Molecular Brain最新文献

Transient receptor potential melastatin type 2 (TRPM2) is a nonselective cation channel involved in synaptic plasticity. We investigated its role in contextual fear conditioning and extinction of conditioned fear using Trpm2-deficient (Trpm2^-/-) mice. Trpm2^-/- mice exhibited reduced acquisition of contextual fear memory during conditioning but had an intact freezing response to conditioning context 24 h after conditioning. They also showed a reduced freezing response to extinction training, indicating facilitated extinction. Consistent with this, infusion of flufenamic acid (FFA), a TRPM2 antagonist, into the dentate gyrus (DG) of the hippocampus in fear-conditioned mice facilitated extinction of contextual fear. The enhanced extinction in Trpm2^-/- and FFA-treated mice was associated with down-regulation of immediate-early genes (IEGs) including Npas4, c-Fos, Arc and Egr1 in the hippocampus after extinction training. Our results indicate that TRPM2 plays a positive role in retention of contextual fear memory by modulating neuronal activity in the hippocampus, and suggest that TRPM2 activity could potentially be targeted to strengthen extinction-based exposure therapies for post-traumatic stress disorder (PTSD).

The TREM1 receptor, a member of the TREMs family, is expressed by myeloid cells and functions as an initiator or enhancer of the inflammatory response, playing a pivotal role in the regulation of inflammation. In recent years, it has been found that TREM1-mediated inflammatory response is involved in the regulation of pain-related diseases. This article provides an extensive review on the structural characteristics and distribution patterns, ligand, signaling pathways, inhibitors, and pathophysiological roles of TREM1 in pain disorders aiming to further elucidate its biological function and offer novel insights for clinical interventions targeting pain-related diseases.

Observational fear (OF) is the ability to vicariously experience and learn from another's fearful situation, enabling adaptive responses crucial for survival. It has been shown that the anterior cingulate cortex (ACC) and basolateral amygdala (BLA) are crucial for OF. A subset of neurons in the ACC is activated when observing aversive events in the demonstrator, which elicits OF. However, the neural circuit mechanisms underlying the expression of OF-related activity in the ACC remain unexplored. Previous studies have shown that the mediodorsal thalamus (MD) is crucial for OF, and MD neurons project to the ACC. Therefore, we hypothesize that the projection from MD to ACC may facilitate the OF-related activity in the ACC. By utilizing in vivo calcium imaging combined with the optogenetic terminal inhibition of MD-ACC pathway, we found that a subset of ACC neurons was activated when observing demonstrator's fearful situation in male mice. Furthermore, the optogenetic inhibition of the MD-ACC projection during the demonstrator's aversive moments significantly suppressed the OF-related activity in the ACC. Our data suggests that the MD-ACC projection plays a role in OF-related activity in ACC neurons.

Cardiac arrest (CA) is one of the most common illnesses worldwide. Post-CA brain injury (PCABI) is a major cause of death and poor recovery in CA patients and the current CA treatments are not very effective. The microbiome-gut-brain axis has been found to significantly affect brain ischemia injury. Furthermore, in ischemic stroke patients, short-chain fatty acids (SCFA), especially sodium butyrate (SB), have been observed to promote neuroprotective effects by modulating inflammatory response and microglial polarization in the cortex. However, the precise mechanism of SB on CA-induced injury remains elusive. Therefore, this research study established an oxygen-glucose deprivation and reoxygenation (OGD/R) model using BV-2 microglial and HT22 cells to simulate cerebral ischemia/reperfusion injury in vitro and a potassium chloride-induced CA mouse model to mimic CA in vivo. The data revealed that SB markedly improved neurological scores and reduced neuronal death and apoptosis. Moreover, it reduced M1 microglia and neuroinflammation in CA mice. In addition, SB increased intestinal integrity and alleviated systemic inflammation. The 16S rDNA sequencing analysis indicated that SB intervention mitigated CA-induced gut microbiota dysbiosis and SCFA depletion. It was also observed that CA mice's brain and OGD/R-exposed BV2 cells had substantially increased levels of MyD88, phosphorylated NF-κB p65, and TLR4 proteins, which were reduced after SB treatment. In summary, this study revealed that SB can protect against cerebral ischemia-reperfusion injury by controlling microglia polarization and microbiome-gut-brain axis to inhibit brain inflammation via the TLR4/MyD88/NF-κB pathway.

Angiogenesis in the ischemic penumbra compensates for microcirculatory dysfunction and promotes neuronal plasticity after stroke. However, the current understanding may be highly biased because the contribution of veins to angiogenesis has been overlooked. This study revealed that the remodeling processes of veins differ from those of arteries after ischemia. Ligation of the right jugular vein increased the infarct volume, decreased cerebral blood flow and impaired long-term functional restoration after stroke. RNA-seq analysis revealed significant upregulation of the expression of genes associated with angiogenesis in the infarct core during the recovery period. By using gelatin ink-alkaline phosphatase-oil red O (GIAO) staining, we found that venogenesis, the process of creating new veins, was the predominant angiogenic event in the infarct core. Macrophage infiltration and transformation are closely associated with venogenesis in the infarct core. However, depletion of macrophages in the circulation by clodronate liposomes in the acute phase inhibited the proliferation of endothelial progenitor cells and decreased the vascular density in the infarct core. This study demonstrated that dynamic vein remodeling is crucial for cerebral ischemic damage and subsequent neuronal restoration. Angiogenesis occurs in the infarct core during the recovery period, promotes the absorption of necrotic tissue and facilitates functional recovery after stroke.

