Morphological Signatures of Neurogenesis and Neuronal Migration in Hypothalamic Vasopressinergic Magnocellular Nuclei of the Adult Rat.

The arginine vasopressin (AVP)-magnocellular neurosecretory system (AVPMNS) in the hypothalamus plays a critical role in homeostatic regulation as well as in allostatic motivational behaviors. However, it remains unclear whether adult neurogenesis exists in the AVPMNS. By using immunoreaction against AVP, neurophysin II, glial fibrillar acidic protein (GFAP), cell division marker (Ki67), migrating neuroblast markers (doublecortin, DCX), microglial marker (Ionized calcium binding adaptor molecule 1, Iba1), and 5'-bromo-2'-deoxyuridine (BrdU), we report morphological evidence that low-rate neurogenesis and migration occur in adult AVPMNS in the rat hypothalamus. Tangential AVP/GFAP migration routes and AVP/DCX neuronal chains as well as ascending AVP axonal scaffolds were observed. Chronic water deprivation significantly increased the BrdU+ nuclei within both the supraaoptic (SON) and paraventricular (PVN) nuclei. These findings raise new questions about AVPMNS's potential hormonal role for brain physiological adaptation across the lifespan, with possible involvement in coping with homeostatic adversities.

Wnt Signaling in the Adult Hippocampal Neurogenic Niche.

The subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) is a neurogenic niche of the adult brain that contains neural stem cells (NSCs) able to generate excitatory glutamatergic granule neurons, which integrate into the DG circuit and contribute to hippocampal plasticity, learning, and memory. Thus, endogenous NSCs could be harnessed for therapeutic purposes. In this context, it is critical to characterize the molecular mechanisms controlling the generation and functional integration of adult-born neurons. Adult hippocampal neurogenesis is tightly controlled by both cell-autonomous mechanisms and the interaction with the complex niche microenvironment, which harbors the NSCs and provides the signals to support their maintenance, activation, and differentiation. Among niche-derived factors, Wnt ligands play diverse roles. Wnts are secreted glycoproteins that bind to Frizzled receptors and co-receptors to trigger the Wnt signaling pathway. Here, we summarize the current knowledge about the roles of Wnts in the regulation of adult hippocampal neurogenesis. We discuss the possible contribution of the different niche cells to the regulation of local Wnt signaling activity, and how Wnts derived from different cell types could induce differential effects. Finally, we discuss how the effects of Wnt signaling on hippocampal network activity might contribute to neurogenesis regulation. Although the evidence supports relevant roles for Wnt signaling in adult hippocampal neurogenesis, defining the cellular source and the mechanisms controlling secretion and diffusion of Wnts will be crucial to further understand Wnt signaling regulation of adult NSCs, and eventually, to propose this pathway as a therapeutic target to promote neurogenesis.

A Balancing Act: The Immune System Supports Neurodegeneration and Neurogenesis.

Decapod crustaceans, like mammals, retain the ability to make new neurons throughout life. In mammals, immune cells are closely associated with stem cells that generate adult-born neurons. In crayfish, evidence suggests that immune cells (hemocytes) originating in the immune system travel to neurogenic regions and transform into neural progenitor cells. This nontraditional immune activity takes place continuously under normal physiological conditions, but little is known under pathological conditions (neurodegeneration). In this study, the immune system and its relationship with neurogenesis were investigated during neurodegeneration (unilateral antennular ablation) in adult crayfish. Our experiments show that after ablation (1) Proliferating cells decrease in neurogenic areas of the adult crayfish brain; (2) The immune response, but not neurogenesis, is ablation-side dependent; (3) Inducible nitric oxide synthase (iNOS) plays a crucial role in the neurogenic niche containing neural progenitors during the immune response; (4) Brain areas targeted by antennular projections respond acutely (15 min) to the lesion, increasing the number of local immune cells; (5) Immune cells are recruited to the area surrounding the ipsilateral neurogenic niche; and (6) The vasculature in the niche responds acutely by dilation and possibly also neovascularization. We conclude that immune cells are important in both neurodegeneration and neurogenesis by contributing in physiological conditions to the maintenance of the number of neural precursor cells in the neurogenic niche (neurogenesis), and in pathological conditions (neurodegeneration) by coordinating NO release and vascular responses associated with the neurogenic niche. Our data suggest that neural damage and recovery participate in a balance between these competing immune cell roles.

