What is the difference between allostatic load and allostatic overload

Biological differences have been proposed to explain such differences since experimental studies in rodents suggest sex differences in the neural remodeling pattern after stress 10 , However, psychosocial influences cannot be excluded as women are also more exposed to psychosocial stress and trauma 30 , 49 , Women in fertile age are less prone to cardiovascular disease and mortality than men 28 , 31 , 51 , In a previous study of our group in patients with anxiety disorders, women showed higher anxiety levels than men, with a better profile in many individual AL variables, particularly cardiovascular systolic blood pressure , obesity body mass index , and lipids with higher HDL high density lipoprotein cholesterol levels On the opposite, AL inflammatory parameters tended to be higher in women 30 , 46 , Regarding age factors, elderly patients were more vulnerable to stress-related disorders and expressed higher levels of cumulative AL 2 , 6 , 7 , The hippocampus has been in the focus of stress research especially after the finding that glucocorticoids receptors are abundantly expressed in hippocampal cells A large body of evidence in rodents demonstrated that chronic stress, via elevated levels of glucocorticoids, can affect both hippocampal structure and function 16 , 33 , 54 and can also induce depressive-like behavior Adult hippocampal neurogenesis the brain capacity to develop new neurons during adult life 55 , decrease with age and is especially affected by chronic stress 15 , 56 , Hippocampal structure and function might be altered in patients with depression.

Reductions in hippocampal volume based on magnetic resonance imaging studies have been consistently documented in patients with major depression 58 , For example, patients suffering from recurrent depressive episodes showed lower hippocampal volume 60 , Similarly, in Cushing's disease, the duration of the illness predicts a progressive reduction in the hippocampus volume, which was determined by structural magnetic resonance imaging Besides, the atrophy of the hippocampus has also been reported among patients with anxiety-related disorders and post-traumatic stress disorder Moreover, depression is a common comorbidity in patients with resistant temporal lobe epilepsy and hippocampal sclerosis 14 , 64 , In humans, adult hippocampal neurogenesis occurs in the hippocampal dentate gyrus, and newborn neurons can be produced from neural stem cells which can be classified based on their distinctive morphology as radial glia-like 66 and non-radial glial cells Chronic physical stressors, chronic psychosocial stressors, and chronic unpredictable stressors, can inhibit one or more phases of the adult hippocampal neurogenesis process Neurotransmitters systems that regulate adult hippocampal neurogenesis might be affected by chronic stress: The enhance of glutamate release via NMDA N-methyl-D-aspartate receptor , the reduction of GABA Gamma aminobutyric acid levels, the reduction of 5HT serotonin levels and the down regulation of 5HT1A serotonin receptor 1A; stimulation of 5HT1A is pro-neurogenic , and the alterations in noradrenaline, dopamine, and endocannabinoids were described 18 , 57 , Stress can also reduce the expression of neurotrophic factors involved in adult hippocampal neurogenesis regulation e.

Neurotrophic factors have been shown to increase adult hippocampal neurogenesis and also modulate antidepressant-related effects and behavior in experimental models 18 , Adult hippocampal neurogenesis is involved in mediating the response to antidepressant drugs 18 , The suppression of adult hippocampal neurogenesis achieved by chronic stress can be prevented by administering antidepressants 72 , 73 which reverse the inhibitory effect of stress after 3—4 weeks of treatment time course of maturation for newly generated neurons 17 , 72 — Antidepressants require of adult hippocampal neurogenesis mechanisms to be effective 57 , 76 and involve the activation of glucocorticoid receptors in the hippocampus The stimulation of adult hippocampal neurogenesis has been considered a promising property for identifying new antidepressant targets.

At the moment almost all antidepressant treatments including pharmacotherapy and behavioral interventions, proved to stimulate adult hippocampal neurogenesis 15 , 57 , During stress response sympathetic system is simultaneously activated with HPA system, and both noradrenaline and cortisol are released, amplifying the emotional response 4 , 5 , 10 , Anxiety has been proposed as an undifferentiated form of fear or rage, discharged by noradrenaline and cortisol Anxiolytic drugs acting through a positive allosteric modulation of GABA-A receptor benzodiazepines , reduce the sympathetic discharge leading to lower plasma levels of catecholamines 80 — 82 and lower salivary levels of MHPG 44 , 45 , 83 , Benzodiazepines, particularly those of high-potency such as alprazolam, have demonstrated anti-hypertensive pleiotropic properties in patients with high blood pressure without affecting the heart rate 81 , In our previous work 32 , low doses of alprazolam during 12 weeks reduced anxiety levels and the total AL index.

