The brain and the stress axis: The neural correlates of cortisol regulation in response to stress
Introduction
Cortisol, the major stress hormone in humans, targets an array of both peripheral systems and central processes (Lupien et al., 2007, McEwen, 1998); the fine-balanced regulation of stress-induced as well as basal cortisol secretion is thus essential for the maintenance of homeostasis (McEwen, 2000, Tsigos and Chrousos, 2002). When triggered outside of circadian or pulsatile dependencies, cortisol release is specific to stress (Herman et al., 2005). Animal studies have shown that a collection of networks spanning from brainstem nuclei to specific limbic system structures exercises their regulatory functions on HPA axis function and glucocorticoid (mainly cortisol in mammals, corticosterone in rodents) regulation (Herman et al., 2003). The key target of these various direct and indirect pathways is the paraventricular nucleus (PVN) of the hypothalamus (Herman et al., 2003). Stress refers to a situation in which demands are perceived to exceed one's personal resources (Lazarus, 2006). Upon perception of acute stress, cells within the PVN release corticotropin releasing hormone (CRH), which travels through the infundibulum to the pituitary gland, where it stimulates secretion of adrenocorticotropic hormone (ACTH) into the bloodstream (Brown, 2000). ACTH eventually reaches the adrenal cortex, where it binds to receptors that stimulate secretion of cortisol into the bloodstream (Brown, 2000). The majority of cells in the human body have receptors for cortisol, thus cortisol has a broad variety of effects throughout our system, including metabolic, cardiovascular, and immune responses (Buckingham, 2006, McEwen, 1998).
Cortisol regulates its own release via the negative feedback loop in the central nervous system (CNS), where it binds to specific receptors throughout the limbic system, including hippocampus (HC), amygdala (AG), and prefrontal cortex (PFC) (Feldman and Weidenfeld, 1995, Herman and Cullinan, 1997, Herman et al., 2005). The basal, non-stressful secretion of cortisol follows a circadian rhythm, beginning with a distinct sharp rise of cortisol at the time of awakening, followed by a steady decline over the course of the day, with the lowest levels in the early morning hours (Weitzman et al., 1971). In the following article, we will specifically focus on examining neural correlates of cortisol regulation in response to stress, while acknowledging a growing number of articles that investigate neural correlates of basal cortisol secretion and regulation (e.g., Bruehl et al., 2009, Buchanan et al., 2004, Cunningham-Bussel et al., 2009, Pruessner et al., 2007, Putnam et al., 2008, Tessner et al., 2007, Wolf et al., 2005).
The contribution of specific regulatory networks in the CNS to cortisol regulation in response to stress is influenced by a number of factors. First, different stressor types, such as reactive versus anticipatory stressors, lead to stimulation of the HPA axis through activation changes in distinct brain regions involved in glucocorticoid regulation (Herman et al., 2003). Reactive stressors are those that increase the demand on the system through a real sensory stimulus, such as pain, bodily injury, or an immune challenge, while anticipatory stressors tap into innate or memory programs, such as social challenges or unfamiliar situations (Herman et al., 2003). Another useful differentiation is that of physical versus psychological stressors (Dickerson and Kemeny, 2004, Pacak and Palkovits, 2001). An example for a physical stressor could be facing a wild animal, with the anticipation of bodily injury, while social evaluative threat would be considered a typical psychological stressor (Dickerson and Kemeny, 2004). Animal literature suggests that reactive stressors tend to implicate brainstem and specific hypothalamic nuclei, and the bed nucleus of the stria terminalis, which all have direct connections to the PVN (Herman et al., 2003). Anticipatory stressors, for their part, seem to engage limbic system regions, namely the HC, the amygdala AG and medial PFC areas (Herman et al., 2003). We have recently suggested that within the limbic system, physical stressors would engage more heavily the AG, while psychological stressors would emphasize the HC (Pruessner et al., 2008). While HC, AG and medial PFC areas have direct connections to some of the hypothalamic nuclei (Herman et al., 2003, Ongur and Price, 2000, Price, 2003), with respect to stress regulation, at the level of the PVN of the hypothalamus specifically, only indirect connections are found (Fernandes et al., 2007, Floyd et al., 2001, Herman et al., 1996, Hurley et al., 1991).
With recent developments in functional and structural neuroimaging methods, it has become possible to directly investigate these regulatory networks, non-invasively, in humans. There are a number of structural and functional studies that provide evidence for regulatory roles of the HC, AG and PFC areas in response to stressors in humans (Pruessner et al., 2008, Pruessner et al., 2007, Tessner et al., 2007, Wang et al., 2007, Wang et al., 2005). Further, some recent studies suggest a role for brainstem nuclei in cortisol regulation; however, it has to be noted that neuroimaging studies on brain activity changes in response to physical stressors are largely lacking from the literature.
