Mouse Brain Research Articles

The Effect of Donepezil Hydrochloride in the Twitcher Mouse Model of Krabbe Disease.

Krabbe disease (KD) is a rare demyelinating disorder characterized by demyelination caused by mutations in the GALC gene, resulting in toxic accumulation of psychosine. Psychosine has been identified as detrimental to oligodendrocytes, leading to demyelination through diverse hypothesized pathways. Reducing demyelination is essential to maintain neurological function in KD; however, therapeutic interventions are currently limited. Acetylcholinesterase inhibitors (AChEi) are commonly used for symptomatic management of Alzheimer's Disease and are suggested to have potential disease-modifying effects, including regulating myelin state. In particular, donepezil, an AChEi, has demonstrated promising effects in cellular and animal models, including promotion of the expression of myelin-related genes and reduction of glial cell reactivity. This drug also acts as an agonist for sigma-1 receptors (Sig-1R), which are implicated in demyelination diseases. In the context of drug repurposing, here, we demonstrate that administration of donepezil has protective effects in the twitcher mouse model of KD. We provide data showing that donepezil preserves myelin and reduces glial cell reactivity in the brains of twitcher mice. Moreover, donepezil also improves behavioral phenotypes and increases lifespan in twitcher animals. These findings suggest that donepezil, with its dual activity as an AChE inhibitor and Sig-1R agonist, may hold promise as a therapeutic candidate for demyelinating diseases, including KD.

Walnut-derived peptides cross the blood–brain barrier and ameliorate Aβ-induced hypersynchronous neural network activity

Walnut peptides exhibit promising neuroprotective effects; however, they must be absorbed in their intact form through the gastrointestinal tract into the bloodstream and brain. In this study, the effects of the walnut peptide TWLPLPR (TW-7) were evaluated in mice, including its absorption and distribution ability to cross the blood–brain barrier, and inhibitory effects on hyperactivity of primary hippocampal neurons. TW-7 was stable in plasma, and the peptide retention rate was 88.19 ± 0.70 % after 48 h. In vitro imaging indicated that TW-7 was distributed in the brain, liver, lungs, and kidneys of mice after gavage, and an immunofluorescence analysis indicated that TW-7 could accumulate in mouse brain parenchyma; in addition, TW-7 reached its maximum concentration (5.36 ± 1.59 µg/mL) in plasma 2 h after gavage, and reached its peak concentration (0.95 ± 0.19 µg/g) in brain tissue 4 h after gavage. Microelectrode array and immunofluorescence analyses confirmed that TW-7 ameliorates the overexcitation of primary hippocampal neurons induced by Aβ25–35 through inhibiting the excessive release of glutamate and protecting synaptic structure and function. These results suggest that TW-7 can penetrate the blood–brain barrier in mice and positively affect the electrophysiological activity of neurons. More broadly, these findings provide a theoretical basis for the development and application of walnut peptide-based functional food for Alzheimer’s disease intervention.

Lactobacillus plantarum LP104 improved intestinal and brain inflammation by modulating TLR4 pathway and gut flora in alcohol liver injury mice

In this study, Lactobacillus plantarum LP104 (LP104) originating from kimchi was treated to C57BL/6N mice fed a chronic-plus-single-binge ethanol diet for ten days, aiming to evaluate the effects of the probiotics on intestinal and brain inflammation in the alcohol-induced liver injury model. Dietary supplementation with LP104 significantly reduced the concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) in alcoholic hepatic injury mice. The 16S rDNA sequencing results inferred that LP104 modulated the intestinal microbiota by depleting inflammation-related bacterial genera Proteobacteria and enriching Lactobacillus and Roseburia. Furthermore, LP104 intervention attenuated alcohol-induced gut inflammation by the TLR4 signaling pathway, which regulated the expressions of intestinal tight junction proteins such as ZO-1, Claudin-1 and Occludin. Subsequently, LP104 intake exerted neuroprotection by restoring neurotrophic factor levels and the blood-brain barrier (BBB) function to decrease lipopolysaccharide (LPS) levels in the serum. The western blotting results suggested LP104 ameliorated alcohol-induced brain inflammation by inhibiting the LPS/TLR4 signaling pathway in mice. Spearman's correlation analysis demonstrated that differential intestinal bacterial taxa were connected with the expressions of inflammation-related proteins in both gut and brain of alcohol liver injury mice.

