Effects of baicalin pre-treatment on pentylenetetrazole-induced seizures: Insights from zebrafish larvae locomotor behavior and neuronal calcium imaging.

Natural compounds are increasingly being studied for their potential neuroprotective effects against inflammatory neurological diseases. Epilepsy is a common neurological disease associated with inflammatory processes, and around 30% of people with epilepsy do not respond to traditional treatments. Some flavonoids, when taken along with antiseizure medications can help reduce the likelihood of drug-resistant epilepsy. Baicalin, a plant-based compound, has been shown to possess pharmacological properties such as anti-inflammatory, neuroprotective, anticonvulsant, and antioxidant activities. In this study, we tested the effect of baicalin on an established model of pharmacologically induced seizure in zebrafish using measures of both locomotor behavior and calcium imaging of neuronal activity. The results of our study showed that, at the tested concentration, and contrary to other studies in rodents, baicalin did not have an anti-seizure effect in zebrafish larvae. However, given its known properties, other concentrations and approaches should be explored to determine if it could potentially have other beneficial effects, either alone or when administered in combination with classic antiseizure medications.

Intrathecal delivery of AAV-NDNF ameliorates disease progression of ALS mice.

Amyotrophic lateral sclerosis (ALS) is a uniformly lethal neurodegenerative disease characterized by progressive deterioration of motor neurons and neuromuscular denervation. Adeno-associated virus (AAV)-mediated delivery of trophic factors is being considered as a potential disease-modifying therapeutic avenue. Here we show a marked effect of AAV-mediated over-expression of neuron-derived neurotrophic factor (NDNF) on SOD1G93A ALS model mice. First, we adopt AAV-PHP.eB capsid to enable widespread expression of target proteins in the brain and spinal cord when delivered intrathecally. Then we tested the effects of AAV-NDNF on SOD1G93A mice at different stages of disease. Interestingly, AAV-NDNF markedly improved motor performance and alleviated weight loss when delivered at early post-symptomatic stage. Injection in the middle post-symptomatic stages still improved the locomotion ability, although it did not alleviate the loss of body weight. Injection in the late stage also extended the life span of SOD1G93A mice. Furthermore, NDNF expression promoted the survival of spinal motoneurons, reduced abnormal protein aggregation, and preserved the innervated neuromuscular functions. We further analyzed the signaling pathways of NDNF expression and found that it activates cell survival and growth-associated mammalian target of rapamycin signaling pathway and downregulates apoptosis-related pathways. Thus, intrathecally AAV-NDNF delivery has provided a potential strategy for the treatment of ALS.

Morphology and motor behavior of endemic fishes in the upper reaches of the Yangtze River basin.

Dam construction alters the hydrodynamic conditions, consequently impacting the swimming behavior of fish. To explore the effect of flow hydrodynamics on fish swimming behavior, five endemic fish species in the upper Yangtze River basin were selected. Through high-speed video visualization and computer analysis, these species' swimming patterns under different flow velocities (0.1-1.2 m/s) were investigated. The kinematic and morphological characteristics of the fish were presented. The principal component analysis was used to analyse the main factors influencing the swimming ability of fish and to determine the correlation coefficients among fish behavior indicators. Fish exhibited three different swimming patterns under different flow velocities. Low velocity (0.1-0.3 m/s) corresponds to free motion, middle velocity (0.4-0.7 m/s) corresponds to cruising motion, and high velocity corresponds to stress motion (0.8-1.2 m/s). The fish kinematic index curves were obtained, and four of five fish species showed two extreme points, which means the optimal and adverse swimming strategies can be determined. With the increase in flow velocity, the tail-beat frequency showed an increasing trend, whereas the tail-beat angle and amplitude showed a decreasing trend. Morphological and kinematic parameters were the two main indexes that affect the swimming ability of fish, which accounts for 41.9% and 26.9%, respectively.

Frontal-to-visual information flow explains predictive motion tracking.

Predictive tracking demonstrates our ability to maintain a line of vision on moving objects even when they temporarily disappear. Models of smooth pursuit eye movements posit that our brain achieves this ability by directly streamlining motor programming from continuously updated sensory motion information. To test this hypothesis, we obtained sensory motion representation from multivariate electroencephalogram activity while human participants covertly tracked a temporarily occluded moving stimulus with their eyes remaining stationary at the fixation point. The sensory motion representation of the occluded target evolves to its maximum strength at the expected timing of reappearance, suggesting a timely modulation of the internal model of the visual target. We further characterize the spatiotemporal dynamics of the task-relevant motion information by computing the phase gradients of slow oscillations. We discovered a predominant posterior-to-anterior phase gradient immediately after stimulus occlusion; however, at the expected timing of reappearance, the axis reverses the gradient, becoming anterior-to-posterior. The behavioral bias of smooth pursuit eye movements, which is a signature of the predictive process of the pursuit, was correlated with the posterior division of the gradient. These results suggest that the sensory motion area modulated by the prediction signal is involved in updating motor programming.

