Vol 12, No 2 (2018)

Stress, which is an adaptive response of the body, is controlled by the brain. The neuroendocrine system, in particular the hypothalamo–pituitary–adrenal axis (HPAA), is a key player in the stress response. A number of studies have confirmed an association between stress and neurodegenerative and mental diseases and the major role of HPAA dysfunction and cortisol excess in this association. Although many signaling pathways stimulated by HPAA have been discovered, there are many possibilities for switching between these signal transduction pathways and for combining them; numerous factors would determine the involvement of definite mechanisms in the stress response. An aberrant neurochemistry of stress vulnerability and the stress response is the essence of most (if not all) stress-related mental and neurologic diseases, with depressive states being prime example. The neurochemistry of depression is, in fact, the neurochemistry of an abnormal stress response. The stress response may have to be measured; important goals of translational studies include validation of animal models of depression and unification of physiological and biochemical indices of the stress response for comparative analysis of different models and data from depressive patients, as well as elaboration of valid indices of the stress response for patients. For these purposes, it is critical to non-invasively analyze biomaterials such as saliva and hair.

Corticotropin-releasing factor (CRF) is a key neurohormone that triggers the response to stress via stimulation of the hypothalamic–pituitary–adrenocortical (HPA) axis and autonomic nervous system. CRF provides its action through CRF receptors of the first and second types (CRF-1 and CRF-2 receptors) and coordinates the endocrine, autonomic, behavioral, and visceral components of the stress response. This review analyzes the data on the gastroprotective effect of CRF and the mechanisms that underlie this physiological effect. The results of the analysis of the experimental data obtained in our studies suggest that glucocorticoids and CRF-1 receptors, as well as CRF-2 receptors, may be involved in the gastroprotective action of CRF. The presented data suggest that activation of the HPA axis is a gastroprotective component of the stress response.

Using a model of posttraumatic stress disorder (PTSD) in rats, it has been shown that conditioning by moderate hypobaric hypoxia (360 mmHg, three times for 2 h with 24-h interval) or limb ischemia–reperfusion (three times for 5 min with 15-min interval) prevents premature suppression of release of the stress hormone corticosterone to the blood plasma, which is typical of the triggering of pathological fast negative feedback of the hypothalamic–pituitary–adrenal axis (HPA) in this pathology. Hypoxic or remote ischemic preand postconditioning also increased the basal level of this hormone, which is significantly reduced during the formation of experimental PTSD. Thus, the pronounced anxiolytic effect of these conditioning types in the PTSD model may be mediated by the normalization of HPA regulation by a feedback mechanism and prevention of a decrease in its basal activity. Further research on the decoding of neurohumoral mechanisms of the stress-protective action of conditioning will speed up the introduction of these effective non-drug ways of prevention and correction of stress-induced pathologies into medical practice.

Stressing events in the early period of life affect neuronal plasticity and cognitive functions in adulthood. A key role in the mechanisms of formation of memory and attention is played by the glutamatergic system. However, there has been virtually no systematic study on the effect of early postnatal stress on the expression of glutamatergic system genes in various regions of the brain in mice. In this study, we used two types of early postnatal stress: prolonged separation of pups from mothers (for 3 hours per day) and shortterm separation (15 minutes per day) during the first 2 weeks of life. We used an object recognition test to evaluate attention and memory to assess cognitive abilities in adults. We found that prolonged maternal separation reduced the ability to recognize a novel object and also disrupted motor and exploratory activities in adult animals, while short-term separation did not affect the studied parameters. We assessed the expression of the major genes of the glutamatergic system (AMPA receptor subunits Gria1, Gria2; NMDA subunits Grin1, Grin2a, and Grin2b; metabotropic receptor subunits Grm1, Grm2, and Grm3; glutamate transporters Vglut2, Eaat2, and Rab4a) in the frontal cortex, hippocampus, and hypothalamus. In the group with prolonged maternal separation, we found a decrease in the expression of Grin2b in the hypothalamus in comparison with the control, which led to a decrease in the mRNA ratio of this subunit to Grin2a mRNA, and possibly to a change in the ratio of these subunits in the NMDA receptor. In spite of the revealed cognitive impairments, we did not find significant changes in the expression of genes in the frontal cortex and hippocampus. Shortterm daily separation from mothers did not lead to changes in cognitive abilities and expression of genes of the glutamatergic system in mice. Thus, our results show that prolonged maternal separation may lead to a redistribution of the receptor subunits in the hypothalamus, which can modify the activity of the HPAA and determine the response to stress in these mice.

The effects of 2- or 8-week-long daily treatment with fluoxetine at a dose of 7.26–7.70 mg/kg given with drinking water and short-term forced-swim stress on the levels of mRNAs of anti- and pro-apoptotic proteins, that is, Bcl-xL and Bax, respectively, were studied in the brains of adult male rats using the RT-PCR method. Antiapoptotic effects of stress on the expression of these proteins were observed in the hippocampus of rats that were not treated with fluoxetine and in the midbrain after 2 weeks of the antidepressant treatment. Pro-apoptotic effects of stress were revealed in the frontal cortex of animals that were not treated with fluoxetine and after 2 weeks of fluoxetine treatment. An 8-week-long fluoxetine treatment resulted in an increase in the basal Bax expression in the hippocampus and in anti-apoptotic effects in the neocortex, which were more clearly seen after stress. The observed interaction of the effects of stress and fluoxetine on the expression of proteins of neuronal survival and plasticity may provide anti- or proapoptotic action of the antidepressant on the cells of the emotiogenic structures of the brain.

We studied the effects of oral administration of ω-3 polyunsaturated fatty acids (PUFAs) on behavioral characteristics and immunohistochemical, morphological, and biochemical parameters in hippocampi of mice with experimental neuroinflammation. We found that animals with neuroinflammation that were treated with ω-3 PUFAs had higher parameters of locomotor activity and working memory compared to the vehicle-treated group. The immunohistochemical analysis showed that activation of glial cells was less significant in ω-3 PUFA-treated animals than in vehicle-treated animals with neuroinflammation. An increase in the production of pro-inflammatory cytokine IL-1ß and malonic dialdehyde, a marker of lipid peroxidation, in the hippocampus was less pronounced than in the vehicle-treated group. Thus, we assume that the normalization of locomotor activity and working memory after PUFA administration reduce microglial and astroglial activation, the intensity of neuroinflammation and oxidative stress and, as a consequence, prevent changes in the physicochemical characteristics of cellular and mitochondrial membranes.

We studied the long-term effects of neonatal pro-inflammatory stress (NPS) on the expression of corticoliberin and its receptors in the dorsal and ventral hippocampus of juvenile male and female rats. In the dorsal hippocampus of juvenile males, NPS increases the expression of corticoliberin mRNA. This effect is absent in females, where we found a tendency to an increase in the expression of CRHR2 receptor mRNA in the ventral hippocampus. Thus, NPS induces long-term changes in the expression of genes associated with stress, specifically in different parts of the hippocampus; these changes may be related the mechanism of “early programming” of the predisposition to depression and to the gender-related specificity of disease pathogenesis.