Post-stress Rest Research Articles

PRIMING OF MICROGLIA ACTIVITY INCREASES SUSCEPTIBILITY TO DEPRESSION-LIKE BEHAVIORS

This study investigates the role of microglia activity in stress-induced depression and anxiety and the mechanisms associated with the role of certain microbiome derived anti-inflammatory polyphenols in attenuating stress-induced microglia immune priming and symptoms of depression. We implemented a chronic unpredictable stress (CUS) paradigm to exhibit priming of microglia innate immunity in the context of the onset of depression and anxiety phenotypes. Mechanistic studies related to prophylactic treatment using dietary microbiome derived polyphenols were also investigated in this model. Depression and anxiety phenotypes, gene expression in microglia and protein expression in the cortex of mice were measured following a primary exposure to short-term unpredictable stress (US) followed by CUS. We examined the long-term, persistent CUS induced changes at 4-weeks of post-stress rest following a secondary US exposure. We found depression phenotypes resulted from US only following exposure to CUS. This was accompanied by an increase and persistent upregulation of toll-like receptor 4 (TLR4), RAGE, and HMGB1 gene expression in isolated cortical microglia. Priming by CUS also amplified gene expression of IL-1β in microglia and protein IL-1β in the cerebral cortex following US re-exposure. Increased activity of NF-kB was also noted in the period following CUS. Furthermore, polyphenol treatment prevented stress-induced phenotypes, upregulation of HMGB1, IL-1B, and TLR4 gene expression, as well as upregulation of IL-1β and NF-kB. The study suggests that latent activity of the TLR4-NFkB-IL1β pathway contributes to immune priming and increases susceptibility to depression-like behaviors. Anti-depressant effects of polyphenols may result from their ability to attenuate microglia priming.

Chronic stress produces enduring sex- and region-specific alterations in novel stress-induced c-Fos expression

Prolonged or repeated exposure to stress increases risk for a variety of psychological disorders, many of which are marked by dysfunction of corticolimbic brain regions. Notably, women are more likely than men to be diagnosed with these disorders, especially when onset of symptoms follows stressful life events. Using rodent models, investigators have recently begun to elucidate sex-specific changes in the brain and behavior that occur immediately following chronic stress. However, little is known regarding the lasting sequelae of chronic stress, as well as how potential changes may impact responsivity to future stressors. We recently demonstrated that male and female rats show different patterns of dendritic reorganization in medial prefrontal cortex in the days following chronic stress. Here, we examined the immediate and lasting effects of chronic restraint stress (CRS; 3 h/day, 10 days) on neuronal activation, across several corticolimbic brain regions, induced by novel acute stress exposure. Chronically stressed male and female rats were exposed to acute elevated platform stress (EPS) either 1 (CRS-EPS) or 7 (CRS-Rest-EPS) days after CRS. Compared to rats exposed to EPS only, significant reductions in acute stress-induced c-Fos expression were observed in the medial prefrontal cortex, hippocampus, and paraventricular nucleus of the hypothalamus (PVN) in CRS-EPS male rats, some of which persisted to 7 days post-stress. In contrast, we found little modulation of novel stress-induced c-Fos expression in CRS-EPS female rats. However, CRS-Rest-EPS female rats exhibited a significant enhancement of acute stress-induced neuronal activity in the PVN. Together, these data show that prior chronic stress produces sex- and region-specific alterations in novel stress-induced neuronal activation, which are dependent on the presence or absence of a rest period following chronic stress. These findings suggest that the post-stress rest period may give rise to sex-specific neuroadaptations to stress, which may underlie sex differences in stress susceptibility versus resilience.

BDNF and TrkB Mediate the Improvement from Chronic Stress-induced Spatial Memory Deficits and CA3 Dendritic Retraction

The brain is capable of improving from a chronically stressed state. The hippocampus in particular appears to “recover” from chronic stress-induced morphological and functional deficits following a post-stress rest period of several weeks. We previously found that hippocampal brain-derived neurotrophic factor (BDNF) was necessary for spatial ability to improve following a post-stress rest period. The following studies are the first to investigate the involvement of BDNF and its TrkB receptor on the recovery process following the end of chronic stress, as it pertains to hippocampal dendritic retraction and spatial memory deficits. In the first study, hippocampal BDNF was downregulated via RNA interference and then hippocampal CA3 and CA1 dendritic complexity were evaluated following chronic stress and a post-stress rest period in male Sprague–Dawley rats. Downregulating hippocampal BDNF prevented the enhancement of CA3 apical dendritic complexity following the rest period. Moreover, chronic stress and downregulated BDNF in the post-stress rest group led to regionally specific enhancements in CA1 dendritic complexity. In the second study, we tested whether the TrkB receptor was involved by administering daily systemic injections of ANA-12, a TrkB receptor antagonist, during the three-week post-stress rest period. ANA-12 prevented the improvement in spatial ability and CA3 apical dendritic complexity following the post-stress rest period. These data demonstrate that hippocampal BDNF acting via its TrkB receptor is necessary during the post-stress rest period in order to improve the impaired hippocampal structural and cognitive outcomes that occur in response to chronic stress.

