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 dealing with the stress of isolation. In humans, perceived isolation is a painful stimulus that has been posited to be adaptive (Cacioppo & Hawkley, 2009
) because it motivates the formation and nurture of social connections, connections that help regulate physiology and ensure survival. However, when the need for social connections is not satisfied and the pain of isolation persists, HPA dysregulation is more likely to ensue. In human and non-human animals, chronic isolation alters HPA functioning and regulation in ways that are less easily interpreted as adaptive. Instead, chronic isolation has been associated with changes in gene expression and an increased likelihood of glucocorticoid resistance, outcomes that heighten risk for inflammatory processes, reduced immune responses, and disease.
Reduced immune responses and impaired wound healing may seem maladaptive given that an isolated animal is more vulnerable to attack from conspecifics or predators. Evolution should arguably have favored isolation-induced immune enhancement. Such an argument was forwarded by Cole et al. (2011)
, where perceived social isolation, a circumstance that would be expected to increase risk of bacterial infection through its association with increased hostility and social conflict, was associated with a gene transcription profile that favored innate antibacterial and T-helper 2 adaptive immune responses over antiviral and T-helper 1 immune responses. In contrast, for socially connected individuals in socially affine conditions, an environment that would be expected to increase risk of viral infection, the transcriptional profile favored innate antiviral over antibacterial immune responses.
The principle of shifting the immune response toward anticipated bacterial threats may hold, but additional factors superimposed on social isolation may take precedence and determine the observed immune response. Specifically, data indicate that impairment in the early inflammatory response, during which infection is controlled, is attributable to acute or chronic stress, not social isolation per se, in both human and animal models of wound healing (DeVries et al., 2007; Vileikyte, 2007
). For instance, isolation alone was insufficient to alter wound healing rates in hamsters (Detillion et al., 2004
). Only isolated animals subjected to restraint stress exhibited impaired wound healing relative to isolated-no stress and paired-stress or paired no-stress animals. In humans, a meta-analytic review of 22 studies concluded that stress (operationalized as stress appraisals, life events, chronic stress, anxiety, depressive symptoms) was significantly associated with impaired wound healing (Walburn et al., 2009
). Notably, the two studies that included a measure of perceived social isolation or loneliness failed to find an association with wound healing and found, instead, that perceived stress (Ebrecht et al., 2004
) or dysphoria (Bosch et al., 2007
) were associated with impaired wound healing in these same subjects.
Cortisol appears responsible for dampening the inflammatory response that characterizes early stages of wound healing (Padgett, Marucha, & Sheridan, 1998
). In the hamster study by Detillion et al. (2004)
, isolated animals exhibited a significantly higher cortisol response to restraint stress than pair-housed animals. This should not be surprising given that restraint stress (i.e., physical immobilization) is a very significant condition for any animal, much less an already vulnerable socially isolated animal. Thus, even if social isolation inclines the immune system toward an antibacterial response, the addition of a stress like immobilization could arguably be expected to divert the vulnerable isolated animal’s energy (including glucocorticoids) toward heightened vigilance, trying to find the group, etc., rather than to wound healing. Additional stress may be the proverbial straw that breaks the socially isolated animal’s immune system, at least in early stages of the inflammatory response.
Isolation-induced HPA dysregulation may manifest differently at different ages, a phenomenon that can perhaps be best understood in evolutionary terms. Social isolation may represent a different survival challenge to an infant or pre-weaning animal than it does to a sexually mature or aged animal. To a human infant or pre-weaning animal, survival requires not only a reliable caregiver but also protection against the adverse consequences of elevated glucocorticoids on the developing central nervous system (Sapolsky & Meaney, 1986
). This may explain the hyporesponsiveness of pre-weaning animals and human infants to stress (Gunnar & Donzella, 2001; Sapolsky & Meaney, 1986
), a phenomenon that has been postulated to buffer the HPA axis and ensure its healthy development. Good mothering, defined in rats as frequent and regular licking and grooming, effectively protects the infant brain by maintaining low glucocorticoid levels in the infant (Meaney, 2001
), illustrating the importance of the quality of the parental connection for the survival and neural protection of offspring.
