What Loneliness Looks Like in the Brain

Consider three scenarios.  A kid joins a new high school and eats lunch by herself.  A recently separated man is alone for the New Year’s Eve countdown.  A prisoner becomes aggravated in a solitary confinement cell.  The common thread that runs through these disparate experiences is the universal feeling of loneliness.

Humans, as incredibly social beings, are driven to establish a social circle.  This innate behavior allows us to feel safer in a group, exert less time and energy obtaining food, and have healthier offspring with better chances of survival.  It is probably not surprising that social isolation and rejection – that feeling of being alone and an outsider – can trigger strong aversive emotions and, in extreme cases, physical and mental illness.

In the field of neuroscience, years of research have unveiled the neural circuits of reward, especially from warm social interactions.  That oh-so-comfy feeling you get when you’re around your favorite people is caused by the firing of dopaminergic neurons (neurons that release the neurotransmitter dopamine) in the brain’s reward headquarters: the ventral tegmental area (VTA). But what happens in the brain during social isolation?  Is the VTA still involved?  What neural circuitry urges us to spring up from the deep abyss of loneliness to a sheltered social rebound?  A 2016 study published in Cell took a dive into all of these questions with the help of another species that cannot live without their friends – mice.

Yes, some neurons can sense loneliness.

To study the neuroscience of loneliness, Matthews, Nieh, and their colleagues at MIT and Imperial College London used mice with a green fluorescent protein (GFP) label on their dopaminergic neurons – the ones involved in reward behavior.  Some mice were kept in a solitary isolation for 24 hours, while other mice were housed in groups.  The researchers used electrophysiology to record the activity of GFP-labeled dopaminergic neurons in two brain areas from these mice: (1) within the well-studied VTA that houses the majority of dopaminergic neurons, and (2) in a rather underexplored brain region known as the dorsal raphe nucleus (DRN), which contains only a few dopaminergic neurons.  In the VTA, there were no physiological differences between the dopaminergic neurons of lonely and social mice.  However, dopaminergic neurons in the DRN of lonely mice exhibited an increase in synaptic strength compared to social mice.  In other words, their synapses became stronger in response to loneliness.  The results of these experiments suggested that social isolation potentiated the DRN synapses, sensing a state of loneliness.

Social rebound after isolation increases neuronal activity.

In both rodents and humans, a short period of social isolation quickly motivates a lonely individual to find a way to get back into a social circle, a concept known as social rebound.  With that premise in mind, the researchers performed a follow-up experiment to examine the neural basis of social rebound A fluorescent calcium indicator was added to DRN neurons to serve as a reporter of neuronal activity: the more active the DRN neuron, the brighter the fluorescent signal.  To mimic social rebound in mice, a mouse that had been isolated was allowed to socialize with another mouse.  This interaction significantly increased the activity of DRN dopaminergic neurons compared to group-housed social mice.  These results suggest that DRN neurons not only sense loneliness during isolation but also fire away when the mouse bounces back into a social rebound.

Loneliness can be experimentally turned on and off.

So far, this study has shown that mouse social behavior (isolation and social rebound) can modulate the neuronal state in the DRN region.  If these DRN neurons are key to social motivation after loneliness, then simply increasing the neuronal activity of these neurons should prompt mice to be more social.  To test this hypothesis, the researchers used optogenetics to manipulate DRN dopaminergic neurons.  They added a protein called channelrhodopsin into DRN neurons and activated them by shining a blue light.  When DRN neurons were stimulated, mice tended to favor a social activity.  Conversely, upon inhibition of the DRN neurons, mice didn’t spring into a social rebound even after a lonely period; they chose to remain lonely.  The researchers, therefore, concluded that the dopaminergic neurons of the DRN are involved in motivating social behavior.

Deciphering a human’s social state is complicated.

How does this finding explain human behavior?  Well, it’s old news that we are a complicated species.  While one person might define social behavior as having a large number of acquaintances, others feel satisfied with having a few close friends.  Additionally, our perceived social rank in society (i.e. feeling superior versus subordinate) can change our sensitivity to isolation.  Therefore, loneliness in humans is a subjective experience and is not as easily deciphered as with experiments in rodents.  Although the complexity of human sociability is yet to be understood, this study highlights the importance of the DRN as a novel neural substrate for the biology of social interactions.

Social Rebound after Isolation Knowing Neurons


Images by Jooyeun Lee.



Matthews, Gillian A., et al. “Dorsal raphe dopamine neurons represent the experience of social isolation.” Cell 164.4 (2016): 617-631.


Anita met neuroscience during her undergraduate project, and it was love at first sight. While majoring in biotechnology at the B.M.S. College of Engineering, Bangalore, she had the opportunity to learn about biochemical subtyping as a method for biomarker discovery in neurodevelopmental disorders. She then pursued a Master’s in Biochemistry and Molecular Biology at USC. During her thesis project, her interest in translational neuroscience further evolved as she studied a kinase pathway (PI3K) highly implicated in autism. She currently belongs to the Neuroscience Graduate Program at USC and works on components of the blood-brain barrier and its integrity in animal models of neurological disorders. Outside the lab, Anita is very enthusiastic about educational and scientific storytelling! Some of her parallel interests include consumer psychology and behavior.

2 thoughts on “What Loneliness Looks Like in the Brain

  • October 19, 2016 at 9:27 am

    Early childhood trauma is highly correlated with permanent brain damage and all adult illnesses. My recollection is that neglect is the most damaging form of early childhood trauma.

  • October 20, 2016 at 10:27 am

    I think that human loneliness is not undecipherable. The way we subconsciously ‘decide’ to react to people is also shaped by experiences which can traumatize us or make us more sensible to our inner world, therefore explaining the need to disconnect from others that some may feel throughout their lives. Interesting read, hope to see some advancements in the near future.

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