Ambiguous Contribution of Glucocorticosteroids to Acute Neuroinflammation in the Hippocampus of Rat.

Effects of modulation of glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) on acute neuroinflammatory response were studied in the dorsal (DH) and ventral (VH) parts of the hippocampus of male Wistar rats. Local neuroinflammatory response was induced by administration of bacterial lipopolysaccharide (LPS) to the DH. The modulation of GR and MR was performed by dexamethasone (GR activation), mifepristone, and spironolactone (GR and MR inhibition, respectively). Experimental drugs were delivered to the dentate gyrus of the DH bilaterally by stereotaxic injections. Dexamethasone, mifepristone, and spironolactone were administered either alone (basal conditions) or in combination with LPS (neuroinflammatory conditions). Changes in expression levels of neuroinflammation-related genes and morphology of microglia 3 days after intrahippocampal administration of above substances were assessed. Dexamethasone alone induced a weak proinflammatory response in the hippocampal tissue, while neither mifepristone nor spironolactone showed significant effects. During LPS-induced neuroinflammation, GR activation suppressed expression of selected inflammatory genes, though it did not prevent appearance of activated forms of microglia. In contrast to GR activation, GR or MR inhibition had virtually no influence on LPS-induced inflammatory response. The results suggest glucocorticosteroids ambiguously modulate specific aspects of neuroinflammatory response in the hippocampus of rats at molecular and cellular levels.

Neonatal Proinflammatory Stress and Expression of Neuroinflammation-Associated Genes in the Rat Hippocampus.

Differential effect of the neonatal proinflammatory stress (NPS) on the development of neuroinflammation in the hippocampus and induction of the depressive-like behavior in juvenile and adult male and female rats was studied. NPS induction by bacterial lipopolysaccharide in the neonatal period upregulated expression of the Il6 and Tnf mRNAs accompanied by the development of depressive-like behavior in the adult male rats. NPS increased expression of the mRNAs for fractalkine and its receptor in the ventral hippocampus of the juvenile male rats, but did not affect expression of mRNAs for the proinflammatory cytokines and soluble form of fractalkine. NPS downregulated expression of fractalkine mRNA in the dorsal hippocampus of juvenile males. No significant effects of NPS were found in the female rats. Therefore, the NPS induces long-term changes in the expression of neuroinflammation-associated genes in different regions of the hippocampus, which ultimately leads to the induction of neuroinflammation and development of depressive-like behavior in male rats.

N-Pep-Zn Improves Cognitive Functions and Acute Stress Response Affected by Chronic Social Isolation in Aged Spontaneously Hypertensive Rats (SHRs).

BACKGROUND/OBJECTIVES: Aging and chronic stress are regarded as the most important risk factors of cognitive decline. Aged spontaneously hypertensive rats (SHRs) represent a suitable model of age-related vascular brain diseases. The aim of this study was to explore the effects of chronic isolation stress in aging SHRs on their cognitive functions and response to acute stress, as well as the influence of the chronic oral intake of N-Pep-Zn, the Zn derivative of N-PEP-12. METHODS: Nine-month-old SHRs were subjected to social isolation for 3 months (SHRiso group), and one group received N-pep-Zn orally (SHRisoP, 1.5 mg/100 g BW). SHRs housed in groups served as the control (SHRsoc). The behavioral study included the following tests: sucrose preference, open field, elevated plus maze, three-chamber sociability and social novelty and spatial learning and memory in a Barnes maze. Levels of corticosterone, glucose and proinflammatory cytokines in blood plasma as well as salivary amylase activity were measured. Restraint (60 min) was used to test acute stress response. RESULTS: Isolation negatively affected the SHRs learning and memory in the Barnes maze, while the treatment of isolated rats with N-Pep-Zn improved their long-term memory and working memory impairments, making the SHRisoP comparable to the SHRsoc group. Acute stress induced a decrease in the relative thymus weight in the SHRiso group (but not SHRsoc), whereas treatment with N-Pep-Zn prevented thymus involution. N-pep-Zn mitigated the increment in blood cortisol and glucose levels induced by acute stress. CONCLUSIONS: N-pep-Zn enhanced the adaptive capabilities towards chronic (isolation) and acute (immobilization) stress in aged SHRs and prevented cognitive disturbances induced by chronic isolation, probably affecting the hypothalamo-pituitary-adrenal, sympathetic, and immune systems.