The impact from the aftermath of chronic stress on hippocampal structure and function: Is there a recovery?

Chronic stress results in functional and structural changes to the brain and especially the hippocampus. Decades of research have provided insights into the mechanisms by which chronic stress impairs hippocampal-mediated cognition and the corresponding reduction of hippocampal CA3 apical dendritic complexity. Yet, when chronic stress ends and time passes, which we refer to as a "post-stress rest period," hippocampal-mediated spatial memory deficits begin to improve and CA3 apical dendritic arbors increase in complexity. The processes by which the hippocampus improves from a chronically stressed state are not simply the reversal of the mechanisms that produced spatial memory deficits and CA3 apical dendritic retraction. This review will discuss our current understanding of how a chronically stressed hippocampus improves after a post-stress rest period. Untangling the mechanisms that allow for this post-stress plasticity is a critical next step in understanding how to promote resilience in the face of stressors.

Differences in left ventricular ejection fraction and volumes measured at rest and poststress by gated sestamibi SPECT

Some studies suggested that the poststress left ventricle ejection fraction (LV EF) is lower than rest LV EF in patients with stress-induced ischemia. By using a 2-day protocol and 30 mCi Tc-99m sestamibi, LV EF, end-systolic volume (ESV), and end-diastolic volume (EDV) were measured with gated SPECT. Of 99 eligible patients, 91 had technically adequate studies. Poststress LV EF minus rest LV EF was defined as DeltaLV EF. DeltaEDV and DeltaESV were similarly defined. Rest and poststress LV EF (r = 0.89), EDV (r = 0.78), and ESV (r = 0.93) were highly correlated (P <.001). Rest LV EF, EDV, and ESV were not significantly different between patients with and without stress-induced ischemia. DeltaLV EF was significantly lower in patients with stress-induced ischemia (-3.5% +/- 4.5% vs -1.1% +/- 4.7%, P = .02). Mean LV EF poststress in ischemic patients was 55.0% +/- 10.5% vs 61.2% +/- 10.0% in nonischemic patients (P = .008). However, only 1 patient (3%) with ischemia had DeltaLV EF that exceeded the 95% confidence limit of DeltaLV EF for normal patients. Ischemia was significantly associated with increased DeltaEDV and DeltaESV (P < .01). Stress-induced ischemia is associated with poststress reduction in LV EF and increased poststress EDV and ESV. However, the effect of ischemia on the difference between poststress and rest EF measurements is modest and rarely exceeds the confidence limits in normal patients undergoing 2-day protocols. In most patients, poststress LV EF is an accurate reflection of rest LV EF.

Worsening of left ventricular ejection fraction induced by dipyridamole on Tl-201 gated myocardial perfusion imaging predicts significant coronary artery disease

Vasodilator stress on myocardial perfusion imaging has been found to induce ischemic stunning, which may present as transient worsening of left ventricular ejection fraction (LVEF) or regional wall motion abnormality. This study aimed to evaluate the significance of stress-induced worsening of LVEF in the diagnosis of coronary artery disease (CAD) on dipyridamole thallium 201 gated single photon emission computed tomography (SPECT). The study included 126 patients who underwent dipyridamole Tl-201 gated SPECT and coronary angiography within 3 months. Poststress and 4-hour rest images were obtained, and LVEF was calculated by use of automated software (QGS 3.0). A decrease in LVEF of 6% or greater from rest to poststress was considered significant, and this threshold was determined by the serial reproducibility assessment of Tl-201 gated SPECT. If worsening of LVEF was used as the criterion for detecting significant CAD (> or = 70% coronary stenoses in > or = 1 vessel), the sensitivity, specificity, positive predictive value, and negative predictive value were 35%, 93%, 90%, and 44%, respectively. Dipyridamole-induced worsening of LVEF, as shown by Tl-201 gated SPECT, is a valuable nonperfusion marker of significant CAD. Although the sensitivity of LVEF worsening in detecting significant CAD is only 35%, the specificity is as high as 93%.

Psychological, cardiovascular, and metabolic correlates of individual differences in cortisol stress recovery in young men.

