C1q is elevated during chronic central nervous system catheter infection.

Introduction: Significant neurologic morbidity is caused by pediatric cerebrospinal fluid (CSF) shunt infections. The underlying mechanisms leading to impaired school performance and increased risk of seizures are unknown, however, a better understanding of these mechanisms may allow us to temper their consequences. Recent evidence has demonstrated important roles for complement proteins in neurodevelopment and neuroinflammation.

Exploring behavioral phenotypes in a mouse model of fetal alcohol spectrum disorders.

Fetal alcohol spectrum disorders are one of the leading causes of developmental abnormalities worldwide. Maternal consumption of alcohol during pregnancy leads to a diverse range of cognitive and neurobehavioral deficits. Although moderate-to-heavy levels of prenatal alcohol exposure (PAE) have been associated with adverse offspring outcomes, there is limited data on the consequences of chronic low-level PAE.

Impaired AMPARs Translocation into Dendritic Spines with Motor Skill Learning in the Fragile X Mouse Model.

Motor skill learning induces changes in synaptic structure and function in the primary motor cortex (M1). In the fragile X syndrome (FXS) mouse model an impairment in motor skill learning and associated formation of new dendritic spines was previously reported. However, whether modulation of synaptic strength through trafficking of AMPA receptors (AMPARs) with motor skill training is impaired in FXS is not known.

Dysregulated cholesterol metabolism, aberrant excitability and altered cell cycle of astrocytes in fragile X syndrome.

Fragile X syndrome (FXS), the most prevalent heritable form of intellectual disability, is caused by the transcriptional silencing of the FMR1 gene. While neuronal contribution to FXS has been extensively studied in both animal and human-based models of FXS, the roles of astrocytes, a type of glial cells in the brain, are largely unknown. Here, we generated a human-based FXS model via differentiation of astrocytes from human-induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) and characterized their development, function, and proteomic profiles.

Implantation of a Cranial Window for Repeated In Vivo Imaging in Awake Mice.

To fully understand the cellular physiology of neurons and glia in behaving animals, it is necessary to visualize their morphology and record their activity in vivo in behaving mice. This paper describes a method for the implantation of a chronic cranial window to allow for the longitudinal imaging of brain cells in awake, head-restrained mice. In combination with genetic strategies and viral injections, it is possible to label specific cells and regions of interest with structural or physiological markers.

Modeling Neurodevelopmental and Neuropsychiatric Diseases with Astrocytes Derived from Human-Induced Pluripotent Stem Cells.

Accumulating studies demonstrate the morphological and functional diversity of astrocytes, a subtype of glial cells in the central nervous system. Animal models are instrumental in advancing our understanding of the role of astrocytes in brain development and their contribution to neurological disease; however, substantial interspecies differences exist between rodent and human astrocytes, underscoring the importance of studying human astrocytes. Human pluripotent stem cell differentiation approaches allow the study of patient-specific astrocytes in the etiology of neurological disorders.

3D Printed Hydrogels with Aligned Microchannels to Guide Neural Stem Cell Migration.

Following traumatic or ischemic brain injury, rapid cell death and extracellular matrix degradation lead to the formation of a cavity at the brain lesion site, which is responsible for prolonged neurological deficits and permanent disability. Transplantation of neural stem/progenitor cells (NSCs) represents a promising strategy for reconstructing the lesion cavity and promoting tissue regeneration. In particular, the promotion of neuronal migration, organization, and integration of transplanted NSCs is critical to the success of stem cell-based therapy.

Modeling human-specific interlaminar astrocytes in the mouse cerebral cortex.

Astrocytes, a highly heterogeneous population of glial cells, serve as essential regulators of brain development and homeostasis. The heterogeneity of astrocyte populations underlies the diversity in their functions. In addition to the typical mammalian astrocyte architecture, the cerebral cortex of humans exhibits a radial distribution of interlaminar astrocytes in the supragranular layers.

Modulation of excitatory but not inhibitory synaptic inputs in the mouse primary motor cortex in the late phase of motor learning.

Motor skill training induces functional and structural changes in the primary motor cortex. New dendritic spines are formed with training and the horizontal connections in the layer II/III area of the primary motor cortex are strengthened. Here we investigated the functional synaptic properties of pyramidal neurons following motor skill training.

Pluripotent Stem Cell-Derived Cerebral Organoids Reveal Human Oligodendrogenesis with Dorsal and Ventral Origins.

The process of oligodendrogenesis has been relatively well delineated in the rodent brain. However, it remains unknown whether analogous developmental processes are manifested in the human brain. Here we report oligodendrogenesis in forebrain organoids, generated by using OLIG2-GFP knockin human pluripotent stem cell (hPSC) reporter lines.

Brain changes in a maternal immune activation model of neurodevelopmental brain disorders.

The developing brain is sensitive to a variety of insults. Epidemiological studies have identified prenatal exposure to infection as a risk factor for a range of neurological disorders, including autism spectrum disorder and schizophrenia. Animal models corroborate this association and have been used to probe the contribution of gene-environment interactions to the etiology of neurodevelopmental disorders.

Relationship Between Synaptic AMPAR and Spine Dynamics: Impairments in the FXS Mouse.

Structural dynamics of dendritic spines are important for memory and learning and are impaired in neurodevelopmental disorders such as fragile X syndrome. Spine dynamics are regulated by activity-dependent mechanisms that involve modulation of AMPA receptors (AMPAR); however, the relationship between AMPAR and spine dynamics in vivo and how these are altered in FXS mouse model is not known. Here, we tracked AMPAR and spines over multiple days in vivo in the cortex and found that dendritic spines in the fmr1 KO mouse were denser, smaller, had higher turnover rates and contained less sGluA2 compared to littermate controls.

