a scaffolding. cajal–retzius cells (red) release reelin (orange). neuronal migration is the method by which neurons travel from their origin or birthplace to their final position in the brain. there are several ways they can do this, e.g. by radial migration or tangential migration. sequences of radial migration (also known as glial guidance) and somal translocation have been captured by time-lapse microscopy. tangential migration of interneurons from ganglionic eminence radial migration neuronal precursor cells proliferate in the ventricular zone of the developing neocortex, where the principal neural stem cell is the radial glial cell. the first postmitotic cells must leave the stem cell niche and migrate outward to form the preplate, which is destined to become cajal–retzius cells and subplate neurons. these cells do so by somal translocation. neurons migrating with this mode of locomotion are bipolar and attach the leading edge of the process to the pia. the soma is then transported to the pial surface by nucleokinesis, a process by which a microtubule "cage" around the nucleus elongates and contracts in association with the centrosome to guide the nucleus to its final destination. radial glial cells, whose fibers serve as a scaffolding for migrating cells and a means of radial communication mediated by calcium dynamic activity, act as the main excitatory neuronal stem cell of the cerebral cortex or translocate to the cortical plate and differentiate either into astrocytes or neurons. somal translocation can occur at any time during development. subsequent waves of neurons split the preplate by migrating along radial glial fibres to form the cortical plate. each wave of migrating cells travel past their predecessors forming layers in an inside-out manner, meaning that the youngest neurons are the closest to the surface. it is estimated that glial guided migration represents 90% of migrating neurons in human and about 75% in rodents. tangential migration most interneurons migrate tangentially through multiple modes of migration to reach their appropriate location in the cortex. an example of tangential migration is the movement of interneurons from the ganglionic eminence to the cerebral cortex. one example of ongoing tangential migration in a mature organism, observed in some animals, is the rostral migratory stream connecting subventricular zone and olfactory bulb. axophilic migration many neurons migrating along the anterior-posterior axis of the body use existing axon tracts to migrate along; this is called axophilic migration. an example of this mode of migration is in gnrh-expressing neurons, which make a long journey from their birthplace in the nose, through the forebrain, and into the hypothalamus. many of the mechanisms of this migration have been worked out, starting with the extracellular guidance cues that trigger intracellular signaling. these intracellular signals, such as calcium signaling, lead to actin and microtubule cytoskeletal dynamics, which produce cellular forces that interact with the extracellular environment through cell adhesion proteins to cause the movement of these cells. multipolar migration there is also a method of neuronal migration called multipolar migration. this is seen in multipolar cells, which in the human, are abundantly present in the cortical intermediate zone. they do not resemble the cells migrating by locomotion or somal translocation. instead these multipolar cells express neuronal markers and extend multiple thin processes in various directions independently of the radial glial fibers. neurotrophic factors the survival of neurons is regulated by survival factors, called trophic factors. the neurotrophic hypothesis was formulated by victor hamburger and rita levi montalcini based on studies of the developing nervous system. victor hamburger discovered that implanting an extra limb in the developing chick led to an increase in the number of spinal motor neurons. initially he thought that the extra limb was inducing proliferation of motor neurons, but he and his colleagues later showed that there was a great deal of motor neuron death during normal development, and the extra limb prevented this cell death. according to the neurotrophic hypothesis, growing axons compete for limiting amounts of target-derived trophic factors and axons that fail to receive sufficient trophic support die by apoptosis. it is now clear that factors produced by a number of sources contribute to neuronal survival. nerve growth factor (ngf): rita levi montalcini and stanley cohen purified the first trophic factor, nerve growth factor (ngf), for which they received the nobel prize. there are three ngf-related trophic factors: bdnf, nt3, and nt4, which regulate survival of various neuronal populations. the trk proteins act as receptors for ngf and related factors. trk is a receptor tyrosine kinase. trk dimerization and phosphorylation leads to activation of various intracellular signaling pathways including the map kinase, akt, and pkc pathways. cntf: ciliary neurotrophic factor is another protein that acts as a survival factor for motor neurons. cntf acts via a receptor complex that includes cntfrα, gp130, and lifrβ. activation of the receptor leads to phosphorylation and recruitment of the jak kinase, which in turn phosphorylates lifrβ. lifrβ acts as a docking site for the stat transcription factors. jak kinase phosphorylates stat proteins, which dissociate from the receptor and translocate to the nucleus to regulate gene expression. gdnf: glial derived neurotrophic factor is a member of the tgfb family of proteins, and is a potent trophic factor for striatal neurons. the functional receptor is a heterodimer, composed of type 1 and type 2 receptors. activation of the type 1 receptor leads to phosphorylation of smad proteins, which translocate to the nucleus to activate gene expression. synapse formation neuromuscular junction main article: neuromuscular junction much of our understanding of synapse formation comes from studies at the neuromuscular junction. the transmitter at this synapse is acetylcholine. the acetylcholine receptor (achr) is present at the surface of muscle cells before synapse formation. the arrival of the nerve induces clustering of the receptors at the synapse. mcmahan and sanes showed that the synaptogenic signal is concentrated at the basal lamina. they also showed that the synaptogenic signal is produced by the nerve, and they identified the factor as agrin. agrin induces clustering of achrs on the muscle surface and synapse formation is disrupted in agrin knockout mice. agrin transduces the signal via musk receptor to rapsyn. fischbach and colleagues showed that receptor subunits are selectively transcribed from nuclei next to the synaptic site. this is mediated by neuregulins. in the mature synapse each muscle fiber is innervated by one motor neuron. however, during development, many of the