Impact of Aerobic Exercise on Brain Metabolism: Insights from Spatial Metabolomic Analysis.

Exercise is acknowledged for its beneficial effects on brain health; however, the intricate underlying molecular mechanisms remain poorly understood. This study aimed to explore aerobic exercise-induced metabolic alterations in the brain. We conducted an eight-week treadmill running exercise program in two-month-old male C57/BL6J mice. Body weight, serum lipid, glucose levels, and spatial cognition were measured. Spatial metabolomic analysis was performed to compare the metabolomic profiles across different brain regions. Immunohistochemical methods were used to compare the expression of carnitine palmitoyltransferase 1c (CPT1c). Exercise induced significant changes in the analysed metabolomic profiles. There were 904 differentially expressed metabolites (DEMs) detected in the whole brain section. Notable alterations in lipid profiles were observed, and among the 292 lipids detected, there were 74 (25.34%), 85 (29.11%), and 78 (26.71%) lipids differentially expressed in the hippocampus, thalamus, and hypothalamus of the Exe group, respectively. Lipid metabolism related pathways and enzymes were also altered, with L-carnitine and CPT1c upregulated in the three regions (p<0.05), and epinephrine levels decreased in the hippocampus (p<0.05). Furthermore, the vitamin B6 metabolism pathway was altered in the hypothalamus. This study highlighted the significant changes in lipid metabolism induced by involuntary exercise in the brains of young male mice. Exercise also altered epinephrine levels and the vitamin B12 metabolic pathway in specific brain regions, which indicated the multifaceted effects of exercise on the brain.

Acorus tatarinowii alleviates D-galactose-induced Alzheimer’s-like disease cognitive impairment and Aβ-induced pericytes dysfunction in mice

Pericytes regulate cerebral blood flow (CBF) and excess amyloid in the brain. Pericyte dysfunction may contribute to the pathology of Alzheimer’s disease (AD). Acorus tatarinowii (AT), a Chinese medicine commonly used to treat AD, protects the central nervous system. However, whether AT can regulate pericyte function and ameliorate cognitive dysfunction remains unclear. We employed a novel target recognition assay, quantitative measurement of CBF, hematoxylin and eosin staining, immunofluorescence staining, and Western blot to investigate the role of AT in improving cognitive function in patients with AD. Additionally, we investigated the therapeutic potential of β-Asarone, the primary active compound in AT, for treating AD by modulating pericyte function using transmission electron microscopy, silver staining, electrical impedance, and other methodologies. The results revealed that administration of AT effectively alleviated the cognitive impairments induced by D-galactose in mice, as evidenced by enhanced CBF, improved histological characteristics of damaged brain tissue cells, increased expression of platelet-derived growth factor-β (PDGF-β), decreased Aβ accumulation via enhanced lipoprotein receptor-related protein 1 (LRP1), and reduced beta-site APP-cleaving enzyme 1 (BACE1). β-Asarone treatment mitigated ROS release and BACE1 expression while elevating the cell index in Aβ1-40 injured mouse brain vascular pericytes (MBVP). These findings suggest that AT has the potential to enhance CBF and mitigate pericellular dysfunction, thereby ameliorating Aβ deposition in the brain and improving cognitive impairment in patients with AD

Decreased lipidated ApoE-receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes.

While apolipoprotein E (APOE) is the strongest genetic modifier for late-onset Alzheimer's disease (LOAD), the molecular mechanisms underlying isoform-dependent risk and the relevance of ApoE-associated lipids remain elusive. Here, we report that impaired low-density lipoprotein (LDL) receptor (LDLR) binding of lipidated ApoE2 (lipApoE2) avoids LDLR recycling defects observed with lipApoE3/E4 and decreases the uptake of cholesteryl esters (CEs), which are lipids linked to neurodegeneration. In human neurons, the addition of ApoE carrying polyunsaturated fatty acids (PUFAs)-CE revealed an allelic series (ApoE4>ApoE3>ApoE2) associated with lipofuscinosis, an age-related lysosomal pathology resulting from lipid peroxidation. Lipofuscin increased lysosomal accumulation of tau fibrils and was elevated in the APOE4 mouse brain with exacerbation by tau pathology. Intrahippocampal injection of PUFA-CE-lipApoE4 was sufficient to induce lipofuscinosis in wild-type mice. Finally, the protective Christchurch mutation also reduced LDLR binding and phenocopied ApoE2. Collectively, our data strongly suggest decreased lipApoE-LDLR interactions minimize LOAD risk by reducing the deleterious effects of endolysosomal targeting of ApoE and associated pathogenic lipids.

