Edited by: Bertrand Kaeffer, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), France
Reviewed by: Gopal Pandi, Madurai Kamaraj University, India; Murray John Cairns, The University of Newcastle, Australia
†Present address: Ali Jawaid, EMBL-Nencki BRAINCITY Center of Excellence for Neural Plasticity and Brain Disorders, Nencki Institute of Experimental Biology, Warsaw, Poland
This article was submitted to RNA, a section of the journal Frontiers in Genetics
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Prolonged periods of social isolation can have detrimental effects on the physiology and behavior of exposed individuals in humans and animal models. This involves complex molecular mechanisms across tissues in the body which remain partly identified. This review discusses the biology of social isolation and describes the acute and lasting effects of prolonged periods of social isolation with a focus on the molecular events leading to behavioral alterations. We highlight the role of epigenetic mechanisms and non-coding RNA in the control of gene expression as a response to social isolation, and the consequences for behavior. Considering the use of strict quarantine during epidemics, like currently with COVID-19, we provide a cautionary tale on the indiscriminate implementation of such form of social isolation and its potential damaging and lasting effects in mental health.
Social behavior is a major life component of many organisms. Proper behavior in response to environmental conditions and signals is critical for development, reproduction, and survival (
This review provides a comprehensive overview of the effects of prolonged periods of social isolation on the body and describes the known molecular events leading to behavioral alterations. We review the current evidence linking social isolation with changes in gene expression in the brain, and the effects on regulators of genome activity such as epigenetic modifiers, ncRNA and transcription factors. Direct functional evidence supporting the role of miRNAs and long ncRNAs (lncRNAs) as modulators of social behavior and their link to behavioral abnormalities observed during and after prolonged social isolation are discussed. Finally, we reflect on the effects that prolonged social isolation, such as observed during strict quarantine in epidemics, can have on mental health and discuss interventions that may help to ameliorate their burden.
In humans, chronic social isolation can have detrimental health effects (
Physiological and mental health effects of decreased social interactions in humans.
Effects of non-enforced loneliness and social isolation |
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Exposure | Age | Participants ( |
Effects of exposure | References |
Loneliness Social isolation Old age | 50+ Mean: 66.9 | 8,688 | -Social isolation was positively associated with blood pressure, C-reactive protein, and fibrinogen levels. |
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Social disconnectedness Perceived isolation Old age | 57–85 | 2910 | -The correlation between social disconnectedness and perceived isolation is only weak to moderate in strength ( |
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Social isolation Loneliness Old age | 65–84 | 4004 | -The mortality hazard ratio for feelings of loneliness was 1.30 [95% confidence interval (CI) 1.04–1.63] in men and 1.04 (95% CI 0.90–1.24) in women. |
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Feelings of loneliness (FoL) Living alone Old age | Elderly people mean age: 76.5 | 3620 community-dwelling elderly people | -Living alone and FoL were both independent predictors of death after 22 years of follow-up (hazard ratio, 1.14; 95% CI, 1.05–1.23; |
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Feelings of loneliness Social isolation | Older persons | 2173 non-demented community-living older persons | -Factors positively associated with developing dementia: living alone ( |
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Loneliness Old age | Older people Average age: 79.67 | 985 persons without dementia ∼25% male | -The level of loneliness at baseline was associated with the rate of motor decline (Estimate, −0.016; |
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Social isolation Loneliness Old age | Older adults | 11,825 | -Loneliness and social isolation were not highly correlated with one another ( |
