Predictable Chronic Stress Research Articles

Predictable chronic stress modulates behavioral and neuroendocrine phenotypes of zebrafish: Influence of two homotypic stressors on stress-mediated responses

The zebrafish (Danio rerio) has been considered a suitable model organism to assess the evolutionarily conserved bases of behavioral and neuroendocrine responses to stress. Depending on the nature of the stressor, prolonged stress may elicit habituation or evoke long-term changes in the central nervous systems (CNS) often associated with various neuropsychiatric disorders. Conspecific alarm substance (CAS) and net chasing (NC) constitute chemical and physical stressors, respectively, which cause aversive behaviors and physiological changes in fishes. Here, we investigate whether predictable chronic stress (PCS) using two homotypic stressors differently modulates behavioral and physiological responses in zebrafish. PCS-CAS or PCS-NC were performed for 14 days, 2-times daily, while locomotion, exploratory activity, anxiety-like behaviors, and whole-body cortisol levels were measured on day 15. PCS-CAS reduced distance traveled, the number of transitions and time in top area, as well as increased the latency to enter the top in the novel tank test. In the light/dark test, CAS-exposed fish showed decreased time spent in lit area, shorter latency to enter the dark area, and increased risk assessments. PCS-CAS also increased whole-body cortisol levels in zebrafish. Although PCS-NC reduced the latency to enter the dark area, whole-body cortisol levels did not change. Moreover, acute experiments revealed that both CAS and NC promoted anxiogenesis and increased cortisol levels, suggesting habituation to stress following PCS-NC. Overall, our novel findings demonstrate that PCS induces behavioral and physiological changes in zebrafish depending on the nature of the stressor.

Effect of enriched environment and predictable chronic stress on spatial memory in adolescent rats: Predominant expression of BDNF, nNOS, and interestingly malondialdehyde in the right hippocampus

Little is known about the mechanisms that promote divergence of function between left and right in the hippocampus, which is most affected by external factors and critical for spatial memory. We investigated the levels of memory-related mediators in the left and right hippocampus and spatial memory in rats exposed to predictable chronic stress (PCS) and an enriched environment (EE) during adolescence. Twenty-eight-day-old Sprague-Dawley rats were divided into control (standard cages), PCS (15 min/day immobilization stress for four weeks), and EE (one hour/day environmentally enriched cages for four weeks) groups. After the applications, spatial memory was tested with the Morris water maze, and the serum levels of corticosterone were evaluated. The levels of brain-derived neurotrophic factor (BDNF) and neuronal nitric oxide synthase (nNOS), which are critical for synaptic plasticity; malondialdehyde (MDA; lipid-peroxidation indicator); protein carbonyl (protein-oxidation indicator); and superoxide dismutase (antioxidant enzyme) were evaluated in the left and right hippocampus. Corticosterone levels in both the PCS and EE groups did not change compared with control. In both the PCS and EE groups, spatial memory improved and BDNF was increased in both halves of the hippocampus, still there was an asymmetry. nNOS levels were increased in the dentate gyrus and CA1 regions of the right hippocampus in both PCS and EE groups. MDA levels were increased but PCO levels were decreased in the right hippocampus in both the PCS and EE groups, but SOD did not change in either half of the hippocampus. Our results suggest that both PCS and EE improved spatial memory by increasing BDNF and nNOS in the right hippocampus and that, interestingly; MDA could be the physiological signal molecule in the right hippocampus for spatial memory process.

Experimental studies on possible regulatory role of nitric oxide on the differential effects of chronic predictable and unpredictable stress on adaptive immune responses

The present study was designed to investigate the effects of chronic predictable stress (CPS) and chronic unpredictable stress (CUS) on immunological responses in KLH-sensitized rats and involvement of NOergic signaling pathways mediating such responses. Male Wistar rats (200–250g) were exposed to either CPS or CUS for 14days and IgG antibody levels and delayed type hypersensitivity (DTH) response was determined to assess changes in adaptive immunity. To evaluate the role of nitric oxide during such immunomodulation, biochemical estimation of stable metabolite of nitric oxide (NOx) and 3-nitrotyrosine (3-NT, a marker of peroxynitrite formation) were done in both blood and brain. Chronic stress exposure resulted in suppression of IgG and DTH response and elevated NOx and 3-NT levels, with a difference in magnitude of response in CPS vs CUS. Pretreatment with aminoguanidine (iNOS inhibitor) caused further reduction of adaptive immune responses and attenuated the increased NOx and 3-NT levels in CPS or CUS exposed rats. On the other hand 7-NI (nNOS inhibitor) did not significantly affect these estimated parameters. The results suggest involvement of iNOS and lesser/no role of nNOS during modulation of adaptive immunity to stress. Thus, the result showed that predictability of stressors results in differential degree of modulation of immune responses and complex NO-mediated signaling mechanisms may be involved during responses.

