Research reportCA3 hippocampal field: Cellular changes and its relation with blood nitro-oxidative stress reveal a balancing function of CA3 area in rats exposed to repetead restraint stress
Graphical abstract
Introduction
Stress is a multidimensional concept which can be seen both as an adaptive behavior and as disease generator. In psychology, stress is considered a factor which bolsters coping mechanisms to environmental conditions. However, all biological forms of stress described involve reactive oxygen (ROS) and nitrogen species (NOS) with a stressor-dependent behavior. ROS and NOS are not harmful for the organism while the biological limits are not exceeded. In fact, at low levels, ROS and NOS activate the defensosome and prepare the cells in order to survive in severe (nitro-oxidative) stress conditions which do not exceed the biological limits of the cell. Frequently, the stressors operate over the organism’s ability to counteract the negative effects of free radicals, which may consequently cause the biosystem to go from biological to pathological status. Although stress is a “necessary evil“ for survival, severe and long-term stress disrupts brain structure and function. Mental stress is the most important stressor which affects the nervous system. In this paper we used employ repeated restraint stress which corroborates physical and neuropsychological stress in rats (Buynitsky and Mostofsky, 2009). Also, rodents exposed to repeated restraint stress exhibit structural and functional deficits in the amygdala that are similar to those observed in patients with depressive illnesses. This includes studies that have demonstrated that repeated stress may elicit dendritic hypertrophy (Vyas et al., 2002, Johnson et al., 2009, Grillo et al., 2015) or dendritic atrophy (Vyas et al., 2002, Gilabert-Juan et al., 2011, Grillo et al., 2015) on amygdalar neurons. Chronic restraint stress exposure induces hipothalamic-pituitary-adrenal axis activation and hippocampal disorders such as dendritic retraction of CA3 pyramidal neurons (Christian et al., 2011), a remodeling of apical dendrites of CA3 neurons (Magariños et al., 1998),a decrease in the rate of adult neurogenesis in dentate gyrus and the thinning of CA1 hippocampal field, (Magariños and McEwen, 1995, Magariños et al., 1996) an area correlated with CA3 field by Schaffer collateral pathway via NMDA receptors (Christian et al., 2011). Along this line, the CA3 field plays a relay role in hippocampal formation in the light of the trisynaptic neural circuit whereas the mossy fibers extend into the CA3 region from dentate gyrus and then the axons from the CA3 neurons bifurcates: one part is directed down to the septum, while the other gives rise to Schaffer collaterals that complete the trisynaptic circuit by innervating the pyramidal neurons in the CA1 region and ensures its glutamate input. The CA3 region has attracted major attention in recent years for its specific role in episodic memory, spatial representations and neuro-degeneration. Internal connectivity in the CA3 subfiled is more rich than in other hippocampal fields (Cherubini and Miles, 2015). and CA3 area is a region especially vulnerable to stress and seizure-induced damage (Belvindrah et al., 2014). By the activation of HPA axis, glucocorticoids are increased (Alkadhi, 2013) and act synergistically with excitatory aminoacids to cause dose-dependent hippocampal neuronal destruction (Saplosky, 1990; Watanabe and Gould, 1992, Ohl et al., 2000, Abercrombie et al., 2003). Furthermore,while restraint stress is correlated with blood and tissue nitro-oxidative disturbance, the exact role of NO in this type of stress is not widely known. Whereas any tissue changes have echoes in blood, the determination of oxidative markers and corticosteron levels is like a mirror of the phenomena occurring in the hippocampus. These issues have led us to evaluates both the CA3 behavior in repeated restraint stress as well as its correlations with blood dynamics of the oxidative markers. Our research is also mentioned the hypothesis that restraint stress decreased the NO blood flow by modulating of iNOS activity. Therefore, the purpose of the current study was to investigate the dynamic relation between CA3 hippocampal field and blood nitro-oxidative status in rats exposed to chronic repeated restraint stress (i) and to characterize the dynamic changes of the CA3 structure in stressed rats (ii).
Section snippets
Blood concentration of 3-nitrotyrosine is reduced while the catalase and glutathione-peroxidase activity is increased
Biochemical analyses of nitro-oxidative blood markers,- 3-nitrotyrosine (3NTyr), glutathione-peroxidase (GPX), catalase (CAT) − were performed in non-stressed rats (Control group, C), 3-days repeated stressed rats (Stress 3 days group, S3d) and 7-days repeated stressed rats (Stress 7 days group, S7d). In this regard, S3d and S7d rats exhibited significant decreases in blood 3NTyr concentration in comparison with C rats; a one-way ANOVA revealed a significant dynamic interaction between restraint
Discussion
Endothelial-derived relaxing factor (EDRF), known as nitric oxide (NO), is synthesized via enzymatic conversion of L-arginine to L-citruline by NO synthase. Chen and co-workers (2015 a) mentioned that in restraint stress the neuronal isoform of NOS (nNOS) is down regulated while the inducible isoform of NOS (iNOS) is upregulated. Endothelial NOS (eNOS) is activated in stress conditions (Fleming, 2010). Gądek-Michalskaet al. (2012) described the time-dependent and region-dependent reactivity of
Animals
Adult (3-month-old) Wistar female rats weighing 180–200 g were provided ad libitum access to standard rat chow and water. Animals were maintained in a light/temperature controlled room with a light/dark cycle of 12/12 h under 22 °C constant temperature. Rats were housed 8/cage and all rats in the same cage corresponded to one of the experimental groups. Animal care and procedures were carried out in accordance to the European Communities Council Directive 2010/63/UE.
Stress induction
Restraint stress was induced by
Acknowledgements
Financial support from the National Authority for Scientific Research and Innovation − Core Programme, Project PN16-30 02 03 is gratefully acknowledged. I.R. thanks to NASRI Core Programme, Project PN16-19 BIODIVERS.
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