We observed a significant reduction on salivary levels of MHPG and on systolic blood pressure 12 , Many studies based on experimental research in rodents demonstrated that physical activity interventions may promote hippocampal neuroplasticity, counteracting the negative effects of chronic stress on the brain 15 , 19 , 90 — Also, higher synaptic plasticity and higher levels of BDNF Brain Derived Neurotrophic Factor , were observed in hippocampus, after voluntary and involuntary exercise 91 , Additionally, the use of combined treatments e.

In humans, neuroimaging studies using MRI Magnetic Resonance Image demonstrated that physical activity increased the hippocampal volume and positively correlated with better performances on hippocampus dependent tasks episodic memory Physical activity can enhance some indirect signs of neuroplasticity e.

Plasma levels of BDNF have been proposed as a potential biomarker of depression treatment. Serum BDNF is decreased in depressed patients and can be normalized with antidepressant treatment together with moderate to intense physical activity 97 , Physical activity has been considered a non-stigmatizing intervention with few side effects and has been associated with the relief of depression and anxiety symptoms in different studies 20 , 21 , 99 , Different types of physical activity aerobic, stretching, leisure-physical activities, dance, yoga asanas , have been associated with lower depression and anxiety prevalence in population-based studies 23 , — , with a better outcome in patients with depressive disorders — and with lower scores of self-reported stress, anxiety, and depression scales in healthy subjects — In a meta-analysis of relevant randomized controlled clinical trials, aerobic exercise showed moderate to large effects for patients with major depression and favoured over classical psychological treatments or antidepressants drugs Physical activity may act as an adjunctive treatment to traditional medication and psychotherapy, resulting in a more effective approach toward relief of psychiatric symptoms and AL 19 , 20 , 99 , All resumed studies, population-based studies and clinical trials, found a positive effect on depression and anxiety symptoms outcome in healthy subjects and in patients with depression.

Although the total AL index was not measured, some of these studies analyzed certain AL parameters outcome. Obesity factors were positively associated with depression and negatively with physical activity A lower fitness level in cardiopulmonary exercises was observed in patients with depression Minor resting pulse was associated with physical activity and lower risk to develop depression in healthy subjects Also, lower heart rate and diastolic blood pressure and higher HDL cholesterol, were observed among inpatients with major depressive disorder who underwent to a physical activity-training program Regarding the effects of physical activity on AL parameters sex differences were also reported , Women showed higher levels of c-reactive protein, which positively correlated with measures of adiposity and inversely associated with fitness, suggesting that adiposity may play a more substantial role in inflammation in women Although these preliminary findings are promising, larger and adequately powered randomised controlled trials are needed to better evaluate the combined effect of physical activity and classical treatments on allostatic load and on depression and anxiety.

Table 2 Description of the studies that have been analyzed the physiological AL parameters and the effects of physical activity and yoga asanas on anxiety and depression outcome.

In the last years, yoga has become popular in western cultures and constitutes an interesting tool for stress management. Although yoga originated in India, different yoga styles are practiced in western societies at present. Most of the different styles contain physical postures termed asana in Sanskrit , as well as breath control exercises pranayama and meditation dyana A meta-analysis of randomised controlled trials performed on healthy subjects and on patients with medical conditions e.

Also, yoga practice showed positive effects on depression and on anxiety symptoms in pregnant women , improved the mood states in psychiatric inpatients and had beneficial effects on depression outcome in patients with major depressive disorder — Regarding AL parameters, attenuated and decreased levels of salivary cortisol after yoga practice were reported in clinical trials on healthy patients , These results correlated with lower perceived stress and negative affect and with better cognitive functions, lower self-reported stress, and minor anxiety levels Table 2.

Clinical evidences showed that yoga asanas can modulate the autonomic nervous system inducing higher parasympathetic activity, lower blood pressure, lower heart rate, higher relaxation and approach behaviors 21 , In a recent study using magnetic resonance spectroscopy yoga practice has been associated to higher GABA levels in patients with major depressive disorder A combination of body awareness-yoga asanas and mindfulness meditation has been developed in a complete program for stress reduction 21 and has been proposed to clinicians as a safe and effective technique to reduce stress and anxiety in diverse patient populations 21 , , reducing stress, anxiety and depression, increasing the quality of life and well-being , — Yoga practice effectively decreases depressive and anxious symptomatology, although the neurobiological mechanisms involved are not totally elucidated Regarding brain effects, neuroimaging studies demonstrated that hippocampus is activated during yoga practice , , Moreover, a significantly greater hippocampal volume has been found in experienced yoga practitioners , , and higher volumetric measures in different brain areas were positively correlated with the years of yoga practice Non-pharmacological interventions such as physical activity and yoga practice may exert synergizing effects to antidepressant and anxiolytic treatments.

