functional Neurogenesis and you can undoubtedly read about his experiments from the man himself.

Reference: Snyder, Soumier, Brewer, Pickel & Cameron. 2011. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature http://dx.doi.org/10.1038/nature10287