- Email: [email protected]
Translational Implications of Oxytocin-Mediated Social Buffering Following Immobilization Stress in Female Prairie Voles
COMMENTARY
Translational Implications of Oxytocin-Mediated Social Buffering Following Immobilization Stress in Female Prairie Voles Hagit Cohen, Israel Liberzon, and Michael A. Matar
T
he supportive interpersonal social network resources available to individuals to provide help and assistance in times of need are one of the most studied aspects of resilience and recuperation in trauma research (1). Both the perceived availability and the objective presence of social support moderate the relationship between stress, stress response, and stress-induced psychopathology (1). A more recent report indicated that unstable family and social relationships impair coping and rehabilitation after trauma (2). Two meta-analysis studies of the predictors of posttraumatic stress disorder (PTSD) in adults likewise confirmed that the lack of social support is one of the most important risk factors for posttraumatic stress reactions (3,4). Social support protects against various adverse physical and mental disorders (e.g., cardiovascular reactivity, metabolic syndromes, and hypertension and depression and schizophrenia) (1). However, despite such accumulating evidence, the precise neurobiological mechanisms mediating the positive effects of social contact and social interactions on stress-responsive physiologic systems remain unknown. The neurohypophysial hormone oxytocin (OT) may offer an answer to this long-standing question because it is involved both in prosocial behavior and in the regulation of stress responses in mammals. In animals, OT has been implicated in a range of socially related behaviors, from sexual receptivity and grooming to territorial and protective maternal aggression. In humans, OT appears to have similarly variable effects, ranging from social receptiveness to suspiciousness and envy (5). After being synthesized in the magnocellular neurons of the paraventricular nucleus (PVN) and supraoptic nuclei OT is transported to the posterior lobe of the pituitary gland for storage and release. In addition to its peripheral actions, OT acts as a neurotransmitter in regions integrally involved in the stress response, especially the amygdala, hippocampus, and hypothalamus, via projections from the PVN (5–7). Accumulating evidence indicates that OT is involved in modulating stress responses, and its potential beneficial effects in secondary prevention—and possibly treatment—of PTSD have been investigated (5). However, the exact neurobiological mechanisms mediating effects of positive social contact and social interactions on stress-responsive physiologic systems are unknown. The study by Smith and Wang (8) in this issue of Biological Psychiatry offers exciting new evidence that points to OT levels in the PVN in mediating the effects of social support on the From the Ministry of Health (HC, MAM), Anxiety and Stress Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; and Department of Psychiatry (IL), University of Michigan Medical School, Ann Arbor, Michigan. Address correspondence to Hagit Cohen, Ph.D., Anxiety and Stress Research Unit, Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 4600, Beer-Sheva 84170 Israel; E-mail: [email protected]. Received Jun 9, 2014; accepted Jun 27, 2014.
0006-3223/$36.00 http://dx.doi.org/10.1016/j.biopsych.2014.06.017
behavioral, physiologic, and molecular responses to acute stress. The authors used prairie voles (Microtus ochrogaster), which constitute a useful model for understanding social influences on stress-related psychopathology and uncovering the underlying neurobiological mechanisms because they show specific social attachments, including monogamous male-female pair-bonds, biparental caregiving, and extended families. The authors report that when female voles stressed by immobilization were allowed to recover together with their male partners, OT levels in the PVN markedly increased, and anxiety-like behavior and corticosterone levels were buffered; this was in marked contrast to findings in stressed voles that recovered alone. Microinfusions of OT or of an OT receptor antagonist into the PVN further confirmed the direct involvement of endogenous PVN OT levels in mediating the social buffering of the stress response in the presence of the partner. The involvement of OT in stress responses has also been demonstrated in other species and brain areas (7,9). Our group provided support for an OT treatment as a promising strategy for preventing a PTSD-like behavior in male rats (10). A single dose of OT, microinfused into the hippocampus either 1 hour or 7 days after the exposure to stress, was associated with reduced PTSDlike behavior 1 week after OT administration (compared with placebo). Administration of OT into the hippocampus has been shown to increase the initial responsiveness of the hypothalamicpituitary-adrenal (HPA) axis under baseline conditions and after stress exposure. Administration of OT resulted in a more rapid return of the corticosterone stress response to baseline levels after the stressor has been terminated, implying increased OT-mediated suppression of the HPA axis (9,10). Considering this accumulating evidence, it seems plausible that the HPA axis stress response increases OT release both peripherally and centrally. This increase exerts two