The relationship of free salivary cortisol stress recovery and basal cortisol with psychological, cardiovascular and metabolic factors was investigated in 82 healthy young men. Blood pressure, heart rate, cortisol and mood were assessed during a single laboratory session involving mental arithmetic and speech tasks, and lipid profiles were analysed from a fasting blood sample. Participants were divided into high (n=31) and low (n=51) cortisol stress recovery groups on the basis of the magnitude of changes between the peak cortisol responses to tasks and the lowest levels recorded at the end of a 30 min post-stress rest period. The high recovery group showed consistent increases in cortisol following each of the tasks, while the low recovery group showed little change across the session. Cortisol levels in the two groups did not differ at the end of the post-stress recovery period. The groups were indistinguishable in age, body mass index, smoking and alcohol consumption, and did not differ in psychological characteristics including anxiety, depression and perceived social support. However, the high stress recovery group had elevated low density lipoprotein cholesterol and total cholesterol/high density lipoprotein ratios, suggesting raised cardiovascular disease risk. The high stress recovery group also reported greater psychological activation during tasks, and greater recent minor life stress, than did the low recovery group. There was no association between rate of cortisol recovery and cardiovascular responses to tasks. But resting cortisol was related to blood pressure stress reactivity, suggesting that cortisol played a permissive role in augmenting sympathetically-driven cardiovascular responses. The results suggest that the rate of cortisol stress recovery is associated with variations in metabolic risk, and with differences in psychological state but not trait characteristics.

Amino Acid Effects on Post-Stress Ulcers: Relationship to Brain Serotonin, 5-HIAA and Norepinephrine

To replicate and extend results of earlier studies on amino acid effects on post-stress ulcers, rats were subjected to i.p. injections of (a) saline, (b) tryptophan, (c) tyrosine + valine or (d) tryptophan + tyrosine + valine, either 30 minutes before or immediately after one hour of water restraint stress. Gastric lesions, brain norepinephrine, serotonin and 5-hydroxyin-doleacetic acid (5-HIAA) were examined after one hour of poststress rest. We hypothesised that post-stress lesions could be aggravated by central noradrenergic hypoactivity and serotonergic hyperactivity during the post-stress period. Other studies have indicated that tyrosine + valine reduces central serotonergic activity, while additional tryptophan blocks this effect. We therefore expected post-stress lesions to be reduced in tyrosine + valine but not in tryptophan + tyrosine + valine treated animals. Although these expectations were met tentatively in animals injected prior to stress, thus replicating tyrosine + valine effects we had observed earlier, opposite results were found in animals treated post-stress. The brain analyses indicate that the data cannot be explained by a norepinephrine/serotonin imbalance hypothesis. The time dependency of the effects underlines the need for caution in clinical applications of these amino acid treatments.

Anticipatory and residual effects of an active coping task on pre- and post-stress baselines

This study examined several issues concerning baseline measurement in cardiovascular reactivity testing: effects of anticipation of stress on baseline, point at which initial baseline stabilizes, effects of a stressful task on a succeeding baseline, and gender differences in baseline patterns. Ten males and ten females sat for a 30-min initial baseline period, a 2-min stressor (mental arithmetic), and a 15-min post-stress period. An additional ten males and ten females participated only in the 30-min initial baseline (no stressor). There was no difference in initial baseline between the stress and no-stress conditions; nor were there interactions between this factor and gender. Initial baseline stabilized at resting levels after approximately one minute. Post-stress rest levels were significantly higher than initial baseline levels for blood pressure (5.8 and 4.8 mmHg for systolic and diastolic pressure, respectively), but not for heart rate. Implications of recovery of baseline are discussed.

Stress-induced changes in the rate of sodium excretion in healthy black and white men

The effects of exposure to competitive mental stressors on rates of excretion of sodium (Na), potassium (K) and fluid, together with cardiovascular responses, were evaluated in 14 black and 14 white normotensive men after 3 days of controlled diet (200 mEq Na, 100 mEq K daily). In the first hour of a 5-hr protocol, subjects ingested a standard dinner and drank 1 liter of water. In hours 2–5, they voided to provide urine collections every 30 min, and drank 200 ml additional water after each collection. Hours 1–2 were for stabilization of excretion, hour 3 was baseline, hour 4 was stress and hour 5 was post-stress rest. During stress, 20 men showed faster natriuresis and 8 showed slower natriuresis than at baseline. These subgroups did not differ in any excretion measure at baseline. During stress, the slow stress natriuresis group showed slower excretion of potassium and fluid as well as sodium; slow natriuresis and kaliuresis persisted 30 min after stress. Creatinine clearance rate was also decreased, but only during the first 30 min of stress. Slow stress natriuresis subjects were found to have higher blood pressures during baseline and stress, greater heart rate and cardiac output increases during stress, and a larger percentage had hypertensive parents (63 vs 37%) compared to fast stress natriuresis subjects. Slow stress natriuresis was observed in 50 vs 17% of men with resting diastolic levels above vs below 80 mmHg, and in 43% of blacks vs 18% of whites tested. Overall, black subjects tended to excrete sodium more slowly than whites at baseline, and showed significantly lesser increases in sodium excretion rate when pressures rose during stress.

