Development Of Cortical Circuits Research Articles

Visual Deprivation Alters the Development of Cortical Multisensory Integration

It has recently been demonstrated that the maturation of normal multisensory circuits in the cortex of the cat takes place over an extended period of postnatal life. Such a finding suggests that the sensory experiences received during this time may play an important role in this developmental process. To test the necessity of sensory experience for normal cortical multisensory development, cats were raised in the absence of visual experience from birth until adulthood, effectively precluding all visual and visual-nonvisual multisensory experiences. As adults, semichronic single-unit recording experiments targeting the anterior ectosylvian sulcus (AES), a well-defined multisensory cortical area in the cat, were initiated and continued at weekly intervals in anesthetized animals. Despite having very little impact on the overall sensory representations in AES, dark-rearing had a substantial impact on the integrative capabilities of multisensory AES neurons. A significant increase was seen in the proportion of multisensory neurons that were modulated by, rather than driven by, a second sensory modality. More important, perhaps, there was a dramatic shift in the percentage of these modulated neurons in which the pairing of weakly effective and spatially and temporally coincident stimuli resulted in response depressions. In normally reared animals such combinations typically give rise to robust response enhancements. These results illustrate the important role sensory experience plays in shaping the development of mature multisensory cortical circuits and suggest that dark-rearing shifts the relative balance of excitation and inhibition in these circuits.

Development of cortical GABAergic circuits and its implications for neurodevelopmental disorders

GABAergic interneurons powerfully control the function of cortical networks. In addition, they strongly regulate cortical development by modulating several cellular processes such as neuronal proliferation, migration, differentiation and connectivity. Not surprisingly, aberrant development of GABAergic circuits has been implicated in many neurodevelopmental disorders including schizophrenia, autism and Tourette's syndrome. Unfortunately, efforts directed towards the comprehension of the mechanisms regulating GABAergic circuits formation and function have been impaired by the strikingly heterogeneity, both at the morphological and functional level, of GABAergic interneurons. Recent technical advances, including the improvement of interneurons-specific labelling techniques, have started to reveal the basic principles underlying this process. This review summarizes recent findings on the mechanisms underlying the construction of GABAergic circuits in the cortex, with a particular focus on potential implications for brain diseases with neurodevelopmental origin.

Embryonic and Postnatal Development of the Layer I–Directed (“Matrix”) Thalamocortical System in the Rat

Inputs to the layer I apical dendritic tufts of pyramidal cells are crucial in "top-down" interactions in the cerebral cortex. A large population of thalamocortical cells, the "matrix" (M-type) cells, provides a direct robust input to layer I that is anatomically and functionally different from the thalamocortical input to layer VI. The developmental timecourse of M-type axons is examined here in rats aged E (embryonic day) 16 to P (postnatal day) 30. Anterograde techniques were used to label axons arising from 2 thalamic nuclei mainly made up of M-type cells, the Posterior and the Ventromedial. The primary growth cones of M-type axons rapidly reached the subplate of dorsally situated cortical areas. After this, interstitial branches would sprout from these axons under more lateral cortical regions to invade the overlying cortical plate forming secondary arbors. Moreover, retrograde labeling of M-type cell somata in the thalamus after tracer deposits confined to layer I revealed that large numbers of axons from multiple thalamic nuclei had already converged in a given spot of layer I by P3. Because of early ingrowth in such large numbers, interactions of M-type axons may significantly influence the early development of cortical circuits.

In Vivo Imaging Reveals Dendritic Targeting of Laminated Afferents by Zebrafish Retinal Ganglion Cells

Targeting of axons and dendrites to particular synaptic laminae is an important mechanism by which precise patterns of neuronal connectivity are established. Although axons target specific laminae during development, dendritic lamination has been thought to occur largely by pruning of inappropriately placed arbors. We discovered by in vivo time-lapse imaging that retinal ganglion cell (RGC) dendrites in zebrafish show growth patterns implicating dendritic targeting as a mechanism for contacting appropriate synaptic partners. Populations of RGCs labeled in transgenic animals establish distinct dendritic strata sequentially, predominantly from the inner to outer retina. Imaging individual cells over successive days confirmed that multistratified RGCs generate strata sequentially, each arbor elaborating within a specific lamina. Simultaneous imaging of RGCs and subpopulations of presynaptic amacrine interneurons revealed that RGC dendrites appear to target amacrine plexuses that had already laminated. Dendritic targeting of prepatterned afferents may thus be a novel mechanism for establishing proper synaptic connectivity.