Ginsenoside Compound K Alleviates Brain Aging by Inhibiting Ferroptosis through Modulation of the ASK1-MKK7-JNK Signaling Pathway

Background: Aging of the brain is a major contributor to the onset and progression of neurodegenerative diseases. Conventional treatments for these diseases are often limited by significant side effects and a lack of efficacy in halting disease progression. Ginsenoside compound K (CK), a bioactive secondary metabolite derived from ginseng, has shown promise because of its potent antioxidant properties. Purpose: This study aimed to elucidate the molecular mechanisms underlying the impact of CK on brain senescence, with a particular focus on its role in modulating oxidative stress and related signaling pathways. Methods: We employed a d-galactose (D-gal)-induced PC-12 senescent cell model and a mouse brain aging model to explore the antioxidant properties of CK in the context of brain aging. The effects of CK on mitochondrial dysfunction associated with brain aging were assessed using immunofluorescence and western blotting techniques. The potential molecular mechanisms by CK influences brain aging were investigated using transcriptomic analysis and western blotting. Additionally, CK's regulatory effect on apoptosis signal-regulating kinase 1 (ASK1) was validated by molecular docking, microscale thermophoresis, and small interfering RNA transfection. Results: Our findings demonstrate that CK effectively alleviates cognitive decline associated with brain aging. CK reduces the number of senescent cells, alleviates neuronal damage, and enhances the activity of key antioxidant enzymes, including catalase, superoxide dismutase, and glutathione peroxidase. Additionally, CK restores mitochondrial function and upregulated the expression of solute carrier family 7 member 11 and glutathione peroxidase 4, thereby inhibiting ferroptosis. Furthermore, CK targets ASK1 and suppresses the hyperphosphorylation of MAPK kinase 7 (MKK7) and c-Jun N-terminal kinase (JNK). This suppression promotes the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), effectively reducing ferroptosis and oxidative damage linked to brain aging. Conclusion: In summary, our research demonstrates that CK effectively delays brain aging by inhibiting the ASK1-MKK7-JNK signaling pathway, enhancing nuclear Nrf2 expression, and suppressing the ferroptosis response. These findings highlight CK as a promising therapeutic agent for slowing brain aging and alleviating neurodegenerative diseases.

A new knockin mouse carrying the E364X patient mutation for CDKL5 deficiency disorder: neurological, behavioral and molecular profiling

CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental syndrome caused by mutations in the X-linked CDKL5 gene. Hundreds of pathogenic variants have been described, associated with a significant phenotypic heterogeneity observed among patients. To date, different knockout mouse models have been generated. Here we present a new knockin CDKL5 mouse model carrying a humanized, well-characterized nonsense variant (c.1090G > T; p.E364X) described in the C-terminal domain of the CDKL5 protein in a female patient with a milder phenotype. Both male and female Cdkl5E364X mice were analyzed. The novel Cdkl5E364X mouse showed altered neurological and motor neuron maturation, hyperactivity, defective coordination and impaired memory and cognition. Gene expression analysis highlighted an unexpected reduction of Cdkl5 expression in Cdkl5E364X mice brain tissues, with a significant increase in overall neuron-specific gene expression and an area-dependent alteration of astrocyte- and oligodendrocyte-specific transcripts. Moreover, our results showed that the loss of CDKL5 protein had the most significant impact on the cerebellum and hippocampus, compared to other analyzed tissues. A targeted analysis to study synaptic plasticity in cerebellum and hippocampus showed reduced Gabra1 and Gabra5 expression levels in females, whereas Gabra1 expression was increased in males, suggesting an opposite, sex-dependent regulation of the GABA receptor expression already described in humans. In conclusion, the novel Cdkl5E364X mouse model is characterized by robust neurological and neurobehavioral alterations, associated with a molecular profile related to synaptic function indicative of a cerebellar GABAergic hypofunction, pointing to Gabra1 and Gabra5 as novel druggable target candidates for CDD.

