The choroid plexus- cerebrospinal fluid axis as a lifespan regulator of neural stem cells and circuit plasticity.

Microglia: actively surveying and shaping neuronal circuit structure and function

Balancing plasticity and stability in neural circuits is essential for an animal's ability to learn from its environment while preserving proper processing and perception of sensory information. However, unlike the mechanisms that drive plasticity in neural circuits, the activity-induced molecular mechanisms that convey functional stability remain poorly understood. Focusing on the visual cortex of adult mice and combining transcriptomics, electrophysiology, and invivo calcium imaging, we find that the daily appearance of light induces, in excitatory neurons, a large gene program along with rapid and transient increases in the ratio of excitation and inhibition (E/I ratio) and neural activity. Furthermore, we find that the light-induced transcription factor NPAS4 drives these daily normalizations of the E/I ratio and neural activity rates and that it stabilizes the neurons' response properties. These findings indicate that daily sensory-induced transcription normalizes the E/I ratio and drives downward firing rate homeostasis to maintain proper sensory processing and perception.

The Cold Spring Harbour Asia conference on 'Assembly, Plasticity, Dysfunction and Repair of Neural Circuits' took place in Suzhou, China, in October 2011. Developmental, cell, molecular and systems neuroscientists convened to discuss the establishment, function and plasticity of neural circuits in diverse organisms.

The neural stem cell (NSC) niche has been partially characterized and defined in the mammalian brain. Two adult niches have been identified: the dentate gyrus (DG) in the hippocampus and the subventricular zone (SVZ). Neural stem cells reside in these microenvironments near to vascular cells, with which they communicate through paracrine factors. This review summarizes the latest vascular paracrine factors identified to play a role in the NSC niche. Soluble factors released by the vasculature, such as pigment epithelium-derived factor (PEDF), platelet-derived growth factor (PDGF), betacellulin (BTC), vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), neurotropin (NT)-3, and Notch ligand Jagged 1, regulate NSC behavior in the niche. New paracrine factors, like APP and EGFL-7, have been recently identified as part of the NSC niche. The choroid plexus of the lateral ventricle (LVCP) has also been identified as a key regulator of the NSC niche. Finally, exosomes containing proteins or microRNAs are released by different cell types in the NSC niche and are considered to play a role in the regulation of NSCs. The niche vasculature and the choroid plexus are key components of the NSC niche that determine NSC fate by releasing paracrine factors, either directly or contained in exosomes. Understanding the complexity of the microenvironment and NSC niche cytoarchitecture will help to unveil the regulatory mechanisms that control NSC biology.

Identification of c-Kit receptor as a regulator of adult neural stem cells in the mammalian eye: interactions with Notch signaling

Neural Stem Cells Neuroscientists are keen to tap into the brain's reservoir of neural stem cells to treat age-associated cognitive decline, neurodegeneration, and other illnesses. In the mouse brain, quiescent stem cells in the central subependymal zone are poised to produce new neuroblasts during adulthood. Lepko et al. have linked mobile microRNA signals to regulation of stem cell quiescence. Low amounts of neurogenic fate determinants can be expressed in the stem cells as RNA but are not translated into proteins. Analysis of posttranscriptional regulation fingered the microRNA miR-204, which is abundant in the brain, as the block on the stem cells. The source of miR-204 was the choroid plexus, which delivered miR-204 into the cerebrospinal fluid and, from there, to the neural stem cells. Thus, at the blood–brain interface, the choroid plexus is ready to integrate external, systemic signals with demands for adult brain neurogenesis. EMBO J. 10.15252/embj.2018100481 (2019).

Engineered extracellular vesicles for ischemic stroke treatment

Regulation of neural stem cells by choroid plexus cells population

The choroid plexus secrets cerebrospinal fluid (CSF) composed of electrolytes, cytokines, growth factors, metabolites and extracellular vesicles (EVs) that flow through the interconnected brain ventricles. On their course, CSF components can act as signals that affect, for example, neural stem cells (NSCs) residing in niches of the ventricular wall. We studied EV-born CSF signals in an in vitro culture system. We purified EVs from the secretome of a choroid plexus cell line (Z310 cells), and from primary choroid plexus cultures and co-cultured those EVs with NSCs isolated from the niche of the lateral and the third ventricle. EVsZ310 and EVsCHP were purified by differential centrifugation. This yielded fractions of EVs of 50-150-nm diameter that induced a complex multicellular network formation and NSC differentiation. Both types of EV converted the round NSCs to cells that extended long processes that contacted nearby, alike-shaped cells. Mass spectrometry showed that the differentiation-inducing EVZ310 were enriched for membrane and membrane-associated proteins involved in cell differentiation, membrane trafficking, and membrane organization. We hypothesize that this type of EV Z310 cargo causes changes of stem cell morphology that leads to multicellular networks in the niches. This cell-shape transition may represent an initial step in NSC differentiation.