Early Retinal Activity and Visual Circuit Development

Does spontaneous retinal activity prior to vision play a role in the establishment of visual maps? In this issue of Neuron, two separate papers by Huberman et al. and Hooks and Chen demonstrate a role for early spontaneous retinal activity in the establishment of ocular dominance columns and synaptic refinement at retinogeniculate synapses.

Synaptic strength at the thalamocortical input to layer IV neonatal barrel cortex is regulated by protein kinase C

Long-term synaptic plasticity is an important mechanism underlying the development of cortical circuits in a number of brain regions. In barrel cortex NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD) play a critical role in the development and experience-dependent plasticity of the topographical map of the rodent whiskers. However, the mechanisms underlying the induction and expression of these forms of plasticity are poorly characterised. Here we investigate the role of PKC in the regulation of synaptic strength in neonatal barrel cortex using patch-clamp recordings in brain slices. We demonstrate that PKC activity tonically maintains AMPA receptor-mediated transmission at thalamocortical synapses, and that basal transmission can be potentiated by PKC activation using postsynaptic infusion of phorbol ester. Furthermore, we show that induction of NMDAR-dependent LTP requires PKC activity. These findings demonstrate that PKC is required for the regulation of transmission at thalamocortical synapses, the major ascending sensory input to barrel cortex. Thalamocortical inputs in barrel cortex only express LTP during the first postnatal week during a critical period for experience-dependent plasticity in layer IV. Therefore, the requirement for PKC in LTP suggests an important role for this kinase in the development of the barrel cortex sensory map.

Highly ordered arrangement of single neurons in orientation pinwheels

In the visual cortex of higher mammals, neurons are arranged across the cortical surface in an orderly map of preferred stimulus orientations. This map contains 'orientation pinwheels', structures that are arranged like the spokes of a wheel such that orientation changes continuously around a centre. Conventional optical imaging first demonstrated these pinwheels, but the technique lacked the spatial resolution to determine the response properties and arrangement of cells near pinwheel centres. Electrophysiological recordings later demonstrated sharply selective neurons near pinwheel centres, but it remained unclear whether they were arranged randomly or in an orderly fashion. Here we use two-photon calcium imaging in vivo to determine the microstructure of pinwheel centres in cat visual cortex with single-cell resolution. We find that pinwheel centres are highly ordered: neurons selective to different orientations are clearly segregated even in the very centre. Thus, pinwheel centres truly represent singularities in the cortical map. This highly ordered arrangement at the level of single cells suggests great precision in the development of cortical circuits underlying orientation selectivity.

Abnormal development of zinc-containing cortical circuits in the absence of the transcription factor Tailless

Absence of the transcription factor tailless ( tlx) leads to premature laminar development and thinning of neocortex. We used zinc autometallography to determine if tailless deletion alters the organization of cortical circuits. In tlx−/− mice, layer 4 barrels, which normally lack synaptic zinc, are densely innervated by zinc-containing terminals. Furthermore, barrels with zinc inputs are constructed, in part, from zinc-sequestering neurons, a phenotype not normally found in layer 4.

Synaptic homeostasis and input selectivity follow from a calcium-dependent plasticity model.

Modifications in the strengths of synapses are thought to underlie memory, learning, and development of cortical circuits. Many cellular mechanisms of synaptic plasticity have been investigated in which differential elevations of postsynaptic calcium concentrations play a key role in determining the direction and magnitude of synaptic changes. We have previously described a model of plasticity that uses calcium currents mediated by N-methyl-D-aspartate receptors as the associative signal for Hebbian learning. However, this model is not completely stable. Here, we propose a mechanism of stabilization through homeostatic regulation of intracellular calcium levels. With this model, synapses are stable and exhibit properties such as those observed in metaplasticity and synaptic scaling. In addition, the model displays synaptic competition, allowing structures to emerge in the synaptic space that reflect the statistical properties of the inputs. Therefore, the combination of a fast calcium-dependent learning and a slow stabilization mechanism can account for both the formation of selective receptive fields and the maintenance of neural circuits in a state of equilibrium.

