Mapping the developmental trajectory of stress effects: Pubescence as the risk window
Introduction
The term “stress” was coined in 1940s by Hans Selye as “a nonspecific response of the body to any demand made on it” (Selye, 1998). Currently, “stress response” is understood as an adaptive response (caused by internal mechanisms developed through evolution), that allows the individual to maximize the chance of survival when confronted with stress” (Kalueff and LaPorte, 2008). Stress is not necessarily a harmful or pathological factor to be avoided. Only when the adaptive mechanisms cannot be recruited, stress will result in a number of deleterious effects and health may be endangered. Nevertheless, stress seems to be an integral part of any species life. Thus, the desire to better understand its effects and underlying mechanisms turn the field of stress to be extensively researched.
There is a long history attempting to evaluate the developmental trajectory of stress in humans (Hildyard and Wolfe, 2002, Ethier et al., 2004), but these studies are limited by their retrospective nature. Thus, an animal model is ideal for studying developmental and longitudinal processes, or the developmental programming of the stress system, such as the hypothalamic–pituitary–adrenal (HPA) axis which is activated in response to a stressor (de Kloet et al., 2005). Many animal models evolved for this purpose, in an effort to investigate the existence of a possible hyper-sensitive developmental period for applying a stressor. Some models applied a physical stressor whereas others applied a psychological one, either in acute or chronic paradigms. Moreover, stressors were applied at different time points during development, together with various time points of evaluation of the either short- or long-term effects of the original stress paradigm (see rev. Bhatia et al., 2011, Holder and Blaustein, 2014). In support of this idea, long-term changes have been previously reported following stress in early stages of life. Increased anxiety-like behaviors were observed in adult rats following juvenile stress (Tsoory et al., 2007, Jacobson-Pick and Richter-Levin, 2012) as well as decreased locomotion in an open field (Avital and Richter-Levin, 2005), elevated plus-maze (Jacobson-Pick and Richter-Levin, 2012) or a novel environment (Tsoory et al., 2007). Increased startle response in adulthood has also been described (Avital et al., 2006, Tsoory et al., 2007). Moreover, a single maternal deprivation was reported to produce long-term changes when applied within the stress hypo-responsive period between postnatal days 1–12 (Enthoven et al., 2008). Other studies, which applied stressors in early adolescence, have observed no specific effect on adulthood behavior (Kubala et al., 2012, Saul et al., 2012).
Since the accumulated data suggest the outcome of early life experiences largely depends on the timing, frequency, and duration of the particular environmental experience (Meaney and Aitken, 1985, Enthoven et al., 2008, Champagne et al., 2009) and although stress is highly investigated, the current literature cannot offer a consistent behavioral overview of a suggested stress-sensitive period with relation to its long-term effects in adulthood.
When exploring the underlying physiological explanations of the behavioral effects, the broad spectrum of corticosteroids activity is well recognized, suggesting their short- or long-term effects, when mediating a stress response through many expression and regulation processes in various brain regions. A breakthrough in the field of developmental programming came with the discovery of epigenetic modifications in the promoter area of the glucocorticoid receptor gene, revealing a mechanism underlying the environmentally driven effects on later life stress phenotype. Specifically, it has been shown that prenatal stress resulted in decreased hippocampal glucocorticoid receptor expression in the adult offspring together with maladaptive behavioral stress responsivity (McCormick et al., 1995). However, the impact of the prenatal factors is strongly influenced by postnatal experiences (Meaney et al., 2007). Recently, it has also been shown that stress during adolescence induces epigenetic control of dopaminergic neurons via glucocorticoids (Niwa et al., 2013).
Thus, the current literature suggests that stress has enduring effects on the brain, with a heightened impact on developing structures. Moreover, it has been implied that the HPA axis response to acute stress depends on the animal's developmental stage (Romeo et al., 2006). These observations are supported by human studies, demonstrating the ‘programming’ effects of stress in early life on the HPA axis and the brain (Barker, 1991), and further presented in adult patients suffering from major depressive disorders who had experienced early life stress, and show persistent hyper activity of the HPA axis and of the autonomous nervous system, as well as increased sensitivity of these systems to stress (Heim et al., 2000a, Heim et al., 2000b).
Carefully considering the complex translation of rat to human lifespan (Quinn, 2005), together with the vigorous maturation which the brain undergoes during the transition period between childhood to adulthood (Sowell et al., 1999, Rubinow and Juraska, 2009, Avital et al., 2011), it seems that the available data supports the hypothesis that adolescence is a ‘stress-sensitive’ period (Andersen and Teicher, 2008, Leussis and Andersen, 2008). However, it has been also suggested that the development of emotionality and its underlying neural systems, remain highly plastic during the juvenile and pubescence periods (Holmes et al., 2005, Holder and Blaustein, 2014).
Again, since previous studies have applied diverse stressors in distinctive developmental time points, while observing different short- or long-term physiological and behavioral changes (Cadet et al., 1986, Koehl et al., 1999, Avital and Richter-Levin, 2005, Saul et al., 2012), the long-term effects of the possibly hypersensitive-stress time point during the rats’ developmental trajectory remains unclear.
In the current study we conducted a systematic research, aimed to map the long-term effects of an exposure to an acute stress applied at different developmental time-points. In order to allow an overall comparison between the various time points, we applied an equivalent three days acute stress protocol for all 11 groups (starting prenatally until PND 150), and tested its long-term consequences in adulthood (postnatal days 127 or 180) on behavior as well as corticosterone serum level.
Unfortunately, the stress protocol we chose may not be applied on rats before weaning (postnatal day 21), therefore we had to apply maternal separation. Nevertheless, we utilized a protocol (5 h separation on 3 consecutive days) that meets the criteria for a stressor: a set of physical events that together create an aversive, uncontrollable and unpredictable experience (Kim and Diamond, 2002, Koolhaas et al., 2011) and has been associated with negative consequences later in life (Nylander and Roman, 2013).
Thus, we believe the impact of the chosen stress protocols is potentially comparable, and given the systemic approach of this study, a consistent mapping of the rat developmental trajectory examining the possible hyper-sensitive periods, for a long-lasting effect is achievable.
Section snippets
Animals and study design
Twenty-five females and fifty males Wistar rats (weighing between 200 and 220 g) were purchased from Harlan (Jerusalem, Israel). Following five days of acclimation in the institutional animal facility, rats were randomly allocated for breeding (2 males and one female in each cage). Offspring were weaned at postnatal day (PND) 21 and only males were assigned for the various groups (a total of 128 males), with an emphasis on maintaining a genetic heterogeneity between the groups. Rats were housed
Results
Across all tests, we found no significant differences between the control groups that were tested on PND 127 or 180. Thus, we combined these groups into one control group.
Measuring activity by distance made in the Open-field test (Fig. 1A), a One-way ANOVA revealed a significant effect for group [F(11, 116) = 10.94, P < 0.0001]. Post hoc Tukey test revealed a significant hypoactivity in groups AS35, AS45 and AS55 compared with their counterpart controls (P < 0.0001), as well as with the lowest (MS10)
Discussion
Many animal models evolved in an effort to investigate the existence of a possible hyper-sensitive developmental period for the exposure to stress (Enthoven et al., 2008, Jacobson-Pick and Richter-Levin, 2012). Some studied physical stress and others psychological stress, either in acute or chronic paradigms (Bhatia et al., 2011, Holder and Blaustein, 2014). Likewise, utilizing various time points of evaluation of the either short- or long-term effects of stress, along the rats’ developmental
Role of the funding source
No funding was received for this study.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgement
No acknowledgements.
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