Fetal behavior during MRI changes with age and relates to network dynamics.

Fetal motor behavior is an important clinical indicator of healthy development. However, our understanding of associations between fetal behavior and fetal brain development is limited. To fill this gap, this study introduced an approach to automatically and objectively classify long durations of fetal movement from a continuous four-dimensional functional magnetic resonance imaging (fMRI) data set, and paired behavior features with brain activity indicated by the fMRI time series. Twelve-minute fMRI scans were conducted in 120 normal fetuses. Postnatal motor function was evaluated at 7 and 36 months age. Fetal motor behavior was quantified by calculating the frame-wise displacement (FD) of fetal brains extracted by a deep-learning model along the whole time series. Analyzing only low motion data, we characterized the recurring coactivation patterns (CAPs) of the supplementary motor area (SMA). Results showed reduced motor activity with advancing gestational age (GA), likely due in part to loss of space (r = -.51, p < .001). Evaluation of individual variation in motor movement revealed a negative association between movement and the occurrence of coactivations within the left parietotemporal network, controlling for age and sex (p = .003). Further, we found that the occurrence of coactivations between the SMA to posterior brain regions, including visual cortex, was prospectively associated with postnatal motor function at 7 months (r = .43, p = .03). This is the first study to pair fetal movement and fMRI, highlighting potential for comparisons of fetal behavior and neural network development to enhance our understanding of fetal brain organization.

Brain network dynamics in people with visual snow syndrome.

Visual snow syndrome (VSS) is a neurological disorder characterized by a range of continuous visual disturbances. Little is known about the functional pathological mechanisms underlying VSS and their effect on brain network topology, studied using high-resolution resting-state (RS) 7 T MRI. Forty VSS patients and 60 healthy controls underwent RS MRI. Functional connectivity matrices were calculated, and global efficiency (network integration), modularity (network segregation), local efficiency (LE, connectedness neighbors) and eigenvector centrality (significance node in network) were derived using a dynamic approach (temporal fluctuations during acquisition). Network measures were compared between groups, with regions of significant difference correlated with known aberrant ocular motor VSS metrics (shortened latencies and higher number of inhibitory errors) in VSS patients. Lastly, nodal co-modularity, a binary measure of node pairs belonging to the same module, was studied. VSS patients had lower modularity, supramarginal centrality and LE dynamics of multiple (sub)cortical regions, centered around occipital and parietal lobules. In VSS patients, lateral occipital cortex LE dynamics correlated positively with shortened prosaccade latencies (p = .041, r = .353). In VSS patients, occipital, parietal, and motor nodes belonged more often to the same module and demonstrated lower nodal co-modularity with temporal and frontal regions. This study revealed reduced dynamic variation in modularity and local efficiency strength in the VSS brain, suggesting that brain network dynamics are less variable in terms of segregation and local clustering. Further investigation of these changes could inform our understanding of the pathogenesis of the disorder and potentially lead to treatment strategies.

Double-Edged Effects of Venglustat on Behavior and Pathology in Mice Overexpressing α-Synuclein.

BACKGROUND: Venglustat is a brain-penetrant, small molecule inhibitor of glucosylceramide synthase used in clinical testing for treatment of Parkinson's disease (PD). Despite beneficial effects in certain cellular and rodent models, patients with PD with mutations in GBA, the gene for lysosomal glucocerebrosidase, experienced worsening of their motor function under venglustat treatment (NCT02906020, MOVES-PD, phase 2 trial). OBJECTIVE: The objective of this study was to evaluate venglustat in mouse models of PD with overexpression of wild-type α-synuclein. METHODS: Mice overexpressing α-synuclein (Thy1-aSyn line 61) or Gba-mutated mice with viral vector-induced overexpression of α-synuclein in the substantia nigra were administered venglustat as food admixture. Motor and cognitive performance, α-synuclein-related pathology, and microgliosis were compared with untreated controls. RESULTS: Venglustat worsened motor function in Thy1-aSyn transgenics on the challenging beam and the pole test. Although venglustat did not alter the cognitive deficit in the Y-maze test, it alleviated anxiety-related behavior in the novel object recognition test. Venglustat reduced soluble and membrane-bound α-synuclein in the striatum and phosphorylated α-synuclein in limbic brain regions. Although venglustat reversed the loss of parvalbumin immunoreactivity in the basolateral amygdala, it tended to increase microgliosis and phosphorylated α-synuclein in the substantia nigra. Furthermore, venglustat also partially worsened motor performance and tended to increase neurofilament light chain in the cerebrospinal fluid in the Gba-deficient model with nigral α-synuclein overexpression and neurodegeneration. CONCLUSIONS: Venglustat treatment in two mouse models of α-synuclein overexpression showed that glucosylceramide synthase inhibition had differential detrimental or beneficial effects on behavior and neuropathology possibly related to brain region-specific effects. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Genetic and environmental mouse models of autism reproduce the spectrum of the disease.