fibers are innervated by multiple axons. lichtman and colleagues have studied the process of synapses elimination. this is an activity-dependent event. partial blockage of the receptor leads to retraction of corresponding presynaptic terminals. later they used a connectomic approach, i.e., tracing out all the connections between motor neurons and muscle fibers, to characterize developmental synapse elimination on the level of a full circuit. analysis confirmed the massive rewiring, 10-fold decrease in the number of synapses, that takes place as axons prune their motor units but add more synaptic areas at the nmjs with which they remain in contact. cns synapses agrin appears not to be a central mediator of cns synapse formation and there is active interest in identifying signals that mediate cns synaptogenesis. neurons in culture develop synapses that are similar to those that form in vivo, suggesting that synaptogenic signals can function properly in vitro. cns synaptogenesis studies have focused mainly on glutamatergic synapses. imaging experiments show that dendrites are highly dynamic during development and often initiate contact with axons. this is followed by recruitment of postsynaptic proteins to the site of contact. stephen smith and colleagues have shown that contact initiated by dendritic filopodia can develop into synapses. induction of synapse formation by glial factors: barres and colleagues made the observation that factors in glial conditioned media induce synapse formation in retinal ganglion cell cultures. synapse formation in the cns is correlated with astrocyte differentiation suggesting that astrocytes might provide a synaptogenic factor. the identity of the astrocytic factors is not yet known. neuroligins and syncam as synaptogenic signals: sudhof, serafini, scheiffele and colleagues have shown that neuroligins and syncam can act as factors that induce presynaptic differentiation. neuroligins are concentrated at the postsynaptic site and act via neurexins concentrated in the presynaptic axons. syncam is a cell adhesion molecule that is present in both pre- and post-synaptic membranes. activity dependent mechanisms in the assembly of neural circuits the processes of neuronal migration, differentiation and axon guidance are generally believed to be activity-independent mechanisms and rely on hard-wired genetic programs in the neurons themselves. research findings however have implicated a role for activity-dependent mechanisms in mediating some aspects of these processes such as the rate of neuronal migration, aspects of neuronal differentiation and axon pathfinding. activity-dependent mechanisms influence neural circuit development and are crucial for laying out early connectivity maps and the continued refinement of synapses which occurs during development. there are two distinct types of neural activity we observe in developing circuits -early spontaneous activity and sensory-evoked activity. spontaneous activity occurs early during neural circuit development even when sensory input is absent and is observed in many systems such as the developing visual system, auditory system, motor system, hippocampus, cerebellum and neocortex. experimental techniques such as direct electrophysiological recording, fluorescence imaging using calcium indicators and optogenetic techniques have shed light on the nature and function of these early bursts of activity. they have distinct spatial and temporal patterns during development and their ablation during development has been known to result in deficits in network refinement in the visual system. in the immature retina, waves of spontaneous action potentials arise from the retinal ganglion cells and sweep across the retinal surface in the first few postnatal weeks. these waves are mediated by neurotransmitter acetylcholine in the initial phase and later on by glutamate. they are thought to instruct the formation of two sensory maps- the retinotopic map and eye-specific segregation. retinotopic map refinement occurs in downstream visual targets in the brain-the superior colliculus (sc) and dorsal lateral geniculate nucleus (lgn). pharmacological disruption and mouse models lacking the β2 subunit of the nicotinic acetylcholine receptor has shown that the lack of spontaneous activity leads to marked defects in retinotopy and eye-specific segregation. recent studies confirm that microglia, the resident immune cell of the brain, establish direct contacts with the cell bodies of developing neurons, and through these connections, regulate neurogenesis, migration, integration and the formation of neuronal networks in an activity-dependent manner. in the developing auditory system, developing cochlea generate bursts of activity which spreads across the inner hair cells and spiral ganglion neurons which relay auditory information to the brain. atp release from supporting cells triggers action potentials in inner hair cells. in the auditory system, spontaneous activity is thought to be involved in tonotopic map formation by segregating cochlear neuron axons tuned to high and low frequencies. in the motor system, periodic bursts of spontaneous activity are driven by excitatory gaba and glutamate during the early stages and by acetylcholine and glutamate at later stages. in the developing zebrafish spinal cord, early spontaneous activity is required for the formation of increasingly synchronous alternating bursts between ipsilateral and contralateral regions of the spinal cord and for the integration of new cells into the circuit. motor neurons innervating the same twitch muscle fibers are thought to maintain synchronous activity which allows both neurons to remain in contact with the muscle fiber in adulthood. in the cortex, early waves of activity have been observed in the cerebellum and cortical slices. once sensory stimulus becomes available, final fine-tuning of sensory-coding maps and circuit refinement begins to rely more and more on sensory-evoked activity as demonstrated by classic experiments about the effects of sensory deprivation during critical periods. contemporary diffusion-weighted mri techniques may also uncover the macroscopic process of axonal development. the connectome can be constructed from diffusion mri data: the vertices of the graph correspond to anatomically labelled gray matter areas, and two such vertices, say u and v, are connected by an edge if the tractography phase of the data processing finds an axonal fiber that connects the two areas, corresponding to u and v. numerous braingraphs, computed from the human connectome project can be downloaded from the http://braingraph.org site. the consensus connectome dynamics (ccd) is a remarkable phenomenon that was discovered by continuously decreasing the minimum confidence-parameter at the graphical interface of the budapest reference connectome server. the budapest reference connectome server (http://connectome.pitgroup.org)