ReviewEffects of social isolation on glucocorticoid regulation in social mammals
Highlights
► Social isolation represents a survival threat to social species. ► Objective and perceived social isolation alter HPA regulation in social mammals. ► HPA responses to isolation differ among species and with age and duration. ► Chronic isolation is associated with a pro-inflammatory gene expression profile. ► Glucocorticoid resistance may explain higher morbidity in isolated individuals.
Introduction
All vertebrates possess a hypothalamic–pituitary–adrenocortical (HPA) axis that mediates physiological and behavioral change and adaptation through its regulation of corticosteroid production and release (Denver, 2009, Schulkin, 2011). Indeed, the emergence of the vertebrate lineage some 500 million years ago coincided with, and may have been impelled by, the evolution of steroid-specific receptors (e.g., mineralocorticoid, glucocorticoid) from an ancestral nuclear receptor gene already evident in arthropods (Baker et al., 2007, Laudet et al., 1992). The regulation and function of the HPA axis and glucocorticoids (GCs) have been well conserved across vertebrate species (Schulkin, 2011). Glucocorticoids influence a wide range of physiological functions that include glucose regulation, metabolism, inflammatory control, as well as cardiovascular, reproductive, and neuronal effects. Some of these are relatively quick-acting non-genomic effects (Borski, 2000), but most are mediated by slower-acting genomic effects. Up to 20% of the expressed genome in a tissue is susceptible to the direct and indirect influences of GCs, estrogens, and androgens (Chrousos, 2010). Thus, any stimulus that affects HPA function has the potential to exert wide-ranging short-term and long-term effects on much of vertebrate physiology.
The HPA axis is exquisitely sensitive to internal and external environmental perturbations, as would be expected from a system that plays a crucial role in modifying physiology and behavior to subserve energy, immune, and survival needs. In social species, the HPA contributes to physiological and behavioral mechanisms that support a superorganismal (i.e., group) structure that enhances survival of children and grandchildren (Cacioppo and Hawkley, 2009, Cameron et al., 2009, Silk et al., 2009, Waynforth, 2011). Thus, in social species, social isolation is a potent stressor that often leads to increases in cortisol (Cacioppo et al., 2011). In contrast, in solitary species such as the mouse lemur, substantial increases in cortisol are elicited when typically solitary animals are socially housed (Perret and Predine, 1984). A similar difference has been shown in the increased cortical response to isolation in the highly social prairie vole pup versus the solitary montane vole pup (Shapiro and Insel, 1990). The regulation of HPA activity by the presence of some aspects of sociality has been reviewed previously (e.g., Blanchard et al., 2001, DeVries et al., 2003, Hennessy et al., 2009), but to date, research on the regulation of HPA activity in the absence of social others has not undergone a similar review. Here, we review the effects of social isolation on the functioning of the HPA axis in social species, and on glucocorticoid physiology in social mammals in particular. We include the effects on HPA functioning of perceived social isolation in humans. Perceived isolation is not synonymous with objective isolation. People can lead relatively solitary lives and still feel connected to others, and conversely, people can lead ostensibly rich social lives but feel disconnected and lonely nevertheless. Loneliness is defined as a distressing feeling that accompanies the perception that one's social needs are not being met by the quantity or especially the quality of one's social relationships (Peplau and Perlman, 1982). Its effects on HPA functioning are relevant in light of the fact that perceived isolation is associated with increased morbidity and mortality, even after adjusting for objective isolation (Hawkley and Cacioppo, 2010, Luo et al., 2012).
