They are free of overlying ectoderm and form irregular bundle of tissue surrounding tube. These clumps of cells migrate and differentiate to form ganglia. The alterations may impair normal development or impair recovery from brain trauma in a transient or long-term way.
Environmental enrichment may increase neuronal complexity, improve brain function, and facilitate recovery from brain injury. The authors hypothesize that this late-stage migration may play a role in establishing fundamentally human cognitive abilities and that its disruption could underlie a number of neurodevelopmental diseases.
Most neurons of the cerebral cortex -- the outermost layer of the brain responsible for advanced cognition -- migrate outward from their birthplaces deep in the brain to take up their positions within the cortex. Developmental neuroscientists have long thought that most neural migration ends well before an infant is born, but the new paper -- published October 6, in Science -- suggests for the first time that many neurons continue to migrate and integrate into neural circuits well into infancy.
The new study was a collaboration between the labs of co-senior authors Arturo Alvarez-Buylla, PhD, a UCSF professor of neurological surgery who specializes in understanding the migration of immature neurons in the developing brain, and in whose lab Paredes is a postdoctoral researcher, and Eric J.
Several recent studies -- including work by Alvarez-Buylla and Huang -- identified small populations of immature neurons deep in the front of the brain that migrate after birth into the orbito-frontal cortex -- a small region of the frontal cortex just above the eyes.
Given that the entire frontal cortex continues to expand massively after birth, the researchers sought to discover whether neural migration continues after birth in the rest of the frontal cortex. The team examined brain tissue from the Pediatric Brain Tissue Bank using histological stains for migratory neurons.
These studies revealed clusters of immature, migratory neurons widely distributed deep within the frontal lobe of the newborn brain, above the fluid-filled lateral ventricles. MRI imaging of the three-dimensional structure of these clusters revealed a long arc of migratory neurons sitting like a cap in front and on top of the ventricles and stretching from deep behind the eyebrows all the way to the top of the head.
To determine whether these immature neurons -- which the researchers dubbed "the Arc" -- actively migrate in the newborn brain, researchers used viruses to label immature neurons in tissue samples collected immediately after death and observed that Arc cells move inch-worm style through the brain, much as neurons migrate in the fetal brain. Further histological studies of the cingulate cortex, a portion of the brain's frontal lobe, show that Arc neurons migrate outward from the ventricles into the cortex primarily within the first three months of life, where they differentiate into multiple different subtypes of inhibitory neurons.
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To compare individual means, an independent samples t -test employing a Bonferroni correction with an initial a value of 0. To determine whether Reelin alters the migratory kinetics of cell migration, we monitored brain slice cultures from wild-type and reeler embryos. Previous studies have shown that at embryonic E day 13, reeler embryos cannot be distinguished from their wild-type counterparts Caviness and Sidman ; Caviness ; therefore, to investigate potential differences in the initial migration of wild-type versus reeler neurons, E At this stage, the first cohort of pyramidal neurons have split the preplate Polleux et al.
This migratory zone allows us to determine whether either or both multipolar and bipolar modes of locomotory behavior are affected. To visualize migrating cells born at E The viral titer was adjusted to allow discrimination between individually labeled cells Noctor et al.
Infected cells in the dorsal part of the cortical wall Fig. Infected radial glial fibers may be seen as elongated processes attached at the ventricular surface with nuclei migrating between pial and ventricular surfaces Fig. Following division at the apical surface of the VZ, a postmitotic cell emerges with a bipolar morphology Fig. Previous reports have shown Noctor et al.
Multipolar neurons are known to be transitory cells obtained by the conversion of bipolar cells during migration through the SVZ and IZ Tabata and Nakajima , while neurons adopt bipolar morphologies during saltatory locomotion Nadarajah et al.
Time-lapse imaging of bipolar and multipolar modes of migration in the neocortex. A Schematic showing a single hemisphere of the embryonic brain highlighting the region that was imaged green dashed box. B Time series of migrating cell in the neocortex exhibiting nuclei division arrowhead and glial-guided bipolar migration asterisk in the VZ, while multipolar neurons arrow are typically found in the SVZ and IZ.
C Higher magnification images of bipolar cells showing the close association with a radial glial fiber and having an oval shaped nucleus. D Higher magnification of multipolar cells showing no association with radial glial fiber, a round or irregular shaped nuclei with multiple branches extending from the soma. To track migration, slice cultures were monitored for up to 12 h. The position of a migrating cells in each frame was recorded with reference to the preexisting somal position, and neuron migration was recorded in the region of the VZ, SVZ, and IZ.
To qualify for the study, each cell was tracked minimally for 5 h 20 frames of min intervals. Despite the fact that some multipolar soma remain stationary between imaging intervals Noctor et al. GFP-positive cells whose processes were not visible in the focal plane were excluded from analysis; in addition, cells undergoing division at the VZ and SVZ at the time of tracking were also excluded.
Immunohistochemical staining performed postculture revealed that a proportion of the GFP-positive cells express Tbr2 and are prospective basal progenitor cells data not shown.
