What Lonely Humans Can Learn From Lonely Mice

Elizabeth G. Dunn

Loneliness was once seen as a minor social woe — a misfortune affecting nursing home patients and extreme introverts — but lately, researchers have begun to view it as something of a public health crisis. Loneliness seems to exacerbate dementia, diabetes, high blood pressure, even cancer. It’s as bad for one’s health as a pack-a-day smoking habit. Meanwhile, at least one in four Americans today report that they don’t feel close to people, and those numbers appear to be worsening.

Despite a growing body of research into the problem, we’re still fumbling for solutions. Treatments fall into four main categories: helping lonely people improve their social skills, increasing their opportunities for social contact, enhancing their social support, and using cognitive behavioral therapy (CBT) to change the way they think about their own self-worth. The most comprehensive analysis of loneliness treatments to date concluded that while CBT showed some promise, none of the methods were all that effective.

But what if a pill could provide the answer? A rising-star neuroscientist named Moriel Zelikowsky has been studying the brains of lonely mice at Caltech and published a paper in the journal Cell earlier this year showing how a little-known drug might help them. Medium spoke to Zelikowsky about her research and what it could mean for the future of loneliness.

Talk about what led you to start looking into loneliness.

Moriel Zelikowsky: I have a PhD in behavioral neuroscience, and one thing in social neuroscience that’s always been really interesting to me, and that I thought was timely, was this question of social isolation and how it affects the brain. Today, we’re seeing a huge increase in feelings of loneliness despite the fact that we’re more connected than ever before. So I spent a lot of time studying the effects of social isolation on behavior in mice and found that a lot of things are altered when animals are isolated. Then I looked at the neurobiology underlying it all.

When you talk about social isolation, does that only mean being physically isolated from others? Or can it apply to feelings of social isolation?

When you’re working with mice, there’s no way you can put them in a group together and then find the ones who feel lonely. The best thing you can do is create physical isolation. But the experiment is definitely meant to model feelings of loneliness, not necessarily just being physically lonely. I would generalize this to feelings of loneliness in the human population, but taken with a grain of salt, like you do with any animal research.

What did you find was happening in the brain when a mouse became socially isolated?

I looked at one particular gene, called tachykinin 2 (Tac2), which produces a neuropeptide called neurokinin B. I was interested in seeing if this gene and neuropeptide played a role in social isolation.

The first surprising finding was that in a mouse that was isolated, versus one socializing normally with its friends, the gene showed a huge [increase in activity] everywhere in the brain, and the neuropeptide was also increased. I marked the gene with a little fluorescent neon green tag. The first thing I noticed as soon as I looked at the brain of a socially isolated mouse was that the whole thing was neon green compared to an animal that was socialized. It was a very large, very obvious increase in the expression of the Tac2 gene.

That’s interesting for a number of reasons. One is that modern research on emotion states and mental illness tends to focus on neurotransmitters: big systems like serotonin or dopamine or norepinephrine that have huge circulating levels in the brain and are expressed in many, many cells across the whole brain. Perhaps less attention has been given to neuropeptides—these molecules that are expressed more discreetly in the brain. I think it’s interesting that this one neuropeptide was heavily upregulated, because it suggests that one way we can approach things like social isolation or other mental health issues is by looking at systems that are more discrete and in limited brain regions.

Socially isolated mice given a certain drug were less aggressive when reintroduced to other mice, which made it easier for them to have social interactions.

The other interesting thing, after doing a number of experiments, was looking at how the gene and neuropeptide seemed to control different responses to social isolation depending on where in the brain you looked. So, for instance, we found that social isolation caused a persistent fear response, and that seemed to be stimulated by Tac2 in the fear part of the brain. Normally, when a mouse sees something that scares him, when the fear stimulus moves away, his fear levels start coming down, and the mouse is no longer afraid. But if the mouse has been socially isolated, his response to a fear stimulus persists well beyond the period when the stimulus is gone. Other parts of the brain, like the hypothalamus, seemed to control the social effects of isolation; for instance, the increase in aggression we see when animals are isolated. Isolated animals are much more aggressive than a non-isolated animal. The idea is you have this increase in Tac2 in many brain regions, and each brain region selectively controls one behavior versus another depending on where in the brain you’re looking. It explains the state you’re in when you’re isolated for a long time—your whole brain really changes.

And then you also looked at a drug treatment.

We looked at a drug called osanetant that has already been shown to be well-tolerated in humans. I found that at a low dosage, I was able to get rid of a lot of the effects of the social isolation in mice.

How does it work?

It’s what’s called a receptor antagonist and blocks Tac2-specific Nk3 receptors. We gave it to mice that had been socially isolated. Normally, when we reintroduced them to other mice, they’d be really aggressive, which would keep the loneliness cycle going. But this drug stopped them from fighting the animals they encountered. It helped buffer against enhanced aggression and helped them have some social interactions.

Based on that animal study, how hopeful are you that it could have the same effect in humans?

I’m pretty hopeful. It’s something one would need to test rigorously, of course, but the idea that it would translate in humans is totally natural and not far-fetched. You have to remember that almost every single drug that’s used right now in humans for anxiety or depression was tested in rodents first.

How soon could the drug be in use for humans?

I have no idea. A lot of it depends on who would want to take up the further testing.

How does it compare to other loneliness treatments already out there?

I don’t think anyone is getting medication for loneliness. People who are lonely are often also depressed and may be taking medication for treating depression. I think people are still grappling with seeing this as its own social disorder. In terms of behavioral changes, what we’ve seen from our work is that just having one friend helps mitigate a lot of the effects of loneliness. You don’t need to have a million friends—just one. You just need to have one animal in the cage with you, and you do a lot better.

What led you to become interested in loneliness to begin with?

I was interested in how stress affects violent behavior, because at the time — and obviously now, even just today, I’m in L.A. after this horrible shooting we just had — mass shootings had become a more common phenomenon. So I was interested in looking at things that could lead an individual to show an increase in violence. If you look back on a lot of these shooters, they’ve either had some kind of mental health disorder or they’ve been isolated for an extended period of time. I’m also interested in how PTSD, another form of stress, can create an increase of violence. I was coming at this from wondering how this inappropriate level of violence is produced, so we can better understand it and target this population that’s more susceptible to showing these maladaptive forms of violence.

Just having one friend helps mitigate a lot of the effects of loneliness. You don’t need to have a million friends — just one. You just need to have one animal in the cage with you, and you do a lot better.

Where is your research headed next?

I’m about to start my own lab at the University of Utah, focusing on age-related questions: Is there a critical period where isolation has more of an effect on mental health? Also some female-specific questions: How does it affect females compared to males? I just had a baby, so I’m kind of biased toward understanding women who feel isolated postpartum. No one’s looking at that.

Overall, do you see loneliness getting better or worse going forward?

I guess I see it getting worse, unfortunately. A lot of these social networking tools help people find other like-minded people, but the more we go down that rabbit hole, the less quality time people spend together. There are things we could do to change that, but it’s only now beginning to be on peoples’ radar. So there is hope in terms of being able to make real changes that will help people connect more and form more meaningful relationships.