Subcellular localization of brain mast cell histamine in developing rat

The intracerebroventricular administration of compound 48/80 or polymixin B to rats 0 to 60 days old, produced a decrease both in the histamine which sediments in the crude nuclear fraction, as well as in the number of mast cells in the brain. In contrast, the histamine-releasers did not affect histamine levels in subcellular fractions where neuronal histamine is found. Once released, histamine disappeared rapidly (t 1/2 = 3.8 min). In untreated animals and in those treated with histamine releasers, the number of mast cells/g in the whole brains of developing rats and in the cerebral regions of adult rats showed a close correlation with the histamine levels in the crude nuclear fraction. The content of histamine per mast cell in adult rat brain was estimated to be about 13 pg/cell. Histologic examination of the subcellular fractions revealed the presence of intact mast cells in the crude nuclear fraction obtained from untreated animals, and of degranulated mast cells in the same fraction obtained from animals treated with histamine releasers. The mast cell contribution to adult rat brain histamine levels was about 22%. Our results strongly support that most of the histamine which sediments in the crude nuclear fraction of the rat brain is located in mast cells. Determination of histamine in the crude nuclear fraction and in the supernatant of this fraction is proposed as an easy way for identifying the cellular pool altered by any treatment affecting brain histamine levels.     

Ion movements in a developing fucoid egg

Radioisotopes were used to measure the fluxes of K, Cl, Na, Ca (and to some extent, Mg) across the membranes of the eggs of the brown algae Fucus and Pelvetia at different stages of development. The membranes of unfertilized eggs have a relatively nonselective permeability to K, Na, and Cl but develop a high degree of specificity for K within a few hours after fertilization. At this time, the outward leakage of Cl falls to a very small fraction of the inward flux. This allows the eggs to accumulate KCl, which provides the osmotic driving force for growth. The internal [K]:[Na] ratio increases by about 6-fold by the time of first division; this results (at least partially) from a 60% fall in the sodium permeability. Finally, membrane conductances were calculated from these tracer data. Multiplication of these conductance values by the transcellular voltages previously found sufficient to polarize such eggs gives effective transcellular current values comparable to those driven by the egg through itself. This suggests that the endogenous current acts back to further polarize this egg.     

Changes in the levels of neural cell specific proteins in the developing rat brain

The levels of S-100 protein (S-100) and neuron-specific enolase (NSE) in the developing rat brain were determined by a sensitive enzyme immunoassay and the results were compared with those obtained by other methods. Changes with development in the levels of S-100, NSE, and 2, 3-cyclic nucleotide 3-phosphodiesterase (CNPase), biochemical markers for astroglia, neurons and oligodendroglia respectively, were determined in various brain regions including the cerebral hemisphere (CH), brain stem (BS) and cerebellum (Ce). The peak increments of S-100, NSE, and CNPase activity were reached later than that of the brain weight in all of the regions. The ratios of S-100/NSE and CNPase/NSE rose during the 21 days after birth in the CH and BS; the S-100/NSE ratio in the CH began to decrease from the 21st day, whereas the CNPase/NSE ratio continued to rise even after the 30th day, suggesting different maturation periods of the different glial cells. In the Ce, the change of these ratios showed a pattern different from those in the other regions. In the CH of rats with experimental microencephaly induced by methylazoxymethanol (MAM), the ratios were almost normal, in spite of the reduction of the brain weight to about 50% of the control.Dedicated to Professor Yasuzo Tsukada.     

Calcium signaling in developing embryos: focus on the regulation of cell shape changes and collective movements

During morphogenesis tissues significantly remodel by coordinated cell migrations and cell rearrangements. Central to this problem are cell shape changes that are driven by distinct cytoskeletal reorganization responsible for force generation. Calcium is a versatile and universal messenger that is implicated in the regulation of embryonic development. Although calcium transients accrue clearly and more intensely in tissues undergoing rearrangement/migration, it is far from clear what the role of these calcium signals is. Here we summarize the evidence implicating calcium participation in tissue movements, cell shape changes and the reorganization of contractile cytoskeletal elements in developing embryos. We also discuss a novel hypothesis that short-lived calcium spikes are required in cells and tissues undergoing migration and rearrangements as a fine tuning response mechanism to prevent local, abnormally high fluctuations in cytoskeletal activities.     