Protracted development of responses to whisker deflection in rat trigeminal ganglion neurons.

The rodent whisker-to-barrel pathway constitutes a major model system for studying experience-dependent brain development. Yet little is known about responses of neurons to whisker stimulation in young animals. Response properties of trigeminal ganglion (NV) neurons in 2-, 3-, and 4-week-old and adult rats were examined using extracellular single-unit recordings and controlled whisker stimuli. We found that the receptive field size of NV neurons is mature in 2-week-old animals while response latencies, magnitudes, and angular tuning continue to develop between 2 weeks of age and adulthood. At the earliest time recorded, NV neurons respond to stimulation of only one whisker and can be characterized as slowly or rapidly adapting (SA, RA). The proportion of SA and RA neurons remains constant during development. Consistent with known on-going myelination of NV axons, response latencies decrease with age, becoming adult-like during the third and fourth postnatal weeks for RA and SA neurons, respectively. Unexpectedly, we found that evoked response magnitudes increase several-fold during development becoming adult-like only during the fourth postnatal week. In addition, RA neurons become less selective for whisker deflection angle with age. Maturation of response magnitude and angular tuning is consistent with developmental changes in the mechanical properties of the whisker, the whisker follicle, and the surrounding tissues. The findings indicate that whisker-derived tactile inputs mature during the first postnatal month when whisker-related cortical circuits are susceptible to long-term modification by sensory experience. Thus normal developmental changes in sensory input may influence functional development of cortical circuits.

Towards a theory of the laminar architecture of cerebral cortex: computational clues from the visual system.

One of the most exciting and open research frontiers in neuroscience is that of seeking to understand the functional roles of the layers of cerebral cortex. New experimental techniques for probing the laminar circuitry of cortex have recently been developed, opening up novel opportunities for investigating how its six-layered architecture contributes to perception and cognition. The task of trying to interpret this complex structure can be facilitated by theoretical analyses of the types of computations that cortex is carrying out, and of how these might be implemented in specific cortical circuits. We have recently developed a detailed neural model of how the parvocellular stream of the visual cortex utilizes its feedforward, feedback and horizontal interactions for purposes of visual filtering, attention and perceptual grouping. This model, called LAMINART, shows how these perceptual processes relate to the mechanisms that ensure the stable development of cortical circuits in the infant, and to the continued stability of learning in the adult. The present article reviews this laminar theory of visual cortex, considers how it may be generalized towards a more comprehensive theory that encompasses other cortical areas and cognitive processes, and shows how its laminar framework generates a variety of testable predictions.

Experience-dependent plasticity of zinc-containing cortical circuits during a critical period of postnatal development.

Distinctive subsets of glutamatergic neurons in cerebral cortex sequester the transition metal zinc within the synaptic vesicles of their axon terminals. In the present study we used histochemical localization of synaptic zinc to investigate normal postnatal development and experience-dependent plasticity of zinc-containing circuits in somatosensory barrel cortex of rats. First, we found that zinc-containing cortical circuits are dynamically reorganized between postnatal day (P) 0 and P28. Whereas most cortical laminae exhibited idiosyncratic increases in zinc histochemical staining with advancing age, lamina IV barrels were darkly reactive early in life and then lost much of their complement of synaptic zinc during postnatal weeks 2-4. Second, we established that sensory experience plays a major role in sculpting the zinc-containing innervation of cortical barrels. Trimming a particular facial whisker arrested the normal postnatal decline in synaptic zinc in the corresponding, deprived barrel. This resulted in more intense zinc staining in deprived barrels compared with adjacent, nondeprived barrels. Notably, the influence of experience on development of zinc circuits was most robust during a critical period extending from about P14, when an effect of whisker trimming first could be observed, through P28, after which time chronic deprivation no longer resulted in heightened levels of synaptic zinc in lamina IV. These findings indicate that sensory input can have a marked influence on development of cortical circuits, including those within lamina IV, throughout the first postnatal month.

Development of cortical circuits: lessons from ocular dominance columns.

