Recent years have witnessed a growing interest in the effects of adversities such as terror attacks, natural disasters, car accidents, and other traumatic life events on brain functions and risk for psychiatric illness (Yehuda, 2002).

Stress may be broadly defined as any form of threat (real or inferred) to the physiological or psychological integrity of an individual which results in physiological and/or behavioral responses (Kalueff & Tuohimaa, 2004). While some individuals find stressful situations interesting, challenging or even strengthening, others exhibit maladaptive responses, which in turn, may result in psychological and/or physiological pathology. Of these maladaptive responses to stressful events, mood and anxiety disorders are most common, particularly depression and PTSD (Nemeroff, 1999).

It is estimated that in a given year in the adult US population, approximately 9.5 % (20.9 million individuals) will suffer from a mood disorder and about 18.1 % (40 million individuals) will suffer from an anxiety disorder (Kessler, Berglund et al., 2005); furthermore, mood disorders often co-occur with anxiety disorders (Kessler, Chiu, Demler, Merikangas, & Walters, 2005).

Factors that play an important role in the intensity of the response to a certain stressful experience include “event-related factors” such as the degree of controllability, predictability, the actual perceived threat, the relative success of attempts to minimize injury to oneself or others, and the actual loss (Yehuda, 2002) but also “personal factors” like genetic background, gender, and previous exposure to stressors, particularly exposure to stressors early in life (Anisman & Matheson, 2005; Arborelius, Owens, Plotsky, & Nemeroff, 1999; Heim & Nemeroff, 2001; Horovitz, Tsoory, Hall, Jacobson-Pick, & Richter-Levin, 2012; Levine, 2005; Nemeroff, 2004a; Nemeroff et al., 2006; Piccinelli & Wilkinson, 2000). Here we will focus on stress early in life as a risk factor for stress-related disorders, and particularly PTSD, later in life.

Freud was amongst the first to highlight the importance of early life experiences in shaping an individual’s mental functions for the rest of his/her life (Freud, 1987). This emphasis on the importance of early developmental experiences still holds and with it the notion that stress early in life may induce a vulnerability to the effects of stress later in life, possibly by inducing a persistent sensitization in stress-responsive neural circuits, which augments the consequences of later adverse experiences (Agid, Kohn, & Lerer, 2000; Heim & Nemeroff, 2001; Nemeroff, 2004b).

Across species, including humans, the early adolescent or juvenile brain is considered to be a transition phase, differing markedly both anatomically and neurochemically from that of newborns, weanlings, or adults. Preteens and adolescent humans have enhanced stress perception and responses. Stressful life events during this period have been suggested as being associated with later socio-emotional maladaptive behaviors, and to represent a significant risk factor for the later development of stress-related psychopathologies (Maughan & McCarthy, 1997; Spear, 2004).

There is increasing evidence that the adolescent brain is particularly vulnerable to effects of stress. Recently Casey, Getz, and Galvan (2008) addressed human adolescent brain development and suggested that during adolescence a unique imbalance exists between levels of activity in subcortical regions and cortical regions. Based on both preclinical evidence and brain imaging studies of children, adolescents, and adults, it appears that during adolescence, subcortical activity is relatively higher than cortical activity. It was suggested that these findings may indicate that during the processing of negative emotional information, this bias between unregulated and prominent subcortical activity (e.g., limbic regions) and a relatively reduced activity in the prefrontal cortex may relate to the emergence of affective disorders during adolescence (Casey et al., 2008).