Post-weaning and sexually mature animals, on the other hand, are confronted with survival challenges that emphasize heightened HPA sensitivity to environmental input as this may determine their reproductive strategies (Ruscio et al., 2007
). Physiological trade-offs between the reproductive and immune systems are common (Martin, Weil, & Nelson, 2008), and sexual maturity would be expected to differentially influence the primacy of immunity versus reproduction. In broad evolutionary terms, the threat to survival posed by social isolation should, in a post-weaning sexually immature animal, preferentially shift energy to immune defenses to preserve its own survival to reproductive age. In contrast, evolutionary pressures would be expected to have primed an isolated sexually mature animal to preferentially shift energy to accelerated and intensified reproductive efforts before it’s too late to perpetuate one’s genes. These scenarios are supported by our argument that the pain of social isolation motivates individuals to return to their social group where they will find safety and enhanced likelihood of survival, and where reproductive activity is most likely to occur. Importantly, increased glucocorticoid output that accompanies social isolation does not necessarily inhibit reproduction. Recent research has shown that although stress-related cytokines such as TNF-alpha activate the HPA and inhibit the HPG (hypothalamic pituitary gonadal) axis, glucocorticoids protect activity of the HPG. Specifically, GCs inhibit COX-2 (cyclooxygenase-2) in the brain, thus inhibiting PG synthesis and protecting the secretion of luteinizing hormone, a key reproductive hormone released by the pituitary (Matsuwaki et al., 2006
). In the context of social isolation, increased glucocorticoid output provides the energy to accomplish immune and reproductive goals.
Cortisol is in itself incapable of adverse or advantageous effects; only binding to the receptor enables its functional consequences. This places a premium on understanding regulation of the glucocorticoid receptor, and isolation-induced changes in gene expression in humans and non-human primates appear to be a promising avenue of future research. Additional research is needed to determine the extent to which social isolation acts directly on upstream HPA-related gene expression and indirectly through, for example, proinflammatory cytokines that influence glucocorticoid gene expression directly or indirectly through their activation of the NF-κB transcriptional pathway. Functional assessments to evaluate the extent to which changes in gene expression are reflected in protein production (e.g., GR’s) will help elucidate a possible mechanism for enhanced morbidity and mortality risk in isolated individuals. In this regard, GR subtypes could be quantified to evaluate the effect on glucocorticoid resistance of imbalances in the ratio of GRα to GRβ GRα is the active form responsible for initiating glucocorticoid effects, whereas inactive GRβ competes with GRα for the binding of glucocorticoid response element, thus inhibiting GR actions (Barnes & Adcock, 2009
Our review of the research linking social isolation and HPA functioning revealed some consistency within species and across some animal species. As is shown in , however, inconsistencies are also evident in the direction and nature of HPA effects within and across species. These inconsistencies have implications for drawing cross-species conclusions about the effects of social isolation, and are particularly problematic for understanding HPA-related physiological processes in humans. The animal and human data are incommensurate because, for example, animal studies of objective isolation have typically not been modeled on, or for comparability with, the subjective experience of isolation in humans. An animal model of human isolation must be taken more seriously if we want to advance our understanding of the mechanisms for the effects of objective and perceived isolation in humans. A model of isolation in animals that is conceptually equivalent to perceived isolation in humans is not sufficient, of course. Measurements (type, timing) have to be expanded to see whether and how the animal model is relevant for humans. For instance, research in humans has tended to find an association between loneliness and an increased cortisol response to awakening and/or a flatter diurnal slope, but research in animals has focused on basal glucocorticoid levels or stress responses. Do isolated animals exhibit an elevated cortisol awakening response? Does the cortisol awakening response represent anticipated demands of the environment as has been suggested by human research (Adam et al., 2006
)? Cortisol measurement in humans needs to be considered more carefully as well. Publications are littered with inconsistencies at least in part because researchers employ different cortisol parameters (morning levels, awakening response, evening levels, diurnal slope, area under the curve, plasma vs. saliva, etc.) or choose to report only those parameters that have significant associations with the predictor or outcome of interest. Careful selection and comprehensive reporting of cortisol parameters are important considerations to facilitate cross-species and cross-study comparisons.
Of course, to capitalize on an animal model, research in humans must be informed by animal findings and reciprocate in parallel fashion to ensure the integrity of the model. For instance, research in animals could identify behavioral phenotypes that distinguish between animals that could be construed as lonely or not, and, in parallel, research in humans could generate, as nearly as possible, an equivalent behavioral phenotype in humans that does not rely solely on explicit self-reports of isolation or loneliness. If the human behavioral phenotype of loneliness exhibits a similar pattern of correlations with outcomes as is exhibited with self-reported loneliness, this may permit greater comparability of findings across animal and human phenotypes.
Finally, the matchless advantage of an animal model of human isolation is the capacity to conduct invasive experimental studies that provide inroads into mechanisms for the effects of isolation on HPA activity and its diverse consequences in humans AND animals. One of the mechanistic questions of interest is the extent to which social isolation has a direct effect on pro- and anti-inflammatory gene expression, including expression of genes in the glucocorticoid receptor family, and an indirect effect on gene expression through the effects of social isolation on circulating glucocorticoids and other neuroendocrine and immune signals. Beyond gene expression, a mechanistic question of interest is how, when, and in which tissue(s) altered gene expression is translated into changes in functional proteins. HPA activity has the potential to exert wide-ranging short-term and long-term effects on much of vertebrate physiology. The potential health implications for humans are substantial. We challenge researchers to undertake both animal and human studies with heightened attention to the development of a unified model of social isolation, the integration of findings across species, and the specification of boundary conditions that account for differences among species.