Neurobiology of Disease最新文献

Neurodegenerative diseases (ND) are characterized by the accumulation of aggregated proteins. The glymphatic system, through its rapid exchange mechanisms between cerebrospinal fluid (CSF) and interstitial fluid (ISF), facilitates the movement of metabolic substances within the brain, serving functions akin to those of the peripheral lymphatic system. This emerging waste clearance mechanism offers a novel perspective on the removal of pathological substances in ND. This article elucidates recent discoveries regarding the glymphatic system and updates relevant concepts within its model. It discusses the potential roles of the glymphatic system in ND, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple system atrophy (MSA), and proposes the glymphatic system as a novel therapeutic target for these conditions.

Pericytes (PCs) are vascular mural cells embedded in the basement membrane of micro blood vessels. It has been proposed using a C·B-17 mouse model of stroke that normal brain PCs are converted to ischemic PCs (iPCs), some of which express various stem cell markers. We previously reported that nuclear factor erythroid-2-related factor 2 (Nrf2) protected against oxidative stress following ischemia and promoted the PC reprogramming process. The present study examined the molecular mechanisms underlying the induction of Nrf2. We revealed that oxidative stress and pNrf2 induced by stroke proceeded the expression of nestin in meningeal cells and reactive PCs within the post-stroke area. PKCδ inhibitor treatment suppressed pNrf2 activation and restored the down-regulated expression of stem cell markers in iPCs in vitro. The PKCδ inhibitor treatment also suppressed the production of iPCs. These results suggest the potential of Nrf2 phosphorylation via PKCδ as a novel strategy for the treatment of ischemic injury.

The legalization of recreational cannabis use has expanded the availability of this psychoactive substance in the United States. Research has shown that chronic cannabis use is associated with altered working memory function, however, the brain areas and neural dynamics underlying these affects remain poorly understood. In this study, we leveraged magnetoencephalography (MEG) to investigate neurophysiological activity in 45 participants (22 heavy cannabis users) during a numerical WM task, whereby participants were asked to either maintain or manipulate (i.e., rearrange in ascending order) a group of visually presented numbers. Significant oscillatory responses were imaged using a beamformer and subjected to whole-brain ANOVAs. Notably, we found that cannabis users exhibited significantly weaker alpha oscillations in superior parietal, occipital, and other regions during the encoding phase relative to nonusers. Interestingly, during the maintenance phase, there was a group-by-condition interaction in the right inferior frontal gyrus, left prefrontal, parietal, and other regions, such that cannabis users exhibited weaker alpha and beta oscillations relative to nonusers during maintain trials. Additionally, chronic cannabis users exhibited stronger alpha and beta maintenance responses in these same brain regions and prolonged reaction times during manipulate relative to maintain trials, while no such differences were found in nonusers. Neurobehavioral relationships were also detected in the prefrontal cortices of nonusers, but not cannabis users. In sum, chronic cannabis users exhibit weaker neural oscillations during working memory encoding but may compensate for these deficiencies through stronger oscillatory responses during memory maintenance, especially during strenuous tasks such as manipulating the to-be remembered items.

Corticobasal syndrome (CBS) is characterized not only by parkinsonism but also by higher-order cortical dysfunctions, such as apraxia. However, the electrophysiological mechanisms underlying these symptoms remain poorly understood. To explore the pathophysiology of CBS, we recorded magnetoencephalographic (MEG) data from 17 CBS patients and 20 age-matched controls during an observe-to-imitate task. This task involved observing a tool-use video (action observation), withholding movement upon a Go cue (movement preparation), and subsequently imitating the tool-use action. We analyzed spectral power modulations at the source level. During action observation, event-related beta power (13-30 Hz) suppression was weaker in CBS patients compared to controls. This reduction was evident bilaterally in superior parietal, primary motor, premotor and inferior frontal cortex. During movement preparation, beta power suppression was also reduced in CBS patients, correlating with longer reaction times. Immediately prior to movement onset, however, beta suppression was comparable between groups. Our findings suggest that action observation induces beta suppression, likely indicative of motor cortical disinhibition, which is impaired in CBS patients. This alteration may represent a neural correlate of disrupted visuo-motor mapping in CBS. The altered timing of beta suppression to the Go cue suggests deficits in learning the task's temporal structure rather than in movement initiation itself.