Many studies in humans point to late childhood and early adolescence as periods of particular vulnerability development of psychopathologies later in life (Maercker, Michael, Fehm, Becker, & Margraf, 2004; Pynoos, Steinberg, & Piacentini, 1999). The net consequence of stress in the juvenile/adolescent brain that has been suggested is the sensitization of the emotional brain to the effects of later life stress, increasing the likelihood of depression and anxiety (Agid et al., 2000; Anisman & Matheson, 2005; Costello et al., 2002; Gregory et al., 2007; Heim & Nemeroff, 2001; Levine, 2005; Maughan & McCarthy, 1997; Nemeroff, 2004a; Nemeroff et al., 2006; Spear, 2004). However, it is important to note that some epidemiological studies suggest that stress early in life, but at different developmental stages, may result in the development of different psychopathologies. Childhood trauma (under the age of 12 years) was found to increase the risk of developing major depression, while trauma during adolescence was associated with a greater predisposition to PTSD (Maercker et al., 2004), suggesting challenging maturing mechanisms of emotional or mood regulation at different developmental phases may predispose to different psychopathologies later in life (Maercker et al., 2004; Pynoos et al., 1999).

Many of the rodent early life stress (ELS) models focus on the perinatal preweaning period and involve some form of maternal deprivation or separation (Kehoe, Shoemaker, Arons, Triano, & Suresh, 1998; Levine, Huchton, Wiener, & Rosenfeld, 1991; Ogawa et al., 1994; Plotsky, Thrivikraman, & Meaney, 1993; Rosenfeld, Wetmore, & Levine, 1992; van Oers, de Kloet, & Levine, 1998; Vazquez, Van Oers, Levine, & Akil, 1996; von Hoersten, Dimitrijevic, Markovic, & Jankovic, 1993), producing acute and long-term effects that vary with the pups’ age (Levine, 1994). For example, prolonged early maternal separation attenuated rates of synaptic development in the hippocampus, which was evident only after sexual maturation (Andersen & Teicher, 2004). Evidence from ELS animal models suggests persistent changes in the function of brain regions pivotal to the meditation of stress and emotion, which are similar to the neurobiological alterations found in patients suffering from depression or anxiety disorders (Nemeroff, 2004a). For example, these studies have demonstrated that stressful experiences which occur during critical periods of brain development (perinatal to preweaning) persistently change the responses to stressors at both the behavioral level and the endocrine levels, the response of the hypothalamic–pituitary–adrenal (HPA) axis, thereby increasing the vulnerability to mood and anxiety disorders later in life (Nemeroff, 2004a; Wang et al., 2011, 2012). Likewise, other studies indicated that a brief separation of pups from their dams during early development enhances adrenocorticotropic hormone (ACTH) and corticosterone (CORT) secretion in response to a stressor in adulthood (Anisman, Zaharia, Meaney, & Merali, 1998), while also reducing the number/density of pituitary corticotrophin-releasing factor (CRF) binding sites, possibly relating to increased CRF release in response to the stressor in adulthood (Nemeroff, 2004b). Accumulating evidence has thus raised the possibility that ELS induces a sensitization of stress response mechanisms that may be due to altered limbic functioning, thereby augmenting the consequences of stressors later in life (Nemeroff, 2004a, 2004b).

However the brain’s development continues well after the preweaning period, and substantial maturation processes like myelination continue with varying dynamics well into puberty (Hamano et al., 1998). The ongoing maturational changes render the postweaning brain susceptible to the harmful effects of stress. Prolonged postweaning isolation rearing compromises the development and function of central aminergic neurotransmission, which is associated with altered behaviors in adulthood (Lapiz et al., 2001; Muchimapura, Fulford, Mason, & Marsden, 2002; Muchimapura, Mason, & Marsden, 2003).

While most ELS rodent models focus on the perinatal to preweaning periods (for a review see: Sanchez, Ladd, & Plotsky, 2001), recent work in our laboratory and others, focused on an alternative period in the rat ontology, “juvenility” (~28 days), the earlier phase of the adolescent/postweaning to the prepubertal period (Avital, Ram, Maayan, Weizman, & Richter-Levin, 2006; Avital & Richter-Levin, 2005; Horovitz et al., 2012; Ilin & Richter-Levin, 2009; Jacobson-Pick, Elkobi, Vander, Rosenblum, & Richter-Levin, 2008; Jacobson-Pick & Richter-Levin, 2012; Tsoory, Cohen, & Richter-Levin, 2007; Tsoory, Guterman, & Richter-Levin, 2008; Tsoory & Richter-Levin, 2006; Tsoory, Vouimba et al., 2008). This period is likely to relate closely to human childhood, a developmental period known to be relevant to the pathogenesis of a range of psychiatric disorders (Lapiz et al., 2001; Muchimapura et al., 2002, 2003). The rationale behind the “Juvenile Stress” model is that this is expected to induce long-term alterations in stress responsiveness, by exposing rats to stressors during juvenility, thus augmenting the consequences of additional exposure to stressors in adulthood.