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Social isolation Loneliness | Mean age at baseline: 65.6 years | 6034 | -Baseline isolation was associated with decreases in all cognitive function measures at follow-up (β = −0.05 to −0.03, |
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Social isolation Loneliness Old age | Aged 50–81 years (mean 66.01) | 267 community-based men ( |
-Total 24 h activity counts were lower in isolated compared with non-isolated respondents (β = −0.130, |
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Transition to living alone, Old age | 65+ | 4587 | -Living consistently alone did confer increased odds for caseness. |
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Solitude | Mean age: 21 | 44 female college students | -Cortisol levels were significantly higher when individuals were alone. |
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30 days isolation | (Age mean: 36.3 ± 7.2) (Age mean: 31.8 ± 8.7) | 16 isolated participants 17 non-isolated | 30 days of isolation do not have a significant impact on brain activity, neurotrophic factors, cognition, or mood, even though stress levels were significantly increased during isolation. | |
Quarantine | 64% were 26–45 years of age | 129 quarantined persons | -Symptoms of post-traumatic stress disorder (PTSD) and depression were observed in 28.9% and 31.2% of responders. (median duration of quarantine: 10 days). |
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Stress related to epidemic | Mean age: ∼39 | Randomly selected employees ( |
-About 10% of the respondents had experienced high levels of post-traumatic stress (PTS) symptoms since the SARS outbreak. |
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SARS quarantine | Mean age: 49 | 1057 | -Self-reported compliance with all required quarantine measures was low (15.8 ± 2.3%), although significantly higher when the rationale for quarantine was understood ( |
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9 days SARS quarantine | Mean age: 39 | 338 hospital staff | -Quarantine was detected as a relevant factor leading to acute stress disorder (5%) |
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2 weeks after contact with MERS patients | Mean age: 44 | 1656 | -During the isolation period, 7.6% of participants had anxiety symptoms, 16.6% had feelings of anger. |
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SARS quarantine | Mean age: 39 | 903 | -Most residents of the first officially recognized site of community outbreak were affected by stigma. |
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Hospital staff SARS quarantine | Mean age: ∼40 | 549 hospital employees, 104 quarantined | -Increased odds of having depression 3 years later: being single, having been quarantined, exposure to other traumatic events before SARS, perceived SARS-related risk level. -Decreased odds: altruistic acceptance of risk. | |
SARS quarantine | Mean age: 44 | 333 nurses | -Lower levels of avoidance behavior, emotional exhaustion, anger, and burnout: high levels of vigor, organizational support, trust in equipment, low levels of contact with SARS patients, time spent in quarantine. | |
10 days SARS quarantine | ND∗ | 99 Health care workers 19 patients with SARS | -Patients with SARS reported fear, loneliness, boredom, anger, and worries about family members, anxiety, insomnia, uncertainty, and stigmatization. |
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City isolation because of SARS | ND∗ | 187 | -26.2% of participants had psychological disorders. |
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Ebola quarantine | ND∗ | 432 (focus group) and 30 (interviews) | -High level of social insecurity. |
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10 days SARS quarantine | Mean age: 43 | 10 health-care workers | Experienced stigma, fear, frustration. | |
Equine influenza quarantine | Mean age: ∼40 | 2760 horse owners | 34% reported high psychological distress (12% in the general population). | |
H1N1 quarantine | Mean age: 20 | 419 undergraduates | No significant differences between quarantined and non-quarantined group. | |
MERS quarantine | ND* | 6231 | 1221 people placed in quarantine experienced psychological and emotional difficulties, 350 required continuing services. |
In rodents, social isolation has multiple effects on physiology and behavior (summarized in
Effects of social isolation (SI) in animal models.
