Rethinking Homeostasis: Allostatic Regulation in Physiology and Pathophysiology

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The concept of allostasis, maintaining stability through change, is a fundamental process through which organisms actively adjust to both predictable and unpredictable events Allostatic load refers to the cumulative cost to the body of allostasis, with allostatic overload Using the balance between energy input and expenditure as the basis for applying the concept of allostasis, two types of allostatic overload have been proposed Wingfield Sterling proposed six interrelated principles that underlie allostasis:.

The difference between allostasis and homeostasis is popularized by Robert Sapolsky 's book Why Zebras Don't Get Ulcers : [ This quote needs a citation ]. Type 1 allostatic overload occurs when energy demand exceeds supply, resulting in activation of the emergency life history stage. This serves to direct the animal away from normal life history stages into a survival mode that decreases allostatic load and regains positive energy balance.

The normal life cycle can be resumed when the perturbation passes. Type 2 allostatic overload begins when there is sufficient or even excess energy consumption accompanied by social conflict and other types of social dysfunction. The latter is the case in human society and certain situations affecting animals in captivity. In all cases, secretion of glucocorticosteroids and activity of other mediators of allostasis such as the autonomic nervous system, CNS neurotransmitters , and inflammatory cytokines wax and wane with allostatic load.

The sum of the identified z-scores, each transformed, if necessary, to directly reflect magnitude of vulnerability, created a "dyadic vulnerability" index. Normality of distribution was satisfied for key variables, and no outliers were noted. Vertical bars denote standard errors. The mean group change was The mean of individual cortisol change was 7. By contrast, larger, more dominant females started out with relatively low cortisol and showed plasma cortisol elevations.

These data implied that heavier, relatively advantaged mothers increased plasma cortisol in response to VFD exposure whereas lighter, hence generally vulnerable, subjects showed reduced cortisol Tables 3 and 4. Results were obtained while controlling for infant age. The core variables were each, using a post hoc cutoff, less than 50 Euclidian Linkage Units from each other. Pre-VFD cortisol is closely associated but not included in the core grouping.


We therefore created a "dyadic vulnerability" index that included the sum of a z-score converted maternal weight inverted , b maternal social rank, c infant weight at VFD onset inverted and d dyadic proximity inverted during the final high foraging demand two-week phase of the VFD procedure. The final HFD phase was selected for study as that two-week period representing the greatest cumulative dyadic stress incurred by the VFD exposure paradigm.

The cluster analysis demonstrates the factors that promote maternal cortisol decrements include lighter, more subordinate mothers with lighter infants at the time of VFD onset, with reduced maternal-infant dyadic distance suggesting an association between socioecological vulnerability and cortisol suppression. The black arrow indicates that core variables were each less than 50 Euclidian Linkage Units from each other.

However, given that the VFD group mean cortisol remains stable, cortisol decrements are evidently exquisitely matched by cortisol increments in relatively advantaged, yet equivalently challenged, dyads, hence the concept of social allostasis. For the cross-sectional analysis Fig 7 , the relationship between maternal plasma cortisol level and maternal body mass as a function of VFD exposure was examined in a factorial design fashion.

To counter the notion that our findings represented a non-specific time effect we analyzed the early and late VFD onset groups. The groups were equivalent for maternal and infant variables, except for infant age at the point of onset of VFD exposure [ 21 ]. Effects were unchanged when controlling for infant age at the onset of VFD or infant sex.

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Variable Foraging Demand VFD is typically utilized as an experimental model for examining the behavioral and neurobiological sequelae of early life stress in grown offspring exposed to a socioecological stressor [ 14 , 44 ]. In the current study, however, we used VFD as a model of maternal allostasis [ 18 ], wherein we analyzed maternal HPA axis alterations after socioecological instability on both an individual and at a group level. However, the within-group distribution of maternal cortisol post-VFD exposure values was significantly altered.

