Mechanism of neurogenesis in adult avian brain

Summary Adult neurogenesis in birds offers unique opportunities to study basic questions addressing the birth, migration and differentiation of neurons. Neurons in adult canaries originate from discrete proliferative regions on the walls of the lateral ventricles. They migrate away from their site of birth, initially at high rates, along the processes of radial cells. The rates of dispersal diminish as the young neurons invade regions devoid of radial fibers, probably under the guidance of other cues. The discrete sites of birth in the ventricular zone generate neurons that end up differentiating throughout the telencephelon. New neurons may become interneurons or projection neurons; the latter connect two song control nuclei between neostriatum and archistriatum. Radial cells, that in mammals disappear as neurogenesis comes to an end, persist in the adult avian brain. The presence of radial cells may be key to adult neurogenesis. Not only do they serve as guides for initial dispersal, they also divide and may be the progenitors of new neurons.     

Injury-induced neurogenesis in the mammalian forebrain

It has been accepted that new neurons are added to the olfactory bulb and the hippocampal dentate gyrus throughout life in the healthy adult mammalian brain. Recent studies have clarified that brain insult raises the proliferation of neural stem cells/neural progenitor cells existing in the subventricular zone and the subgranular zone, which become sources of new neurons for the olfactory bulb and the dentate gyrus, respectively. Interestingly, convincing data has shown that brain insult invokes neurogenesis in various brain regions, such as the hippocampal cornu ammonis region, striatum, and cortex. These reports suggest that neural stem cells/neural progenitor cells, which can be activated by brain injury, might be broadly located in the adult brain or that new neurons may migrate widely from the neurogenic regions. This review focuses on brain insult-induced neurogenesis in the mammalian forebrain, especially in the neocortex.     

Stress,glucocorticoid receptors,and adult neurogenesis: a balance between excitation and inhibition?

Adult neurogenesis, the birth of new neurons in the mature brain, has attracted considerable attention in the last decade. One of the earliest identified and most profound factors that affect adult neurogenesis both positively and negatively is stress. Here, we review the complex interplay between stress and adult neurogenesis. In particular, we review the role of the glucocorticoid receptor, the main mediator of the stress response in the proliferation, differentiation, migration, and functional integration of newborn neurons in the hippocampus. We review a multitude of mechanisms regulating glucocorticoid receptor activity in relationship to adult neurogenesis. We postulate a novel concept in which the level of glucocorticoid receptor expression directly regulates the excitation-inhibition balance, which is key for proper neurogenesis. We furthermore argue that an excitation-inhibition dis-balance may underlie aberrant functional integration of newborn neurons that is associated with psychiatric and paroxysmal brain disorders.     

Adult hippocampal neurogenesis: regulation by HIV and drugs of abuse

New dentate granule cells are continuously generated from neural progenitor cells and integrated into the existing hippocampal circuitry in the adult mammalian brain through an orchestrated process termed adult neurogenesis. While the exact function remains elusive, adult neurogenesis has been suggested to play important roles in specific cognitive functions. Adult hippocampal neurogenesis is regulated by a variety of physiological and pathological stimulations. Here we review emerging evidence showing that HIV infection and several drugs of abuse result in molecular changes that may affect different aspects of adult hippocampal neurogenesis. These new findings raise the possibility that cognitive dysfunction in the setting of HIV infection or drug abuse may, in part, be related to alterations in hippocampal neurogenesis. A better understanding of how HIV and drugs of abuse affect both molecular and cellular aspects of adult neurogenesis may lead to development of more effective therapeutic interventions for these interlinked epidemics. Received 6 February 2007; received after revision 26 March 2007; accepted 25 April 2007     

Adult neurogenesis in Parkinson’s disease

Parkinson’s disease (PD), the second most common neurodegenerative disorder, affects 1–2 % of humans aged 60 years and older. The diagnosis of PD is based on motor symptoms such as bradykinesia, rigidity, tremor, and postural instability associated with the striatal dopaminergic deficit that is linked to neurodegenerative processes in the substantia nigra (SN). In the past, cellular replacement strategies have been evaluated for their potential to alleviate these symptoms. Adult neurogenesis, the generation of new neurons within two proliferative niches in the adult brain, is being intensively studied as one potential mode for cell-based therapies. The subventricular zone provides new neurons for the olfactory bulb functionally contributing to olfaction. The subgranular zone of the hippocampus produces new granule neurons for the dentate gyrus, required for memory formation and proper processing of anxiety provoking stimuli. Recent years have revealed that PD is associated with non-motor symptoms such as hyposmia, anhedonia, lack of novelty seeking behavior, depression, and anxiety that are not directly associated with neurodegenerative processes in the SN. This broad spectrum of non-motor symptoms may partly rely on proper olfactorial processing and hippocampal function. Therefore, it is conceivable that some non-motor deficits in PD are related to defective adult neurogenesis. Accordingly, in animal models and postmortem studies of PD, adult neurogenesis is severely affected, although the exact mechanisms and effects of these changes are not yet fully understood or are under debate due to conflicting results. Here, we review the current concepts related to the dynamic interplay between endogenous cellular plasticity and PD-associated pathology.     