One of the underlying mechanisms of epilepsy (EP), a brain disease characterized by recurrent seizures, is considered to be cell death. Disulfidptosis, a proposed novel cell death mechanism, is thought to play a part in the pathogenesis of epilepsy, but the exact role is unclear. The gene expression omnibus series (GSE) 33000 and GSE63808 datasets were used to search for differentially expressed disulfidptosis-related molecules (DE-DRMs). A correlation between the DE-DRMs was discovered. Individuals with epilepsy were then used to investigate molecular clusters based on the expression of DE-DRMs. Following that, the best machine learning model which is validated by GSE143272 dataset and predictor molecules were identified. The correlation between predictive molecules and clinical traits was determined. Based on the in vitro and in vivo seizures models, experimental analyses were applied to verify the DE-DRMs expressions and the correlation between them. Nine molecules were identified as DE-DRMs: glycogen synthase 1 (GYS1), solute carrier family 3 member 2 (SLC3A2), solute carrier family 7 member 11 (SLC7A11), NADH:ubiquinone oxidoreductase core subunit S1 (NDUFS1), 3-oxoacyl-ACP synthase, mitochondrial (OXSM), leucine rich pentatricopeptide repeat containing (LRPPRC), NADH:ubiquinone oxidoreductase subunit A11 (NDUFA11), NUBP iron‑sulfur cluster assembly factor, mitochondrial (NUBPL), and NCK associated protein 1 (NCKAP1). NDUFS1 interacted with NDUFA11, NUBPL, and LRPPRC, while SLC3A2 interacted with SLC7A11. The optimal machine learning model was revealed to be the random forest (RF) model. G protein guanine nucleotide-binding protein alpha subunit q (GNAQ) was linked to sodium valproate resistance. The experimental analyses suggested an upregulated SLC7A11 expression, an increased number of formed SLC3A2 and SLC7A11 complexes, and a decreased number of formed NDUFS1 and NDUFA11 complexes. This study provides previously undocumented evidence of the relationship between disulfidptosis and EP. In addition to suggesting that SLC7A11 may be a specific DRM for EP, this research demonstrates the alterations in two disulfidptosis-related protein complexes: SLC7A11-SLC3A2 and NDUFS1-NDUFA11.

Neuropathic pain presents a significant challenge, with its underlying mechanisms still not fully understood. Here, we investigated the role of GluN2C- and GluN2D-containing NMDA receptors in the development of neuropathic pain induced by cisplatin, a widely used chemotherapeutic agent. Through genetic and pharmacological strategies, we found that GluN2D-containing NMDA receptors play a targeted role in regulating cisplatin-induced neuropathic pain (CINP), while sparing inflammatory or acute pain responses. Specifically, both GluN2D knockout (KO) mice and pharmacological blockade of GluN2D-containing receptors produced robust reduction in mechanical nocifensive response in CINP. In contrast, GluN2C KO mice behaved similar to wildtype mice in CINP but showed reduced mechanical hypersensitivity in inflammatory pain. Using conditional KO strategy, we addressed the region- and cell-type involved in GluN2D-mediated changes in CINP. Animals with conditional deletion of GluN2D receptors from parvalbumin interneurons (PVIs) or local ablation of GluN2D from nucleus accumbens (NAc) displayed reduced mechanical hypersensitivity in CINP, underscoring the pivotal role of accumbal GluN2D in PVIs in neuropathic pain. Furthermore, CINP increased excitatory neurotransmission in the NAc in wildtype mice and this effect is dampened in PV-GluN2D KO mice. Other changes in CINP in NAc included an increase in vGluT1 and c-fos labeled neurons in wildtype which were absent in PV-GluN2D KO mice. G_iDREADD-induced inhibition of PVIs in the NAc produced reduction in mechanical hypersensitivity in CINP. These findings unveil a novel cell-type and region-specific role of GluN2D-containing NMDA receptors in neuropathic pain and identify PVIs in NAc as a novel mediator of pain behaviors.

Phosphodiesterase 2 A (PDE2A) function is stimulated by cGMP to catabolize cAMP. However, neurological and neurochemical effects of PDE2A deficiency are poorly understood. To address this gap, we studied behavioral characteristics and cerebral morpho-chemical changes of adult male heterozygous C57BL/6-PDE2A+/- (HET), and wild type C57BL/6-PDE2A+/+ (WT) mice. Behavioral functions of mice were evaluated by a wide test battery. HET mice exhibited greater tendency to explore novel environments in comparison to WT mice, but spatial working memory, anxiety, and sociability were similar in adult HET and WT mice. In HET mice, PDE2A mRNA, PDE2A protein expression, and cGMP hydrolyzing enzymatic activity were consistently reduced by about 50 %. Consequently, the cyclic nucleotide levels were significantly increased in HET mice, but unexpectedly the mean percentage variation was higher for cGMP equal to 153.23 %, and lower for cAMP equal to 16.41 %. Therefore, to try to explain the preponderant increase of cGMP to cAMP we evaluated other PDE enzymes functionally related to PDE2A. Surprisingly, results were quite contradictory: in HET mice protein levels of the other dual-specificity enzyme PDE3A and PDE10A were reduced, whereas the expressions of PDE5A and PDE9A that selectively hydrolyze cGMP were increased. Therefore, we investigated the involvement of neuronal nitric oxide synthase (nNOS) expression, as determinant of a possible increased synthesis of NO/cGMP signaling. Interestingly, in HET mice the expression level of brain nNOS, measured by western blot and immune-histochemistry was significantly increased, particularly in interneurons from the striatum. In conclusion, the deficiency of PDE2A could be compensated in the striatum by upregulating nNOS/NO/cGMP pathway, which in turn likely upregulates PDE2A-dependent cAMP hydrolysis. The neuroanatomical correlation between striatal nNOS upregulation and the behavioral phenotype of increased exploratory behavior in HET mice is advanced.