Regulating the balance between symmetric and asymmetric stem cell division in the developing brain

Stem cells proliferate through symmetric division or self-renew through asymmetric division whilst generating differentiating cell types. The balance between symmetric and asymmetric division requires tight control to either expand a stem cell pool or to generate cell diversity. In the Drosophila optic lobe, symmetrically dividing neuroepithelial cells transform into asymmetrically dividing neuroblasts. The switch from neuroepithelial cells to neuroblasts is triggered by a proneural wave that sweeps across the neuroepithelium. Here we review recent findings showing that the orchestrated action of the Notch, EGFR, Fat-Hippo, and JAK/STAT signalling pathways controls the progression of the proneural wave and the sequential transition from symmetric to asymmetric division. The neuroepithelial to neuroblast transition in the optic lobe bears many similarities to the switch from neuroepithelial cell to radial glial cell in the developing mammalian cerebral cortex. The Notch signalling pathway has a similar role in the transition from proliferating to differentiating stem cell pools in the developing vertebrate retina and in the neural tube. Therefore, findings in the Drosophila optic lobe provide insights into the transitions between proliferative and differentiative division in the stem cell pools of higher organisms.     

Regulating the balance between symmetric and asymmetric stem cell division in the developing brain

Stem cells proliferate through symmetric division or self-renew through asymmetric division whilst generating differentiating cell types. The balance between symmetric and asymmetric division requires tight control to either expand a stem cell pool or to generate cell diversity. In the Drosophila optic lobe, symmetrically dividing neuroepithelial cells transform into asymmetrically dividing neuroblasts. The switch from neuroepithelial cells to neuroblasts is triggered by a proneural wave that sweeps across the neuroepithelium. Here we review recent findings showing that the orchestrated action of the Notch, EGFR, Fat-Hippo, and JAK/STAT signalling pathways controls the progression of the proneural wave and the sequential transition from symmetric to asymmetric division. The neuroepithelial to neuroblast transition in the optic lobe bears many similarities to the switch from neuroepithelial cell to radial glial cell in the developing mammalian cerebral cortex. The Notch signalling pathway has a similar role in the transition from proliferating to differentiating stem cell pools in the developing vertebrate retina and in the neural tube. Therefore, findings in the Drosophila optic lobe provide insights into the transitions between proliferative and differentiative division in the stem cell pools of higher organisms.     

Pathological apoptosis in the developing brain

More than half of the initially-formed neurons are deleted in certain brain regions during normal development. This process, whereby cells are discretely removed without interfering with the further development of remaining cells, is called programmed cell death (PCD). The term apoptosis is used to describe certain morphological manifestations of PCD. Many of the effectors of this developmental cell death program are highly expressed in the developing brain, making it more susceptible to accidental activation of the death machinery, e.g. following hypoxia-ischemia or irradiation. Recent evidence suggests, however, that activation and regulation of cell death mechanisms under pathological conditions do not exactly mirror physiological, developmentally regulated PCD. It may be argued that the conditions after e.g. ischemia are not even compatible with the execution of PCD as we know it. Under pathological conditions cells are exposed to various stressors, including energy failure, oxidative stress and unbalanced ion fluxes. This results in parallel triggering and potential overshooting of several different cell death pathways, which then interact with one another and result in complex patterns of biochemical manifestations and cellular morphological features. These types of cell death are here called "pathological apoptosis," where classical hallmarks of PCD, like pyknosis, nuclear condensation and caspase-3 activation, are combined with non-PCD features of cell death. Here we review our current knowledge of the mechanisms involved, with special focus on the potential for therapeutic intervention tailored to the needs of the developing brain.     