Neurogenic effects of β-amyloid in the choroid plexus epithelial cells in Alzheimer’s disease

β-amyloid (Aβ) can promote neurogenesis, both in vitro and in vivo, by inducing neural progenitor cells to differentiate into neurons. The choroid plexus in Alzheimer’s disease (AD) is burdened with amyloid deposits and hosts neuronal progenitor cells. However, neurogenesis in this brain tissue is not firmly established. To investigate this issue further, we examined the effect of Aβ on the neuronal differentiation of choroid plexus epithelial cells in several experimental models of AD. Here we show that Aβ regulates neurogenesis in vitro in cultured choroid plexus epithelial cells as well as in vivo in the choroid plexus of APP/Ps1 mice. Treatment with oligomeric Aβ increased proliferation and differentiation of neuronal progenitor cells in cultured choroid plexus epithelial cells, but decreased survival of newly born neurons. These Aβ-induced neurogenic effects were also observed in choroid plexus of APP/PS1 mice, and detected also in autopsy tissue from AD patients. Analysis of signaling pathways revealed that pre-treating the choroid plexus epithelial cells with specific inhibitors of TyrK or MAPK diminished Aβ-induced neuronal proliferation. Taken together, our results support a role of Aβ in proliferation and differentiation in the choroid plexus epithelial cells in Alzheimer’s disease.     

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, leading to a variety of motor and non-motor symptoms. Interestingly, non-motor symptoms often appear a decade or more before the first signs of motor symptoms. Some of these non-motor symptoms are remarkably similar to those observed in cases of impaired neurogenesis and several PD-related genes have been shown to play a role in embryonic or adult neurogenesis. Indeed, animal models deficient in Nurr1, Pitx3, SNCA and PINK1 display deregulated embryonic neurogenesis and LRRK2 and VPS35 have been implicated in neuronal development-related processes such as Wnt/β-catenin signaling and neurite outgrowth. Moreover, adult neurogenesis is affected in both PD patients and PD animal models and is regulated by dopamine and dopaminergic (DA) receptors, by chronic neuroinflammation, such as that observed in PD, and by differential expression of wild-type or mutant forms of PD-related genes. Indeed, an increasing number of in vivo studies demonstrate a role for SNCA and LRRK2 in adult neurogenesis and in the generation and maintenance of DA neurons. Finally, the roles of PD-related genes, SNCA, LRRK2, VPS35, Parkin, PINK1 and DJ-1 have been studied in NSCs, progenitor cells and induced pluripotent stem cells, demonstrating a role for some of these genes in stem/progenitor cell proliferation and maintenance. Together, these studies strongly suggest a link between deregulated neurogenesis and the onset and progression of PD and present strong evidence that, in addition to a neurodegenerative disorder, PD can also be regarded as a developmental disorder.     

Principles of neural cell migration

Summary A basic property of immature neurons is their ability to change position from the place of their final mitotic division in proliferative centers of the developing brain to the specific positions they will occupy in a given structure of the adult nervous system. Proper acquisition of neuron position, attained through the process of active migration, ultimately affects a cell's morphology, synaptic connectivity and function. Although various classes of neurons may use different molecular cues to guide their migration to distant structures, a surface-mediated interaction between neighboring cells is considered essential for all types of migration. Disturbance of this cell-cell interaction may be important in several congenital and/or acquired brain abnormalities. The present article considers the basic mechanisms and principles of neuronal cell migration in the mammalian central nervous system.     

Human embryonic stem cell-derived neurons establish region-specific, long-range projections in the adult brain

While the availability of pluripotent stem cells has opened new prospects for generating neural donor cells for nervous system repair, their capability to integrate with adult brain tissue in a structurally relevant way is still largely unresolved. We addressed the potential of human embryonic stem cell-derived long-term self-renewing neuroepithelial stem cells (lt-NES cells) to establish axonal projections after transplantation into the adult rodent brain. Transgenic and species-specific markers were used to trace the innervation pattern established by transplants in the hippocampus and motor cortex. In vitro, lt-NES cells formed a complex axonal network within several weeks after the initiation of differentiation and expressed a composition of surface receptors known to be instrumental in axonal growth and pathfinding. In vivo, these donor cells adopted projection patterns closely mimicking endogenous projections in two different regions of the adult rodent brain. Hippocampal grafts placed in the dentate gyrus projected to both the ipsilateral and contralateral pyramidal cell layers, while axons of donor neurons placed in the motor cortex extended via the external and internal capsule into the cervical spinal cord and via the corpus callosum into the contralateral cortex. Interestingly, acquisition of these region-specific projection profiles was not correlated with the adoption of a regional phenotype. Upon reaching their destination, human axons established ultrastructural correlates of synaptic connections with host neurons. Together, these data indicate that neurons derived from human pluripotent stem cells are endowed with a remarkable potential to establish orthotopic long-range projections in the adult mammalian brain.     

