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  • It may help to frame this variability

    2018-11-03

    It may help to frame this variability in the context of two models that are used to discuss how the hydroxypropyl beta cyclodextrin and body respond to stress (Hostinar and Gunnar, 2013). In one, the allostatic load model (McEwen and Stellar, 1993), repeated stress has negative impacts on the brain. In another, the adaptive calibration model (Del Giudice, Ellis and Shirtcliff, 2011), stress calibrates or tunes developmental processes to allow an hydroxypropyl beta cyclodextrin animal to match its behavior to the environment. The allostatic load model attempts to explain how organisms respond to insults, positing that adaptations, in the short-term, can provide benefits, however if experienced for longer periods can lead to negative consequences (Hostinar and Gunnar, 2013). The adaptive calibration model attempts to answer why systems act the way they do in the context of life history strategies instead of viewing certain outcomes as dysfunctional or pathological. Under the umbrella of adaptive calibration model, there is a growing body of literature suggesting that early social deprivation may accelerate the maturation of threat related behavior. A series of studies focused on extinction and recovery of fear conditioning memory have noted that rats exposed to MS show early adult-like fear extinction and recovery behavior (Callaghan and Richardson, 2011). Stress in the early homecage has also been shown to alter the developmental trajectory of attachment and avoidance learning (Moriceau et al., 2009). This has been echoed by discovery of adult-like functional connectivity in the amygdala-ventromedial PFC of children who were institutionalized during early life (Gee et al., 2013). Consistent with the earlier maturation hypothesis, the juvenile MS mice tested in our 4-choice reversal paradigm performed in a manner indistinguishable from littermate adults (reversal trials to criterion: MS juvenile M=34.86±3.20, LM adults (LM 60) M=29.50±2.98, t(20)=1.11, P=.3) or untreated adults from previously published data (Control adults M=36.18±4.78, t(23)=0.24, P=.8; data from Johnson and Wilbrecht, 2011). The age at which we observe a significant effect of MS (P25-26) is likely a transitional phase of life in which the animal is moving from parental dependence to independence and in which the animal must quickly learn about its changing environment and make adjustments based on those experiences (Spear, 2000). In our prior study which described a developmental decrease in flexibility in a 4-choice reversal task (Johnson and Wilbrecht, 2011), we hypothesized that this heightened flexibility observed in juveniles may be particularly important for navigating the ambiguous and/or uncertain environment that an animal faces at this unique life stage. Periods of enhanced flexibility have been observed in other developmental studies in rats (Simon and Moghaddam, 2015) and humans (Van Der Schaaf et al., 2011). Interpreted in the context of the adaptive calibration model and the earlier maturation hypothesis, our current MS results could suggest that in the face of adversity Cyclins might be adaptive for mice to use more perseverative, adult-like strategies during the juvenile period. Our results can also be interpreted in the context of the chronic stress and allostatic load model. We can compare our MS data to studies of chronic restraint stress, that have found repeated stress in adulthood can lead to alteration in frontal circuit neural morphology (Radley et al., 2004; Radley et al., 2009) and disrupt cognitive flexibility in the 2-choice ASST task (Liston et al., 2006). Although chronic restraint stress in adulthood selectively affected attentional set shifting (changing a rule from odor to texture) and not reversal learning (switching from odor 1 to odor 2) (Liston et al., 2006), it is possible that early MS might simply impair circuit function underlying reversal learning in an analogous fashion. Loss of function could thus be quite different than acceleration of maturation. In summary, both the allostatic load and adaptive calibration model could be used to explain our current data. We speculate that different strategies adopted at the time of dispersal (whether evolutionarily adaptive or maladaptive) could potentially influence the criteria and timing of territory and reproductive decisions that could influence the whole life trajectory of a wild living rodent. This idea could also be applied to human society and decision making in its greater complexity. Future work on the biological changes following MS in rodents should shed light on the appropriateness of the adaptive calibration model versus the allostatic load model and help guide translational efforts to ameliorate the impact of early life adversity on human health.