Neuronal autophagy is essential for maintaining protein and organelle turnover, thereby safeguarding neuronal health. LC3, a central autophagy protein, exists in lipidated (LC3-II) and non-lipidated (LC3-I) forms, both critical for neurons due to their sensitivity to metabolic and proteostatic stress. To elucidate the specific roles of membrane-anchored LC3A/B in post-mitotic neurons, we engineered deconjugases with enhanced selectivity for lipidated LC3. By modifying LC3-interacting regions (LIRs) at the deconjugase termini, we significantly improved targeting specificity toward LC3A/B. Deconjugases with N-terminal LIR modifications reduced LC3A/B-associated autophagosomes, highlighting the importance of LIR positioning for specificity. Sequential N-terminal LIR arrangements further refined LC3A/B targeting without affecting GABARAP-associated autophagosomes. Moreover, reducing the hydrophobicity of the α3 helix to limit membrane residence time further improved selectivity. These targeted modifications demonstrate the potential of customized deconjugases to dissect and modulate specific autophagic pathways in neurons, paving the way for novel therapeutic strategies against neurodegenerative diseases associated with autophagy dysregulation.

The microenvironment of the central nervous system is highly complex and plays a crucial role in maintaining the function of neurons, which influences Alzheimer's disease (AD) progression. The pH value of the brain is a critical aspect of the brain microenvironment in regulating various physiological processes. However, the specific mechanisms and role of this mechanism are not yet fully understood. To better understand the relationship between brain pH and AD, we analyzed the brain pH of the frontal lobe and AD pathology scores in postmortem brain samples from 368 donors from the National Human Brain Bank for Development and Function, 96 of whom were diagnosed with AD pathology. Analysis revealed a significant decrease in brain pH in AD patients, which was strongly correlated with β-amyloid plaques and phosphorylated tau proteins. Here, we elucidated the differential protein expression level of CD68-positive microglia between control and AD groups (t = 3.198, df = 20, P = 0.0045), and its protein expression level was correlated negatively with the brain pH value (F = 26.93, p = 0.0006). Our findings revealed that increased activation of CD68-positive microglia and disrupted lysosomal homeostasis in the pathological brain tissue of individuals with AD may lead to a decrease in brain pH.

Brain regions drive multiple physiological functions through specific gene expression patterns that adapt to environmental influences, drug treatments and disease conditions. To generate a detailed atlas of the brain transcriptome in the context of diabetes, we carried out RNA sequencing in hypothalamus, hippocampus, brainstem and striatum of the Goto-Kakizaki (GK) rat model of spontaneous type 2 diabetes, which was applied to identify gene transcription adaptation to improved glycemic control following vertical sleeve gastrectomy (VSG) in the GK. Over 19,000 distinct transcripts were detected in the rat brain, including 2794 which were consistently expressed in the four brain regions. Region-specific gene expression was identified in hypothalamus (n = 477), hippocampus (n = 468), brainstem (n = 1173) and striatum (n = 791), resulting in differential regulation of biological processes between regions. Differentially expressed genes between VSG and sham operated rats were only found in the hypothalamus and were predominantly involved in the regulation of endothelium and extracellular matrix. These results provide a detailed atlas of regional gene expression in the diabetic rat brain and suggest that the long term effects of gastrectomy-promoted diabetes remission involve functional changes in the hypothalamus endothelium.

Recent studies have shown that abnormal activity of acid sphingomyelinase (Asm) has been associated with a range of psychiatric disorders including schizophrenia and depression. However, the role of Asm in the regulation of anxiety remains unclear. In the present study, we employed Asm-knockout (Asm KO) mice to investigate the association between Asm and anxiety using behavioral tests, RNA sequencing, q-PCR, immunohistochemical staining, and other methods. The behavioral results showed that Asm KO mice exhibit enhanced anxiety-like behaviors, such as restricted activity, reduced cumulative times in the central area, diminished exploratory interest, delayed latency to feed, through behavioral tests including open field, novelty-suppressed feeding test, elevated plus maze test, ect. Transcriptional profiling combined with bioinformatics analysis revealed the upregulation of Toll-like receptor signaling pathway related gene including Tlr1/2, Ccl3, Ccl4, Ccl5 and Cd86 in Asm KO mice, which was further confirmed by the detection of activated microglia and astrocytes through iba-1 and GFAP immunohistochemical staining. Collectively, our findings uncover a role for Asm in regulating anxiety-like behavior and suggest that it may be essential for the maintenance of emotional stability, indicating its potential as a promising target for treating anxiety disorders.

Delirium is a common complication in elderly surgical patients and is associated with an increased risk of dementia. Although advanced age is a major risk factor, the mechanisms underlying postoperative delirium remain poorly understood. The glymphatic system, a brain-wide network of perivascular pathways, facilitates cerebrospinal fluid (CSF) flow and supports the clearance of metabolic waste. Impairments in glymphatic function have been observed in aging brains and various neurodegenerative conditions. Using in vivo two-photon imaging, we examined the effects of surgery (laparotomy) on glymphatic function in adult (6 months) and aged (18 months) mice 24 h post-surgery. In adult mice, CSF tracer entry into the brain parenchyma along periarteriolar spaces occurred rapidly following intracisternal tracer injection, with no significant differences between sham and surgery groups. In contrast, aged mice exhibited delayed tracer influx, with further impairments observed in the surgery group compared to sham controls. This glymphatic dysfunction correlated with poorer T-maze performance in aged mice. These findings suggest that surgery exacerbates glymphatic impairment in aging brains, potentially hindering brain waste clearance and contributing to postoperative delirium.