Maternal Immune Activation Causes Behavioral Impairments and Altered Cerebellar Cytokine and Synaptic Protein Expression.

Emerging epidemiology studies indicate that maternal immune activation (MIA) resulting from inflammatory stimuli such as viral or bacterial infections during pregnancy serves as a risk factor for multiple neurodevelopmental disorders including autism spectrum disorders and schizophrenia. Although alterations in the cortex and hippocampus of MIA offspring have been described, less evidence exists on the impact on the cerebellum. Here, we report altered expression of cytokines and chemokines in the cerebellum of MIA offspring, including increase in the neuroinflammatory cytokine TNFα and its receptor TNFR1.

Motor-Skill Learning Is Dependent on Astrocytic Activity.

Motor-skill learning induces changes in synaptic structure and function in the primary motor cortex through the involvement of a long-term potentiation- (LTP-) like mechanism. Although there is evidence that calcium-dependent release of gliotransmitters by astrocytes plays an important role in synaptic transmission and plasticity, the role of astrocytes in motor-skill learning is not known. To test the hypothesis that astrocytic activity is necessary for motor-skill learning, we perturbed astrocytic function using pharmacological and genetic approaches.

Impaired synaptic development in a maternal immune activation mouse model of neurodevelopmental disorders.

Both genetic and environmental factors are thought to contribute to neurodevelopmental and neuropsychiatric disorders with maternal immune activation (MIA) being a risk factor for both autism spectrum disorders and schizophrenia. Although MIA mouse offspring exhibit behavioral impairments, the synaptic alterations in vivo that mediate these behaviors are not known. Here we employed in vivo multiphoton imaging to determine that in the cortex of young MIA offspring there is a reduction in number and turnover rates of dendritic spines, sites of majority of excitatory synaptic inputs.

Deficit in motor training-induced clustering, but not stabilization, of new dendritic spines in FMR1 knock-out mice.

Fragile X Syndrome is the most common inherited intellectual disability, and Fragile X Syndrome patients often exhibit motor and learning deficits. It was previously shown that the fmr1 knock-out mice, a common mouse model of Fragile X Syndrome, recapitulates this motor learning deficit and that the deficit is associated with altered plasticity of dendritic spines. Here, we investigated the motor learning-induced turnover, stabilization and clustering of dendritic spines in the fmr1 knock-out mouse using a single forelimb reaching task and in vivo multiphoton imaging.

Preparation of Synaptosomes from the Motor Cortex of Motor Skill Trained Mice.

Learning and memory are thought to occur due to changes in synaptic strength. Strengthening of synapses due to Long Term Potentiation mechanisms are mediated by increases in synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) levels. Here we describe a protocol to isolate and quantify synaptic AMPAR subunit GluA1 levels from the motor cortex of mice which have undergone motor skill training.

Altered structural and functional synaptic plasticity with motor skill learning in a mouse model of fragile X syndrome.

Fragile X syndrome (FXS) is the most common inherited intellectual disability. FXS results from a mutation that causes silencing of the FMR1 gene, which encodes the fragile X mental retardation protein. Patients with FXS exhibit a range of neurological deficits, including motor skill deficits.

The gene-gun approach for transfection and labeling of cells in brain slices.

Biolistic transfection and diolistic labeling are techniques in which subcellular-sized particles, coated with DNA and lipophilic dyes, respectively, are propelled into cells. The gene-gun approach is particularly applicable for use on ex vivo organized tissue such as brain slices, where cells are not accessible for transfection with methods used in dissociated cell preparations. This simple and rapid method results in targeting of individual cells in a Golgi-like manner, allowing investigating structural and functional aspects of neuronal development.

Neuron-glial interactions in the developing cerebellum.

Advances in microscopy allow one to probe the structure of neurons and their interactions with astrocytes in brain slices and in vivo at ever increasing resolution. Moreover, the dynamic interactions between the cells can be examined in live preparation. In this paper we discuss how a variety of imaging approaches: confocal microscopy, electron microscopy, and multiphoton time-lapse microscopy are employed to probe neuron glia interactions in the developing cerebellum.

Active Targeted Macrophage-mediated Delivery of Catalase to Affected Brain Regions in Models of Parkinson's Disease.

We previously demonstrated that monocyte-macrophage based drug delivery can be applied to a spectrum of infectious, neoplastic, and degenerative disorders. In particular, bone marrow-derived macrophages (BMM) loaded with nano formulated catalase, "nanozyme", were shown to attenuate neuro inflammation and nigrostriatal degeneration in rodent models of Parkinson's disease (PD). Nonetheless, the pharmacokinetics and biodistribution of BMM-incorporated nanozyme has not been explored.

Bergmann glial ensheathment of dendritic spines regulates synapse number without affecting spine motility.

In the cerebellum, lamellar Bergmann glial (BG) appendages wrap tightly around almost every Purkinje cell dendritic spine. The function of this glial ensheathment of spines is not entirely understood. The development of ensheathment begins near the onset of synaptogenesis, when motility of both BG processes and dendritic spines are high.

Morphogenesis and regulation of Bergmann glial processes during Purkinje cell dendritic spine ensheathment and synaptogenesis.

Astrocytes have an important role in synaptic formation and function but how astrocytic processes become associated with synaptic structures during development is not well understood. Here we analyzed the pattern of growth of the processes extending off the main Bergmann glial (BG) shafts during synaptogenesis in the cerebellum. We found that during this period, BG process outgrowth was correlated with increased ensheathment of dendritic spines.