Imbalance in Sirt1 Alternative Splicing in Response to Chronic Stress during the Adolescence Period in Female Mice.

Stressful unpredictable life events have been implicated in numerous diseases. It is now becoming clear that some life periods are more vulnerable than others. As adolescence is a sensitive period in brain development, the long-term effects of stress during this period could be significant. We investigated the long-term effects of exposure to unpredictable chronic mild stress in adolescent mice on alternative splicing of Sirtuin 1. One-month-old mice were exposed to 4 weeks of UCMS and examined for anxiety and cognition at the age of 2, 4 and 6 months. We found a rise in anxious behavior immediately after the exposure to stress. Notably, there was a long-term impairment of performance in cognitive tasks and an imbalance in Sirtuin 1 and TrkB receptor alternative splicing in the stress-exposed mice compared with controls. To conclude, our results show that exposure to unpredictable chronic mild stress during adolescence affects cognition in adulthood. Understanding pathways affiliated with stress may help minimize the long-term emotional effects of an unpredictable, stressful event.

Anxiolytic and antidepressants' effect of Crataegus pinnatifida (Shan Zha): biochemical mechanisms.

Depression and anxiety disorders are highly prevalent. Selective serotonin reuptake inhibitors (SSRIs) are the current first-line treatment for depression, but they have pronounced limitations. Traditional Chinese medicine can serve as a safe and effective alternative to conventional drugs, particularly since many herbal remedies have already been approved for human use as food additives, making the transition from bench to bedside more efficient. We previously demonstrated that a novel herbal treatment (NHT) induces anxiolytic- and antidepressant-like effects. NHT consists of four herbs: Crataegus pinnatifida (Shan Zha), Triticum aestivum (Fu Xiao Mai), Lilium brownii (Baihe), and the fruit of Ziziphus jujuba (Da Zao). In the current study, we examined the antidepressant-like and anxiolytic-like activities of each individual herb on stressed mice and compared those to the effects of NHT and escitalopram. We show here that Shan Zha is sufficient to produce an anxiolytic and antidepressant-like effect similar to NHT or the escitalopram through activation of 5-HT1A receptor and an elevation in BDNF levels in the hippocampus and Pre-frontal cortex (PFC). Chronic treatment with Shan Zha did not alter serotonin transporter levels in the PFC, as opposed to escitalopram treatment. These results were confirmed in vitro, as none of the herbs blocked SERT activity in Xenopus oocytes. Notably, Shan Zha is sold as a nutritional supplement; thus, its transition to clinical trials can be easier. Once its efficacy and safety are substantiated, Shan Zha may serve as an alternative to conventional antidepressants.

Impact of interpregnancy interval on long-term childhood neoplasm of the offspring.

BACKGROUND: The possible impact of interpregnancy interval (IPI) on perinatal outcomes has long been studied, however, a definition of the optimal interval is still not clear. Both short and long IPIs have been associated with obstetrical syndromes and short and long-term complications. In this study, we sought to explore the impact of IPI on the hazard for neoplasm of the offspring, thus contribute to the present literature in determining the preferred birth spacing. OBJECTIVE: We aim to investigate the association between short and long IPIs and the hazard for childhood neoplasm of the offspring. METHODS: A population-based retrospective cohort analysis comparing offspring neoplasm hazard following three different IPIs. Exposure was defined as short (<6 months), or long (>60 months) IPIs, whereas intermediate IPI (6 months - 60 months) served as the comparison group. The study included singleton live births in a tertiary regional hospital between 1991 and 2014. Offspring were followed for 18 years, and all hospitalization records for neoplasm diagnoses were collected. Kaplan-Meier survival curves were used for the cumulative incidence of neoplasm morbidity, and Cox proportional hazards models were used to control for confounders. RESULTS: During the study period, 144,397 deliveries met the inclusion criteria. Of those, 18,947 (13.1%) occurred in women with short IPI, 114,012 (79%) in women with intermediate IPI, and 11,438 (7.9%) in women with long IPI. 61 benign neoplasms and 80 malignant neoplasms were registered in offspring born after long IPI. The total percentage of neoplasm were the highest in the long IPI group versus the intermediate and short IPI groups (malignant - 0.7%, 0.6%, 0.5% respectively, benign - 0.5%, 0.4%, 0.3% respectively). Controlling for maternal age, diabetes mellitus, preterm delivery, birth weight, smoking, cesarean section, and fertility treatments, long IPI was found to be independently associated with high hazard for long-term pediatric neoplasm related hospitalizations (adjusted HR 1.39, 95% CI 1.09, 1.77). Short IPI may be associated to decreased hazard for childhood neoplasms (adjusted HR 0.74, 95% Cl 0.59, 0.92). CONCLUSIONS: Long IPI is associated with a high hazard for childhood neoplasms, compared with intermediate and short IPIs. Short IPI may be associated with decreased hazard for childhood neoplasms.

Behavioral Characterizing of CD24 Knockout Mouse-Cognitive and Emotional Alternations.

CD24 is a small, glycophosphatidylinositol-anchored cell surface protein, mostly investigated with respect to cancer, inflammation, and autoimmune diseases. CD24 knockdown or inhibition has been used to test various biochemical mechanisms and neurological conditions; however, the association between CD24 and behavioral phenotypes has not yet been examined. This study aims to characterize cognitive and emotional functions of CD24 knockout mice (CD24-/-) compared with CD24 wild-type mice at three time-points: adolescence, young adulthood, and adulthood. Our results show that CD24-/- mice exhibited better cognitive performance and less anxiety-like behavior compared with WT mice, with no effect on depression-like behavior. This phenotype was constant from childhood (2 months old) to adulthood (6 months old). The results from our study suggest that CD24 may influence important behavioral aspects at the whole-organism level, which should be taken into consideration when using CD24 knockout models.