Genetic and environmental factors increase autism spectrum disorder (ASD) incidence, and this has led to the generation of corresponding animal models, with some showing strong construct and face validity. This short review focuses on results we have recently obtained with environmental and genetic mouse models of ASD and that are the valproic acid, the poly I:C and the Shank 3 models. This has allowed us to provide a comparative description of these widely used animal models providing an interesting perspective as to the pros and cons of each one of them, in our experimental settings. In these papers, we focused on motor and gait disorders which are currently not included in the diagnosis criteria, but which may provide new insights to ASD pathophysiology potentially leading to innovative therapies for a disease that currently has none. In all these models, we reported behavioral, cellular and molecular alterations related to the cerebellum. Motor and gait deficits were observed to various degrees in animal models and, when strongly present, they were correlated to the severity of social deficits as well as to the number of cerebellar Purkinje cells. Additionally, we also reported that, like in humans, males are more severely affected than females in these ASD models. These findings, along with an increasing body of literature, open new hopes in the ASD field pointing to brain regions, such the cerebellum, that are at the crossroads between cognitive, social and motor deficits. Targeting these brain regions and their underlying pathways and synaptic connections may prove of significant benefits.

Trehalose consumption ameliorates pathogenesis in an inducible mouse model of the Fragile X-associated tremor/ataxia syndrome.

Trehalose is a naturally occurring sugar found in various food and pharmaceutical preparations with the ability to enhance cellular proteostasis and reduce the formation of toxic intracellular protein aggregates, making it a promising therapeutic candidate for various neurodegenerative disorders. OBJECTIVES: Here, we explored the effectiveness of nutritional trehalose supplementation in ameliorating symptoms in a mouse model of Fragile X-associated tremor/ataxia syndrome (FXTAS), an incurable late onset manifestation of moderately expanded trinucleotide CGG repeat expansion mutations in the 5' untranslated region of the fragile X messenger ribonucleoprotein 1 gene (FMR1). METHODS: An inducible mouse model of FXTAS expressing 90 CGG repeats in the brain had been previously developed, which faithfully captures hallmarks of the disorder, the formation of intracellular inclusions, and the disturbance of motor function. Taking advantage of the inducible nature of the model, we investigated the therapeutic potential of orally administered trehalose under two regimens, modelling disease prevention and disease treatment. RESULTS AND DISCUSSION: Trehalose's effectiveness in combating protein aggregation is frequently attributed to its ability to induce autophagy. Accordingly, trehalose supplementation under the prevention regimen ameliorated the formation of intranuclear inclusions and improved the motor deficiencies resulting from the induced expression of 90 CGG repeats, but it failed to reverse the existing nuclear pathology as a treatment strategy. Given the favorable safety profile of trehalose, it is promising to further explore the potential of this agent for early stage FXTAS.

MicroRNA-124-3p-enriched small extracellular vesicles as a therapeutic approach for Parkinson's disease.

Parkinson's disease is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra with no effective cure available. MicroRNA-124 has been regarded as a promising therapeutic entity for Parkinson's disease due to its pro-neurogenic and neuroprotective roles. However, its efficient delivery to the brain remains challenging. Here, we used umbilical cord blood mononuclear cell-derived extracellular vesicles as a biological vehicle to deliver microRNA (miR)-124-3p and evaluate its therapeutic effects in a mouse model of Parkinson's disease. In vitro, miR-124-3p-loaded small extracellular vesicles induced neuronal differentiation in subventricular zone neural stem cell cultures and protected N27 dopaminergic cells against 6-hydroxydopamine-induced toxicity. In vivo, intracerebroventricularly administered small extracellular vesicles were detected in the subventricular zone lining the lateral ventricles and in the striatum and substantia nigra, the brain regions most affected by the disease. Most importantly, although miR-124-3p-loaded small extracellular vesicles did not increase the number of new neurons in the 6-hydroxydopamine-lesioned striatum, the formulation protected dopaminergic neurons in the substantia nigra and striatal fibers, which fully counteracted motor behavior symptoms. Our findings reveal a novel promising therapeutic application of small extracellular vesicles as delivery agents for miR-124-3p in the context of Parkinson's disease.