The development of ocular dominance columns has served as a Rosetta stone for understanding the mechanisms that guide the construction of cortical circuits. Traditionally, the emergence of ocular dominance columns was thought to be closely tied to the critical period, during which columnar architecture is highly susceptible to alterations in visual input. However, recent findings in cats, monkeys and ferrets indicate that columns develop far earlier, more rapidly and with considerably greater precision than was previously suspected. These observations indicate that the initial establishment of cortical functional architecture, and its subsequent plasticity during the critical period, are distinct developmental phases that might reflect distinct mechanisms.

Abnormal Development of Dendritic Spines inFMR1Knock-Out Mice

Fragile X syndrome is caused by a mutation in the FMR1 gene leading to absence of the fragile X mental retardation protein (FMRP). Reports that patients and adult FMR1 knock-out mice have abnormally long dendritic spines of increased density suggested that the disorder might involve abnormal spine development. Because spine length, density, and motility change dramatically in the first postnatal weeks, we analyzed these properties in mutant mice and littermate controls at 1, 2, and 4 weeks of age. To label neurons, a viral vector carrying the enhanced green fluorescent protein gene was injected into the barrel cortex. Layer V neurons were imaged on a two-photon laser scanning microscope in fixed tissue sections. Analysis of >16,000 spines showed clear developmental patterns. Between 1 and 4 weeks of age, spine density increased 2.5-fold, and mean spine length decreased by 17% in normal animals. Early during cortical synaptogenesis, pyramidal cells in mutant mice had longer spines than controls. At 1 week, spine length was 28% greater in mutants than in controls. At 2 weeks, this difference was 10%, and at 4 weeks only 3%. Similarly, spine density was 33% greater in mutants than in controls at 1 week of age. At 2 or 4 weeks of age, differences were not detectable. The spine abnormality was not detected in neocortical organotypic cultures. The transient nature of the spine abnormality in the intact animal suggests that FMRP might play a role in the normal process of dendritic spine growth in coordination with the experience-dependent development of cortical circuits.

Organization and development of cortical circuits expressing latexin

Organization and development of cortical circuits expressing latexin

Dual Action of a Ligand for Eph Receptor Tyrosine Kinases on Specific Populations of Axons during the Development of Cortical Circuits

The structural basis of cortical columns are radially oriented axon collaterals that form precise connections between distinct cortical layers. During development, these connections are highly specified from the initial outgrowth of collateral branches. Our previous work provided evidence for positional cues confined to individual layers that induce and/or prevent the formation of axon collaterals in specific populations of cortical neurons. Here we demonstrated with in situ hybridization techniques that mRNA of the Eph receptor tyrosine kinase EphA5 and one of its ligands, ephrin-A5, are present in distinct cortical layers, at a time when intrinsic connections are being formed in the cortex. Axonal guidance assays indicate that ephrin-A5 is a repellent signal for a populations of axons that in vivo avoid the cortical layer expressing ephrin-A5. In contrast to its established role as a repulsive axonal guidance signal, ephrin-A5 specifically mediates sprouting of those cortical axons that target the ephrin-A5-expressing layer in vivo. These results identify a novel function of ephrin-A5 on axonal arbor formation. The laminar distribution and the dual action on specific populations of axons suggest that ephrin-A5 plays a role in the assembly of local cortical circuits.

Distribution of parvalbumin immunoreactivity in the neocortex of hypothyroid adult rats

Early hypothyroidism produces a generalized damage in the brain and in particular, changes in the connectivity of neocortical sensory areas. In this paper, the potential alterations in local neocortical circuits have been explored using immunocytochemistry for parvalbumin (PV) in normal and hypothyroid adult rats. The number and radial distribution of PV-positive cells were similar in both groups, but in hypothyroid rats, the density of PV-positive terminal-like puncta and processes was dramatically reduced, especially in layers II–III and the lower part of layers IV–V and VI. These results suggest that thyroid hormones are necessary for normal development of cortical circuits in which PV-positive cells are involved.

Properties of excitatory synaptic events in neurons of primary somatosensory cortex of neonatal rats.

