Neurobiology of Disease最新文献

Background: Deep brain stimulation (DBS) targeting globus pallidus internus (GPi) is a recognised therapy for drug-refractory dystonia. However, the mechanisms underlying this effect are not fully understood. This study explores how pallidal DBS alters spatiotemporal pattern formation of neuronal dynamics within the cerebellar cortex in a dystonic animal model, the dt^sz hamster.

Methods: We conducted in vitro analysis using a high-density microelectrode array (HD-MEA) in the cerebellar cortex. For investigating the spatiotemporal pattern, mean firing rates (MFR), interspike intervals (ISI), spike amplitudes, and cerebellar connectivity among healthy control hamsters, dystonic dt^sz hamsters, DBS- and sham-DBS-treated dt^sz hamsters were analysed. A nonlinear data-driven method characterised the low-dimensional representation of the patterns in MEA data.

Results: Our HD-MEA recordings revealed reduced MFR and spike amplitudes in the dt^sz hamsters compared to healthy controls. Pallidal DBS induced network-wide effects, normalising MFR, spike amplitudes, and connectivity measures in hamsters, thereby countervailing these electrophysiological abnormalities. Additionally, network analysis showed neural activity patterns organised into communities, with higher connectivity in both healthy and DBS groups compared to dt^sz.

Conclusions: These findings suggest that pallidal DBS exerts some of its therapeutic effects on dystonia by normalising neuronal activity within the cerebellar cortex. Our findings of reduced MFR and spike amplitudes in the dt^sz hamsters could be a hint of a decrease in neuronal fibres and synaptic plasticity. Treatment with pallidal DBS led to cerebellar cortical activity similar to healthy controls, displaying the network-wide impact of local stimulation.

Spike-wave-discharges (SWD) are the electrophysiological hallmark of absence epilepsy. SWD are generated in the thalamo-cortical network and a seizure onset zone was identified in the somatosensory cortex (S1). We have shown before that inhibition of the centromedian thalamic nucleus (CM) in GAERS rats resulted in a selective suppression of the spike component while rhythmic cortical 5-9 Hz oscillations remained present. Such oscillations are often seen to precede SWD activity in this well-validated genetic rat model of absence epilepsy, but are also seen in seizure-free periods. The present study characterizes the profile of 5-9 Hz oscillations in thalamo-cortical circuits during pre- and inter-ictal states. Here we recorded local-field-potentials in S1, CM and the secondary motor cortex of GAERS. Time-frequency analysis was used to assess spectral power and non-linear-association analysis was used to determine coupling strength and directionality between brain areas. Phase-specific electrical stimulation was used to compare cortical excitability and to assess the risk for epileptic afterdischarges. Coupling strength and spectral power were higher for the inter-ictal compared to the pre-ictal 5-9 Hz oscillations. However, coupling strength during pre-ictal oscillations was higher than during passive wakefulness. Double pulse stimulation during 5-9 Hz oscillations was more likely to induce epileptic afterdischarges compared to stimulation during passive wakefulness. While no overall differences in cortical excitability were revealed, phase-specific differences in excitability were noticed during the oscillation. Our findings indicate that intermediate coupling between S1 and CM favors SWD generation, thereby adding to the previous notion that 5-9 Hz oscillations represent high-risk periods for seizure generation. In general, pre-ictal oscillations display a unique electrophysiological profile in GAERS that might pave the way for qualification as biomarker for SWD generation and seizure prediction.

DYT-THAP1 dystonia is a monogenetic form of dystonia, a movement disorder characterized by the involuntary co-contraction of agonistic and antagonistic muscles. The disease is caused by mutations in the THAP1 gene, although the precise mechanisms by which these mutations contribute to the pathophysiology of dystonia remain unclear. The incomplete penetrance of DYT-THAP1 dystonia, estimated at 40 to 60 %, suggests that an environmental trigger may be required for the manifestation of the disease in genetically predisposed individuals. To investigate the gene-environment interaction in the development of dystonic features, we performed a sciatic nerve crush injury in a genetically predisposed DYT-THAP1 heterozygous knockout mouse model (Thap1^+/-). We employed a multi-omic assessment to study the pathophysiological pathways underlying the disease. Phenotypic analysis using an unbiased deep learning algorithm revealed that nerve-injured Thap1^+/- mice exhibited significantly more dystonia like movements (DLM) over the course of the 12-week experiment compared to naive Thap1^+/- mice. In contrast, nerve-injured wildtype (wt) mice only showed a significant increase in DLM compared to their naive counterpart during the first weeks after injury. Furthermore, at week 11 after nerve crush, nerve-injured Thap1^+/- mice displayed significantly more DLM than nerve-injured wt counterparts. Multi-omic analysis of the cerebellum, striatum and cortex in nerve-injured Thap1^+/- mice revealed differences that are indicative of an altered energy metabolism compared to naive Thap1^+/- and nerve-injured wt animals. These findings suggest that aberrant energy metabolism in brain regions relevant to dystonia may underlie the dystonic phenotype observed in nerve injured Thap1^+/- mice.

