Repeated inhibition of sigma-1 receptor suppresses GABAA receptor expression and long-term depression in the nucleus accumbens leading to depressive-like behaviors.

Sigma-1 receptor (σ1R) downregulation in male mice is known to cause a depressive-like phenotype. The nucleus accumbens (NAc), a region associated with affective regulation, has high levels of σ1R. Here, we investigated the effect of repeated inhibition of σ1R in the NAc on depressive-like behaviors and synaptic plasticity by microinjecting σ1R antagonist NE-100 into NAc nuclei in mice (NE-100 mice); this was followed by behavioral tests and field potentials recordings. We first examined the effect of NE-100 administration on σ1R expression and found that cell surface levels of σ1R were significantly reduced in the NAc of NE-100 mice. Compared to control mice, NE-100 mice exhibited significantly prolonged immobility in forced swim test (FST) and tail suspension test (TST), impaired long-term depression (LTD) as well as multi-spike waveform field excitatory postsynaptic potential (fEPSP) with an extended duration and an increased paired-pulse ratio (PPR). Reduced levels of GABAA receptor (GABAAR)-α1, -α2, -ß2, and -ß3 subunits, membrane D2R, and PKC phosphorylation in the NAc were observed in NE-100 mice. Activation of GABAAR by muscimol corrected the extended fEPSP duration and increased PPR, restored LTD maintenance as well as alleviated depressive-like behaviors in NE-100 mice. The decline of PKC phosphorylation in the NAc of NE-100 mice was corrected by injecting NAc with quinpirole, a D2R agonist. Injections of quinpirole or PMA (a PKC activator) into NAc of NE-100 mice rescued the expression levels of GABAAR, and alleviated the increase in PPR and impairment in LTD; these effects were sensitive to GF109203X, a PKC inhibitor. Furthermore, injecting NAc with quinpirole or PMA relieved depressive-like behaviors in NE-100 mice. Collectively, these results indicate that repeated inhibition of σ1R in the NAc reduces D2R-mediated PKC phosphorylation and suppresses GABAAR expression, thus impairing LTD maintenance and leading to depressive-like behaviors.

Digital economy, technological progress, and city export trade.

The development of the digital economy is conducive to the innovative development of foreign trade and the formation of a "dual circulation" development pattern in China. Based on the panel data of 285 prefecture-level cities in China from 2005 to 2019, this paper examines the influence of the digital economy on urban export trade and its heterogeneity. And we use a mediating effect model to explore the possible mediating role of technological progress in the above influences. The results find that: (1) The improvement of the digital economy can promote cities export; (2) The promotion of the digital economy to the growth of city export scale is heterogeneous, which is more significant in the western and northeastern cities with relatively remote geographical locations, and the third-tier and lower cities with relatively backward economic development. (3) Technological progress has played a significant role in promoting the growth of export for the digital economy. Thus, it's of great importance for China to increase investment in digital economy infrastructure and pay more attention to the differences in diverse city development processes. It should also support basic research and development in information technology to promote high-quality development of China's foreign trade through the digital economy.

Transmission dynamics of brucellosis with patch model: Shanxi and Hebei Provinces as cases.

Brucellosis is a zoonotic disease caused by Brucella, and it is an important infectious disease all over the world. The prevalence of brucellosis in the Chinese mainland has some spatial characteristics besides the temporal trend in recent years. Due to the large-scale breeding of sheep and the frequent transportation of sheep in various regions, brucellosis spreads wantonly in pastoral areas, and human brucellosis spreads from traditional pastoral areas and semi-pastoral areas in the north to non-pastoral areas with low incidence in the south. In order to study the influence of sheep immigration on the epidemic transmission, a patch dynamics model was established. In each patch, the sub-model was composed of humans, sheep and Brucella. The basic reproduction number, disease-free equilibrium and positive equilibrium of the model were discussed. On the other hand, taking Shanxi Province and Hebei Province as examples, we carried out numerical simulations. The results show that the basic reproduction numbers of Shanxi Province and Hebei Province are 0.7497 and 0.5022, respectively, which indicates that the current brucellosis in the two regions has been effectively controlled. To reduce brucellosis faster in the two provinces, there should be a certain degree of sheep immigration from high-infection area to low-infection areas, and reduce the immigration of sheep from low-infection areas to high-infection areas.