seemingly opposite effects at different levels of the HPA axis—rapid activation and suppression. Immediately after stress exposure, elevated OT levels increase corticosterone secretion from the adrenal cortex. Activation of the HPA axis modulates stress responses and enables the individual to adjust to the (altered) prevailing conditions and reestablish homeostasis. Finally, OT suppresses, directly or indirectly, the activation of the HPA axis terminating the neuroendocrine stress response (6,7,10). In addition to the bidirectional network association between OT and the HPA axis, elevated endogenous OT signaling in specific brain regions (as well as in the periphery) enhances prosocial behaviors and social interactions. These further “terminate” stress responses. Because prosocial behavior also facilitates OT signaling, it constitutes an additional feed-forward mechanism (Figure 1). This association may explain the long-term benefits of social contact and support, especially in light of the short half-life of OT (minutes only). It is possible that the oxytocinergic system, by modulating stressrelated responses via the redundancy and overlapping functionality of this system, provides additional regulatory mechanisms of the function of the HPA axis in social animals. From an evolutionary perspective, social contact, social interactions, and the BIOL PSYCHIATRY 2014;76:268–269 & 2014 Society of Biological Psychiatry
BIOL PSYCHIATRY 2014;76:268–269 269
Commentary
STRESS 1) Oxytocin Receptor blockage
Hypothalamic smulaon
2) Exogenous Oxytocin
CRH release
Pituitary smulaon
Oxytocin Female prairie vole
ACTH release
Adrenal Cortex smulaon -
Glucocorticoid Male prairie vole
Social contact Pro-social Behavior: Social contact and interacon Adapve stress responses – Stress buffering Promong Health
No / negave social contact and interacon Maladapve stress responses
Figure 1. Stress exposure encourages social approach behavior as a coping strategy by stimulating oxytocin (OT) release. Positive social contact and interactions are associated with OT release, which further promotes social-approach behaviors. This recurrent association between OT release and the subsequent expression of social behaviors may explain the long-term benefits of social contact and support, especially in light of the short half-life of OT. In addition, OT release after social exposure appears to enable a more effective hypothalamic-pituitary-adrenal axis response to stress, possibly acting both to trigger and to regulate the initial sharp peak in the activity of the hypothalamic-pituitary-adrenal axis and the subsequent feedback downregulation that terminates the neuroendocrine stress response. 1) Knockdown of OT production in the paraventricular nucleus of the hypothalamus in female voles recovering with their male partner predictably impairs behavior and increases corticosterone concentrations. 2) Microinfusions of OT into the paraventricular nucleus of female voles that recovered alone improve their behavioral response patterns and reduce circulating corticosterone concentrations. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone.
Stress-related (psycho)pathology
tendency to form social groups have a significant role in reducing predation risk. The oxytocinergic system appears to play a pivotal role in the “fight or flight” response to stress—including reducing predation risk by grouping, improving physiologic preparedness for rapid activation of the acute stress response, and efficiently terminating the stress response and expediting return to baseline function. In addition to contributing to understanding of how OT signaling mechanisms mediate the effects of social support on stress-response systems and to localizing these neurobiological mechanisms to the PVN, the work of Smith and Wang (8) raises interesting questions, as follows: Does the effectiveness of the biomolecular mechanism by which OT promotes affiliation and social support depend on the availability of OT in the central nervous system? With respect to clinical implication, are we ready to broaden the scope of clinical studies to examine the inclusion of intranasal OT in treatment regimens, especially in light of the variability in its effects related to gender, personality, and time? Do the study findings suggest that social/partner support and involvement in recovery from traumatic stress exposure should be studied both clinically and neurobiologically? Although clinical evidence indicates that acceptance and support from peers and family help in dealing with traumatic stress, and the lack of these has an aggravating effect, intrusive, hyperarousal, and avoidance/numbing symptoms of PTSD often hamper the ability of patients to perceive the intentions of others as supportive and to make use of the support adaptively. One aspect in which OT may be relevant is in improving the ability of the patients to perceive better the intentions of others as supportive and to make use of such support more adaptively. In light of the elevation in endogenous PVN OT levels induced by the mutual care in the vole pairs, another question arises: Should conjoint therapy have a more central place in trauma care, possibly in combination with intranasal OT? The prairie voles study does emphasize the focal role of the patients’ families and the need to support and reinforce this resource as an integral component of treatment from early on.
