Age-related changes after intracerebral hemorrhage: a comparative proteomics analysis of perihematomal tissue.

The risk factors and causes of intracerebral hemorrhage (ICH) and the degree of functional recovery after ICH are distinct between young and elderly patients. The increasing incidence of ICH in young adults has become a concern; however, research on the molecules and pathways involved ICH in subjects of different ages is lacking. In this study, tandem mass tag (TMT)-based proteomics was utilized to examine the protein expression profiles of perihematomal tissue from young and aged mice 24 h after collagenase-induced ICH. Among the 5,129 quantified proteins, ICH induced 108 and 143 differentially expressed proteins (DEPs) in young and aged mice, respectively; specifically, there were 54 common DEPs, 54 unique DEPs in young mice and 89 unique DEPs in aged mice. In contrast, aging altered the expression of 58 proteins in the brain, resulting in 39 upregulated DEPs and 19 downregulated DEPs. Bioinformatics analysis indicated that ICH activated different proteins in complement pathways, coagulation cascades, the acute phase response, and the iron homeostasis signaling pathway in mice of both age groups. Protein-protein interaction (PPI) analysis and ingenuity pathway analysis (IPA) demonstrated that the unique DEPs in the young and aged mice were related to lipid metabolism and carbohydrate metabolism, respectively. Deeper paired-comparison analysis demonstrated that apolipoprotein M exhibited the most significant change in expression as a result of both aging and ICH. These results help illustrate age-related protein expression changes in the acute phase of ICH.

Spatial memory requires hypocretins to elevate medial entorhinal gamma oscillations.

The hypocretin (Hcrt) (also known as orexin) neuropeptidic wakefulness-promoting system is implicated in the regulation of spatial memory, but its specific role and mechanisms remain poorly understood. In this study, we revealed the innervation of the medial entorhinal cortex (MEC) by Hcrt neurons in mice. Using the genetically encoded G-protein-coupled receptor activation-based Hcrt sensor, we observed a significant increase in Hcrt levels in the MEC during novel object-place exploration. We identified the function of Hcrt at presynaptic glutamatergic terminals, where it recruits fast-spiking parvalbumin-positive neurons and promotes gamma oscillations. Bidirectional manipulations of Hcrt neurons' projections from the lateral hypothalamus (LHHcrt) to MEC revealed the essential role of this pathway in regulating object-place memory encoding, but not recall, through the modulation of gamma oscillations. Our findings highlight the significance of the LHHcrt-MEC circuitry in supporting spatial memory and reveal a unique neural basis for the hypothalamic regulation of spatial memory.

Analysis of Age-Dependent Transcriptomic Changes in Response to Intracerebral Hemorrhage in Mice.

Age is a well-known risk factor that is independently associated with poor outcomes after intracerebral hemorrhage (ICH). However, the interrelationship between age and poor outcomes after ICH is not well defined. In this study, we aimed to investigate this relationship based on collagenase-induced ICH mice models. After being assessed neurological deficit 24 h after ICH, mice were euthanized and brain perihematomal tissues were used for RNA-sequencing (RNA-seq). And then the functions of differentially expressed genes (DEGs) identified by RNA-seq were analyzed using Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, Ingenuity Pathway Analysis (IPA) and protein-protein interaction (PPI) analysis. In addition, we performed real-time quantitative polymerase chain reaction (RT-qPCR) for validation of candidate DEGs. In the behavioral tests, aged mice presented significantly worse neurological function than young mice and greater weight loss than aged sham controls 24 h after ICH. In DEGs analysis, ICH affected the expression of more genes in young mice (2,337 DEGs) compared with aged mice (2,005 DEGs). We found aged mice exhibited increased brain inflammatory responses compared with young animals and ICH induced significant activation of the interferon-ß (IFN-ß) and IFN signaling pathways exclusively in aged mice. Moreover, further analysis demonstrated that ICH resulted in the activation of cytosolic DNA-sensing pathway with the production of downstream molecule type I IFN, and the response to type I IFN was more significant in aged mice than in young mice. In agreement with the results of RNA-seq, RT-qPCR indicated that the expression of candidate genes of cyclic GMP-AMP synthase (cGAS), Z-DNA-binding protein 1 (ZBP1), and IFN-ß was significantly altered in aged mice after ICH. Taken together, our study indicated that compared to young animals, aged mice exhibit increased vulnerability to ICH and that the differences in transcriptional response patterns to ICH between young and aged mice. We believe that these findings will facilitate our understanding of ICH pathology and help to translate the results of preclinical studies into a clinical setting.

Edaravone ameliorates depressive and anxiety-like behaviors via Sirt1/Nrf2/HO-1/Gpx4 pathway.