Increasing evidence points to infectious diseases as contributor to the pathogenesis of neurodegeneration in Parkinson's disease (PD), probably driven by a peripheral and CNS inflammatory response together with alpha-synuclein (aSyn) pathology. Pro-inflammatory lipopolysaccharide (LPS) endotoxin is suggested as a risk factor, and LPS shedding gram-negative bacteria are more prevalent in the gut-microbiome of PD patients. Here, we investigated whether LPS could contribute to the neurodegenerative disease progression via neuroinflammation, especially under conditions of aSyn pathology. To investigate this, we created a double-hit model based on the Thy1-aSyn mouse line (line 61), an established aSyn-overexpression model of PD, exposed to a single intraperitoneal injection of LPS at a dose of 0.8 mg/kg (equivalent to approximately 1,200,000 EU/kg). Clinical parameters, flow cytometry of blood and immune cells in the brain, brain immunohistology and motor behavior were evaluated over time. As expected, the LPS dosage induced transient acute symptoms and mild weight loss in mice, with full recovery after 7 days. In aSyn over-expressing mice, this single low dose of LPS was sufficient to alter the expression of specific markers on blood and brain immune cells and induced brain region-specific microgliosis that were present at 7 days post LPS injection. At 14 days post injection of LPS, aSyn expression was reduced in wild-type mice, indicating a specific response of the endogenous protein to the endotoxin. At this early time point, motor behavior is not yet robustly impacted by the observed pathological alterations. In conclusion, aSyn pathology renders the peripheral and central immune response more sensitive to a single low dose of bacterial endotoxin, which mimics a transient dysbiosis or gut infection. Thus, this data suggests that such peripheral triggers should be monitored in PD patients for instance by blood immune cell response as biomarkers. Furthermore, results from this study lend further support to the development of treatments aiming to reduce the impact of bacterial dysbiosis as a promising strategy to mitigate PD progression.

Background: Fabry disease (FD) patients are known to be at high risk of developing neuropsychiatric symptoms such as anxiety, depression and cognitive deficits. Despite this, they are underdiagnosed and inadequately treated. It is unknown whether these symptoms arise from pathological glycosphingolipid deposits or from cerebrovascular abnormalities affecting neuronal functions in the central nervous system. We therefore aimed to fill this knowledge gap by exploring a transgenic FD mouse model with a combination of behavior, transcriptomic, functional and morphological assessments, with a particular focus on the hippocampus.

Results: Male FD mice exhibited increased anxiety-like behavior in the open field test, accompanied by a reduced exploratory drive in the Barnes maze, which could be related to the increased deposition of globotriaosylceramide (Gb3) identified in the dentate gyrus (DG). Hippocampus single-cell sequencing further revealed that Gb3 accumulation was associated with differential gene expression in neuronal and non-neuronal cell populations with granule, excitatory and interneurons, as well as microglia and endothelial cells as the main clusters with the most dysregulated genes. Particularly FD hippocampal neurons showed decreased electrical baseline activity in the DG and increased activity in the CA3 region of acutely dissected hippocampal slices.

Conclusions: Our study highlights transcriptional and functional alterations in non-neuronal and neuronal cell clusters in the hippocampus of FD mice, which are suggested to be causally related to anxiety-like behavior developing as a consequence of FD pathology in mouse models of the disease and in patients.

Loss of function in the subunits of the GTPase-activating protein (GAP) activity toward Rags-1 (GATOR1) complex, an amino-acid sensitive negative regulator of the mechanistic target of rapamycin complex 1 (mTORC1), is implicated in both genetic familial epilepsies and Neurodevelopmental Disorders (NDDs) (Baldassari et al., 2018). Previous studies have found seizure phenotypes and increased activity resulting from conditional deletion of GATOR1 function from forebrain excitatory neurons (Yuskaitis et al., 2018; Dentel et al., 2022); however, studies focused on understanding mechanisms contributing to NDD-relevant behaviors are lacking, especially studies understanding the contributions of GATOR1's critical GAP catalytic subunit, nitrogen permease regulator like-2 (Nprl2). Given the clinical phenotypes observed in patients with Nprl2 mutations, in this study, we sought to investigate the neuronal cell type contributions of Nprl2 to NDD behaviors. We conditionally deleted Nprl2 broadly in most neurons (Synapsin1^cre), in inhibitory neurons only (Vgat^cre), and in Purkinje cells within the cerebellum (L7^cre). Broad neuronal deletion of Nprl2 resulted in seizures, social and learning deficits, and hyperactivity. In contrast, deleting Nprl2 from inhibitory neurons led to increased motor learning, hyperactive behavior, in addition to social and learning deficits. Lastly, Purkinje cell (PC) loss of Nprl2 also led to learning and social deficits but did not affect locomotor activity. These phenotypes enhance understanding of the spectrum of disease found in human populations with GATOR1 loss of function and highlight the significance of distinct cellular populations to NDD-related behaviors. SIGNIFICANCE STATEMENT: We aim to elucidate the neuronal-specific contributions of nitrogen permease regulator like-2 (Nprl2) to its neurodevelopmental disorder (NDD)-relevant phenotypes. We conditionally deleted Nprl2 broadly in neurons (Syn1^cre), in inhibitory neurons (Vgat^cre), and in cerebellar Purkinje cells (L7^cre). We identify seizures only in the Syn1^cre conditional mutant (cKO); hyperactivity, learning difficulties, social deficits, and impulsivity in the Syn1^cre and Vgat^cre cKOs; and social deficits, and fear learning deficits in L7^cre cKOs. To our knowledge, we are the first to describe the behavioral contributions of Nprl2's function across multiple cell types. Our findings highlight both critical roles for Nprl2 in learning and behavior and also distinct contributions of select neuronal populations to these NDD-relevant behaviors.

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.

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.