Changes in the Number of Primary Sensory Neurons in Normal and Vitamin-E-Deficient Rats during Aging

In the dorsal root ganglia (DRGs) of vitamin-E-deficient rats, we previously found an increase in the number of neurons during the first 5 months of life (Cecchini et al., 1993, 1994). This neurogenetic event seems to bring forward in time the increase in the number of primary sensory neurons that Devor et al. (1985) found in normal rats aged more than 1 year, but that other authors have not confirmed. The present study had two aims: first, to verify whether neurogenesis spontaneously occurs in DRGs of 14-month-old Sprague-Dawley rats; and, second, to determine whether the neurogenesis enhanced by vitamin E deficiency continues further in the long run, or whether it stops or reverses into neuron loss.

A quantitative and morphometric analysis was performed on neurons of L₃-L₆ DRGs in 14-month-old normal and vitamin-E-deficient rats: the results obtained were compared to those previously obtained in 1-month-old and 5-month-old animals of both dietetic treatment groups, in order to observe the effects of aging on these neuronal populations. The total number of DRG neurons in the control group was higher in older than in younger animals, whereas the value in the vitamin-E-deficient group was lower in older than in younger animals. The present data confirm that neurogenesis occurs in DRGs of normal rats during adult life. Moreover, they show that once the premature neurogenesis in the deficient rats is completed, no further increase in the number of neurons takes place.     

Doubling up on microtubule stabilizers: synergistic functions of doublecortin-like kinase and doublecortin in the developing cerebral cortex

Dynamic regulation of neuronal cytoskeletal machinery in response to extracellular cues enables distinct changes in neuronal development in the cerebral cortex. In this issue of Neuron, three related studies on doublecortin-like kinase, a microtubule-associated protein related to doublecortin, by Shu et al., Koizumi et al., and Deuel et al., provide evidence that doublecortin-like kinase is essential for proper neurogenesis, neuronal migration, and axonal wiring.     

综述: 大脑新皮层和神经发育疾病

哺乳动物进化过程中,大脑皮层逐渐增大增厚和脑容量增大,从而构成了脑神经环路复杂性的细胞生物学基础.皮层出现皱褶是非人类灵长类演化的重要特征.成体人脑大约由近860多亿个神经细胞组成,其中,在人脑神经发生高峰,每小时有近400多万个兴奋性神经细胞产生.如此高速的神经生成过程需要精确的细胞与分子调控机制.本文主要讨论调控大脑皮层增大增厚的细胞与分子机制和相关的脑发育疾病.     

Circadian control of neurogenesis

The life-long addition of new neurons has been documented in many regions of the vertebrate and invertebrate brain, including the hippocampus of mammals (Altman and Das, 1965; Eriksson et al., 1998; Jacobs et al., 2000), song control nuclei of birds (Alvarez-Buylla et al., 1990), and olfactory pathway of rodents (Lois and Alvarez-Buylla, 1994), insects (Cayre et al., 1996) and crustaceans (Harzsch and Dawirs, 1996; Sandeman et al., 1998; Harzsch et al., 1999; Schmidt, 2001). The possibility of persistent neurogenesis in the neocortex of primates is also being widely discussed (Gould et al., 1999; Kornack and Rakic, 2001). In these systems, an effort is underway to understand the regulatory mechanisms that control the timing and rate of neurogenesis. Hormonal cycles (Rasika et al., 1994; Harrison et al., 2001), serotonin (Gould, 1999; Brezun and Daszuta, 2000; Beltz et al., 2001), physical activity (Van Praag et al., 1999) and living conditions (Kemperman and Gage, 1999; Sandeman and Sandeman, 2000) influence the rate of neuronal proliferation and survival in a variety of organisms, suggesting that mechanisms controlling life-long neurogenesis are conserved across a range of vertebrate and invertebrate species. The present article extends these findings by demonstrating circadian control of neurogenesis. Data show a diurnal rhythm of neurogenesis among the olfactory projection neurons in the crustacean brain, with peak proliferation during the hours surrounding dusk, the most active period for lobsters. These data raise the possibility that light-controlled rhythms are a primary regulator of neuronal proliferation, and that previously-demonstrated hormonal and activity-driven influences over neurogenesis may be secondary events in a complex circadian control pathway.     

