University of Toronto Researchers May Have Found The Reason Loneliness Leads To Depression

“The most terrible poverty is loneliness, and the feeling of being unloved.”
-Mother Teresa

At one time or another, everyone experiences moments of social isolation, when there is no one around and the world is confined to one’s own existence. In short bursts these moments of solitude can be therapeutic and may lead to moments of emotional regeneration or creativity. Yet when loneliness becomes chronic, the effects may be deleterious to one’s emotional health.
Humans have a fundamental desire to be needed. The absence of this can lead to a variety of mental health conditions, including addiction, antisocial behaviour and depression. While from a purely psychological perspective, this consequence of isolation is well-defined, at the physiological level, the mechanisms have remained only vaguely understood.
But that may now change thanks to a team of researchers from the University of Toronto, led by Dr. Evelyn Lambe. The group published a study examining the effects on social isolation on the mouse brain. The results, published by Sargin et al. in the journal, eLife,  point to a specific mechanism and more importantly, a possible route for treatment.

The experimental procedure was relatively straightforward. Fifty-seven mice were kept either individually (29), or in small groups (28) for at least seven weeks. Some of the mice were tested to determine any anxiety and/or depressive behaviours. The brains of these and other mice housed under these conditions were examined to determine if there were any differences in physiological function.

The first noticeable change in socially isolated mice was an increased level of anxiety as well as propensity to eat more food. This in essence mimicked what is seen in humans when they are in similar states. The mice also appeared more likely to give up in the face of a challenge and to have less interest in seeking pleasure. This too mirrored the symptoms seen in humans  suffering from depression.

The researchers ventured into the brain to find out what might be happening at the molecular level. The group focused on an emotional and reward centre of the brain, known as the dorsal raphe nucleus and its key cells, 5-HT neurons.  If the suspicions were correct, the neurons in socially isolated mice would react differently than those from those living in groups.

As expected, the neurons in lonely mice were less excitable and did not respond to normal levels of stimulation. Upon further analysis, this change was due to an elongated resting period between neuron firings. This condition, known as increased afterhyperpolarization, not only offered perspective on the effect of social isolation, but also pointed to a particular suspect.

The state of afterhyperpolarization is partially controlled by a number of proteins known as small-conductance Ca2+-activated K+, or SK channels.  These proteins are found in various parts of the body including the brain. If the group’s hunch was correct, then blocking these proteins from working properly would reverse the effects of isolation.

Thankfully, there was a rapid means to perform this experiment as a chemical known as apamin had been shown to block these channels and restore normal firing. When the molecule was used in the experiments, sure enough, the difference between the isolated mice and the group-housed ones disappeared. The team then went even further to identify which specific SK channels were responsible. It turned out the subtype known as SK3 was uniquely involved in the process.

At this point, it was time for the ultimate test. Dr Sargin and colleagues attempted to restore normal behaviour in the socially isolated mice by administering apamin to the animals. In every case, when the chemical was used, the mice improved. The team had found – at least in mice – exactly how loneliness leads to depression.

For the authors, this discovery, while incredibly important, is just the first step. With the mechanism unveiled and a map to a possible treatment in hand, they can perform even more experiments targeting SK3 in the hopes of finding a possible therapeutic approach to depression. Should they be successful in this venture, they may be able to explore avenues for human treatment.

While this remains years in the future, the team can rest easy knowing they have finally unlocked a long-standing mystery. Though there is no cure, this information may offer those who suffer from social isolation an appreciation of what is happening at the molecular level. It may also engage them to find solutions as they now know the effects may be reversible.

Original research article:

Sargin D, Oliver DK, Lambe EK. Chronic social isolation reduces 5-HT neuronal activity via upregulated SK3 calcium-activated potassium channels. Elife. 2016 Nov 22;5. pii: e21416. doi: 10.7554/eLife.21416.