BackgroundPrenatal alcohol (ethanol) exposure (PAE) results in brain growth restriction, in part, by reprogramming self-renewal and maturation of fetal neural stem cells (NSCs) during neurogenesis. We recently showed that ethanol resulted in enrichment of both proteins and pro-maturation microRNAs in sub-200-nm-sized extracellular vesicles (EVs) secreted by fetal NSCs. Moreover, EVs secreted by ethanol-exposed NSCs exhibited diminished efficacy in controlling NSC metabolism and maturation. Here we tested the hypothesis that ethanol may also influence the packaging of RNAs into EVs from cell-of-origin NSCs.MethodsSex-specified fetal murine iso-cortical neuroepithelia from three separate pregnancies were maintained ex vivo, as neurosphere cultures to model the early neurogenic niche. EVs were isolated by ultracentrifugation from NSCs exposed to a dose range of ethanol. RNA from paired EV and cell-of-origin NSC samples was processed for ribosomal RNA-depleted RNA sequencing. Differential expression analysis and exploratory weighted gene co-expression network analysis (WGCNA) identified candidate genes and gene networks that were drivers of alterations to the transcriptome of EVs relative to cells.ResultsThe RNA content of EVs differed significantly from cell-of-origin NSCs. Biological sex contributed to unique transcriptome variance in EV samples, where > 75% of the most variant transcripts were also sex-variant in EVs but not in cell-of-origin NSCs. WGCNA analysis also identified sex-dependent enrichment of pathways, including dopamine receptor binding and ectoderm formation in female EVs and cell-substrate adhesion in male EVs, with the top significant DEGs from differential analysis of overall individual gene expressions, i.e., Arhgap15, enriched in female EVs, and Cenpa, enriched in male EVs, also serving as WCGNA hub genes of sex-biased EV WGCNA clusters. In addition to the baseline RNA content differences, ethanol exposure resulted in a significant dose-dependent change in transcript expression in both EVs and cell-of-origin NSCs that predominantly altered sex-invariant RNAs. Moreover, at the highest dose, ~ 73% of significantly altered RNAs were enriched in EVs, but depleted in NSCs.ConclusionsThe EV transcriptome is distinctly different from, and more sex-variant than, the transcriptome of cell-of-origin NSCs. Ethanol, a common teratogen, results in dose-dependent sorting of RNA transcripts from NSCs to EVs which may reprogram the EV-mediated endocrine environment during neurogenesis.

Adult Neural Stem Cells Bridge Their Niche

Home at Last: Neural Stem Cell Niches Defined

Chronic pain is not simply a temporal continuum of acute pain. Studies on functional plasticity in neural circuits of pain have provided mechanistic insights and linked various modulatory factors to a change in perception and behaviour. However, plasticity also occurs in the context of structural remodelling and reorganisation of synapses, cells and circuits, potentially contributing to the long-term nature of chronic pain. This Review discusses maladaptive structural plasticity in neural circuits of pain, spanning multiple anatomical and spatial scales in animal models and human patients, and addresses key questions on structure-function relationships.

Background:Although progress has been made in the detection and characterization of neural plasticity in depression, it has not been fully understood in individual synaptic changes in the neural circuits under chronic stress and antidepressant treatment.Methods:Using electron microscopy and Western-blot analyses, the present study quantitatively examined the changes in the Gray’s Type I synaptic ultrastructures and the expression of synapse-associated proteins in the key brain regions of rats’ depressive-related neural circuit after chronic unpredicted mild stress and/or escitalopram administration. Meanwhile, their depressive behaviors were also determined by several tests.Results:The Type I synapses underwent considerable remodeling after chronic unpredicted mild stress, which resulted in the changed width of the synaptic cleft, length of the active zone, postsynaptic density thickness, and/or synaptic curvature in the subregions of medial prefrontal cortex and hippocampus, as well as the basolateral amygdaloid nucleus of the amygdala, accompanied by changed expression of several synapse-associated proteins. Chronic escitalopram administration significantly changed the above alternations in the chronic unpredicted mild stress rats but had little effect on normal controls. Also, there was a positive correlation between the locomotor activity and the maximal synaptic postsynaptic density thickness in the stratum radiatum of the Cornu Ammonis 1 region and a negative correlation between the sucrose preference and the length of the active zone in the basolateral amygdaloid nucleus region in chronic unpredicted mild stress rats.Conclusion:These findings strongly indicate that chronic stress and escitalopram can alter synaptic plasticity in the neural circuits, and the remodeled synaptic ultrastructure was correlated with the rats’ depressive behaviors, suggesting a therapeutic target for further exploration.

The Review "The malleable brain: plasticity of neural circuits and behavior - A review from students to students" has been written by a group of students following the International Society for Neurochemistry and Journal of Neurochemistry Flagship School. Comprehensively written by students for students, it provides both an excellent educational opportunity and a state-of-the-art insight into the field of neuronal plasticity specifically targeted to young researchers, and thus fulfills an important aspect of the ISN's educational mission. Read the highlighted article 'The malleable brain: plasticity of neural circuits and behavior - a review from students to students' on page 790.