Glial dependent survival of neurons in Drosophila

According to the classical model of insect neurogenesis, neuron fate and survival is determined largely by cell autonomous mechanisms with no requirement for cell-cell interactions to control the total number of neurons. In a recent paper by Booth et al.,(1) however, the central tenet of this model has been called into question. Using a combination of mutations and targeted glial ablation, this paper shows that, contrary to common thinking, neuron survival in the embryonic nervous system of Drosophila is dependent upon normal glial function. This surprising result suggests that insect neurogenesis may have more in common with vertebrate neurogenesis than previously thought.     

Postnatal neurogenesis in the human forebrain: from two migratory streams to dribbles

Subventricular zone neurogenesis occurs throughout life from rodents to primates, but the existence of a rostral migratory stream of immature neurons in postnatal human brains is controversial. A recent report in Nature (Sanai et?al., 2011) identifies two neuronal migratory streams in infant human brains targeting the olfactory bulb and prefrontal cortex.     

Autoradiographical Studies of in Vitro and Chronic in Vivo Effects of Propentofylline on Adenosine A1 and A2 Receptors and NBMPR-Sensitive Nucleoside Transporters

Abstract

Propentofylline is a novel xanthine that has been shown to limit the extent neuronal damage induced by cerebral ischemia in gerbils (DeLeo et al., 1987). This is in contrast to other xanthines, including, caffeine and theophylline, that increase the extent of damage (Rudolphi et al., 1987; Dux et al., 1987). Propentofylline has been demonstrated to decrease adenosine uptake into human erythrocytes (Fredholm and Lindström, 1986), and to increase extracellular concentration of adenosine in ischemic barain (Andine et al., 1990). Therefore, it was proposed that this compound provides protection in cerebral ischemia, in part, by adenosine receptor stimulation due to increased endogenous adenosine levels.     

Developmental studies with the 14-3-2 antigen and the neuron specific enolase (NSE) associated activities—I

We have compared the rodent developmental pattern of the 14-3-2 antigen estimated by a microcomplement fixation technique with that of the cerebral enolases. Chromatographic separation of enolase isozymes on microcolumns demonstrates that the embryonic neuron specific enolase is firstly and mostly represented by the αγ isozyme. The most important increase in 14-3-2 antigen and γγ enolase occurs between post-natal days 7th and 15th. By post-natal day 30, adult levels have been reached. An interesting observation is—during embryonic development—the decrease in the specific activity of the cerebral enolase isozyme αα. This could be explained by the replacement—in neuroblasts—of αα enolase by neuron specific enolase. A comparison between 14-3-2 antigen and neuron specific enolase (γγ) purified by completely different methods is presented. The 14-3-2 antigen exhibits an enolase specific activity comparable to that of purified enzyme and has the same electrophoretic mobility. Antibodies raised against either antigen have an identical specificity. Pre and post-natal developmental pattern in rodent brains are similar for both proteins. Thus neuron specific 14-3-2 antigen is identical to neuron specific enolase.Thus we have precisely described the ontogenic transition between the three cerebral enolase isozymes at the tissue level. This study is completed by the analysis of these transitions at the neuronal cell level, using homogenous cell lines (Part II of this paper).     

Comparative analysis of the subventricular zone in rat, ferret and macaque: evidence for an outer subventricular zone in rodents