Gonadal hormone regulation of neuronal-glial interactions in the developing neuroendocrine hypothalamus

Recent evidence indicates that, in addition to their well known effects on neurons, gonadal steroids may exert part of their neural effects through astroglia. In adult female rats astroglia participate in the phasic remodelling of synapses that takes place during the estrous cycle in the arcuate nucleus of the hypothalamus under the influence of estradiol. Astroglia also appear to be involved in the genesis of sex differences in synaptic connectivity. Gonadal steroids influence hypothalamic astroglia differentiation in vitro and in vivo. In monolayer mixed neuronal-glial cultures from fetal rat hypothalami, estradiol induces a progressive differentiation of astrocytes from a flattened epithelioid morphology to bipolar, radial and stellate shapes. This effect of estradiol on astroglia is dependent on the expression of specific molecules on the neuronal surface, such as the polysialic acid-rich form of the neural cell adhesion molecule. In the rat arcuate nucleus in situ, perinatal androgen influences astroglia gene expression and differentiation, resulting in a sex difference in astroglia organization by postnatal day 20. By this day, the amount of neuronal surface covered by astroglial processes is higher in males than in females. This difference in the coverage of neuronal surface by astroglia may be directly related to the reduced number of synaptic contacts that is established on the soma of male neurons compared to females.     

Snf2l regulates Foxg1-dependent progenitor cell expansion in the developing brain

Balancing progenitor cell self-renewal and differentiation is essential for brain development and is regulated by the activity of chromatin remodeling complexes. Nevertheless, linking chromatin changes to specific pathways that control cortical histogenesis remains a challenge. Here we identify a genetic interaction between the chromatin remodeler Snf2l and Foxg1, a key regulator of neurogenesis. Snf2l mutant mice exhibit forebrain hypercellularity arising from increased Foxg1 expression, increased progenitor cell expansion, and delayed differentiation. We demonstrate that Snf2l binds to the Foxg1 locus at midneurogenesis and that the phenotype is rescued by reducing Foxg1 dosage, thus revealing that Snf2l and Foxg1 function antagonistically to regulate brain size.     

Ethanol-induced apoptotic neurodegeneration in the developing brain

It has been known for three decades that ethanol, the most widely abused drug in the world, has deleterious effects on the developing human brain, but progress has been slow in developing animal models for studying this problem, and the underlying mechanisms have remained elusive. Recently, we have shown that during the synaptogenesis period, also known as the brain growth spurt period, ethanol has the potential to trigger massive neuronal suicide in the in vivo mammalian brain. The brain growth spurt period in humans spans the last trimester of pregnancy and first several years after birth. The NMDA antagonist and GABAmimetic properties of ethanol may be responsible for its apoptogenic action, in that other drugs with either NMDA antagonist or GABAmimetic actions also trigger apoptotic neurodegeneration in the developing brain. Our findings provide a likely explanation for the reduced brain mass and neurobehavioral disturbances associated with the human fetal alcohol syndrome. Furthermore, since NMDA antagonist and GABAmimetic drugs are sometimes abused by pregnant women and also are used as anticonvulsants, sedatives or anesthetics in pediatric medicine, our findings raise several complex drug safety issues. In addition, the observation that ethanol and several other drugs trigger massive neuronal apoptosis in the developing brain provides an unprecedented opportunity to study both neuropathological aspects and molecular mechanisms of apoptotic neurodegeneration in the in vivo mammalian brain.     

Membrane-bound neuraminidase in the developing mouse brain

The specific activity of membrane-bound neuraminidase towards exogenously added gangliosides in the developing mouse brain was investigated. While whole brain was examined in fetuses, studies were carried out comparatively in cortex and cerebellum of postnatal stages. Considerable differences were found among brain areas. There was a rapid increase in forebrain neuraminidase activity before birth. This high level of activity was maintained throughout the first postnatal week, followed by a slow leveling-off to adult values on the 30th day. In the cerebellum a rapid increase in neuraminidase activity occurred between the 10th and 16th postnatal day. After having reached the maximum, enzyme activity declined rapidly, with adult values being reached on the 21st day. Neuraminidase activity in the adult cerebellum exceeds that in the cortex by 65.9 %. The results are discussed in reference to developmental changes in ganglioside metabolism and the possible involvement of neuraminidase in its regulation is pointed out.     

