The environmental enrichment ameliorates chronic cerebral hypoperfusion-induced cognitive impairment by activating autophagy signaling pathway and improving synaptic function in hippocampus.

BACKGROUND: Chronic cerebral hypoperfusion (CCH) is a frequently observed underlying pathology of both Alzheimer's disease (AD) and vascular dementia (VD), which is a common consequence of cerebral blood flow (CBF) dysregulation. Synaptic damage has been proven as a crucial causative factor for CCH-related cognitive impairment. This study aimed to investigate the neuroprotective impact of environmental enrichment (EE) intervention on CCH-induced synaptic destruction and the consequent cognitive impairment. Furthermore, the underlying mechanism of this neuroprotective effect was explored to provide new insights into therapeutic interventions for individuals suffering from AD or VD. METHODS: In this experiment, all rats were initially acclimatized to a standard environment (SE) for a period of one week. On the seventh day, rats underwent either bilateral common carotid artery occlusion (2VO) surgery or sham surgery (Sham) before being subjected to a four-week procedure of exposure to an EE, except for the control group. During the EE or SE procedure, intraperitoneal injection of chloroquine (CQ) into rats was performed once daily for four weeks. Following this, cognitive function was assessed using the Morris water maze (MWM) test. The synapse ultrastructure was subsequently observed using transmission electron microscopy. Expression levels of autophagy-related proteins (LC3, LAMP1, and P62) and synapse-related proteins (Synapsin I and PSD-95) were detected through Western blotting. Finally, immunofluorescence was used to examine the expression levels of Synapsin I and PSD-95 and the colocalization of LAMP-1 and LC3 in the hippocampus. RESULTS: After undergoing 2VO, rats exposed to SE exhibited cognitive impairment, autophagic dysfunction, and synapse damage. The synapse damage was evidenced by ultrastructural damage and degradation of synapse-related proteins. However, these effects were significantly mitigated by exposure to an EE intervention. Moreover, the intervention led to an improvement in autophagic dysfunction. CONCLUSION: The study found that EE had a positive impact on CCH-induced synaptic damage. Specifically, EE was found to increase synaptic plasticity-associated proteins and postsynaptic density thickness, while decreasing synaptic space. This multifaceted effect resulted in an amelioration of CCH-induced cognitive impairment. It was shown that this beneficial outcome was mediated via the activation of the autophagy-lysosomal pathway. Overall, the findings suggest that EE may have a therapeutic potential for cognitive impairments associated with CCH through autophagy-mediated synaptic improvement.

The environmental enrichment ameliorates chronic unpredictable mild stress-induced depressive-like behaviors and cognitive decline by inducing autophagy-mediated inflammation inhibition.

BACKGROUND: People exposed to prolonged chronic unpredictable mild stress (CUMS) are easy to suffer from depression and cognitive impairment. Environmental enrichment (EE) had a beneficial effect on depressive-like and cognition-like behaviors by inhibiting inflammation. However, the specific mechanism involved in the inflammation inhibition that occurs after EE treatment for the depression and cognitive decline induced by CUMS remains unclear. In this study, we evaluated the possible mechanism of the beneficial effects on depression and cognition by EE. METHODS: Rats were randomly divided into 5 groups as follows: (1) Control + standard environment (SE), (2) CUMS + SE, (3) CUMS + EE, (4) CUMS + EE+ 3-methiladenine (3-MA), (5) CUMS + SE + 3-MA. They were exposed to CUMS procedure for 5 weeks except the control group. After CUMS procedure, rats were housed in the EE or SE for 3 weeks. During EE or SE treatment, rats were injected with normal saline or 3-MA every day. 3-MA as an autophagy inhibitor suppresses autophagy via inhibition of class III PI3K. Behavioral tests were used to investigate depressive-like and cognition-like behaviors after EE treatment. Then, autophagy-related proteins, inflammation-related molecules, transmission electron microscopy (TEM) and immunofluoresence were determined. RESULTS: We found that CUMS induced depressive-like behaviors and cognitive impairment, reflected in worse behavioral test, such as reduced sucrose preference ratio, decreased locomotor and exploratory activity, prolonged immobility and spatial learning and memory impairment. In addition, CUMS rats exhibited the reduced expression of autophagy related proteins including LC3 and Beclin-1 and the increased inflammation activation including microglia cells, NLRP3 inflammasome and proinflammatory cytokines (IL-1ß, IL-6 and TNF-α). After EE treatment, these changes were reversed. However, 3-MA, the inhibitor of autophagy, eliminated the neuroprotective effects of EE on depressive-like behaviors and cognitive decline. CONCLUSION: This study demonstrates that EE can play neuroprotective effects on depression and cognitive impairment by inducing autophagy-mediated inflammation inhibition, which accounts for the reduction of proinflammatory cytokines, including IL-1ß, IL-6 and TNF-α.

Enriched environment priors to TET1 hippocampal administration for regulating psychiatric behaviors via glial reactivity in chronic cerebral hypoperfusion models.