Additional factors such as the sex of the subject might also play a role in cortisol regulation. For example, men and women differ in the cortisol secretion depending on the stressor type (Stroud et al., 2002), and this may be due to differences between the sexes in engagement of frontal and limbic structures in cortisol regulation (Wang et al., 2007). However, literature on this topic is just emerging and thus more studies are needed before sound conclusions can be drawn. Further, both animal and human studies on effects of early life experiences on cortisol regulation have shown that adverse events during critical development periods can change the stress sensitivity and responsivity of the HPA axis throughout life (Champagne et al., 2008, Fries et al., 2008, Lupien et al., 2000, McGowan et al., 2009). While a number of different mechanisms may mediate these effects, we will focus on the contribution of the dopaminergic neurotransmitter system and limbic system structures in HPA axis regulation, as this has been the focus of much of our research efforts of the past years.
Thus, in this review, we will first discuss methods to induce stress in neuroimaging, followed by a discussion of the contributions of limbic system structures such as the HC, the AG, and the PFC in regulating the HPA axis, and comparing it to brainstem and physiological regulation mechanisms of this system. Finally, we will review the impact of specific developmental factors on brain development and HPA axis regulation.
Section snippets
Methods to induce stress in neuroimaging paradigms
Recently, psychological stress paradigms suitable for neuroimaging environments have been developed in order to examine brain networks involved in regulation of cortisol in humans. To date, there are two psychological stress paradigms suitable for functional Magnetic Resonance Imaging environment that have been able to elicit a stress response: the Montreal Imaging Stress Task (MIST; Dedovic et al., 2005), and a serial subtraction paradigm (Wang et al., 2005). The MIST requires performing
The Hippocampus and the HPA axis
A few studies have investigated the association between hippocampal structural integrity and the cortisol stress response. We recently observed a positive association between HC volume and the levels of self-esteem (Pruessner et al., 2005). Furthermore, we observed an inverse correlation between self-esteem and the cortisol stress response (Kirschbaum et al., 1995, Pruessner et al., 1999). Thus, it seems that self-esteem is both functionally and structurally associated with HC volume, which
The Amygdala and the HPA axis
The amygdala (AG), a critical part of the limbic system, is traditionally known for its role in processing threatening stimuli (Adolphs, 2008, Bishop, 2008, Roozendaal et al., 2008). Composed of several sub-nuclei, the AG has extensive reciprocal connections with several structures implicated in processing of sensory information: the olfactory cortex, the posterior thalamus, the ascending taste and visceral pathway, and the sensory association cortical areas (McDonald, 1998). Projections from
Prefrontal cortex and the HPA axis
Initial reports from animal studies on the involvement of the PFC in the regulation of the HPA axis and the subsequent stress response suggested a purely inhibitory role of the PFC (Herman et al., 2003). However, recent work indicates that specific components of the prefrontal cortex may play quite different roles in the regulation of cortisol secretion and that these may be stressor specific (Herman et al., 2003, Herman et al., 2005). Evidence from human studies on the role of PFC in cortisol
Physiological/physical stressors and the HPA axis
Up until now we have addressed the roles of HC, AG and PFC in cortisol regulation in response to mainly psychological stressors. A second group of stressors, termed physical, have been investigated mainly within the animal research field. These studies, employing an array of protocols such as ether exposure, hemorrhage or hypoxia (Herman and Cullinan, 1997), have shown that the major structure involved in the regulation of the HPA axis to physical stressors is the brainstem via the nucleus of
Summarizing the functional findings on the contribution of hippocampus, amygdala, prefrontal cortex and brainstem in cortisol regulation
Functional neuroimaging studies have allowed us to investigate the contribution of HC, AG and PFC in cortisol regulation in response to psychological stress, non-invasively, in humans. On an individual basis, each study provides explanation of a specific set of processes that are involved in stress response and regulation. However, overall interpretation of the findings is hindered by the fact that these studies differ with respect to their methodological approaches. Nevertheless, we will
Development and other neurotransmitter systems interaction with cortisol
Apart from the nature of the stressor, factors such as early life experiences also play a role in cortisol regulation, most likely mediated through differential development of the stress processing areas in the brain. Studies investigating early life experience suggest that adverse events during critical development periods can change the responsivity of the HPA axis as well as HC integrity throughout lifetime. Pioneering rodent studies have shown subtle variations in maternal care to have
Conclusion
A complex network of structures contributes to cortisol regulation both during basal conditions, and in particular, in times of stress. The involvement of each of the regulatory agents from the brainstem structures to the limbic system and prefrontal cortex depends upon specific factors such as the nature of the stressors, sex of the subject and early life experience. While great strides have been made in furthering the understanding of the neurocircuitry of cortisol regulation in response to
Acknowledgments
This study was supported in part by an operating grant from the Canadian Institutes of Health Research (67071) and by a grant from the Natural Sciences and Engineering Research Council (249996) to JCP. VE is supported by a Postdoctoral grant from the German Research Foundation. JCP holds a CIHR New Investigator award. KD and AD hold a CIHR Doctoral Research award.
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