mGluR5 in hippocampal CA1 pyramidal neurons mediates stress-induced anxiety-like behavior.

Pharmacological manipulation of mGluR5 has showed that mGluR5 is implicated in the pathophysiology of anxiety and mGluR5 has been proposed as a potential drug target for anxiety disorders. Nevertheless, the mechanism underlying the mGluR5 involvement in stress-induced anxiety-like behavior remains largely unknown. Here, we found that chronic restraint stress induced anxiety-like behavior and decreased the expression of mGluR5 in hippocampal CA1. Specific knockdown of mGluR5 in hippocampal CA1 pyramidal neurons produced anxiety-like behavior. Furthermore, both chronic restraint stress and mGluR5 knockdown impaired inhibitory synaptic inputs in hippocampal CA1 pyramidal neurons. Notably, positive allosteric modulator of mGluR5 rescued stress-induced anxiety-like behavior and restored the inhibitory synaptic inputs. These findings point to an essential role for mGluR5 in hippocampal CA1 pyramidal neurons in mediating stress-induced anxiety-like behavior.

Blood Eosinophil Endotypes across Asthma and Chronic Obstructive Pulmonary Disease (COPD).

Background: Eosinophils were common inflammatory cells involved in the occurrence and development of various inflammatory diseases. Multiple recent studies have pointed to the increasingly important role of eosinophils in respiratory diseases. This article aims to compare the expression differences of blood eosinophil counts between asthma, chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap (ACO). Methods: Patients with asthma, COPD, and ACO who were seen in the First Affiliated Hospital of Guangzhou Medical University from January 2012 to June 2019 were included. We collected information such as age, gender, diagnosis, the eosinophil counts from the medical records. Moreover, the levels of 10 cytokines in the plasma of each group were detected by using the Meso Scale Discovery method. Results: We included 9787 patients with asthma, 15806 patients with COPD, and 831 ACO patients. From our results, it can be first found that eosinophil levels were age-related in the three diseases (asthma and ACO: p < 0.001; COPD: P = 0.001); in asthma and COPD, the number of eosinophils in males was more significant than that in females (asthma: p < 0.001; COPD: p = 0.012). Second, asthma patients had higher blood eosinophil counts than those with COPD and ACO (p < 0.001). Moreover, we found out that eosinophil levels were highly expressed in the stable group of all three diseases. Finally, we found that most cytokines in ACO patients showed a downward trend when the level of eosinophils was low, whereas the results were reversed in asthma patients; 7 cytokines had similar trends in COPD and ACO patients. Conclusions: In conclusion, eosinophils have their own unique endotypes in asthma, COPD, and ACO patients, which were reflected in the fluctuation of their levels and changes in cytokine secretion.

The effects of tamoxifen on mouse behavior.

The CreERT2 recombinase system is an advanced method to temporally control site-specific mutagenesis in adult rodents. In this process, tamoxifen is injected to induce Cre recombinase expression, and then, Cre recombinase can excise LoxP-flanked DNA. However, tamoxifen is a nonselective estrogen receptor antagonist that may influence behavioral alterations. Therefore, we designed five different protocols (acute effects, chronic effects, chronic effects after social defeat model, chronic effects after learned helplessness model, chronic effects after isolation models) to explore whether tamoxifen affects mouse behavior. Researching the acute/chronic effects of tamoxifen, we found that tamoxifen could influence locomotor activity, anxiety and immobility time in the forced swimming test. Researching the chronic effects of tamoxifen after social defeat/learned helplessness/isolation models, we found that tamoxifen could also influence locomotor activity, social interaction and anxiety. Therefore, the effects of tamoxifen are more complex than previously reported. Our results show, for the first time, that tamoxifen affects behavior in mouse models. Meanwhile, we compare the effects of tamoxifen in different protocols. These results will provide important information when designing similar experiments.

The BACE1-Specific DNA Aptamer A1 Rescues Amyloid-ß Pathology and Behavioral Deficits in a Mouse Model of Alzheimer's Disease.

Amyloid-ß (Aß) plaque deposits in the brain are considered to be one of the main pathological markers of Alzheimer's disease (AD). The sequential proteolytic cleavage of amyloid precursor protein (APP) by the aspartyl proteases ß-site APP-cleaving enzyme 1 (BACE1) and γ-secretase produces Aß. Therefore, BACE1 inhibition is a very attractive target for the treatment of AD. Our previous work identified a DNA aptamer named A1 that can bind to BACE1 with high affinity and specificity and exhibits a distinct inhibitory effect on BACE1 activity in an AD cell model. The purpose of this research was to test the effect of aptamer A1 in Tg6799 mice. Four-month-old Tg6799 mice were randomly divided into two groups and treated with aptamer A1 and ineffective aptamer A1scr, respectively, by intracerebroventricular injection. Subsequent behavioral experiments showed that treatment with the aptamer A1 improved the cognitive abilities of the AD mice. Western blot indicated that BACE1 and soluble amyloid precursor protein ß (sAPPß) expression significantly decreased in the A1-treated mice. Moreover, aptamer A1 reduced the content of Aß42 and the number and density of senile plaques in AD mice. Therefore, our results indicate that aptamer A1 is a novel specific and potent BACE1 inhibitor and is a promising potential target for the treatment of AD.

Resveratrol improves cognition and decreases amyloid plaque formation in Tg6799 mice.

Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disorder of the central nervous system that causes severe cognitive impairment. One of the most significant pathological features of AD is the accumulation of ß­amyloid (Aß) peptide in the brain. Resveratrol (Res) is a polyphenol derived from peanuts, red grapes and other plants, which has received increasing attention due to its neuroprotective features. Tg6799 mice are transgenic mice with five familial AD (FAD) mutations that are also known as 5XFAD mice. The present study aimed to investigate the effects of Res on Tg6799 mice. The transgenic mice were randomly divided into the Res treatment group and the vehicle control group, and were treated with 0.5% Res solution (60 mg/kg) or volume­matched normal saline, respectively. Treatment was administered by oral gavage daily for 60 consecutive days. Res reduced amyloid plaque formation and the levels of Aß42, and ß­secretase 1 levels were also significantly decreased. Furthermore, Res was able to reduce the expression of amyloid precursor protein and its cleavage products. The administration of Res to Tg6799 mice also improved their spatial working memory, as measured by the Y­maze test, and rescued spatial memory deficits, as measured using the Morris water maze test; however, Res did not affect their motor function. In conclusion, this study suggested that Res may reduce Aß­induced neuronal damage, thus preventing memory loss.