The mammalian cerebral cortex arises from precursor cells that reside in a proliferative region surrounding the lateral ventricles of the developing brain. Recent work has shown that precursor cells in the subventricular zone (SVZ) provide a major contribution to prenatal cortical neurogenesis, and that the SVZ is significantly thicker in gyrencephalic mammals such as primates than it is in lissencephalic mammals including rodents. Identifying characteristics that are shared by or that distinguish cortical precursor cells across mammalian species will shed light on factors that regulate cortical neurogenesis and may point toward mechanisms that underlie the evolutionary expansion of the neocortex in gyrencephalic mammals. We immunostained sections of the developing cerebral cortex from lissencephalic rats, and from gyrencephalic ferrets and macaques to compare the distribution of precursor cell types in each species. We also performed time-lapse imaging of precursor cells in the developing rat neocortex. We show that the distribution of Pax6+ and Tbr2+ precursor cells is similar in lissencephalic rat and gyrencephalic ferret, and different in the gyrencephalic cortex of macaque. We show that mitotic Pax6+ translocating radial glial cells (tRG) are present in the cerebral cortex of each species during and after neurogenesis, demonstrating that the function of Pax6+ tRG cells is not restricted to neurogenesis. Furthermore, we show that Olig2 expression distinguishes two distinct subtypes of Pax6+ tRG cells. Finally we present a novel method for discriminating the inner and outer SVZ across mammalian species and show that the key cytoarchitectural features and cell types that define the outer SVZ in developing primates are present in the developing rat neocortex. Our data demonstrate that the developing rat cerebral cortex possesses an outer subventricular zone during late stages of cortical neurogenesis and that the developing rodent cortex shares important features with that of primates.     

Molecular mechanisms of projection neuron production and maturation in the developing cerebral cortex

The cerebral cortex is a brain structure unique to mammals and highly adapted to process complex information. Through multiple developmental steps, the cerebral cortex is assembled as a huge diversity of neurons comprising a complex laminar structure, and with both local and long-distance connectivity within the nervous system. Key processes must take place during its construction, including: (i) regulation of the correct number of neurons produced by progenitor cells, (ii) temporal and spatial generation of neuronal diversity, and (iii) control of neuron migration and laminar positioning as well as terminal differentiation within the mature cortex. Here, we seek to highlight recent cellular and molecular findings underlying these sequential steps of neurogenesis, cell fate specification and migration during cortical development, with particular emphasis on cortical projection neurons.     

Fetal neurogenesis: breathe HIF you can

Microvascular circulation creates a supporting niche for neurogenesis through the secretion of angiocrine factors. The emerging concept that energy balance and metabolic status play a role in the modulation of stem cells suggests that oxygen delivery by nearby capillary vascular beds could also regulate neurogenesis. Blood vessel formation and neuron production proceed in a coordinated fashion in the developing cerebral cortex, providing a unique opportunity to test the possibility that oxygen supply regulates cell fate decisions in neurogenic niches. The interesting study by the Carmeliet laboratory yields evidence that this is indeed the case and identifies HIF‐1α as the central element.     

Positive selection on NIN,a gene involved in neurogenesis,and primate brain evolution

A long‐held dogma in comparative neurobiology has been that the number of neurons under a given area of cortical surface is constant. As such, the attention of those seeking to understand the genetic basis of brain evolution has focused on genes with functions in the lateral expansion of the developing cerebral cortex. However, new data suggest that cortical cytoarchitecture is not constant across primates, raising the possibility that changes in radial cortical development played a role in primate brain evolution. We present the first analysis of a gene with functions relevant to this dimension of brain evolution. We show that NIN, a gene necessary for maintaining asymmetric, neurogenic divisions of radial glial cells (RGCs), evolved adaptively during anthropoid evolution. We explored how this selection relates to neural phenotypes and find a significant association between selection on NIN and neonatal brain size in catarrhines. Our analyses suggest a relationship with prenatal neurogenesis and identify the human data point as an outlier, possibly explained by postnatal changes in development on the human lineage. A similar pattern is found in platyrrhines, but the highly encephalized genus Cebus departs from the general trend. We further show that the evolution of NIN may be associated with variation in neuron number not explained by increases in surface area, a result consistent with NIN's role in neurogenic divisions of RGCs. Our combined results suggest a role for NIN in the evolution of cortical development.     

Brief communication: How much larger is the relative volume of area 10 of the prefrontal cortex in humans?