The classical treatment of patients with anxiety disorders and depression is psychotherapy, but pharmacotherapy is recommended when psychiatric symptoms are severe enough to induce a significant functional impairment However, pharmacological treatments may be associated with adverse side effects. Physical activity and yoga practice have been shown to elicit improvements in anxiety and depression symptoms conducting to a better social, physical, and affective well-being optimizing the pharmacological treatment duration and the risk of pharmacological adverse side effects.

However, larger and adequately powered randomized controlled trials are needed to evaluate the combined effect of physical activity on allostatic load and on depression and anxiety. Also, is important to emphasize that future studies are needed to reveal the biological mechanisms involved in the therapeutic actions of physical activity and yoga, in particular on depression and anxiety.

Furthermore, stratified interventions according to sex and age should be considered in the future to track the therapies toward an individualized schedule in agreement with the current medical practice.

LD'A and ER have given the final approval of the version to be published. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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The rats were anesthetized with gas Isoflurane; Baxter Healthcare Corp. All proton spectra of the rat amygdala and hippocampus were recorded with transmitter volume TV3 and rat brain receiver surface TV3 1 H radiofrequency coils Bruker, Ettlingen, Germany. High-resolution T2-weighted images of the rat brain in three axial, sagittal, and coronal dimensions section thickness, 0.

Voxel dimensions were 3. Uniformity of the magnetic field was tuned within the selected voxel using FastMap Gruetter, before each spectroscopic recording. The experimental 1 H magnetic resonance spectra were processed, and the quantitative composition of metabolites was determined with a custom program similar to the LC Model software package Provencher, , which assume that the spectrum of a mixture of known compounds is a linear combination of analyzed components.

The details of the data processing were published Moshkin et al. The baseline correction is conducted automatically by the program in order to determine the spectral base-line for fitting of the spectrum obtained by 1 H MRS. The process of fitting is presented on the real-time plot Figure 3 , and the fitting results data are stored in numerical form.

Between a. The assay sensitivity was 0. To induce chronic stress rats were exposed to cat urine scent in a Petri dish with litter for 10 min daily for 10 days 20 rats were submitted to stress exposure; 8 control rats were exposed to a neutral scent. All procedures were performed between and p. During the scent exposure protocol, stress-related behavior was captured daily via web-camera. Days 1— PSS. Days 11— Rest. Day Elevated plus-maze test. Day Amygdala metabolite measurement by MRS.

Day Euthanasia, harvest blood and organs. AOR; control vs. Chronically stressed rats were divided into two phenotypes based on their behavior in anxiety-related situations, as described above. The first phenotype was labeled AOR, i. The second phenotype was labeled PDR, i. However, exploring in OA was similar in both groups subjected to PSS, and there were no differences with control. Overall, the different behavioral phenotypes in response to PSS exposures were characterized by the differences in anxiety levels 14 days post PSS cessation.

The anxiety levels between control and PDR rats were not significantly different. Figure 4. There was no significant difference in Lact concentrations between PDR and control 3. PDR rats No significant differences in the concentrations of other metabolites were found between the groups one-way ANOVA. Thus, as with the other parameters measured, the significant differences were found only in the AOR group when compared to PDR or control groups.

Figure 5. Figure 6. Spectral fitting Proton-MRS of metabolites in the amygdala of one representative rat from each of the three behavioral subtypes. PDR rats after chronic predator stress, suggesting a possible endogenous calming psychophysiological mechanism in the AOR phenotype. In addition, Lact levels were elevated in the amygdala of AOR compared to PDR animals, which would be consistent with increased metabolic demand Riske et al. Interestingly, time in the open-arm of the maze indicating less-anxious behavior was positively correlated with lactate levels in the amygdala of AOR rats, suggesting a possible link between the behavioral phenotype and physiology.

Such changes were not found in the hippocampus, suggesting this may be a local rather than global phenomena, and future studies in additional brain regions can shed further light on the regional vs.

The progression from homeostasis to allostatic overload has been well-established and includes hormonal, structural and epigenetic changes Mathew et al.

As evidence of increased dendritic remodeling in the hippocampus during allostatic load, it has been shown that dendritic remodeling can be blocked by phenytoin, which in turn inhibits Glu release and antagonizes sodium and likely T-type calcium channels that are activated during glutamate-induced excitation Korte et al.