The ulcerogenic effect of a rest period after exposure to water-restraint stress in rats

Shock-induced gastric ulceration in rats is exacerbated by allowing animals to rest between the period of stress and sacrifice. Conflicting data have been reported for similar post-stress rest effects using restraint stress. In Experiment 1, rats restrained in water for 2 h and then allowed a 2-h rest period exhibited significantly greater gastric ulceration than rats sacrificed immediately after the 2-h restraint-in-water stress period. The strength of this phenomenon is confirmed by Experiment 2, in which rats challenged with restraint in water for 1.25 h and then allowed a 1.25-h rest period before sacrifice exhibited greater ulceration than animals maintained in the restraint-in-water stress for the full 2 1/2 h. Corticosterone levels for these two treatment groups were similar at the time of sacrifice. Post-stressor rest therefore actively contributes to the ulcerogenic processes initiated by this form of stress challenge.

Interactions amongst factors which influence severity of gastric ulceration in rats

A number of factors have previously been demonstrated to influence the severity of stress-induced gastric ulceration in rats, including prior exposure to pre-shock and allowing animals a post-stress rest or recovery period. The primary purpose of this experiment was to investigate how one of these factors might modulate the expression of the other. Animals were pre-exposed to either signalled or unsignalled shock (using “learned helplessness” parameters), or no shock. They were later subjected to 2 hours restraint-in-water (immersion) stress, or appropriate handling control procedures. Half of the animals were sacrificed immediately on removal from the water-restraint, and half were sacrificed after a 2 hour recovery period in their home cages. Analysis of the severity and number of glandular stomach lesions indicated that animals subjected to the pre-shock exhibited greater ulceration than unshocked animals, as long as no post-stress rest period was allowed. Additionally, the effect of post-stress rest was masked by experience with pre-shock. This reciprocal modulation of treatment influences may offer suggestions for understanding discrepancies in the literature on the effects of these two modulating variables.

A new experimental model of stress ulcers employing aggressive behavior in 6-OHDA-treated rats

Rats receiving intraventricular injection of 6-hydroxydopamine (6-OHDA) were housed in isolation for one month and placed in the same cage as an untreated rat while being subjected to continuous tail pinching. 6-OHDA-treated rats violently attacked the untreated rat and stabilized fighting between the two animals persisted for over 1 hr. The 6-OHDA-treated rats consistently played the dominant role in the dominant-subordinate relationship established between the rats. By allowing this fighting to continue for 1 hr, gastric erosion associated with severe hemorrhage occurred with a high incidence in the untreated rats. These erosions were comparable in rats examined immediately after fighting and in those examined after 1 hr and 3 hr. Poststress rest was not required for erosion to occur. The presence of bite wounds incurred during fighting was unrelated to the incidence of gastric erosion. In addition, it was unnecessary to fast the untreated rats beforehand. Based on these findings, the present model apparently does not rely on physical stimulation. These factors and the ease of its execution make the present new experimental model of stress ulcers very useful.

Stomach mucosal lesions in stressed rats with and without post-stress rest

A post-stress increase in stomach lesioning has been previously reported in the literature on animal stress. In an effort to examine this phenomenon, we performed four different experiments, three with restraint-tail shock and one with a conflict-footshock design. Stomachs of post-stressed rested rats were compared to stomachs of rats sacrificed immediately after the stress session an additional period of time equal to the rest period. None of the experiments gave any evidence that the rest period aggravated stomach lesioning. The conclusion is that the rest period effect must depend on factors unstated in previous work and that it appears to be a fragile phenomenon.

Reduction of stomach ulceration by hypothalamic stimulation in the unrestrained rat

Gastric lesions were produced in unrestrained rats subjected to a 6 hr shock stress session followed by a 2 hr rest period. Electrical stimulation of the brain (posterior lateral hypothalamus) administered during the 2 hr post stress rest period significantly decreased ulcer development (i.e., percentage of animals showing lesions, number of lesions per animal, and severity of lesions) in the test group.