BACKGROUND: The inflammation and oxidative stress (OS) have been considered crucial components of the pathogenesis of depression. Edaravone (EDA), a free radical scavenger, processes strong biological activities including antioxidant, anti-inflammatory and neuroprotective properties. However, its role and potential molecular mechanisms in depression remain unclear. The present study aimed to investigate the antidepressant activity of EDA and its underlying mechanisms. METHODS: A chronic social defeat stress (CSDS) depression model was performed to explore whether EDA could produce antidepressant effects. Behaviors tests were carried out to examine depressive, anxiety-like and cognitive behaviors including social interaction (SI) test, sucrose preference test (SPT), open field test (OFT), elevated plus maze (EPM), novel object recognition (NOR), tail suspension test (TST) and forced swim test (FST). Hippocampal and medial prefrontal cortex (mPFC) tissues were collected for Nissl staining, immunofluorescence, targeted energy metabolomics analysis, enzyme-linked immunosorbent assay (ELISA), measurement of MDA, SOD, GSH, GSH-PX, T-AOC and transmission electron microscopy (TEM). Western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) detected the Sirt1/Nrf2/HO-1/Gpx4 signaling pathway. EX527, a Sirt1 inhibitor and ML385, a Nrf2 inhibitor were injected intraperitoneally 30 min before EDA injection daily. Knockdown experiments were performed to determine the effects of Gpx4 on CSDS mice with EDA treatment by an adeno-associated virus (AAV) vector containing miRNAi (Gpx4)-EGFP infusion. RESULTS: The administrated of EDA dramatically ameliorated CSDS-induced depressive and anxiety-like behaviors. In addition, EDA notably attenuated neuronal loss, microglial activation, astrocyte dysfunction, oxidative stress damage, energy metabolism and pro-inflammatory cytokines activation in the hippocampus (Hip) and mPFC of CSDS-induced mice. Further examination indicated that the application of EDA after the CSDS model significantly increased the protein expressions of Sirt1, Nrf2, HO-1 and Gpx4 in the Hip. EX527 abolished the antidepressant effect of EDA as well as the protein levels of Nrf2, HO-1 and Gpx4. Similarly, ML385 reversed the antidepressant and anxiolytic effects of EDA via decreased expressions of HO-1 and Gpx4. In addition, Gpx4 knockdown in CSDS mice abolished EDA-generated efficacy on depressive and anxiety-like behaviors. CONCLUSION: These findings suggest that EDA possesses potent antidepressant and anxiolytic properties through Sirt1/Nrf2/HO-1/Gpx4 axis and Gpx4-mediated ferroptosis may play a key role in this effect.

Metabolomic abnormalities of purine and lipids implicated olfactory bulb dysfunction of CUMS depressive rats.

Major depressive disorder (MDD) is a serious mood disorder and leads to a high suicide rate as well as financial burden. The volume and function (the sensitivity and neurogenesis) of the olfactory bulb (OB) were reported to be altered among the MDD patients and rodent models of depression. In addition, the olfactory epithelium was newly reported to decrease its volume and function under chronic unpredictable mild stress (CUMS) treatment. However, the underlying molecular mechanism still remains unclear. Herein, we conducted the non-targeted metabolomics method based on gas chromatography-mass spectrometry (GC-MS) coupled with multivariate statistical analysis to characterize the differential metabolites in OB of CUMS rats. Our results showed that 19 metabolites were categorized into two perturbed pathways: purine metabolism and lipid metabolism, which were regarded as the vital pathways concerned with dysfunction of OB. These findings indicated that the turbulence of metabolic pathways may be partly responsible for the dysfunction of OB in MDD.

Lactate Deficit in an Alzheimer Disease Mouse Model: The Relationship With Neuronal Damage.

Cerebral energy metabolism in Alzheimer disease (AD) has recently been given increasing attention. This study focuses on the alterations of cerebral lactate metabolism in the double-transgenic amyloid precursor protein/presenilin 1 (APP/PS1) mouse model of AD. Immunofluorescence staining and Western blotting analysis were used to identify the alterations of lactate content and lactate transporters (MCT1, MCT2, MCT4) in APP/PS1 mouse brains, which display amyloid beta plaques, reduced amounts of neurons and oligodendrocytes, and increased quantity of astrocytes. We found that lactate content and expressions of cerebral MCT1, MCT2, and MCT4 were decreased in APP/PS1 mice. In particular, lactate dehydrogenase A (LDHA) and B (LDHB) were reduced in neurons with increased ratios of LDHA and LDHB. This study suggests that the decreases of cerebral lactate content and lactate transporters may lead to the blockage of lactate transport from glia to neurons, resulting in neuronal lactate deficit. The increased ratio of neuronal LDHA and LDHB may represent a reaction of neurons to lactate deficit, although it cannot reverse the energy deficiency in neurons.

The paraventricular thalamus is a critical thalamic area for wakefulness.

Clinical observations indicate that the paramedian region of the thalamus is a critical node for controlling wakefulness. However, the specific nucleus and neural circuitry for this function remain unknown. Using in vivo fiber photometry or multichannel electrophysiological recordings in mice, we found that glutamatergic neurons of the paraventricular thalamus (PVT) exhibited high activities during wakefulness. Suppression of PVT neuronal activity caused a reduction in wakefulness, whereas activation of PVT neurons induced a transition from sleep to wakefulness and an acceleration of emergence from general anesthesia. Moreover, our findings indicate that the PVT-nucleus accumbens projections and hypocretin neurons in the lateral hypothalamus to PVT glutamatergic neurons' projections are the effector pathways for wakefulness control. These results demonstrate that the PVT is a key wakefulness-controlling nucleus in the thalamus.

Orexin knockout mice exhibit impaired spatial working memory.

Orexins play a crucial role in the maintenance of arousal and are involved in the modulation of diverse physiological process, including cognitive function. Recent data have suggested that orexins are involved in learning and memory processes. The purpose of this study was to assess the effects of orexin deficiency on working memory. A delayed non-matching-to-place T-maze task was used to evaluate spatial working memory in mice lacking orexin prepro-peptide (orexin knockout; KO) and wild-type controls. We demonstrated that the number of correct choices in the orexin KO mice became lower than that of the controls over training. In an object exploration task, the controls explored the displaced object more than the mutants did, whereas this difference was not observed for the nondisplaced objects in either group. The orexin KO mice showed locomotor activity comparable to the control mice in terms of total distance traveled across training in both the object exploration task and the open field test. These findings indicate that the orexin system plays an important role in working memory of spatial cues.