Midori Ninomiya

Chronic restraint stress causes anxiety- and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex

Stress and the resulting increase in glucocorticoid levels have been implicated in the pathophysiology of depressive disorders. We investigated the effects of chronic restraint stress (CRS: 6 hours × 28 days) on anxiety- and depression-like behaviors in rats and on the possible changes in glucocorticoid receptor (GR) expression as well as brain-derived neurotrophic factor (BDNF)-dependent neural function in the prefrontal cortex (PFC). We observed significant reductions in body weight gain, food intake and sucrose preference from 1 week after the onset of CRS. In the 5th week of CRS, we conducted open-field (OFT), elevated plus-maze (EPM) and forced swim tests (FST). We observed a decrease in the number of entries into open arms during the EPM (anxiety-like behavior) and increased immobility during the FST (depression-like behavior). When the PFC was removed after CRS and subject to western blot analysis, the GR expression reduced compared with control, while the levels of BDNF and its receptors remained unchanged. Basal glutamate concentrations in PFC acute slice which were measured by high performance liquid chromatography were not influenced by CRS. However, BDNF-induced glutamate release was attenuated after CRS. These results suggest that reduced GR expression and altered BDNF function may be involved in chronic stress-induced anxiety--and depression-like behaviors.

Estrogen, Predominantly via Estrogen Receptor α, Attenuates Postpartum-Induced Anxiety- and Depression-Like Behaviors in Female Rats

Contributions from estrogen receptor (ER) subtypes (ERα and ERβ) to postpartum anxiogenic and depressive responses remain unresolved in rats. Using the elevated-plus maze (EPM) and forced swim (FS) tests, we confirmed that primiparous rats exhibited anxiogenic and depressive responses 3 weeks postpartum, improved 5 weeks postpartum (EPM), and recovered at 5 (FS) or 10 weeks postpartum (EPM) compared with diestrus nulliparous females. Immunohistochemistry suggested that these behavioral changes were temporally associated with decreased ERα but not ERβ expression in the medial amygdala (MEA). Additionally, ERα expression in the medial preoptic area (MPOA) significantly increased 10 weeks postpartum. Brain-derived neurotrophic factor (BDNF) expression was significantly elevated in the MEA 3 weeks postpartum. BDNF receptor tropomyosin-related kinase expression was significantly elevated in the MEA at 3 and 10 weeks but not at 5 weeks postpartum. The phosphorylation of ERK (pERK)-2 in the MEA, MPOA, and hippocampal CA1 region was significantly elevated 3 and 5 weeks postpartum. The effects of single daily sc injections of the ERα-selective agonist, propyl pyrazoletriol (PPT); ERβ-selective agonist, diarylpropionitrile; 17β-estradiol (E₂); and vehicle for 6 days in primiparous rats were assessed. PPT and E₂ significantly produced anxiolytic and antidepressant actions in the EPM and FS tests but PPT to a lesser degree than E₂ in the EPM test. Diarylpropionitrile affected the EPM test but was not significantly different from vehicle. BDNF expression was significantly increased 3 weeks postpartum by all treatments in the MPOA but not the CA1 and MEA. E₂ and PPT treatment significantly increased tropomyosin-related kinase and pERK1/2 expression in the MEA and MPOA and increased pERK1/2 expression in the CA1. The onset of anxiety- and depression-like behaviors in postpartum rats may be partly caused by a complex estrogen-mediated mechanism; nevertheless, changes in the ERα-related system, likely in the MEA, are predominantly involved.

Prednisolone causes anxiety- and depression-like behaviors and altered expression of apoptotic genes in mice hippocampus.

Glucocorticoids are known to cause psychiatric disorders including depression. Prednisolone (PSL) is one of the most widely used synthetic glucocorticoids to treat various medical diseases; however, little is known about PSL-induced behavioral changes and its molecular basis in the brain. Growing evidence has implicated that hippocampal remodeling or damage play a role in the pathogenic effect of glucocorticoids. In this study, mice were administered PSL (50 or 100mg/kg) or vehicle for 6 or 7 days and subjected to a series of behavioral tests, i.e., open field, elevated plus maze, prepulse inhibition, forced swim, and tail suspension tests. Hippocampal tissues were subject to microarray analysis using the GeneChip Mouse Genome 430 2.0 Array (Affymetrix) containing 45,101 probes of transcripts. Increased anxiety- and depression-like behaviors assessed with open field, elevated plus maze, and tail suspension tests were observed. Microarray analysis detected 108 transcripts with a fold change of >2.0 or <0.5 in which many cell-death-related genes were found. The microarray data was validated by quantitative reverse transcriptase-polymerase chain reaction analysis. Our results demonstrated that PSL causes anxiety- and depression-like behaviors, and suggest that altered gene expressions related to hippocampal remodeling or damage are involved in the effect of PSL on such behaviors.

Antidepressant- and anxiolytic-like properties of dopamine receptor agonist cabergoline

The “excitement stage” of the anesthesia is the period following loss of consciousness and marked by excited and delirious activity. During this stage, there may be uncontrolled movements in addition to other complications such as vomiting, breath holding, pupillary dilation, and irregularity of respirations and heart rate. To explore how volatile anesthetics induce uncontrolled movements, we studied the effects of a widely used volatile anesthetic sevoflurane on activities of the striatal neurons with patch-clamp technique using slice preparation taken from mouse striatum. We found that, in the beginning, sevoflurane slightly depolarized and then hyperpolarized the striatal medium spiny projection neurons. The firing pattern induced by current injection changed from regular to irregular during treatment. Evoked IPSCs were suppressed faster and stronger than evoked EPSCs. The frequency of spontaneous IPSCs was significantly diminished whereas that of spontaneous EPSCs were increased transiently but returned to the control level. In the presence of tetrodotoxin, the frequency of miniature IPSCs was diminished significantly but that of miniature EPSCs were unchanged. By contrast, the amplitudes of both spontaneous and miniature IPSCs and EPSCs were unchanged. These results suggest that sevoflurane suppresses the release probability of GABA significantly, and thus transiently excites rather than inhibits the striatal projection neurons, thereby causing involuntary movements.

Cultured neurons from intrauterine growth retardation rats display lower response to brain-derived neurotrophic factors

The neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces Parkinsonism in human via its metabolite MPP+ (1-methyl-4phenylpyridinium ion). MPP+ is selectively accumulated in dopamine neurons by the dopamine transporter and inhibits complex I of the mitochondrial respiratory chain. Therefore, studies of precise mechanisms of mitochondrial dysfunction are essential to clarify the mechanism of MPTP neurotoxicity. In this study, we investigate that effect of MPP+ on mitochondrial oxidation–reduction (REDOX) activity and the correlation with membrane potential in human neuroblastoma SH-SY5Y cells. The neuroblastoma cells were treated with MPP+ in DMEM containing N2 supplement. Mitochondrial REDOX activity and membrane potential were measured by Alamar blue fluorescence and JC-1 fluorescence ratio, respectively. After 24 h treatment with MPP+ (1–5 mM), mitochondrial REDOX activity was reduced in a concentration-dependent manner, and mitochondrial membrane potential was also decreased. After 4 h treatment with different concentrations of MPP+, mitochondrial REDOX activity was near normal level, whereas decrease of mitochondrial membrane potential was detected. These results indicate that MPP+ can cause a depolarization of mitochondrial membrane potential without early changes in the activity of respiratory chain. Current study is ongoing to elucidate whether the mitochondrial membrane depolarization at an early stage is involved in MPP+ toxicity in the cells.