We have characterized the development of synaptic responses from neurons of rat parietal cortex. Whole-cell recording was used in slice preparations in vitro. Neurons were stained with biocytin to allow their identification, and the sample included pyramidal neurons and Cajal-Retzius cells. Dye-coupling of 3-12 cells was frequently observed from the day of birth (P0) to P3. On average, when recorded with Cs(+)-filled electrodes, the input resistances of neonatal cells were large (mean = 1.1 G omega) and resting membrane potentials were relatively depolarized (mean = -45 mV) when compared to mature neocortical neurons. The application of an NMDA receptor antagonist usually hyperpolarized cells by 5-10 mV and increased their input resistance (mean increase = 83%), suggesting that immature neurons are tonically activated by excitatory amino acids (EAA) in our preparation. Excitatory postsynaptic potentials (EPSPs) or currents (EPSCs) could be obtained from animals as young as P0 by brief stimulation of the subplate. Synaptic responses at these early ages had long durations, often lasting over hundreds of milliseconds, they reversed polarity around 0 mV, and they were blocked by tetrodotoxin and EAA antagonists. Pharmacology and current-voltage relationships demonstrated the presence of both NMDA receptor- and non-NMDA receptor-dependent components in most EPSPs. Unlike synaptic responses of mature neurons, neonatal synaptic responses were composed largely of NMDA receptor-dependent components. We did not observe inhibitory synaptic inputs before P6. In some neurons, single shocks to the subplate region initiated spontaneous EPSPs that lasted > 1 min. This study clearly demonstrates functional synapses in the neocortex of rats on the day of birth. Large NMDA receptor-mediated EPSPs with long duration could have a major influence on the development of cortical circuits in the neonate.

Applications of Video Microscopy to Studies of the Developing Nervous System

Growing neurites are guided to their correct targets in the developing nervous system by their highly motile tips, nerve growth cones. To understand how the mammalian cerebral cortex establishes appropriate neural circuits, we have used several light microscopic video techniques to observe growth cones as they extend from developing hamster cerebral cortical neurons and interact with their cellular environment. We describe how Nomarski optics can be combined with video and image processing techniques, termed VEC-DIC (video-enhanced contrast-differential interference contrast) microscopy, to observe the behaviors of neuronal growth cones and the intracellular events that accompany these behaviors. Results from our laboratory on dissociated cortical cell cultures and explants suggest that positive and inhibitory cell-cell interactions in which growth cones grow along other cellular processes or collapse and withdraw from them play a central role in the development of cortical circuits. We show how low-light-level video microscopy of living fluorescently labeled neurons can be used to observe developmental events within intact or semi-intact preparations of the nervous system. With these video techniques we have observed behaviors of fluorescently labeled cortical growth cones as they extend within living neonatal brain slices. Dynamic shape changes of callosal growth cones, growing toward their targets in the contralateral cortex, suggest distinct axon guidance cues in different regions of the corpus callosal pathway. Together these advances in video techniques for Nomarski and fluorescence microscopy will be important in observing directly the mechanisms underlying formation of connections in the developing nervous system.

Ontogeny of radial and other astroglial cells in murine cerebral cortex

Three cell forms of astroglial lineage populate the prenatal and early postnatal murine cerebral wall. In the present review we consider the ontogeny of these cell forms with respect to histogenetic events of the perinatal period. Classic bipolar radial glial cells predominate prior to E17. The bipolar coexist with monopolar radial forms in the perinatal period. Both bipolar and monopolar radial forms coexist with multipolar astrocytes in the course of the first postnatal week and are ultimately succeeded by the multipolar cells. The shift from bipolar to monopolar radial forms is initially coincident with translocation of somata of bipolar cells from the ventricular zone to the upper intermediate zone and cortical strata. Arborization appears to occur both at the growing tips and along the shaft of the processes of both bipolar and monopolar radial cell types. As arborization continues, the processes of the monopolar radial cells come to resemble those of the multipolar astrocytes. Eventually the radial cells are fully transformed into the multipolar astrocytic forms. During this period of transition, radial processes in the cortex appear to be degenerating, suggesting that regressive processes contribute to the cytologic transformation. This sequence of transformations begins late in the period of neuronal migration and continues through the early stages of growth and differentiation in the murine cerebral cortex. The signals that induce these changes may arise from differentiating neurons within the cortex. These transformations occur at a time when radial glial fibers are no longer required as guides for neuronal migration, and the glial population assumes new roles related to the development and operation of cortical neuronal circuits.