In conclusion, Smith and Wang (8) offer important and novel translational perspectives of interest for both clinicians and basic scientists, laying the groundwork for further study of where exactly OT signaling and social bonding fit into the clinical approach to PTSD and acute trauma care. The authors report no biomedical financial interests or potential conflicts of interest. 1. Cohen S, Wills TA (1985): Stress, social support, and the buffering hypothesis. Psychol Bull 98:310–357. 2. Karstoft KI, Armour C, Elklit A, Solomon Z (2013): Long-term trajectories of posttraumatic stress disorder in veterans: The role of social resources. J Clin Psychiatry 74:e1163–1168. 3. Brewin CR, Andrews B, Valentine JD (2000): Meta-analysis of risk factors for posttraumatic stress disorder in trauma-exposed adults. J Consult Clin Psychol 68:748–766. 4. Ozer EJ, Best SR, Lipsey TL, Weiss DS (2003): Predictors of posttraumatic stress disorder and symptoms in adults: A meta-analysis. Psychol Bull 129:52–73. 5. Olff M, Frijling JL, Kubzansky LD, Bradley B, Ellenbogen MA, Cardoso C, et al. (2013): The role of oxytocin in social bonding, stress regulation and mental health: An update on the moderating effects of context and interindividual differences. Psychoneuroendocrinology 38:1883–1894. 6. Liberzon I, Young EA (1997): Effects of stress and glucocorticoids on CNS oxytocin receptor binding. Psychoneuroendocrinology 22:411–422. 7. Neumann ID, Torner L, Wigger A (2000): Brain oxytocin: Differential inhibition of neuroendocrine stress responses and anxiety-related behaviour in virgin, pregnant and lactating rats. Neuroscience 95:567–575. 8. Smith AS, Wang Z (2014): Hypothalamic oxytocin mediates social buffering of the stress response. Biol Psychiatry 76:281–288. 9. Heinrichs M, Baumgartner T, Kirschbaum C, Ehlert U (2003): Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biol Psychiatry 54:1389–1398. 10. Cohen H, Kaplan Z, Kozlovsky N, Gidron Y, Matar MA, Zohar J (2010): Hippocampal microinfusion of oxytocin attenuates the behavioural response to stress by means of dynamic interplay with the glucocorticoid-catecholamine responses. J Neuroendocrinol 22: 889–904.
www.sobp.org/journal
Translational Implications of Oxytocin-Mediated Social Buffering Following Immobilization Stress in Female Prairie Voles Hagit Cohen, Israel Liberzon, and Michael A. Matar
T
he supportive interpersonal social network resources available to individuals to provide help and assistance in times of need are one of the most studied aspects of resilience and recuperation in trauma research (1). Both the perceived availability and the objective presence of social support moderate the relationship between stress, stress response, and stress-induced psychopathology (1). A more recent report indicated that unstable family and social relationships impair coping and rehabilitation after trauma (2). Two meta-analysis studies of the predictors of posttraumatic stress disorder (PTSD) in adults likewise confirmed that the lack of social support is one of the most important risk factors for posttraumatic stress reactions (3,4). Social support protects against various adverse physical and mental disorders (e.g., cardiovascular reactivity, metabolic syndromes, and hypertension and depression and schizophrenia) (1). However, despite such accumulating evidence, the precise neurobiological mechanisms mediating the positive effects of social contact and social interactions on stress-responsive physiologic systems remain unknown. The neurohypophysial hormone oxytocin (OT) may offer an answer to this long-standing question because it is involved both in prosocial behavior and in the regulation of stress responses in mammals. In animals, OT has been implicated in a range of socially related behaviors, from sexual receptivity and grooming to territorial and protective maternal aggression. In humans, OT appears to have similarly variable effects, ranging from social receptiveness to suspiciousness and envy (5). After being synthesized in the magnocellular neurons of the paraventricular nucleus (PVN) and supraoptic nuclei OT is transported to the posterior lobe of the pituitary gland for storage and release. In addition to its peripheral actions, OT acts as a neurotransmitter in regions integrally involved in the stress response, especially the amygdala, hippocampus, and hypothalamus, via projections from the PVN (5–7). Accumulating evidence indicates that OT is involved in modulating stress responses, and its potential beneficial effects in secondary prevention—and possibly treatment—of PTSD have been investigated (5). However, the exact neurobiological mechanisms mediating effects of positive social contact and social interactions on stress-responsive physiologic systems are unknown. The study by Smith and Wang (8) in this issue of Biological Psychiatry offers exciting new evidence that points to OT levels in the PVN in mediating the effects of social support on the From the Ministry of Health (HC, MAM), Anxiety and Stress Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; and Department of Psychiatry (IL), University of Michigan Medical School, Ann Arbor, Michigan. Address correspondence to Hagit Cohen, Ph.D., Anxiety and Stress Research Unit, Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 4600, Beer-Sheva 84170 Israel; E-mail: [email protected]. Received Jun 9, 2014; accepted Jun 27, 2014.