Consistent with studies of previous unstable baboon social hierarchies where high levels of cortisol levels are observed in the dominant subjects [ 45 ], relative increases in cortisol levels were observed in dominant mothers, whereas relative suppression of plasma cortisol was observed in subordinate mothers. These data indicate that 1 social rank plays a significant role in determining the directionality and magnitude of the individual's allostatic response to VFD and 2 allostatic mechanisms also function beyond the level of the individual to maintain group homeostasis of cortisol levels for the social group, even when controlling for pen sequence.

One possible hypothesis is that, under conditions of VFD, the dominant animals may be more calorically impacted by the foraging unpredictability, hence the cortisol increments relative to the subordinates as they muster the energy to monopolize resources.

On the other hand, subordinates exhibit lower cortisol, which can provide a number of significant evolutionary adaptations when exposed to allostatic forms of stress: 1 minimizing glucose utilization and oxidative stress when food accessibility is restricted [ 30 ]; 2 promoting increased immunity for wound healing and prevention of infection if injured in a hierarchical encounter with a dominant mother; and 3 increasing sympathetic nervous system output, due to a lack of glucocorticoid dampening effects [ 46 , 30 ].

Although pre-VFD cortisol levels were not associated with social rank, they strongly predicted the magnitude and directionality of the cortisol response. Subjects with relatively low cortisol pre-VFD increased cortisol levels whereas subjects with high pre-VFD plasma cortisol values exhibited reduced cortisol post-VFD and intermediate cortisol values remained relatively unchanged Fig 4.

As can be seen in the cluster analysis Fig 5 , factors that promote maternal cortisol decrements include smaller, more subordinate mothers with smaller infants at the time of VFD onset, with reduced maternal-infant dyadic distance suggesting an association between socioecological vulnerability and cortisol suppression.


These data are consistent with parallel work in our laboratory indicating that juvenile CSF CRF elevations are directly associated with increases in adult monocyte glucocorticoid receptor mRNA expression, which would tend to be associated with cortisol reductions see Appendix. The sizeable range of infant age at the point of VFD onset allowed us to capture the effects of relative infant immaturity vulnerability on maternal glucocorticoid response.

The opposite is true of the relatively light females where at baseline relatively high cortisol is maintained, but VFD exposure promotes cortisol decrements. Our results are consistent with the findings of a recent meta-analysis where it was noted that male and female primates differ in their respective relationships between glucocorticoid production and social status as a result of differences in social behavior and associated costs involved in acquiring and maintaining rank [ 50 ].

More specifically, dominant males typically produce more glucocorticoids than subordinate males since their rank is achieved by violent turnovers of existing hierarchy, and competition over access to mates. On the other hand, subordinate females produce more glucocorticoids than dominant females in hierarchies where rank is achieved via subtle aggressive and affiliative interactions, and competition is over access to quality food resources. In our study, we found that subordinate females also exhibited higher cortisol levels than dominant females at baseline, but a reversal of this pattern occurred after VFD exposure.

Moreover, regression to the mean would be accompanied by a significant reduction in variance measures over time, despite an unchanged mean, which is not the case. The absence of mean change in cortisol in the face of large within group changes, accompanied by an overall increase in CSF CRF concentrations from pre-to post-VFD, indicate that homeostatic adjustments serve to maintain overall group HPA axis function within a narrow range.

The current data are consistent with recent results, where overall mean glutamate levels were maintained within a narrow range in response to VFD, despite the marked within-subject changes [ 52 ] see Appendix. In a previous study of male cynomolgus monkeys, subordinate subjects exhibited significantly higher cortisol concentrations on initial social housing, but by the end of 12 weeks, dominants were found to have higher cortisol and testosterone.

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However, those monkeys were not subjected to experimentally controlled conditions of stress in the week period, and mean cortisol concentrations of the entire group before and after 12 weeks were not addressed [ 47 ]. Our demonstration of allostasis functioning at the group level suggests that all subjects who underwent the VFD stressor exhibited, to some degree, physiological synchronization suggesting functioning as a single mammalian entity or organism.