It has long been thought that the prefrontal cerebral cortex has been greatly expanded in the human brain. Semendeferi et al. ([2001] Am. J. Phys. Anthropol. 114:224-241) showed that Brodmann's area 10 is relatively larger in the human compared to pongid brains. The question is: how much larger relatively is it? Using their data, it can be shown that the relative increase for human prefrontal area 10 is only 6% larger. Looking at the data base of neural structures provided by Stephan et al. ([1981] Folia Primatol. (Basel) 35:1-29), it is apparent that 6% is a relatively low residual value from a predicted value based on allometric considerations between total brain weight and any given neural structure. When this small increase is combined with their earlier findings on area 13 of prefrontal cortex (Semendeferi et al. [1997] J. Hum. Evol. 32:375-388), it appears that the prefrontal cortex in humans is not some 200% larger as claimed by some researchers (Deacon [1997] Symbolic Species, New York: W.W. Norton; cf. Holloway [1998] Am Sci 86:184-186), and that the findings of Semendeferi et al. ([2001] Am. J. Phys. Anthropol. 114:224-241) are in agreement with the earlier work (Semendeferi and Damasio [2000] J. Hum. Evol. 38:317-332; Semendeferi et al. [1997] J. Hum. Evol. 32:375-388), showing that the human frontal lobe volume is what would be expected for a primate of its brain size. While the prefrontal cortex may have increased relatively in Homo sapiens, the increase is likely to have been far less than currently believed.     

Stochastic automaton models for interaction of excitatory and inhibitory impulse sequences in neurons

The mechanisms by which excitatory and inhibitory input impulse sequences interact in changing the spike probability in neurons are examined in the two mathematical neuron models; one is a real-time neuron model which is close to physiological reality, and the other a stochastic automaton model for the temporal pattern discrimination proposed in the previous paper (Tsukada et al., 1976), which is developed in this paper as neuron models for interaction of excitatory and inhibitory input impulse sequences. The interval distributions of the output spike train from these models tend to be multimodal and are compared with those used for experimental data, reported by Bishop et al. (1964) for geniculate neuron activity and Poisson process deleting model analyzed by Ten Hoopen et al. (1966). Special attention, moreover, should be paid to how different forms of inhibitory input are transformed into the output interval distributions through these neuron models. These results exhibit a clear correlation between inhibitory input form and output interval distribution. More detailed information on this mechanism is obtained from the computations of recurrence-time under the stationary condition to go from active state to itself for the first time, each of which is influenced by the inhibitory input forms. In addition to these facts, some resultant characteristics on interval histogram and serial correlation are discussed in relation to physiological data from the literature.     

Cell cycle regulation and interneuron production

The regulation of progenitor proliferation in developing brain in has been extensively studied in the cerebral cortex, but relatively little is known about progenitor divisions in ventral germinal zones. Recent observations pertinent to interneuron genesis in the ventral forebrain, especially in the medial ganglionic eminence, indicate similarities to cerebral cortical neurogenesis and hint at some interesting differences between ventral and dorsal telencephalon progenitors. Proliferation within the ganglionic eminences is discussed from the vantage point of neural precursor cell cycles, especially G1-phase, and current models of neurogenic divisions in cortex that may apply to ventral forebrain as well.     

Type I protein kinase C isozyme in the visual-information-processing pathway of monkey brain

Previously using PKC isozyme-specific antibodies for immunoblot analysis, we demonstrated the heterogeneous distribution of PKC isozymes in various regions of monkey and rat brains and that type I PKC was most abundant in cerebellum, hippocampus, amygdala, and cerebral cortex (Huang et al.: J Biol Chem 262:15714-15720, 1987). Using these antibodies, we have also demonstrated that type I, II, and III PKC are products of PKC genes gamma, beta, and alpha, respectively (Huang et al.: Biochem Biophys Res Commun 149:946-952, 1987). By immunocytochemical analysis, type I PKC-specific antibody showed strong reactivity in various types of neuron in hippocampal formation, amygdala, cerebellum, and neocortex. In hippocampal formation, granule cells of dentate gyrus and pyramidal cells of hippocampus were heavily stained. By immunoblot analysis, relative levels of PKC isozymes in several areas of monkey cerebral cortex involved in the visual information processing and storage were determined. Both type II and III PKCs appeared to be evenly distributed and at moderate levels, type I PKC formed a gradient of increasing concentration rostral along the cerebral cortex of occipital to temporal and then to the limbic areas. Neurobehavioral studies have demonstrated that the neocortical and limbic areas of the anterior and medial temporal regions participate more directly than the striate, prestriate, and posterior temporal regions in the storage of visual representations and that both hippocampus and amygdala are important in the memory formation. As type I PKC is present at high levels in hippocampus, amygdala, and anterior temporal lobe, we predict that the type I protein kinase C may participate in the plastic changes important for mnemonic function.     