A brief exposure to “Juvenile Stress” compromised the ability of rats to cope with stressors in adulthood. The result of exposure to the same stressor in adulthood was more severe and longer lasting if the stressor was presented on the background of previous exposure to the “Juvenile Stress” (Avital et al., 2006; Avital & Richter-Levin, 2005; Brydges, Hall, Nicolson, Holmes, & Hall, 2012; Horovitz et al., 2012; Ilin & Richter-Levin, 2009; Jacobson-Pick et al., 2008; Tsoory et al., 2007; Tsoory, Guterman, et al., 2008; Tsoory & Richter-Levin, 2006; Tsoory, Vouimba, et al., 2008). For example, startle reflex response was higher in adult rats exposed to elevated platform stress in adulthood compared to control, unexposed rats. However, the startle response of rats exposed to the same stress in adulthood but on the background of pre-exposure to “Juvenile” stress was yet significantly higher than that of animals exposed only to the stress in adulthood (Avital & Richter-Levin, 2005). The exacerbation of the effects of the adulthood stress by the “Juvenile Stress” was evident at the behavioral level (Avital et al., 2006; Avital & Richter-Levin, 2005; Brydges et al., 2012; Horovitz et al., 2012; Tsoory et al., 2007; Tsoory & Richter-Levin, 2006), but correlations were found at the physiological (Cohen et al., 2007; Yee, Plassmann, & Fuchs, 2011; Yee, Schwarting, Fuchs, & Wöhr, 2012), biochemical (Bazak et al., 2009; Jacobson-Pick et al., 2008; Jacobson-Pick & Richter-Levin, 2012; Tsoory, Guterman, & Richter-Levin, 2010; Tsoory, Guterman, et al., 2008; Tsoory, Vouimba, et al., 2008), and electrophysiological (Maggio & Segal, 2011) levels. For example, the induction of long-term potentiation (LTP) in the CA1 area of the hippocampus was suppressed by the exposure to forced swim stress in adult rats, when tested 1 day after the exposure, but this ability to induce plasticity was completely recovered within 1 week. However, adult animals exposed to the same stressor but on the background of a history of exposure to “Juvenile” stress exhibited impaired LTP even 1 week after the exposure to the stress in adulthood (Maggio & Segal, 2011).

However, even though early exposure to stress predisposes individuals to the development of both mood and anxiety disorders later in life (Heim & Nemeroff, 2001; Nemeroff, 1999; Nemeroff, 2004a, 2004b ; Yehuda, 2002), individual differences are found in the response to the adulthood stress.

In this respect, it is of significance that there is a significant difference between the way a psychiatric disorder is diagnosed in humans and the way it is conducted in the animal models. In humans, the diagnosis of PTSD is given only when an individual exhibits a certain number of symptoms from each of three quite well-defined symptom clusters over a certain period of time. Yet in animal studies, irrespective of the study design/model or of the stress paradigm, results are presented, discussed, and conceptualized as involving the entire exposed population versus controls, although in practice, the exposed animals display a diverse range of responses. In order to more closely approximate the animal model approach to contemporary understanding of the clinical condition, a novel approach was conceived that enables segregating the study animals into groups according to the degree of their response to the trauma (Cohen et al., 2004).