Section snippets
The threat of social isolation
How does social isolation pose a threat to social mammals? Social species are characterized by structured group living in which the survival of individuals is dependent on the safety and security afforded by a social group. Living on the social perimeter is dangerous. Without the ongoing nurturance and protection of parents, offspring do not survive to reproduce. Without the benefit of shared defense and protection afforded by a protective group, individual members are vulnerable to
HPA physiology
The HPA axis controls circulating GC levels through a cascade that starts with hypothalamic secretion of corticotropin-releasing hormone (CRH) from the paraventricular nucleus into the hypophyseal portal circulatory system, which stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH). Circulating ACTH, in turn, is the key regulator of adrenal secretion of GC hormones (cortisol in humans and most other mammals; corticosterone in rodents). CRH is secreted in a circadian,
Non‐human social mammals
The direct effects of social isolation on basal activity of the HPA axis have been examined in a number of species (Table 1). In non-primate mammals, social isolation is associated with higher basal levels of plasma ACTH and/or corticosterone in some studies (Chida et al., 2005, Dronjak et al., 2004, Ferland and Schrader, 2011, Kanitz et al., 2004, Perelló et al., 2006, Pournajafi-Nazarloo et al., 2011, Ruscio et al., 2007, Weintraub et al., 2010), lower levels in other studies (Djordjevic et
HPA regulation
Effective glucocorticoid feedback inhibition is critical to HPA regulation, and social isolation has been shown to influence these processes, as well. In rats, a 3-week period of isolation in early life followed by 2 weeks of group-rearing resulted in exaggerated recovery of corticosterone levels to below basal levels two hours after an acute restraint stress, indicating heightened negative feedback of the HPA axis in response to acute stress (Lukkes et al., 2009). In contrast, rats chronically
HPA regulation
To date, only one study of loneliness differences in sensitivity to glucocorticoid feedback has been reported. This recent research has employed a novel functional measure of glucocorticoid insensitivity that is based on the logic that exposure to glucocorticoids alters the distribution of leukocytes in circulation. Namely, cortisol stimulates an increase in circulating concentrations of neutrophils and a decrease in concentrations of lymphocytes and monocytes such that the greater the exposure
Non‐human social mammals
The exaggerated effect of acute stress on HPA activity in socially isolated animals has implications for processes regulated by glucocorticoids. For instance, corticosterone responses to acute stress in socially isolated animals affect neuronal activity. Whereas running induced hippocampal neurogenesis in group housed rats, it suppressed hippocampal neurogenesis in individually housed rats, an effect that was attributable to larger corticosterone responses to the additional stress of handling
Non‐human social mammals
The primary upstream determinant of circulating levels of glucocorticoids involves the regulation of the expression of genes that control the synthesis of hypothalamic CRH, pituitary ACTH, adrenal corticosterone (cortisol in humans), and the corticoid receptors. These genes are within reach of the influence of social isolation. In the study of prairie voles mentioned above (Pournajafi-Nazarloo et al., 2011), a single 1-h period of isolation or 4 weeks of daily 1-h periods of isolation resulted
Humans
As was noted above, the function of GCs has been well conserved in social mammals. For instance, in non-human animals, prenatal exposure to glucocorticoids reduces birthweight and causes permanent hypertension, hyperglycemia, and increased HPA activity; in humans, low birthweight infants have higher levels of glucocorticoids and this increase in HPA activity precedes the development of high blood pressure, insulin resistance, glucose intolerance, and hyperlipidemia (Seckl and Meaney, 2004).
Discussion and implications for future research
The responsivity of the HPA axis to the perturbation of social isolation is apparent across a range of social mammals. Social isolation represents a survival threat to social species, and physiology has been sculpted to mount an appropriate response. Increased levels of glucocorticoids mobilize energy and dampen inflammation in a presumably adaptive fashion. These effects are particularly evident in response to acute periods of social isolation and to additional acute stress in animals already
Acknowledgments
This research was supported by the National Institute on Aging (R01‐AG036433 to L.C. Hawkley, and R01‐AG033590 and R01‐AG034052 to J. T. Cacioppo), the National Cancer Institute (R01‐CA116778 to S. W. Cole), and the National Institutes of Health (P51 RR000169 to the California National Primate Research Center [J.P. Capitanio]).
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