However, the recurrent nature of the predator stress stimuli in our study suggests a switch from increased glucocorticoid levels in response to the acute stress, to an allostatic state with decreased glucocorticoid levels following continued predator stress. Others Bowen et al. The physiological changes that were seen within these two threat-induced behavior responses AOR and PDR allowed us to assess the allostatic load in behaviorally active vs.

The amygdala is a glucocorticoid-responsive structure, lower CORT levels lead to lower amygdala activity, and glutamatergic neurons mediate amygdala excitation Mcewen, We posit that lower Glu levels in the AOR animals may represent low level activity of glutamatergic neurons in the amygdala, whereas the higher Glu levels in PDR rats may reflect dendritic remodeling not only in the hippocampus Mcewen et al.

This physiological reaction may occur via gene methylation processes Klengel et al. Historically, some have postulated that corticosteroids and the sympathomimetic amines have analogous roles because their multiple action sites and the nature of their induced responses are often similar Ramey and Goldstein, However, while their roles are complementary and integrative, they are not interchangeable. Many actions of the sympathomimetic amines are not elicited in the absence of corticosteroids.

Steroids maintain the integrity and responsiveness of tissues that are in the process of reacting to the sympathomimetic amines.

This relationship is best seen on exposure to stress, when lower steroid levels may be elicited by heightened sympathetic-medullary activity. In the absence of corticosteroids, responses to neurohormones are diminished, and the deleterious effects of adrenal insufficiency are amplified. Given the closely intertwined roles of the sympathomimetic amines and glucocorticoids, theoretically it would be conceivable that the glucocorticoids may also have roles analogous to sympathetic functions, and vice-versa the sympathomimetic amines may have roles analogous to parasympathetic functions.

Mounting evidence in recent years suggests an interaction between the adrenal medulla and adrenal cortex, and an influence of adrenal innervations on adrenocortical functions Ehrhart-Bornstein et al. Additionally, glutamatergic hippocampal giant mossy fiber terminals MFTs play a crucial role after chronic restraint stress, along with multiple interacting mediators of neuronal remodeling that include brain derived neurotrophic factor BDNF Mcewen et al.

Concerning cholinergic modulation of amygdala circuits in the formation and retention of fear memories Jiang et al. Additionally, the effects of higher physical activity include increased glucose metabolism and, in extreme stress, increased lactate levels, which also ensure that brain and muscle metabolism can continue when glucose levels fall. Increased glucose metabolism in the amygdala of depressed subjects and the positive effect of exercise in subjects with fatigue suggest possible antidepressant effects of Lact Mustian et al.

Integrating these results with supporting studies and existing literature, one possible explanation is that AOR rats enter an allostatic state in which adaptive behavioral responses serve to calm the animal and restore homeostasis following chronic fear and stress. However, our current data cannot exclude the possibility that animals stratify into AOR and PDR groups by their pre-existing underlying physiologies—i. Therefore, follow-up studies will incorporate baseline reads for all animals, to help clarify whether the observed physiologic differences, suggestive of allostatic adaptive states, exist before or newly accompany the AOR vs.

PDR behavioral phenotypes. These studies, together with appropriate blockade studies, will provide a clearer picture of which physiological changes may be causal vs.

PDR phenotypes in a natural environment: perhaps AOR rats would be more likely to get eaten which would make for a poor and evolutionarily short-lived adaptive strategy! Finally, all measurements were done at the end of chronic stress exposure. Thus, our results reflect the end point, and while the amygdala and the hippocampus are critical limbic areas that regulate emotion, other brain areas are also likely involved in these observed behavioral paradigms e.

Dealing with acute and chronic stress is an evolutionary challenge that affects all of us. Based on this and other data shown herein, we posit that allostasis may be a protective mechanism in rats for adapting to chronic stress, and further studies are warranted to expand these findings in rodents, and determine whether similar mechanisms exist for dealing with chronic stress in humans.

Chronic stress affects not only our mental health and well-being, but also our physical health, and plays multiple roles in anxiety, depression, and other psychiatric disorders, as well as diabetes, cardiovascular, and neurologic diseases, and a range of inflammatory and metabolic conditions.

The body and the brain have substantial capacity for adaptive plasticity; thus all changes described here are not necessarily irreversible Korte et al. Our results provide new insights into the regulation of mammalian stress responses. EU and VT organized the study, analyzed the data, drafted the manuscript, and prepared the figures and tables.

All authors reviewed the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This project was part of our TransCampus Initiative. We thank Professor Bruce S. Adamec, R. CRF receptor blockade prevents initiation and consolidation of stress effects on affect in the predator stress model of PTSD. NMDA receptors mediate lasting increases in anxiety-like behavior produced by the stress of predator exposure—implications for anxiety associated with posttraumatic stress disorder.

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