0006-3223/$36.00 http://dx.doi.org/10.1016/j.biopsych.2014.06.017
behavioral, physiologic, and molecular responses to acute stress. The authors used prairie voles (Microtus ochrogaster), which constitute a useful model for understanding social influences on stress-related psychopathology and uncovering the underlying neurobiological mechanisms because they show specific social attachments, including monogamous male-female pair-bonds, biparental caregiving, and extended families. The authors report that when female voles stressed by immobilization were allowed to recover together with their male partners, OT levels in the PVN markedly increased, and anxiety-like behavior and corticosterone levels were buffered; this was in marked contrast to findings in stressed voles that recovered alone. Microinfusions of OT or of an OT receptor antagonist into the PVN further confirmed the direct involvement of endogenous PVN OT levels in mediating the social buffering of the stress response in the presence of the partner. The involvement of OT in stress responses has also been demonstrated in other species and brain areas (7,9). Our group provided support for an OT treatment as a promising strategy for preventing a PTSD-like behavior in male rats (10). A single dose of OT, microinfused into the hippocampus either 1 hour or 7 days after the exposure to stress, was associated with reduced PTSDlike behavior 1 week after OT administration (compared with placebo). Administration of OT into the hippocampus has been shown to increase the initial responsiveness of the hypothalamicpituitary-adrenal (HPA) axis under baseline conditions and after stress exposure. Administration of OT resulted in a more rapid return of the corticosterone stress response to baseline levels after the stressor has been terminated, implying increased OT-mediated suppression of the HPA axis (9,10). Considering this accumulating evidence, it seems plausible that the HPA axis stress response increases OT release both peripherally and centrally. This increase exerts two seemingly opposite effects at different levels of the HPA axis—rapid activation and suppression. Immediately after stress exposure, elevated OT levels increase corticosterone secretion from the adrenal cortex. Activation of the HPA axis modulates stress responses and enables the individual to adjust to the (altered) prevailing conditions and reestablish homeostasis. Finally, OT suppresses, directly or indirectly, the activation of the HPA axis terminating the neuroendocrine stress response (6,7,10). In addition to the bidirectional network association between OT and the HPA axis, elevated endogenous OT signaling in specific brain regions (as well as in the periphery) enhances prosocial behaviors and social interactions. These further “terminate” stress responses. Because prosocial behavior also facilitates OT signaling, it constitutes an additional feed-forward mechanism (Figure 1). This association may explain the long-term benefits of social contact and support, especially in light of the short half-life of OT (minutes only). It is possible that the oxytocinergic system, by modulating stressrelated responses via the redundancy and overlapping functionality of this system, provides additional regulatory mechanisms of the function of the HPA axis in social animals. From an evolutionary perspective, social contact, social interactions, and the BIOL PSYCHIATRY 2014;76:268–269 & 2014 Society of Biological Psychiatry
BIOL PSYCHIATRY 2014;76:268–269 269
Commentary
STRESS 1) Oxytocin Receptor blockage
Hypothalamic smulaon
2) Exogenous Oxytocin
CRH release
Pituitary smulaon
Oxytocin Female prairie vole
ACTH release
Adrenal Cortex smulaon -
Glucocorticoid Male prairie vole
Social contact Pro-social Behavior: Social contact and interacon Adapve stress responses – Stress buffering Promong Health
No / negave social contact and interacon Maladapve stress responses
Figure 1. Stress exposure encourages social approach behavior as a coping strategy by stimulating oxytocin (OT) release. Positive social contact and interactions are associated with OT release, which further promotes social-approach behaviors. This recurrent association between OT release and the subsequent expression of social behaviors may explain the long-term benefits of social contact and support, especially in light of the short half-life of OT. In addition, OT release after social exposure appears to enable a more effective hypothalamic-pituitary-adrenal axis response to stress, possibly acting both to trigger and to regulate the initial sharp peak in the activity of the hypothalamic-pituitary-adrenal axis and the subsequent feedback downregulation that terminates the neuroendocrine stress response. 1) Knockdown of OT production in the paraventricular nucleus of the hypothalamus in female voles recovering with their male partner predictably impairs behavior and increases corticosterone concentrations. 2) Microinfusions of OT into the paraventricular nucleus of female voles that recovered alone improve their behavioral response patterns and reduce circulating corticosterone concentrations. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone.
