CHICAGO — Loneliness can reprogram the brain in ways that push alcohol consumption, reports a new preclinical study led by Northwestern University and the Salk Institute for Biological Studies. The scientists identified, for the first time, a brain mechanism through which isolation escalates alcohol use in male mice but suppresses it in females.
Social isolation is rising worldwide and is now recognized as a major public health risk, with strong links to substance misuse. Yet scientists don't fully understand how feeling isolated rewires the brain in ways that increase vulnerability to alcohol abuse.
"This is the first study to identify a specific brain circuit that explains how social isolation can drive increased alcohol use in males, marking a major advance for the field," said study first author Reesha Patel , assistant professor of general psychiatry and neuroscience at Northwestern University Feinberg School of Medicine.
"These findings provide a much clearer biological target for understanding and eventually treating alcohol misuse that arises from isolation, a problem that is becoming increasingly common."
The study will publish next Tuesday (Aug. 25) in Nature Neuroscience.
Sex differences
Adult male and female mice were first housed socially, then some were moved to single housing to model adult social isolation, while others remained socially housed as controls.
The mice were given daily one-hour opportunities to drink from a bottle of water or a bottle filled with a 15% alcohol solution. Their consumption and choices were tracked over roughly two weeks, during which male mice progressively increased their alcohol intake, while females reduced it.
With miniature microscopes, the scientists recorded activity in specific brain cells while the animals freely moved around and chose whether to drink alcohol. The cells they monitored form a brain pathway, or circuit, connecting the basolateral amygdala, which processes emotional and stress signals, to the medial prefrontal cortex, which regulates decision-making.
"Our work shows that a defined pathway becomes overactive during isolation and directly increases drinking, and that males and females rely on different neural strategies when they're lonely," Patel said. "This may help explain long-standing sex differences in neuropsychiatric disorders."
Patel said she cannot say definitively why isolation increased alcohol consumption in male mice but reduced it in females. But she noted that the sex differences observed in the study mirror patterns reported in some human research .
Turning the circuit on and off
The team then tested whether this brain pathway merely reflected drinking or caused it. Using optogenetics, brief pulses of light that turn brain circuits on or off, they artificially activated the circuit in non-isolated male mice. This caused their brains to respond to alcohol as if they had been socially isolated.
Conversely, when the same circuit was silenced in isolated male mice, alcohol consumption decreased.
Next steps
The scientists say they now want to understand what keeps this circuit overactive during social isolation and how downstream brain regions, including the medial prefrontal cortex, contribute to the effect. They also plan to explore why males and females respond so differently to isolation and whether hormones or deeper circuit-level differences play a role. Another important step is determining how these findings translate to humans.
The study is titled, "Social isolation recruits amygdala–medial prefrontal cortex projections to escalate alcohol drinking in male mice." It was supported by the National Institutes of Health, including the National Institute on Alcohol Abuse and Alcoholism (AA029180), the National Institute on Drug Abuse (K99 DA055111), the National Institute of Mental Health (K00 MH132569, R01 MH115920 and R37 MH102441), the National Institute of General Medical Sciences (K12 GM068524) and the National Center for Complementary and Integrative Health (DP1 AT009925), as well as the Howard Hughes Medical Institute, the Kavli Foundation, the Dolby Family Fund and the Salk Institute for Biological Studies.