Centrosome amplification as a possible mechanism for numerical chromosome aberrations in cerebral primitive neuroectodermal tumors with TP53 mutations

Although alterations in chromosome number have frequently been detected in human tumor cells and associated with tumor initiation and progression, the causal mechanisms are still not understood. One protein known to be involved in maintaining genetic stability is tumor suppressor p53. In mice, p53 has been implicated in the maintenance of diploidy (Cross et al., 1995) and the regulation of centrosome duplication (Fukasawa et al., 1996). Here we report on cerebral primitive neuroectodermal tumors that lacked the wild-type p53 gene (TP53) and showed multiple numerical chromosome aberrations, as detected by comparative genomic hybridization. In these tumors, the centrosome number was significantly higher than in a control tumor without a detected TP53 mutation and with few chromosomal imbalances. These findings indicate that abnormal centrosome amplification can occur in human tumors lacking wild-type TP53 and may be a mechanism by which numerical chromosome aberrations are generated.     

Enhanced Brain Cell Proliferation Following Early Adrenalectomy in Rats

We have previously demonstrated an increase in adult brain DNA content in rats adrenalectomized on postnatal day 11. The present studies examined cell proliferation in cerebral cortex, cerebellum, hippocampus, and midbrain-diencephalon following adrenalectomy at this age. Compared to sham-operated controls, adrenalectomized animals showed increased [3H]thymidine incorporation into DNA (measured at 1 h following a pulse injection) in all brain regions at 7 and 14 days postsurgery. In some areas, the effect was already present as early as 2 days following adrenalectomy. Chronic replacement with corticosterone prevented this increase in DNA labelling in a dose-dependent manner. When cell proliferation in the cerebral cortex and cerebellum was independently assessed by measuring changes in thymidine kinase activity, enzyme activity was significantly elevated in both areas at 7 and 14 days postsurgery. Finally, histological examination of the cerebellar cortex suggested a delayed disappearance of the external granular layer in several cerebellar lobules of adrenalectomized animals. Overall, these findings indicate that day-11 adrenalectomy leads to a prolonged stimulation of mitotic activity in areas where cell formation at this time is exclusively glial (i.e., cerebral cortex and mid-brain-diencephalon) as well as in areas where postnatal neurogenesis is also occurring (cerebellum and hippocampus). It is hypothesized that this stimulation results from the removal of a tonic inhibitory effect exerted by circulating glucocorticoids in the normal intact animal.     

Scaling of brain metabolism with a fixed energy budget per neuron: implications for neuronal activity, plasticity and evolution

It is usually considered that larger brains have larger neurons, which consume more energy individually, and are therefore accompanied by a larger number of glial cells per neuron. These notions, however, have never been tested. Based on glucose and oxygen metabolic rates in awake animals and their recently determined numbers of neurons, here I show that, contrary to the expected, the estimated glucose use per neuron is remarkably constant, varying only by 40% across the six species of rodents and primates (including humans). The estimated average glucose use per neuron does not correlate with neuronal density in any structure. This suggests that the energy budget of the whole brain per neuron is fixed across species and brain sizes, such that total glucose use by the brain as a whole, by the cerebral cortex and also by the cerebellum alone are linear functions of the number of neurons in the structures across the species (although the average glucose consumption per neuron is at least 10× higher in the cerebral cortex than in the cerebellum). These results indicate that the apparently remarkable use in humans of 20% of the whole body energy budget by a brain that represents only 2% of body mass is explained simply by its large number of neurons. Because synaptic activity is considered the major determinant of metabolic cost, a conserved energy budget per neuron has several profound implications for synaptic homeostasis and the regulation of firing rates, synaptic plasticity, brain imaging, pathologies, and for brain scaling in evolution.