BACKGROUND: Chronic cerebral hypoperfusion (CCH) has been gradually regarded as a common etiologic mechanism for cognitive and psychiatric disturbances. Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) played an important role in adult hippocampal neurogenesis (AHN), neuronal circuits formation, cognition and psychiatric disorders. Enriched environment (EE) showed a beneficial effect on cognition and depression via effectively regulating AHN and glial reactivity. This study aimed to assess which strategy was feasible to improve cognition and psychiatric disturbances by comparing the TET1 hippocampal microinjection and EE in CCH models and to investigate the possible mechanisms. METHOD: CCH rats were established via permanent bilateral common carotid artery occlusion (2-VO). Rats were stereotaxically injected with the human catalytic domain of TET1 (hTET1) to overexpress the hTET1 in the hippocampus 10 days before 2-VO. 3 days after 2-VO, rats were subjected to standard environment or EE with free access to food and water. Behavioral tests were used to appraise depression and cognition before sacrifice. Epigenetic molecules, adult neurogenesis, synaptic proteins expression, and glial activation were analyzed using immunofluorescent staining, qRT-PCR and western blot. RESULTS: In the present study, we found both EE and genetical treatment with overexpressing hTET1 were sufficient for stimulating AHN. However, promoting ANH could not deal with the cognitive dysfunction and depressive-like behaviors in CCH rats. Notably, a healthy local brain environment with elevated BDNF and astrocytes was conducive to improving cognitive dysfunction. Meanwhile, astrocytes were involved in the cognitive regulating process of neurons, presynaptic function and microglia. In general, we held that depressive disturbances were determined by BDNF levels, neuronal and presynaptic function, as well as glial activation containing astrocytes and microglia. To further support this point, we investigated severe depressive symptoms that were strongly correlated with the activation of astroglia and microglia. Importantly, causal mediation analysis showed significant mediation by the presence of reactive glial cells in the relation between neural plasticity and depressive symptoms. Finally, we showed EE performed better than hTET1 treatment for cognitive deficits and depression. EE with less glial reactivity was much more resistant to depression, while hTET1 with more glial activation was more vulnerable to depressive disorders. CONCLUSIONS: EE was likely to be superior to TET1 hippocampal administration for cognition and psychiatric behaviors in CCH rats. Furthermore, a healthy local brain environment with elevated BDNF and astrocytes was conducive to improving cognitive dysfunction. More glial activation, and more vulnerable to depressive disorders. These results were important for our understanding of disease mechanisms and provided valuable tools for the overall management of CCH patients.

Nuclear receptor TLX may be through regulating the SIRT1/NF-κB pathway to ameliorate cognitive impairment in chronic cerebral hypoperfusion.

BACKGROUND: Chronic cerebral hypoperfusion (CCH) is a common pathophysiological mechanism in neurodegenerative diseases, such as Alzheimer's disease and vascular dementia. The orphan nuclear receptor TLX plays an important role in neural development, adult neurogenesis and cognition. The aim of this study was to investigate the neuroprotective effects of TLX on cognitive dysfunction, hippocampal neurogenesis and neuroinflammation in a rat model of CCH and to assess the possible mechanisms. METHODS: Permanent bilateral common carotid artery occlusion (2-VO) was used to establish a model of CCH. Stereotaxic injection of an adeno-associated virus vector expressing TLX was used to overexpress TLX in the hippocampus. Cognitive function was evaluated by the Morris Water Maze test. Immunofluorescent staining was used to assess hippocampal neurogenesis. The effects of overexpression of TLX on SIRT1 and inflammatory cytokines were analyzed with qRT-PCR and western blot. RESULT: After 2-VO, CCH rats exhibited cognitive impairment and reduction of hippocampal TLX levels. Overexpression of TLX ameliorated cognitive impairments with increasing number of BrdU + cells and BrdU + NeuN + cells in DG. Furthermore, TLX rescued the reduced SIRT1 usually induced by CCH. Additionally, TLX also inhibited the expression of inflammatory cytokines such as NF-κB and IL-1ß. CONCLUSIONS: The present findings suggested that TLX exerted protective effects against cognitive deficits induced by CCH. The possible mechanisms of TLX may be through regulating the SIRT1/NF-κB pathway, promoting hippocampal neurogenesis and inhibiting the neuroinflammatory response.

Association between LRH-1 single nucleotide polymorphisms and unexplained recurrent spontaneous abortion in Chinese Han couples.

To explore the genetic relationships between LRH-1 (rs2816948), CYP19 (rs727479 and rs700518), and P450scc (rs4077582) as a potential mechanism behind unexplained recurrent spontaneous abortions in a Chinese Han population. A case-control study was used and featured two groups: Patients with unexplained recurrent miscarriage (n = 82, abortion group) and those who voluntary surrendered of a normal early pregnancy (n = 97, control group). Abortion villi samples were obtained from all patients. Genomic DNA was later extracted and sequenced, after which statistical analyses performed to assess the relationship between single nucleotide polymorphisms and unexplained recurrent spontaneous abortions. There were significant differences in the genotypic and allelic distribution (p < .05) for CYP19 (rs727479) between the abortion and the control groups. There were no significant differences in the genotypic or allelic distributions (p > .05) for either the LRH-1 (rs2816948) or CYP19 (rs700518). There were also significant genotypic differences (p < .05) for P450scc (rs4077582), but no significant differences for its allelic distribution (p > .05). There was a significant correlation between the occurrence of unexplained recurrent spontaneous abortion and CYP19 (rs727479) single nucleotide polymorphisms.

Pharmacological Activation of Peroxisome Proliferator-Activated Receptor {Delta} Increases Sphingomyelin Synthase Activity in THP-1 Macrophage-Derived Foam Cell.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which mediate glucose and lipid homeostasis by regulating the expression of a large number of transcription factors. Sphingomyelin synthase (SMS) is a key enzyme in the synthesis of sphingomyelin (SM), and its expression and activity have been reported to be associated with atherosclerosis (AS). Although there have been many functional PPAR and SMS studies on atherosclerosis in recent years, few have investigated the correlation between the activation of PPARδ and the activity of SMS. In his study, macrophage-induced foam cells were utilized to model important pathological changes that occur in AS. The influence of PPARδ agonism by GW501516 on SMS and its product molecule SM were measured. Results indicated that the activation of PPARδ was correlated in a positive manner with the activity of SMS2, and the content of SM was dose dependently increased by GW501516. Together, this study represents the first to suggest that PPARδ activation may be a potential risk of AS through enhancing activity of SMS2.