Mechanisms regulating GABAergic neuron development

Neurons using gamma-aminobutyric acid (GABA) as their neurotransmitter are the main inhibitory neurons in the mature central nervous system (CNS) and show great variation in their form and function. GABAergic neurons are produced in all of the main domains of the CNS, where they develop from discrete regions of the neuroepithelium. Here, we review the gene expression and regulatory mechanisms controlling the main steps of GABAergic neuron development: early patterning of the proliferative neuroepithelium, production of postmitotic neural precursors, establishment of their identity and migration. By comparing the molecular regulation of these events across CNS, we broadly identify three regions utilizing distinct molecular toolkits for GABAergic fate determination: telencephalon–anterior diencephalon (DLX2 type), posterior diencephalon–midbrain (GATA2 type) and hindbrain–spinal cord (PTF1A and TAL1 types). Similarities and differences in the molecular regulatory mechanisms reveal the core determinants of a GABAergic neuron as well as provide insights into generation of the vast diversity of these neurons.     

The subventricular zone: new molecular and cellular developments

The subventricular zone (SVZ), which lines the lateral walls of the lateral ventricle, persists as a neurogenic zone into adulthood and functions as the largest site of neurogenesis in the adult brain. In recent years, with the acceptance of the concept of postembryonic mammalian neurogenesis, neurogenesis in the adult SVZ has been an area of active research. With the rapid accumulation of new information on the SVZ, some of which is contradictory, summarizing existing knowledge on the SVZ and outlining future research directions in this area become important. In this review, we will cover recent molecular and cellular investigations that characterize the SVZ niche, SVZ neurogenesis, and SVZ cell migration within the adult brain.     

The contribution of neuronal–glial–endothelial–epithelial interactions to colon carcinogenesis

Several different cell types constitute the intestinal wall and interact in different manners to maintain tissue homeostasis. Elegant reports have explored these physiological cellular interactions revealing that glial cells and neurons not only modulate peristalsis and mechanical stimulus in the intestines but also control epithelial proliferation and sub-epithelial angiogenesis. Although colon carcinoma arises from epithelial cells, different sub-epithelial cell phenotypes are known to support the manifestation and development of tumors from their early steps on. Therefore, new perspectives in cancer research have been proposed, in which neurons and glial cells not only lead to higher cancer cell proliferation at the tumor invasion front but also further enhance angiogenesis and neurogenesis in tumors. Transformation of physiological neural activity into a pro-cancer event is thus discussed for colon carcinogenesis herein.     

In vitro neurogenesis: development and functional implications of iPSC technology

Neurogenesis is the developmental process regulating cell proliferation of neural stem cells, determining their differentiation into glial and neuronal cells, and orchestrating their organization into finely regulated functional networks. Can this complex process be recapitulated in vitro using induced pluripotent stem cell (iPSC) technology? Can neurodevelopmental and neurodegenerative diseases be modeled using iPSCs? What is the potential of iPSC technology in neurobiology? What are the recent advances in the field of neurological diseases? Since the applications of iPSCs in neurobiology are based on the capacity to regulate in vitro differentiation of human iPSCs into different neuronal subtypes and glial cells, and the possibility of obtaining iPSC-derived neurons and glial cells is based on and hindered by our poor understanding of human embryonic development, we reviewed current knowledge on in vitro neural differentiation from a developmental and cellular biology perspective. We highlight the importance to further advance our understanding on the mechanisms controlling in vivo neurogenesis in order to efficiently guide neurogenesis in vitro for cell modeling and therapeutical applications of iPSCs technology.     

Neurons with dual axons in the substantia gelatinosa (SG) of the adult cat lumbosacral spinal cord

Summary A small percentage of SG neurons possessing two separate and complete axons were observed in the lumbosacral spinal cord of the adult cat. Since they are found in small numbers and are structurally similar to single axon SG cells, dual axon cells may represent a developmental aberrancy rather than a functionally distinct cell type.This research was supported by U.S.P.H.S. grant No.NS-16642-01.