Proteolipids in developing rat brain

In this report data are summarized on changes in the quantity of proteolipid protein (PLP), its amino acid composition, and the lipid moiety of these lipid-protein complexes in rat brain during postnatal development. In all three parts of the central nervous system (CNS) studied (cerebral hemispheres, medulla oblongata and spinal cord) the main pattern of PLP accumulation is on the whole similar. PLP content is very low in the newborn, and it increased 12 to 20-fold during development. The highest rate of PLP accumulation is observed in the periodfrom 10 to 30 days after birth. Against the background of general similarity the concentration of some amino acids such as lysine, proline, tyrosine in PLP somewhat increased during development, while that of aspartic acid, glutamic acid, glycine, and leucine decreased. Soluble proteolipid complexes, purified to various degree from lipids were isolated from brain of rats of different ages. As compared with the original lipid extracts from which they were obtained, the crude and especially purified proteolipids in all the animals studied were enriched in acidic phospholipids (PhL). This prevalence of acidic PhL increased with age. During the development in phospholipid moiety of proteolipids (PL) the content of phosphatidyl serine, sphingomyelin and mainly diphosphatidyl glycerol increases and that of phosphatidyl inositol and especially phosphatidyl choline decreases. The concentration of acidic PhL more tightly bound with PLP appreciably increases with age. Most of these changes occur mainly during the second decade after birth.Special Issue dedicated to Dr. Eugene Kreps.     

Nuclear receptor TLX regulates cell cycle progression in neural stem cells of the developing brain

TLX is an orphan nuclear receptor that is expressed exclusively in vertebrate forebrains. Although TLX is known to be expressed in embryonic brains, the mechanism by which it influences neural development remains largely unknown. We show here that TLX is expressed specifically in periventricular neural stem cells in embryonic brains. Significant thinning of neocortex was observed in embryonic d 14.5 TLX-null brains with reduced nestin labeling and decreased cell proliferation in the germinal zone. Cell cycle analysis revealed both prolonged cell cycles and increased cell cycle exit in TLX-null embryonic brains. Increased expression of a cyclin-dependent kinase inhibitor p21 and decreased expression of cyclin D1 provide a molecular basis for the deficiency of cell cycle progression in embryonic brains of TLX-null mice. Furthermore, transient knockdown of TLX by in utero electroporation led to precocious cell cycle exit and differentiation of neural stem cells followed by outward migration. Together these results indicate that TLX plays an important role in neural development by regulating cell cycle progression and exit of neural stem cells in the developing brain.     

Intelligence and the developing human brain

Determining the brain properties that make people 'brainier' has moved well beyond early demonstrations that increasing intelligence correlates with increasing grey and white matter volumes. Both structural and functional in vivo neuroimaging techniques delineate a distributed network of brain regions, perhaps with a focus in the lateral prefrontal cortex, which varies in extent and connectivity with individual differences in intelligence. Longitudinal studies further show that the neuroanatomic correlates of intelligence are dynamic, changing most rapidly in early childhood. Several promising candidate genes affecting neuronal development and neurotransmission have been proposed that might begin to explain the marked genetic overlap between cortical morphology and intelligence. A major future challenge is to determine the cellular events that underpin the neuroanatomic differences correlated with intelligence.     

How the brain controls repetitive finger movements.

Adequate interaction with our physical and social environment requires accurate timing abilities. Since planning and control of movements is closely related to sensorimotor synchronization, the investigation of synchronization abilities may allow insights into fundamental principles of motor behaviour. The finger-tapping task has frequently been used to study the synchronization of one's own movements in relation to external events. Data from behavioural studies gave rise to the assumption that it is not the peripheral event (i.e., finger-tap or pacing signal) that is synchronized but its central representation. The neural foundations of sensorimotor synchronization have only recently been investigated and are still poorly understood. The present article reviews data from neurophysiological studies investigating sensorimotor synchronization to shed light on the neurophysiological processes associated with sensorimotor synchronization. This review focuses on studies investigating neuroelectric and neuromagnetic activity associated with simple repetitive synchronization tasks.     

Coordinate transformations for eye and arm movements in the brain

Recent work on the coding of spatial information in the brain has significantly advanced our knowledge of sensory to motor transformations on several fronts. The encoding of information referenced to the retina (eye-centered) but modulated by eye position, called a gain field representation, has proved to be very common throughout parietal and occipital cortex. The use of an eye-centered representation as a working memory of spatial location is problematic if the eyes move during the memory period. Details regarding the manner in which the brain solves this problem are beginning to emerge. Finally, the discovery of eye-centered representations of ongoing or intended arm movements has changed the way we think about the order of operations in the sensory to motor coordinate transformation.