Adaptive neurogenesis in the cerebral cortex and contralateral subventricular zone induced by unilateral cortical devascularization: Possible modulation by dopamine neurotransmission.

Understanding endogenous neurogenesis and neuronal replacement to mature circuits is a topic of discussion as a therapeutic alternative under acute and chronic neurodegenerative disorders. Adaptive neurogenic response may result as a result of ischemia which could support long-term recovery of behavioral functions. Endogenous sources of neural progenitors may be stimulated by changes in blood flow or neuromodulation. Using a mouse model of unilateral cortical devascularization, we have observed reactive neurogenesis in the perilesional cortex and subventricular zone neurogenic niche. C57BL/6L 4 weeks old male mice were craneotomized at 1 mm caudal from frontal suture and 1 mm lateral from midline to generate a window of 3 mm side. Brain injury was produced by removal of the meninges and superficial vasculature of dorsal parietal cortex. BrdU agent (50 mg/kg, ip) was injected to lesioned and sham animals, during days 0 and 1 after surgery. Sagittal sections were analyzed at 1, 4, 7, and 10 days post-injury. A time-dependent increase in BrdU+ cells in the perilesional parietal cortex was accompanied by augmented BrdU+ cells in the sub ventricular and rostral migratory stream of ipsilateral and contralateral hemispheres. Neural progenitors and neuroblasts proliferated in the lesioned and non-lesioned subventricular zone and rostral migratory stream on day 4 after injury. Augmented contralateral neurogenesis was associated with an increase in vesicular monoamine transporter 2 protein in the striosomal sub ventricular neurogenic niche of non-lesioned hemisphere.

Differential vulnerability of adult neurogenesis by adult and prenatal inflammation: role of TGF-ß1.

Peripheral inflammation, both during the prenatal period and in adulthood, impairs adult neurogenesis. We hypothesized that, similar to other programming effects of prenatal treatments, only prenatal inflammation causes long-term consequences in adult neurogenesis and its neurogenic niche. To test this, pregnant Wistar rats were subcutaneously injected with lipopolysaccharide (LPS; 0.5 mg/kg) or saline solution every other day from gestational/embryonic day (GD) 14-20. In addition adult animals were injected with a single intraperitoneal saline or LPS injection (1 mg/kg) and the effects on neurogenesis were assessed 7 days later. Alternatively, to evaluate long-term consequences of adult LPS injections, LPS (1 mg/kg) was administered peripherally to adult rats four times every other day, and the effects on neurogenesis were assessed 60 days later. Prenatal and adult LPS treatments reduced adult neurogenesis and provoked specific microglial (but not astroglial) activation in the dentate gyrus (DG). However, only prenatal inflammation-mediated effects were long-lasting (at least 60 days). Moreover, these effects were specific to the DG since the Subventricular Zone (SVZ) and the Rostral Migratory Stream (RMS) were not affected. In addition, these stimuli caused differential effects on the molecular components of the neurogenic niche; only prenatal LPS treatment reduced the local levels of TGF-ß1 mRNA in the DG. Finally, TGF-ß1 exerted its pro-neurogenic effects via the Smad 2/3 pathway in a neural stem cell culture. Taken together, these data add evidence to the duration, regional specificity and dramatic consequences of prenatal immune programming on CNS physiology, compared with the limited response observed in the adult brain.

Typical and atypical stem cells in the brain, vitamin C effect and neuropathology

Stem cells are considered a valuable cellular resource for tissue replacement therapies in most brain disorders. Stem cells have the ability to self-replicate and differentiate into numerous cell types, including neurons, oligodendrocytes and astrocytes. As a result, stem cells have been considered the "holy grail" of modern medical neuroscience. Despite their tremendous therapeutic potential, little is known about the mechanisms that regulate their differentiation. In this review, we analyze stem cells in embryonic and adult brains, and illustrate the differentiation pathways that give origin to most brain cells. We also evaluate the emergent role of the well known anti-oxidant, vitamin C, in stem cell differentiation. We believe that a complete understanding of all molecular players, including vitamin C, in stem cell differentiation will positively impact on the use of stem cell transplantation for neurodegenerative diseases.