Stress-related (psycho)pathology
tendency to form social groups have a significant role in reducing predation risk. The oxytocinergic system appears to play a pivotal role in the “fight or flight” response to stress—including reducing predation risk by grouping, improving physiologic preparedness for rapid activation of the acute stress response, and efficiently terminating the stress response and expediting return to baseline function. In addition to contributing to understanding of how OT signaling mechanisms mediate the effects of social support on stress-response systems and to localizing these neurobiological mechanisms to the PVN, the work of Smith and Wang (8) raises interesting questions, as follows: Does the effectiveness of the biomolecular mechanism by which OT promotes affiliation and social support depend on the availability of OT in the central nervous system? With respect to clinical implication, are we ready to broaden the scope of clinical studies to examine the inclusion of intranasal OT in treatment regimens, especially in light of the variability in its effects related to gender, personality, and time? Do the study findings suggest that social/partner support and involvement in recovery from traumatic stress exposure should be studied both clinically and neurobiologically? Although clinical evidence indicates that acceptance and support from peers and family help in dealing with traumatic stress, and the lack of these has an aggravating effect, intrusive, hyperarousal, and avoidance/numbing symptoms of PTSD often hamper the ability of patients to perceive the intentions of others as supportive and to make use of the support adaptively. One aspect in which OT may be relevant is in improving the ability of the patients to perceive better the intentions of others as supportive and to make use of such support more adaptively. In light of the elevation in endogenous PVN OT levels induced by the mutual care in the vole pairs, another question arises: Should conjoint therapy have a more central place in trauma care, possibly in combination with intranasal OT? The prairie voles study does emphasize the focal role of the patients’ families and the need to support and reinforce this resource as an integral component of treatment from early on.
In conclusion, Smith and Wang (8) offer important and novel translational perspectives of interest for both clinicians and basic scientists, laying the groundwork for further study of where exactly OT signaling and social bonding fit into the clinical approach to PTSD and acute trauma care. The authors report no biomedical financial interests or potential conflicts of interest. 1. Cohen S, Wills TA (1985): Stress, social support, and the buffering hypothesis. Psychol Bull 98:310–357. 2. Karstoft KI, Armour C, Elklit A, Solomon Z (2013): Long-term trajectories of posttraumatic stress disorder in veterans: The role of social resources. J Clin Psychiatry 74:e1163–1168. 3. Brewin CR, Andrews B, Valentine JD (2000): Meta-analysis of risk factors for posttraumatic stress disorder in trauma-exposed adults. J Consult Clin Psychol 68:748–766. 4. Ozer EJ, Best SR, Lipsey TL, Weiss DS (2003): Predictors of posttraumatic stress disorder and symptoms in adults: A meta-analysis. Psychol Bull 129:52–73. 5. Olff M, Frijling JL, Kubzansky LD, Bradley B, Ellenbogen MA, Cardoso C, et al. (2013): The role of oxytocin in social bonding, stress regulation and mental health: An update on the moderating effects of context and interindividual differences. Psychoneuroendocrinology 38:1883–1894. 6. Liberzon I, Young EA (1997): Effects of stress and glucocorticoids on CNS oxytocin receptor binding. Psychoneuroendocrinology 22:411–422. 7. Neumann ID, Torner L, Wigger A (2000): Brain oxytocin: Differential inhibition of neuroendocrine stress responses and anxiety-related behaviour in virgin, pregnant and lactating rats. Neuroscience 95:567–575. 8. Smith AS, Wang Z (2014): Hypothalamic oxytocin mediates social buffering of the stress response. Biol Psychiatry 76:281–288. 9. Heinrichs M, Baumgartner T, Kirschbaum C, Ehlert U (2003): Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biol Psychiatry 54:1389–1398. 10. Cohen H, Kaplan Z, Kozlovsky N, Gidron Y, Matar MA, Zohar J (2010): Hippocampal microinfusion of oxytocin attenuates the behavioural response to stress by means of dynamic interplay with the glucocorticoid-catecholamine responses. J Neuroendocrinol 22: 889–904.
www.sobp.org/journal