Cerebral MAO Activity Is Not Altered by a Novel Herbal Antidepressant Treatment.

Inhibition of monoamine oxidase (MAO)-A/B can ameliorate depressive- and anxiety-related symptoms via increase of monoamine extracellular levels. However, such inhibition can also instigate hypertensive response following exposure to dietary tyramine (i.e., "the cheese effect"). Novel herbal treatment (NHT) is an herbal formula that has been demonstrated to reduce depressive- and anxiety-like symptoms in pre-clinical studies. The aim of the current study was to examine whether the therapeutic potential of NHT is underlain by inhibition of MAO-A/B and whether NHT poses a risk for tyramine hyper-potentiation. Unpredictable chronic mild stress (UCMS)-exposed mice and naïve mice were treated for 3 weeks with NHT (30 mg/kg; i.p.), the selective serotonin reuptake inhibitor (SSRI) escitalopram (15 mg/kg; i.p.), or saline. Subsequently, MAO-A/B activities in the hypothalamus, striatum, and prefrontal cortex (PFC) were assessed. Exposure to UCMS led to significant increases in both MAO-A and MAO-B activities in the hypothalamus (p < 0.001) and in the PFC (p < 0.01 for MAO-A; p < 0.001 for MAO-B). Neither NHT nor escitalopram had any notable effects. Treatment with NHT was supported as safe in terms of risk for inducing a hypertensive response. The antidepressant- and anxiolytic-like effects of NHT are mediated via pathways other than MAO-A/B inhibition.

GABAA Receptor Density Is Not Altered by a Novel Herbal Anxiolytic Treatment.

Anxiety disorders are highly prevalent and considered a major public health concern worldwide. Current anxiolytics are of limited efficacy and associated with various side effects. Our novel herbal treatment (NHT), composed of four constituents, was shown to reduce anxiety-like behavior while precluding a common side effect caused by current anxiolytics, i.e., sexual dysfunction. Nevertheless, NHT's mechanism of action is yet to be determined. There is evidence that some medicinal herbs interact with the GABAergic system. Therefore, we aimed to examine whether NHT's anxiolytic-like effect is exerted by alterations in GABAA receptor density in the hippocampus, prefrontal cortex, and hypothalamus. The effects of 3-weeks treatment with NHT on anxiety-like behavior and locomotion were assessed using the elevated plus maze (EPM) and the open field test (OFT), respectively. Regional GABAA receptor levels were analyzed using [3H] RO15-1788 high-affinity binding assays. In stressed mice, NHT reduced anxiety-like behavior similarly to the benzodiazepine, clonazepam, while locomotion remained intact. Lack of changes or minor changes in regional GABAA receptor density in the brain were induced by NHT or clonazepam. In naive mice, performance in the EPM, locomotion and GABAA receptor densities were not altered by treatment with NHT or clonazepam. These findings support NHT as an efficacious and safe anxiolytic, although the GABAergic involvement remains to be further elucidated.

Reversal of age-related cognitive impairments in mice by an extremely low dose of tetrahydrocannabinol.

This study was designed to test our hypothesis that an ultra-low dose of delta-9 tetrahydrocannabinol (THC) reverses age-dependent cognitive impairments in old mice and to examine the possible biological mechanisms that underlie this behavioral effect. Old female mice aged 24 months that had been injected once with 0.002 mg/kg THC (3-4 orders of magnitudes lower than doses that induce the conventional cannabinoid effects in mice) performed significantly better than vehicle-treated old mice and performed similarly to naive young mice aged 2 months, in 6 different behavioral assays that measured various aspects of memory and learning. The beneficial effect of THC lasted for at least 7 weeks. The single injection of THC increased the level of Sirtuin1, an enzyme that has been previously shown to be involved in neuroprotection and neuroplasticity, in the hippocampus and in the frontal cortex of old mice, for at least 7 weeks. Magnetic resonance imaging demonstrated a larger volume and higher tissue density in various regions of the brain of THC-treated old mice. These findings suggest that extremely low doses of THC that are devoid of any psychotropic effect and do not induce desensitization may provide a safe and effective treatment for cognitive decline in aging humans.

Escitalopram and NHT normalized stress-induced anhedonia and molecular neuroadaptations in a mouse model of depression.

Anhedonia is defined as a diminished ability to obtain pleasure from otherwise positive stimuli. Anxiety and mood disorders have been previously associated with dysregulation of the reward system, with anhedonia as a core element of major depressive disorder (MDD). The aim of the present study was to investigate whether stress-induced anhedonia could be prevented by treatments with escitalopram or novel herbal treatment (NHT) in an animal model of depression. Unpredictable chronic mild stress (UCMS) was administered for 4 weeks on ICR outbred mice. Following stress exposure, animals were randomly assigned to pharmacological treatment groups (i.e., saline, escitalopram or NHT). Treatments were delivered for 3 weeks. Hedonic tone was examined via ethanol and sucrose preferences. Biological indices pertinent to MDD and anhedonia were assessed: namely, hippocampal brain-derived neurotrophic factor (BDNF) and striatal dopamine receptor D2 (Drd2) mRNA expression levels. The results indicate that the UCMS-induced reductions in ethanol or sucrose preferences were normalized by escitalopram or NHT. This implies a resemblance between sucrose and ethanol in their hedonic-eliciting property. On a neurobiological aspect, UCMS-induced reduction in hippocampal BDNF levels was normalized by escitalopram or NHT, while UCMS-induced reduction in striatal Drd2 mRNA levels was normalized solely by NHT. The results accentuate the association of stress and anhedonia, and pinpoint a distinct effect for NHT on striatal Drd2 expression.