MVCLST: A spatial transcriptome data analysis pipeline for cell type classification based on multi-view comparative learning

Recent advancements in spatial transcriptomics sequencing technologies can not only provide gene expression within individual cells or cell clusters (spots) in a tissue but also pinpoint the exact location of this expression and generate detailed images of stained tissue sections, which offers invaluable insights into cell type identification and cell function exploration. However, effectively integratingthegene expression data, spatial location information, and tissue images from spatial transcriptomics data presents a significant challenge for computational methodsin cell classification. In this work, we propose MVCLST, a multi-view comparative learningmethod to analyze spatial transcriptomicsdata for accurate cell type classification. MVCLSTconstructs two views based on gene expression profiles, cell coordinates and image features. The multi-view method we proposed can significantly enhance the effectiveness of feature extraction while avoiding the impact of erroneous information in organizing image or gene expression data. The model employs four separate encoders to capture shared and unique features within each view. To ensure consistency and facilitate information exchange between the two views, MVCLST incorporates a contrastive learning loss function. The extracted shared and private features from both views are fused using corresponding decoders. Finally, the model utilizes the Leiden algorithm to clusterthe learned featuresfor cell type identification. Additionally, we establish a framework called MVCLST-CCFS for spatial transcriptomicsdata analysis based on MVCLST and consistent clustering. Our method achieves excellent results in clustering on human dorsolateral prefrontal cortex data and the mouse brain tissue data. Italso outperforms state-of-the-art techniques in the subsequent search for highly variable genes across cell types on the mouse olfactory bulbdata.

Group 2 innate lymphoid cells promote inhibitory synapse development and social behavior.

The innate immune system shapes brain development and is implicated in neurodevelopmental diseases. It is critical to define the relevant immune cells and signals and their impact on brain circuits. In this work, we found that group 2 innate lymphoid cells (ILC2s) and their cytokine interleukin-13 (IL-13) signaled directly to inhibitory interneurons to increase inhibitory synapse density in the developing mouse brain. ILC2s expanded and produced IL-13 in the developing brain meninges. Loss of ILC2s or IL-13 signaling to interneurons decreased inhibitory, but not excitatory, cortical synapses. Conversely, ILC2s and IL-13 were sufficient to increase inhibitory synapses. Loss of this signaling pathway led to selective impairments in social interaction. These data define a type 2 neuroimmune circuit in early life that shapes inhibitory synapse development and behavior.

Installation of Optical Windows in the Brain of Transgenic Mice to Image Neural Activities

Installation of Optical Windows in the Brain of Transgenic Mice to Image Neural Activities

Installation of Optical Windows in the Brain of Transgenic Mice to Image Neural Activities

Installation of Optical Windows in the Brain of Transgenic Mice to Image Neural Activities

Recording Whole-Cell Currents with GABA Puffing in a Mouse Brain Slice

Recording Whole-Cell Currents with GABA Puffing in a Mouse Brain Slice

Recording of Local Field Potential from Both Hemispheres of the Mouse Brain

Recording of Local Field Potential from Both Hemispheres of the Mouse Brain

An Electrophysiological Study of Retinogeniculate and Corticogeniculate Synapses in Mouse Brain Slices

An Electrophysiological Study of Retinogeniculate and Corticogeniculate Synapses in Mouse Brain Slices

An Electrophysiological Study of Retinogeniculate and Corticogeniculate Synapses in Mouse Brain Slices

An Electrophysiological Study of Retinogeniculate and Corticogeniculate Synapses in Mouse Brain Slices

Electrophysiological Recordings of Reprogrammed Neurons in a Mouse Brain Slice

Electrophysiological Recordings of Reprogrammed Neurons in a Mouse Brain Slice

Recording Whole-Cell Currents with GABA Puffing in a Mouse Brain Slice

Recording Whole-Cell Currents with GABA Puffing in a Mouse Brain Slice

Analyzing the Glutamate Release and Clearance at a Single Neuron Synapse in a Mouse Brain Slice

Analyzing the Glutamate Release and Clearance at a Single Neuron Synapse in a Mouse Brain Slice

Electrophysiological Recordings of Reprogrammed Neurons in a Mouse Brain Slice

Electrophysiological Recordings of Reprogrammed Neurons in a Mouse Brain Slice