Cellular morphology was the prominent criteria used for distinguishing neurons within the germinal zones. Both wild-type and reeler cells were efficiently infected with retroviral-GFP, and time-lapse imaging showed that both bipolar and multipolar cells migrate radially Fig. Apart from the bipolar and multipolar classification, a third category termed transition cells was also discernible, representing bipolar neurons that were seen to detach from glial fibers and begin to adopt multipolar morphologies.
In a single exception, a multipolar neuron was seen to revert to the bipolar mode. Multipolar migration included neurons where, in certain instances, the soma was stationary but the processes were motile. Bipolar and multipolar cells migrate at a greater speed in the absence of Reelin. B Migrating GFP-labeled cells in reeler display a similar distribution to wild-type cells. C The proportion of cells undergoing either bipolar white or multipolar black modes of migration is not altered in the absence of Reelin.
Cells changing between these modes within the imaging period are classified as transitional gray. D Graph showing no change in the average net migratory speed of bipolar white bars and multipolar black bars neurons in wild-type and reeler slices. The proportion of transition cells across different slices increased 4-fold comparing reeler with wild-type; however, this was not significantly different Fig.
Bipolar and multipolar modes of migration have been reported to have different speeds LoTurco and Bai To assess this, 2 analytical methods were used in this study: 1 net speed that measures the distance between start and finish positions over the observation period and 2 accumulated speed that measures the total distance traveled over time and accounts for any deviations from a direct trajectory.
Cells undergoing bipolar or multipolar migration showed no difference in average net speed, in the presence or absence of Reelin Fig. In contrast, when comparing the accumulated distance traveled, there was a modest but significant increase in the accumulated speed of reeler cells undergoing both multipolar and bipolar migration Fig.
Thus, even though cells of both genotypes took about the same time to travel a similar distance, reeler cells appeared to undergo a greater degree of meandering thus covering more distance. Frequency distributions of binned accumulated speeds for wild-type and reeler neurons are shown in Figure 2F,G.
These plots show a curve shift to the right for reeler , indicating greater accumulated speeds for both bipolar Fig. Quantitative analysis confirming a significant difference in accumulated speeds is presented in Table 1.
The proportion of migratory modes and speeds of neurons in the germinal zones. Note: Statistical analysis performed between the following data combinations: wild-type and reeler slices. In the period under study after E The final phase of migration involves somal translocation at the top of the CP Takahashi et al. A radial trajectory represents a direct route, however, it is accepted that locomotory cells can deviate from a straight route LoTurco and Bai A migrating cell may shuttle forward, backward, or even sideways.
Shuttling on the radial axis can be demonstrated by kymographs that portray migratory tracks from individual neurons Fig. At each time interval min , a strip of imaged GFP-labeled cells is compressed and compiled alongside each other to give a clear indication of somal movement in radial direction over time in the VZ and lower SVZ. These results clearly indicate that, compared with the wild-type, reeler cells have a lesser tendency to migrate uniformly and frequently move forward and backward, giving rise to irregular tracks.
Migrating reeler cells exhibit greater deviation from a direct migratory path. A Kymograph of GFP-labeled cells in a wild-type slice shows the somal position during the course of the imaging period.
Cells originally positioned in the VZ migrate toward the pial surface with limited deviations from a direct path. Graphical representation of this somal movement of individual cells is represented in C. B Cells in reeler slices migrate away from the ventricular surface but display no clear direction of migration. This increased meandering nature en route to the CP is graphically represented in D.
Thus far, the results indicate that although the net distance covered by reeler cells is not significantly different to wild-type cells, there is greater accumulated distance covered in the reeler background. This may occur from migrating in multiple trajectories, including backward toward the VZ. This can be quantified by mapping individual soma with reference to the ventricular surface plane.
Cells were categorized as migrating in a positive trajectory away from the plane or negative trajectory toward the plane or no trajectory track does not transect the plane Fig. Migrating cells of both genotypes were individually tracked for a minimum of 5 h, and the proportions of bipolar and multipolar neurons following each trajectory quantified Table 1.
In contrast, there was no difference in the trajectories of multipolar modes of migration Fig. Altered trajectories of bipolar and multipolar neurons in the reeler cortex. A Track of a cell migrating away from the reference plane at the ventricular surface red line is classified as a positive trajectory, B Conversely, a cell migrating toward the reference plane represents a negative trajectory, and C a cell has no trajectory when migrating with directionality that does not transect the ventricular surface plane.
E Reeler neurons utilizing multipolar mode of migration have similar trajectories to wild-type neurons. F Schematic representation of trajectory tracks containing bipolar or multipolar neurons migrating with a positive red , negative green , or no trajectory blue for wild-type and G reeler showing loss of parallel, radial trajectories.
The trajectory data presented thus far were calculated from the position of each cell at the start and end of time-lapse imaging. This does not take into account the degree of deviation from a radial path for a migrating cell.
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