The profiling of animals as “affected” or “non-affected” was based on the cutoff behavioral criteria (CBC) analysis approach, developed by Cohen, Zohar, and Matar (2003). By integrating different levels of responses patterns, classification criteria are formed in a similar manner to that used in clinical diagnosis procedures to form psychopathological symptom clusters; thus sets of classification criteria, representing inclusion and exclusion criteria, produce distinct patterns of stress-induced indices. The “CBC” analysis maximizes the accuracy of the animals’ classifications and minimizes the likelihood of including “false-positives,” by making sure that each animal that meets both sets of criteria (inclusion and exclusion) is defined as “affected” or “unaffected.” The validity of the criteria is affirmed by ascertaining that the vast majority of “unexposed” animals are found within the “unaffected” category and only a minority with the “affected.” Employing a version of that novel analysis approach, we were able to demonstrate a similar individual dissociation in animal models, as in humans (Lanius, Frewen, Vermetten, & Yehuda, 2010; Lanius, Vermetten, et al., 2010), for those animals that demonstrate more anxious symptoms and those that exhibit more depressive symptoms (Horovitz et al., 2012; Tsoory et al., 2007; Tsoory & Richter-Levin, 2006). Examining the impact of “Juvenile Stress” on learning under stressful conditions in adulthood, we compared the effects of pre-exposure to stress at “juvenility” on the ability of animals to acquire a two-way shuttle avoidance task (TWS hereafter) in adulthood (PNDs 59–60). In this task, in which a tone precedes a foot shock, animals first learn to escape the shock by shuttling to the other compartment, but later may learn to avoid the shock completely by shuttling already when the predictive tone comes up. Only very rarely would an animal exhibit a response failure, i.e., will not move to the other compartment until the end of the session. While control animals have learned to effectively avoid the shock, animals pre-exposed to “Juvenile” stress were impaired. Interestingly, some animals were impaired in avoidance because they did not make the shift from escaping to avoiding, despite high rates of escape responses, but about a third of the pre-exposed animals demonstrated high rates of response failure (Tsoory & Richter-Levin, 2006). High escape rates with impaired avoidance was termed “anxious” behavior while high response failure, which is a form of learned helplessness, was termed “depressive” (Tsoory, 2006). In another study we compared the effects of pre-exposure to stress at “juvenility” (PNDs 27–29) or “adolescence” (PNDs 33–35). While among adult adolescence-stressed rats only “anxious” animals were observed, comprising 50 % of the animals, and none conformed to the “depressive” profile, juvenile-stressed rats tested in adulthood exhibited either “anxious” or “depressive” pattern of behavior (Tsoory et al., 2007).

We have further developed the methodology of profiling altered behavioral responses in several ways. First, while in the original “CBC” methodology the lowest 25th percentile was compared with the highest 25th percentile (Cohen et al., 2004), the comparison group we believe should be used is the averaged performance of the control group for each behavioral variable. Second, and probably a most important modification is the implementation of separate male/female comparison groups (Horovitz et al., 2012).

Women are more prone than men to mood disorders, particularly depression (Garde, 2007; Gater et al., 1998; Noble, 2005) and anxiety disorders, including PTSD and generalized anxiety disorder (GAD) (Bekker & van Mens-Verhulst, 2007; Gater et al., 1998; Tolin & Foa, 2006). In addition to the different prevalence’s of mood and anxiety disorders in men and women, there is evidence for gender-dependent differences in the response to psychotropic medications between men and women as well (Gorman, 2006; Yonkers, Kando, Cole, & Blumenthal, 1992). These differences suggest that gender-dependent differences in neuroanatomy and neurophysiology might underlie some of the observed differences in the prevalence and symptom profiles of mood and anxiety disorders between men and women. Consistent with this hypothesis, differences between the genders were reported in several components of the central nervous system. Cahill (2006) for example noted gender differences in hippocampal structure and functions. These gender differences included the adrenergic, serotonergic, cholinergic, and cholecystokinin systems; anatomical structure; relative size (adjusted for total brain size); reactivity to stressors; as well as the effects of CORT and Benzodiazepines.