Exposure | Organism | Duration of SI | Effects of exposure | References |
Social isolation, running, adjusting corticosterone levels | Sprague-Dawley rats:adult, male | 12 days | High corticosterone levels in response to stress after social isolation cause running to decrease neurogenesis. | |
Social isolation Antidepressants (fluoxetine, desipramine) Enriched environment | Swiss mice, adult, male/female | 1 week | -Decreased neurogenesis in the olfactory bulb and ventral hippocampus, reduced norepinephrine in OB, and decreased NE and serotonin in the dorsal hippocampus. -Many effects can be prevented by fluoxetine and desipramine. | |
Social environments | Male Sprague-Dawley rats (young) | 4 or 8 weeks | -Decreased newborn neurons in the dentate gyrus and reduced long-term potentiation in the hippocampus. | |
Social isolation | Male Lister Hooded rats; 28 days old | 8 weeks | -Volume loss of medial prefrontal cortex, but no loss in neuron number- > loss of volume of the neuropil. | |
Social isolation | Mice: male, 9 weeks old | 4 weeks | -Alteration of neuroplasticity related genes. | |
Exposure to chronic stress (social deprivation) | Mice: male, 3-month-old (C57BL/6) | 3 weeks | -Increased HPA axis reactivity and reduced BDNF levels. | |
Chronic social isolation stress (CSIS) Acute stress | Rats | 21 days of chronic social isolation | Changes in redox-status associated with decreased Hsp70i protein expression enabled NF-jB translocation into the nucleus, causing increased cytosolic nNOS and iNOS protein expression- > oxidative stress. | |
Social isolation | Rats | 30 days | The decrease in neuroactive steroids could be due to a decrease in activity of the HPA axis or the peripheral benzodiazepine receptor response. | |
Social isolation | Prairie voles, female/male, adult (2 months old) | 4 weeks | Reduction in hypothalamic CRH-R2 and increase in hippocampal CRH-R2 expression | |
Loss of bonded partner, monogamous rodent | Prairie voles | 4 days separation from partner | Long-term intracerebroventricular infusion of a non-selective corticotropin-releasing factor (CRF) receptor antagonist. | |
Chronic social isolation | Male Wistar rats | 21 days | Suppressed proplastic response and promoted proapoptotic signaling in prefrontal cortex, mediated by unbalance in glucocorticoid receptor and NFkB Transcription factors. | |
Social isolation Intrahippocampal interleukin-1 receptor antagonist | Adult male Sprague-Dawley rats | 6 h after contextual fear conditioning | Hippocampal-dependent memory impairments induced by elevated levels of brain IL-1 could occur via an IL-1 -induced downregulation in hippocampal BDNF. | |
Social isolation | Sprague-Dawley rats, 2 months old, male | 8 weeks | Reduction on BDNF protein concentrations in the hippocampus. | |
Social isolation, oxytocin administration | Prairie voles: female, adult (60–90 days old) | 4 weeks | Oxytocin can prevent effects of social isolation. | |
Social isolation in experiment 1 | Prairie voles: female/male, adult (60–90 days old) | 4 weeks | Elevated plasma oxytocin and oxytocin immunoreactive cell density in females. | |
Social isolation | Male C57BL/6 mice | 3 months | Changes in methylation in the midbrain | |
Individual housing | Male Wistar rats | 12 weeks | Sympathetic nervous system: immunocompetent tissues are depleted of catecholamine, this leads to an impairment of immune response. | |
Social isolation | Male Wistar rats, 45 days old at start | 12 weeks | Increased Neuropeptide Y in caudate putamen, more explorative rats. | |
Social isolation stress | Mice | 2 weeks | -Upregulation of the neuropeptide tachykinin 2 (Tac2)/neurokinin B (NkB). -Nk3R antagonist prevented the effects of SI. | |
Social isolation Breast cancer | Mouse model of “triple-negative” breast cancer | 12 weeks | Increase in mammary tumor growth and metabolic gene expression. | |
Social isolation | Female C3 (1)/SV40 T-antigen mice | 9.5 weeks | Significantly larger mammary gland tumors burden and increased expression of key metabolic genes. | |
Social isolation during adolescence | Male Wistar rats | 3 weeks | -Social isolation in adulthood: reduced systolic arterial pressure and increased diastolic arterial pressure. -Most changes caused in adolescence can be reversed by later group housing, except for body weight and baroreflex sensitivity. | |
Social isolation | Prairie voles | 4 weeks | Beneficial effects of an enriched environment on depression- and anxiety-relevant behaviors. |
Prolonged social isolation also affects different aspects of physiology. It can impair neurogenesis in the olfactory bulb (OB), the ventral hippocampus (VH), and the dentate gyrus (DG), and lead to reduced volume of some of these structures and the prefrontal cortex (
Notably, social isolation can promote tumor progression in animal models (
Loneliness is a social state strongly associated with mortality that is influenced by genetic variation (
Conversely to the observation that loneliness is influenced by genetic makeup, social experiences can themselves alter gene transcription and have consequences for behavioral responses. In particular, social isolation can modulate gene expression across tissues in many species, from
In rodents, chronic social isolation stress can trigger widespread changes in the transcription of protein-coding and non-coding genes (
Social isolation in rodents can also affect the expression of non-coding RNAs like miRNAs (
Changes in miRNAs expression after social isolation can vary depending on sex (