Obesity and metabolic disorders, such as metabolic syndrome (MetS) facilitate the development of neurodegenerative diseases and cognitive decline. Persistent neuroinflammation plays an important role in this process. Pleiotrophin (PTN) is a cytokine that regulates energy metabolism and high-fat diet (HFD)-induced neuroinflammation, suggesting that PTN could play an important role in the connection between obesity and brain alterations, including cognitive decline. To test this hypothesis, we used an HFD-induced obesity model in Ptn genetically deficient mice (Ptn^-/-). First, we confirmed that Ptn deletion prevents HFD-induced obesity. Our findings demonstrate that feeding wild-type (Ptn^+/+) mice with HFD for 6 months results in short- and long-term memory loss in the novel object recognition task. Surprisingly, we did not observe any sign of cognitive impairment in Ptn^-/- mice fed with HFD. In addition, we observed that HFD induced microglial responses, astrocyte depletion, and perineuronal nets (PNNs) alterations in Ptn^+/+ mice, while these effects of HFD were mostly prevented in Ptn^-/- mice. These results show a crucial role of PTN in metabolic responses and brain alterations induced by HFD and suggest the PTN signalling pathway as a promising therapeutic target for brain disorders associated with MetS.

Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia and belongs to the family of nine diseases caused by a polyglutamine expansion in the disease-causing protein. In SCA3, a polyglutamine expansion in ATXN3 causes neuron loss in disease-vulnerable brain regions, resulting in progressive loss of coordination and ultimately death. There are no disease-modifying or preventative treatments for this uniformly fatal disorder. Recent studies demonstrate prominent white matter atrophy and microstructural alterations in disease-vulnerable brain regions of SCA3 patients and mouse models. However, the major constituent of white matter - lipids - remains understudied in SCA3. In this study, we conducted the first unbiased investigation of brain lipids in SCA3, focusing on the disease-vulnerable cerebellum of SCA3 postmortem patients and mouse models. Liquid chromatography-mass spectrometry uncovered widespread lipid reductions in patients with SCA3. Lipid downregulation was recapitulated in early- to mid-stage mouse models of SCA3, including transgenic YACQ84 and Knock-in Q300 mice. End-stage Knock-in Q300 mice displayed a progressive reduction in lipid content, highlighting targets that could benefit from early therapeutic intervention. In contrast, Atxn3-Knock-out mice showed mild lipid upregulation, emphasizing a toxic gain-of-function mechanism underlying lipid downregulation in SCA3. We conclude that lipids are significantly altered in SCA3 and establish a platform for continued exploration of lipids in disease through interactive data visualization websites. Pronounced reductions in myelin-enriched lipids suggest that lipid dysregulation could underlie white matter atrophy in SCA3. This study establishes the basis for future work elucidating the mechanistic, biomarker, and therapeutic potential of lipids in SCA3.

Background: Reports indicate that depression is a common mental health issue following traumatic brain injury (TBI). Our prior research suggests that Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-related neuroinflammation, modulated by glial cells such as astrocytes, is likely to play a crucial role in the progression of anxiety and cognitive dysfunction. However, there is limited understanding of the potential of astrocytic NLRP3 in treating depression under mild TBI condition. This study aimed to determine whether astrocytic NLRP3 knockout (KO) could mitigate depressive-like behaviors following mild TBI and explore potential variations in such behaviors between genders post-mild TBI.

Methods: Mild TBI was induced in mice using Feeney's weight-drop method. Behavioral assessments included neurological severity scores (NSS), social interaction test (SI), tail suspension test (TST), and forced swimming test (FST). Pathological changes were evaluated through immunofluorescence and local field potential (LFP) recordings at various time points post-injury.

Results: Our findings indicated that astrocyte-specific NLRP3 KO decreased cleaved caspase-1 colocalized with astrocytes, decreased pathogenic astrocytes and increased Postsynaptic density protein 95 (PSD95) intensity, and significantly alleviated mild TBI-induced depression-like behaviors. It also led to the upregulation of protective astrocytes and apoptosis-associated factors, including cleaved caspase-3 post-mild TBI. Additionally, astrocyte-specific NLRP3 deletion resulting in improved θ and γ power and θ-γ phase coupling in the social interaction test (SI). Notably, under mild TBI conditions, astrocyte-specific NLRP3 exhibited greater neuroprotective effects in female knockout mice compared to males.

Conclusion: Astrocyte NLRP3 knockout demonstrated a protective mechanism in mice subjected to mild TBI, possibly attributed to the inhibition of pyroptosis through the NLRP3 signaling pathway in astrocytes.