A versatile transcription factor: Multiple roles of orthopedia a (otpa) beyond its restricted localization in dopaminergic systems of developing and adult zebrafish (Danio rerio) brains.

Many transcription factors boost neural development and differentiation in specific directions and serve for identifying similar or homologous structures across species. The expression of Orthopedia (Otp) is critical for the development of certain cell groups along the vertebrate neuraxis, for example, the medial amygdala or hypothalamic neurosecretory neurons. Therefore, the primary focus of the present study is the distribution of Orthopedia a (Otpa) in the larval and adult zebrafish (Danio rerio) brain. Since Otpa is also critical for the development of zebrafish basal diencephalic dopaminergic cells, colocalization of Otpa with the catecholamine synthesizing enzyme tyrosine hydroxylase (TH) is studied. Cellular colocalization of Otpa and dopamine is only seen in magnocellular neurons of the periventricular posterior tubercular nucleus and in the posterior tuberal nucleus. Otpa-positive cells occur in many additional structures along the zebrafish neuraxis, from the secondary prosencephalon down to the hindbrain. Furthermore, Otpa expression is studied in shh-GFP and islet1-GFP transgenic zebrafish. Otpa-positive cells only express shh in dopaminergic magnocellular periventricular posterior tubercular cells, and only colocalize with islet1-GFP in the ventral zone and prerecess caudal periventricular hypothalamic zone and the perilemniscal nucleus. The scarcity of cellular colocalization of Otpa in islet1-GFP cells indicates that the Shh-islet1 neurogenetic pathway is not active in most Otpa-expressing domains. Our analysis reveals detailed correspondences between mouse and zebrafish forebrain territories including the zebrafish intermediate nucleus of the ventral telencephalon and the mouse medial amygdala. The zebrafish preoptic Otpa-positive domain represents the neuropeptidergic supraopto-paraventricular region of all tetrapods. Otpa domains in the zebrafish basal plate hypothalamus suggest that the ventral periventricular hypothalamic zone corresponds to the otp-expressing basal hypothalamic tuberal field in the mouse. Furthermore, the mouse otp domain in the mammillary hypothalamus compares partly to our Otpa-positive domain in the prerecess caudal periventricular hypothalamic zone (Hc-a).

Oligodendrogenesis is a key process for cognitive performance improvement induced by voluntary physical activity.

Physical activity (PA) promotes the proliferation of neural stem cells and enhances neurogenesis in the dentate gyrus resulting in hippocampal circuit remodeling and cognitive enhancement. Nonetheless, knowledge of other neural progenitors affected by PA and the mechanisms through which they could contribute to circuit plasticity and cognitive enhancement are still poorly understood. In this work we demonstrated that NG2-glia, also known as oligodendrocyte progenitor cells, show enhanced proliferation and differentiation in response to voluntary PA in a brain region-dependent manner in adult mice. Surprisingly, preventing NG2-glia differentiation during enhanced PA abolishes the exercise-associated cognitive improvement without affecting neurogenesis or baseline learning capacity. Thus, here we provided new evidence highlighting the requirement of oligodendrogenesis for exercise induced-cognition enhancement.

NG2-Glia Transiently Overcome Their Homeostatic Network and Contribute to Wound Closure After Brain Injury.

In the adult brain, NG2-glia represent a cell population that responds to injury. To further investigate if, how and why NG2-glia are recruited to the injury site, we analyzed in detail the long-term reaction of NG2-glia after a lesion by time-lapse two-photon in vivo microscopy. Live imaging over several weeks of GFP-labeled NG2-glia in the stab wounded cerebral cortex revealed their fast and heterogeneous reaction, including proliferation, migration, polarization, hypertrophy, or a mixed response, while a small subset of cells remained unresponsive. At the peak of the reaction, 2-4 days after the injury, NG2-glia accumulated around and within the lesion core, overcoming the homeostatic control of their density, which normalized back to physiological conditions only 4 weeks after the insult. Genetic ablation of proliferating NG2-glia demonstrated that this accumulation contributed beneficially to wound closure. Thus, NG2-glia show a fast response to traumatic brain injury (TBI) and participate in tissue repair.