Estradiol Replacement at the Critical Period Protects Hippocampal Neural Stem Cells to Improve Cognition in APP/PS1 Mice.

It has been suggested that there is a critical window for estrogen replacement therapy (ERT) in postmenopausal women with Alzheimer's disease (AD); however, supporting evidence is lacking. To address this issue, we investigated the effective period for estradiol (E2) treatment using a mouse model of AD. Four-month-old female APPswe/PSEN1dE9 (APP/PS1) mice were ovariectomized (OVX) and treated with E2 for 2 months starting at the age of 4 months (early period), 6 months (mid-period), or 8 months (late period). We then evaluated hippocampal neurogenesis, ß-amyloid (Aß) accumulation, telomerase activity, and hippocampal-dependent behavior. Compared to age-matched wild type mice, APP/PS1 mice with intact ovaries showed increased proliferation of hippocampal neural stem cells (NSCs) at 8 months of age and decreased proliferation of NSCs at 10 months of age; meanwhile, Aß accumulation progressively increased with age, paralleling the reduced survival of immature neurons. OVX-induced depletion of E2 in APP/PS1 mice resulted in elevated Aß levels accompanied by elevated p75 neurotrophin receptor (p75NTR) expression and increased NSC proliferation at 6 months of age, which subsequently declined; accelerated reduction of immature neurons starting from 6 months of age, and reduced telomerase activity and worsened memory performance at 10 months of age. Treatment with E2 in the early period post-OVX, rather than in the mid or late period, abrogated these effects, and p75NTR inhibition reduced the overproliferation of NSCs in 6-month-old OVX-APP/PS1 mice. Thus, E2 deficiency in young APP/PS1 mice exacerbates cognitive deficits and depletes the hippocampal NSC pool in later life; this can be alleviated by E2 treatment in the early period following OVX, which prevents Aß/p75NTR-induced NSC overproliferation and preserves telomerase activity.

Exposure of female mice to perfluorooctanoic acid suppresses hypothalamic kisspeptin-reproductive endocrine system through enhanced hepatic fibroblast growth factor 21 synthesis, leading to ovulation failure and prolonged dioestrus.

Perfluorooctanoic acid (PFOA) is widely used in household applications. High-dose exposure to PFOA has been associated with increased risks of infertility and premature ovarian insufficiency in woman. PFOA can alter hepatic gene expression by activating peroxisome proliferator-activated receptor α (PPARα). The present study investigated whether exposure to PFOA via PPARα activation alters the synthesis of hepatic fibroblast growth factor 21 (FGF21) to disturb female neuroendocrine and reproductive function. In the present study, we show that the oral administration of PFOA (2 or 5 mg kg-1 ) in adult female mice (PFOA mice) caused prolonged dioestrous, a reduction in the number of corpora lutea and decreased levels of hypothalamic gonadotrophin-releasing hormone, serum progesterone and luteinising hormone (LH). Exposure to PFOA decreased the expression of vasopressin in the suprachiasmatic nucleus (SCN) and kisspeptin in the anteroventral periventricular nucleus (AVPV) with deficits in preovulation or oestrogen-induced LH surge. PFOA via activation of PPARα increased dose-dependently hepatic FGF21 expression, leading to elevated serum and hypothalamic FGF21 concentrations. Treatment of PFOA mice with the PPARα antagonist GW6471 or the FGF21 inhibitor PD173074 rescued SCN vasopressin and AVPV-kisspeptin expression. Either administration of GW6471 and PD173074 or treatment with vasopressin and the G protein coupled receptor 54 agonist kisspeptin-10 in PFOA-mice was able to recover the regular oestrous cycle, ovulation ability, LH surge production and reproductive hormone levels. The present study provides in vivo evidence that exposure to PFOA (≥2 mg kg-1 ) in mice causes down-regulation of the kisspeptin-reproductive endocrine system by enhancing PPARα-mediated hepatic FGF21 expression. The liver-brain reproductive endocrine disorder caused by PFOA exposure may lead to prolonged dioestrous and ovulation failure.