Differential effects of chronic predictable and unpredictable stress on neurobehavioral and biochemical responses in rats

The present study was designed to investigate the effects of exposure to chronic predictable and unpredictable stress on neurobehavioral and biochemical responses in rats. Male Wistar rats (200-250g) were exposed to either chronic predictable stress (CPS) i.e. immobilization for 1 hour/day for 14 days or chronic unpredictable stress (CUS) i.e. daily a different, random, novel stressor sequence (immobilization stress for 1h, footshock, cold stress, overnight food and water deprivation and social isolation) for 14 days. Behavioral responses were assessed by the elevated plus maze (EPM) test and biochemical parameters, viz. malondialdehyde (MDA, a marker of oxidative stress) and stable NO metabolites (NOx, marker of nitrosative stress), were measured in brain homogenates of the rats. Exposure to chronic CPS resulted in adaptation to neurobehavioral suppression in the EPM (as observed after acute Restraint stress), which was not seen after CUS. These behavioral changes after CPS and CUS were closely paralleled by alterations in the levels of brain MDA and NOx. These results suggest that CPS and CUS results in differential modulation of the neurobehavioral profile and oxidative/nitrosative stress markers in the brain.

Sex-dependent effects of chronic unpredictable stress in the water maze

Exposure to chronic predictable stress, such as restraint, can affect performance on spatial memory tasks and these effects have been shown to be sex-specific in rats. It is not known whether unpredictable stress has similar sex-specific effects on spatial memory and whether those effects are present after the stress procedure has ended. Therefore, the current study tested male and female rats in the Morris water maze either immediately or 3 weeks following exposure to 10 days of unpredictable stress (CUS). Male and female rats were exposed to 10 days of stressors that varied by type and time of stressor application. Exposure to CUS decreased the distance swam to locate the hidden platform during acquisition training in the water maze for female but not male rats. Overall, male rats performed better than female rats during the acquisition, probe and matching to place trials. These effects were observed when assessing spatial memory performance immediately or 3 weeks following the last stressor. Plasma corticosterone levels followed the behavioral differences during the acquisition trials in that control female rats had increased basal and swim-stimulated corticosterone levels compared to CUS female rats and control male rats. These data demonstrate that unpredictable stress influences performance on the water maze in a sex-specific manner, which parallel plasma corticosterone levels. The improved performance of female rats following CUS exposure was present 3 weeks after the termination of the stress procedures, suggesting that stress may have lasting effects on underlying neural systems.

Endocannabinoids: Stress, Anxiety, and Fear

Endocannabinoids: Stress, Anxiety, and Fear

Nature of stress: Differential effects on brain acetylcholinesterase activity and memory in rats

Effect of acute, chronic–predictable and chronic–unpredictable stress on memory and acetylcholinesterase (AChE) was investigated in rats. The animals were subjected to 3 type of stressors — (1) acute immobilization stress, (2) chronic–predictable stress i.e., immobilization daily for 5 consecutive days and (3) chronic–unpredictable stress that included reversal of light/dark cycle, over-night fasting, forced-swimming, immobilization and forced exercise in random unpredictable manner daily for 5 consecutive days. Learning and memory function was studied by single trial Passive avoidance test. AChE activity was assayed spectrophotometrically in the detergent (DS) and salt (SS) soluble fractions in different brain regions. Learning was obtained in acute and chronic–predictable stress groups but not in chronic–unpredictable group. Acute, chronic–predictable and chronic–unpredictable stress caused significant decrease in AChE activity in the DS fraction of cortex, hippocampus and hypothalamus as compared to control. Results indicate that AChE in DS fraction is predominantly affected in stressed and stressed-trained group but cognition is affected only by chronic–unpredictable stress. In acute and chronic–predictable groups the decreased AChE activity in the hippocampal DS fraction during learning may be responsible to maintain cognitive function by enhancing the cholinergic activity.

Chronic unpredictable stress, but not chronic predictable stress, enhances the sensitivity to the behavioral effects of cocaine in rats.

Chronic unpredictable stress, in which the type and timing of stress exposures are varied, alters protein levels in the mesolimbic DA system in a manner previously shown to be associated with enhanced behavioral responsiveness to cocaine. Chronic exposure to the same or predictable stress (restraint) does not. Thus, we examined the effects of chronic unpredictable and chronic predictable (restraint) stress on the locomotor activating and place conditioning effects to low cocaine doses. To test whether chronic unpredictable stress enhances the sensitivity to the behavioral effects of cocaine. Rats were exposed to 10 days of chronic unpredictable stress, of chronic predictable (restraint) stress, or were not stressed. One day following cessation of stress exposure, locomotor activity to cocaine (0 or 7.5 mg/kg) was assessed for 4 consecutive days and corticosterone levels on the last day were determined. In other experiments, the effects of the chronic stress procedures on cocaine (0.5 and 7.5 mg/kg) place conditioning using an unbiased procedure were assessed. Chronic unpredictable, but not chronic predictable, stress transiently increased the locomotor activating effects of cocaine and this was correlated positively with corticosterone levels. Chronic unpredictable, but not chronic predictable, stress also enhanced the place conditioning effects of cocaine: increased place preference was seen with the low dose and a pronounced place aversion occurred with the high dose. These data demonstrate that chronic unpredictable stress enhances the behavioral effects of cocaine, including its aversive effects, whereas chronic predictable stress (restraint) is without effect.