Recent Advances in Live Imaging of Cells of the Oligodendrocyte Lineage.

Myelination is an important process that takes place also in the periphery during development and in the adulthood. Myelin serves as an electric isolator for axons, leading to a fast conduction of the action potential, and provides trophic support for the axon, both aspects highly important for the proper function of the nervous system. In the central nervous system, myelination starts shortly after birth and cells from the oligodendrocyte lineage tightly regulate this process during the whole life span. Initially, it was thought that under physiological conditions myelin generation only occurs in early postnatal development and that myelination stops at early adult ages. Historically, the process of myelination has mainly been studied in fixed tissue, and predominantly analyzed by electron microscopy, bringing valuable insights in the structure and distribution of myelin in the central nervous system. Nevertheless, the outdated notion of the static nature of myelin during adulthood was challenged in the past decades by the development of new techniques bringing in a new picture of a lively structure that is in constant remodeling under physiological and disease conditions. As fixed tissue can only provide information at a specific timepoint, the necessity of new techniques to study this process in vivo has become clear. In this chapter, we will review some of the latest techniques developed in order to study myelin and the oligodendrocyte lineage, as these cells are important for the formation and restructuration of the myelin. We will also introduce a protocol to prepare a cranial window to study NG2-glia (also known as oligodendrocyte progenitor cells) of the cerebral cortex in vivo, by 2-photon laser scanning microscopy. However, this technique can also be performed to study other cell populations or structures such as myelin, which will be discussed in this chapter as well. Despite being simple, this protocol has shown to be powerful to study the oligodendrocyte lineage and potentially is applicable to study myelin in vivo, which could turn into a key technique in the understanding of myelination and other functions that the oligodendrocyte lineage might have under physiological and disease conditions.

Glial Cells and Integrity of the Nervous System.

Today, there is enormous progress in understanding the function of glial cells, including astroglia, oligodendroglia, Schwann cells, and microglia. Around 150 years ago, glia were viewed as a glue among neurons. During the course of the twentieth century, microglia were discovered and neuroscientists' views evolved toward considering glia only as auxiliary cells of neurons. However, over the last two to three decades, glial cells' importance has been reconsidered because of the evidence on their involvement in defining central nervous system architecture, brain metabolism, the survival of neurons, development and modulation of synaptic transmission, propagation of nerve impulses, and many other physiological functions. Furthermore, increasing evidence shows that glia are involved in the mechanisms of a broad spectrum of pathologies of the nervous system, including some psychiatric diseases, epilepsy, and neurodegenerative diseases to mention a few. It appears safe to say that no neurological disease can be understood without considering neuron-glia crosstalk. Thus, this book aims to show different roles played by glia in the healthy and diseased nervous system, highlighting some of their properties while considering that the various glial cell types are essential components not only for cell function and integration among neurons, but also for the emergence of important brain homeostasis.

NG2-glia, More Than Progenitor Cells.

NG2-glia are a mysterious and ubiquitous glial population with a highly branched morphology. Initial studies suggested that their unique function is the generation and maintenance of oligodendrocytes in the central nervous system (CNS), important for proper myelination and therefore for axonal support and fast conduction velocity. Over the last years this simplistic notion has been dramatically changed: the wide and homogeneous distribution of NG2-glia within all areas of the developing CNS that is maintained during the whole lifespan, their potential to also differentiate into other cell types in a spatiotemporal manner, their active capability of maintaining their population and their dynamic behavior in altered conditions have raised the question: are NG2-glia simple progenitor cells or do they play further major roles in the normal function of the CNS? In this chapter, we will discuss some important features of NG2-glia like their homeostatic distribution in the CNS and their potential to differentiate into diverse cell types. Additionally, we will give some further insights into the properties that these cells have, like the ability to form synapses with neurons and their plastic behavior triggered by neuronal activity, suggesting that they may play a role specifically in myelin and more generally in brain plasticity. Finally, we will briefly review their behavior in disease models suggesting that their function is extended to repair the brain after insult.