In individual organisms, chronic elevations of glucocorticoids can lead to a multitude of effects, including weight gain [ 53 ], suppressed immune system functioning [ 54 ], and impaired adaptive responses to acute stress [ 50 ].

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It remains to be determined what advantage, if any, would be gained through the maintenance of mean cortisol stability in the face of the VFD form of socioecological stress. According to Williams, group adaptations may arise purely by statistical chance, a possibility in the current study. The question is raised—under what circumstances can the concept of adaptation be applied to groups, rather than individuals [ 56 ].

Several caveats regarding the current data should be considered. Because we elected not to intervene during VFD so as not to disturb the experimental process, we are unable to assess the rate and pattern of maternal cortisol secretion that together comprise the divergent forms of cortisol response observed in response to VFD exposure. Moreover, more detailed HPA axis studies, such as the dexamethasone suppression tests with or without CRF administration [ 57 , 58 ] may have shed light on pathophysiological mechanisms in the current study [ 59 ].

Our main goal, however, was to obtain measures that were reflective of ambient glucocorticoid function within the context of the VFD stressor. Another limitation was the longitudinal design yet the creation of a VFD non-exposed control group was feasible by virtue of the staggered design [ 19 ]. The cross-sectional analysis clearly demonstrates that VFD exposure significantly alters the relationship between maternal weight and HPA axis response in comparison to non-exposed subjects.

These data refute the notion that the results of the study may be attributable solely to a time effect. Another caveat is that we fail to address potential physiological mechanisms that may mediate social allostasis. Additional studies are clearly required, but proof of concept has been provided.

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  5. During acute stress, elevated juvenile CSF CRF concentrations were associated with a rapid reduction in adult GR mRNA expression, evidently a dynamic response to facilitate the observed cortisol elevations in response to acute stress [ 23 ]. The allostatic state of persistent hypocortisolemia facilitates restraint of glucocorticoid output with certain adaptive advantages [ 63 ] while allowing the organism to preserve the flexibility to mount an adequate HPA axis through rapid decrements of monocytic GR receptors [ 23 ]. We have not included this data in this particular study as it is part of a working manuscript relating VFD, maternal glutamate and serotonin neurophysiology in offspring.

    This data was presented as a peer-reviewed poster at SOBP conference [ 52 ]. Browse Subject Areas?

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    Click through the PLOS taxonomy to find articles in your field. Abstract Introduction Food insecurity is a major global contributor to developmental origins of adult disease. Methods Twenty-four socially-housed bonnet macaque maternal-infant dyads were exposed to 16 weeks of alternating two-week epochs of low or high foraging demand shown to compromise normative maternal-infant rearing.

    Introduction Allostasis is a concept developed by McEwen and Stellar which refers to the process whereby the organism achieves homeostasis through physiologic or behavioral changes in response to an allostatic load or chronic stressful conditions [ 1 — 4 ]. Subjects Twenty-four mother-infant bonnet macaque dyads served as subjects, with all subjects born and reared in social groups within SUNY Downstate Nonhuman Primate facility.

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    Download: PPT. Fig 1. Representation of study design with staggered onset of VFD exposure based on infant age allowing for cross-sectional data analysis. Housing All subjects were socially housed in one of four pens and observed in tile-walled pens approximately 6 x 12 x 7 feet high with mesh ceilings, two levels of shelving, and two automatic watering spouts.

    VFD rearing For the VFD rearing exposure [ 15 ], mothers were confronted with an environment in which an adequate amount of food was always available yet the amount of time and effort necessary to obtain daily rations leading to a perception of foraging uncertainty, with persistent psychobiological effects observed in grown offspring [ 33 ].

    Maternal-infant proximity Dyadic-distance During daily behavioral sessions, each mother-infant dyad was observed for 20 seconds in a random sequence on five serial observation periods. Biological samples Peripheral blood and cisternal CSF samples were obtained prior to the onset and during the last week of the VFD cycle. Statistical methods Key variables were tested for normality of distribution using the Kolmogorov-Smirnov test and data inspected for outliers.