Differential early effects of traumatic brain injury on spike-wave discharges in Sprague-Dawley rats.

Unprovoked seizures in the late period of traumatic brain injury (TBI) occur in almost 20% of humans and experimental animals, psychiatric comorbidities being common in both situations. The aim of the study was to evaluate epileptiform activity in the early period of TBI induced by lateral fluid percussion brain injury in adult male Srague-Dawley rats and to reveal potential behavioral and pathomorphological correlates of early electrophysiological alterations. One week after TBI the group of animals was remarkably heterogeneous regarding the incidence of bifrontal 7-Hz spikes and spike-wave discharges (SWDs). It consisted of 3 typical groups: a) rats with low baseline and high post-craniotomy SWD level; b)with constantly low both baseline and post-craniotomy SWD levels; c) constantly high both baseline and post-craniotomy SWD levels. Rats with augmented SWD occurrence after TBI demonstrated freezing episodes accompanying SWDs as well as increased anxiety-like behavior (difficulty of choosing). The discharges were definitely associated with sleep phases. The incidence of SWDs positively correlated with the area of glial activation in the neocortex but not in the hippocampus.The translational potential of the data is revealing new pathophysiological links between epileptiform activity appearance, direct cortical and distant hippocampal damage and anxiety-like behavior, putative early predictors of late posttraumatic pathology.

Cholinergic Deficit Induced by Central Administration of 192IgG-Saporin Is Associated With Activation of Microglia and Cell Loss in the Dorsal Hippocampus of Rats.

Alzheimer's disease (AD) is associated with degeneration of cholinergic neurons in the basal forebrain. Administration of the immunotoxin 192IgG-saporin to rats, an animal model of AD, leads to degeneration of cholinergic neurons in the medial septal area. In the present study, cholinergic cell death was induced by intracerebroventricular administration of 192IgG-saporin. One and a half months after injection, we studied the histopathology of the hippocampus and the responses of microglia and astrocytes using immunohistochemistry and neuroglial gene expression. We found that treatment with 192IgG-saporin resulted in neuronal loss in the CA3 field of the hippocampus. Microglial proliferation was observed in the dentate gyrus of the dorsal hippocampus and white matter. Massive proliferation and activation of microglia in the white matter was associated with strong activation of astrocytes. However, the expression of microglial marker genes significantly increased only in the dorsal hippocampus, not the ventral hippocampus. These effects were not related to non-specific action of 192IgG-saporin because of the absence of the Nerve growth factor receptor in the hippocampus. Additionally, 192IgG-saporin treatment also induced a decrease in the expression of genes that are associated with transport functions of brain vascular cells (Slc22a8, Ptprb, Sdpr), again in the dorsal hippocampus but not in the ventral hippocampus. Taken together, our data suggest that cholinergic degeneration in the medial septal area induced by intracerebroventricular administration of 192IgG-saporin results in an increase in the number of microglial cells and neuron degeneration in the dorsal hippocampus.

Effects of individual stressors used in a battery of "chronic unpredictable stress" on long-term plasticity in the hippocampus of juvenile rats.

We have studied alterations in the properties of long-term potentiation (LTP) in hippocampal slices of juvenile rats induced by the exposure of animals to different individual stressors usually used in batteries of chronic unpredictable stress (CUS), a widely used model of depression. Social isolation for 16 h did substantially affect neither the magnitude and nor the development of LTP. The effects of stroboscopic illumination and water deprivation appeared most severe, though opposite: the first stressor had activating effect, whereas the second one inhibited the development of LTP. In addition to the effects of these factors on the LTP magnitude, they also affected the patterns of LTP development. In this study weak tetanization with different probability of maintenance was used, and most of stressors, in spite of the similar LTP magnitude, influenced significantly on the process of consolidation. In hippocampal slices from rats maintained on wet bedding for 16 h, the time course but not magnitude of LTP significantly differed from that observed in the control or socially isolated rats. The weakest effect on LTP was observed in hippocampal slices of the rats exposed to food deprivation. In these animals, only some differences were observed in the development of LTP as compared to socially isolated rats. These data allow ranging stressors used in CUS paradigms according to the severity of their potential effects on neuronal function and animal behavior.