The mechanisms linking social isolation with changes in gene expression likely involve different molecular cascades with one of the major consequences being perturbed activity of transcription factors (
Classical epigenetic mechanisms for the control of gene expression are also implicated in the effects of prolonged social isolation (
Non-coding RNAs such as miRNAs and lncRNAs are major regulators of gene expression across the animal kingdom (
Different miRNAs have been documented to modulate aggressive-, anxiety-, and depression-like behaviors as responses to prolonged social isolation. For example, miR-206 is responsible for the stress-induced aggressive behavior of socially isolated mice via direct targeting of
MiR-135 can modulate serotonin functions by targeting the serotonin transporter
The miR-379-410 cluster is the best-characterized group of miRNAs with a demonstrated role in fine-tuning social behavior in mammals (
While it is clear that miRNAs are transcriptionally dysregulated by social isolation and some of them directly modulate behaviors characteristic of chronically isolated animals, manipulating specific miRNAs
LncRNAs can also affect social behavior in mice through different mechanisms. The antisense lncRNA of synapsin II (AtLAS) is differentially expressed in the mPFC between dominant and subordinate mice (
Neuropeptides are major modulators of the behavioral effects observed during extended periods of social isolation across the animal kingdom. In
In the past centuries, the timely implementation of isolation and quarantine of human populations has shown to be an effective public health intervention to stop the spread of viruses, such as the Ebola virus, MERS-CoV, SARS-Cov, and more recently, SARS-CoV2, the causal agent of COVID-19 (
Various countries pursued different approaches to prevent and reduce the spread of the virus. The first and strictest type of quarantine was enforced in Wuhan, China, the origin of the coronavirus outbreak (
While isolation refers to the separation of infected people from those who are healthy, quarantine separates and restricts the movement of people who might be infected but are not yet symptomatic. Physical distancing reduces the frequency and closeness of social contact between people. Although quarantine has been successful in slowing down the spread of the virus, poor implementation can cause additional problems in the exposed people (
More than 50 years of research in animal models and humans have conclusively shown the detrimental effects of chronic stress on health, highlighting the necessity for more empathic interventions to protect or reduce the sequelae of confinement on mental health and well-being of the population. Simple yet effective strategies could be implemented to reduce social isolation and perceived loneliness among older people, which are a sector of the population at risk to experience the detrimental effects of social isolation (
Prolonged social isolation has detrimental effects on humans and animals. In humans, chronic social isolation perturbs physical and mental health and we are just starting to uncover the molecular mechanisms driving behavioral effects associated with social withdrawal. Evidence derived from different animal models strongly suggests that social isolation can induce transcriptional changes in different brain areas fundamental for memory and cognition and also relevant for the modulation of mood and even addictive behaviors. Some of the affected genes are major transcriptional regulators such as the AP-1 transcription factors and CREB, both mediators of transcriptional responses due to neuronal activation in mammals (
Furthermore, although available evidence suggests that GR signaling is implicated in the response to acute social isolation in mice (
From a public health perspective, major attention should be paid to the physiological and psychological consequences of social withdrawal on the general population. Given that loneliness in humans has been documented to be linked to all-cause increased mortality and with an effect on mortality comparable to smoking, it is fundamental to gain better knowledge of the molecular mechanisms that promote the behavioral and physiological effects of isolation with the long-term goal to develop new pharmacological and non-pharmacological interventions. While in most cases, social isolation has detrimental effects on the exposed individual in humans and animals, it is possible that some individuals show some resilience. It may be linked to better coping strategies, a isolation habituated state due to a lifestyle based on loneliness, or a natural lower sensitivity to such social stress.
Finally, current actions to mitigate the pandemic of COVID-19 is a call to revisit and implement the best possible public health interventions to protect people against infectious diseases without affecting their physical and mental health. The imposed regulations by governments around the world may have consequences that people do not anticipate and may reverberate for years and possibly decades. Given that the emergence and spread of viruses that infect humans are and will be a constant thread for humankind, a more thoughtful strategy is needed to reduce social interaction while taking into consideration the extraordinary impact that social interactions can have in life.
AJ, ZL, and VS wrote a draft of the review, and RGA-M and IMM finished it.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.