You’re Perfect, Now Change — Redefining the Role of Developmental Plasticity

The receptive field properties of neurons in the developing brain can in many cases be remarkably similar to those of adult neurons. This raises the question of why these same neurons need the capacity for such impressive developmental plasticity, most clearly demonstrated by the rewiring that occurs in response to sensory deprivation. The roles of developmental neuronal plasticity in the assimilation of neurons into a larger network, including temporal and cross-modal integration, are discussed

Insights into activity-dependent map formation from the retinotectal system: a middle-of-the-brain perspective

ABSTRACT: The development of orderly topographic maps in the central nervous system (CNS) results from a collaboration of chemoaffinity cues that establish the coarse organization of the projection and activity-dependent mechanisms that fine-tune the map. Using the retinotectal projection as a model system, we describe evidence that biochemical tags and patterned neural activity work in parallel to produce topographically ordered axonal projections. Finally, we review recent experiments in other CNS projections that support the proposition that cooperation between molecular guidance cues and activity-dependent processes constitutes a general paradigm for CNS map formation

A Developmental Sensitive Period for Spike Timing-Dependent Plasticity in the Retinotectal Projection

The retinotectal projection in Xenopus laevis has been shown to exhibit correlation-based refinement of both anatomical and functional connectivity during development. Spike timing-dependent plasticity (STDP) is an appealing experimental model for correlation-based synaptic plasticity because, in contrast to plasticity induction paradigms using tetanic stimulation or sustained postsynaptic depolarization, its induction protocol more closely resembles natural physiological activity. In Xenopus tadpoles, where anatomical remodeling has been reported throughout much of the life of the animal, in vivo retinotectal STDP has only been examined under a limited set of experimental conditions. Using perforated-patch recordings of retina-evoked EPSCs in tectal neurons, we confirmed that repeatedly driving a retinotectal EPSP 5–10 ms prior to inducing an action potential in the postsynaptic cell, reliably produced timing-dependent long-term potentiation (t-LTP) of the retinotectal synapse in young wild type tadpoles (stages 41–44). At these stages, retinotectal timing-dependent long-term depression (t-LTD) also could be induced by evoking an EPSP to arrive 5–10 ms after an action potential in the tectal cell. However, retinotectal STDP using this standard protocol was limited to a developmental sensitive period, as we were unable to induce t-LTP or t-LTD after stage 44. Surprisingly, this STDP protocol also failed to induce reliable STDP in albino tadpoles at the early ages when it was effective in wild type pigmented animals. Nonetheless, low-frequency flashes to the eye produced a robust NMDA receptor-dependent retinotectal LTD in stage 47 albino tadpoles, demonstrating that the retinotectal synapse can nonetheless be modified in these animals using different plasticity paradigms

White Matter Plasticity Keeps the Brain in Tune: Axons Conduct While Glia Wrap.

Precise timing of neuronal inputs is crucial for brain circuit function and development, where it contributes critically to experience-dependent plasticity. Myelination therefore provides an important adaptation mechanism for vertebrate circuits. Despite its importance to circuit activity, the interplay between neuronal activity and myelination has yet to be fully elucidated. In recent years, significant attention has been devoted to uncovering and explaining the phenomenon of white matter (WM) plasticity. Here, we summarize some of the critical evidence for modulation of the WM by neuronal activity, ranging from human diffusion tensor imaging (DTI) studies to experiments in animal models. These experiments reveal activity-dependent changes in the differentiation and proliferation of the oligodendrocyte lineage, and in the critical properties of the myelin sheaths. We discuss the implications of such changes for synaptic function and plasticity, and present the underlying mechanisms of neuron-glia communication, with a focus on glutamatergic signaling and the axomyelinic synapse. Finally, we examine evidence that myelin plasticity may be subject to critical periods. Taken together, the present review aims to provide insights into myelination in the context of brain circuit formation and function, emphasizing the bidirectional interplay between neurons and myelinating glial cells to better inform future investigations of nervous system plasticity

White Matter Plasticity Keeps the Brain in Tune: Axons Conduct While Glia Wrap

Precise timing of neuronal inputs is crucial for brain circuit function and development, where it contributes critically to experience-dependent plasticity. Myelination therefore provides an important adaptation mechanism for vertebrate circuits. Despite its importance to circuit activity, the interplay between neuronal activity and myelination has yet to be fully elucidated. In recent years, significant attention has been devoted to uncovering and explaining the phenomenon of white matter (WM) plasticity. Here, we summarize some of the critical evidence for modulation of the WM by neuronal activity, ranging from human diffusion tensor imaging (DTI) studies to experiments in animal models. These experiments reveal activity-dependent changes in the differentiation and proliferation of the oligodendrocyte lineage, and in the critical properties of the myelin sheaths. We discuss the implications of such changes for synaptic function and plasticity, and present the underlying mechanisms of neuron–glia communication, with a focus on glutamatergic signaling and the axomyelinic synapse. Finally, we examine evidence that myelin plasticity may be subject to critical periods. Taken together, the present review aims to provide insights into myelination in the context of brain circuit formation and function, emphasizing the bidirectional interplay between neurons and myelinating glial cells to better inform future investigations of nervous system plasticity

Role of interstitial branching in the development of visual corticocortical connections: A time-lapse and fixed-tissue analysis

We combined fixed-tissue and time-lapse analyses to investigate the axonal branching phenomena underlying the development of topographically organized ipsilateral projections from area 17 to area 18a in the rat. These complementary approaches allowed us to relate static, large-scale information provided by traditional fixed-tissue analysis to highly dynamic, local, small-scale branching phenomena observed with two-photon time-lapse microscopy in acute slices of visual cortex. Our fixed-tissue data revealed that labeled area 17 fibers invaded area 18a gray matter at topographically restricted sites, reaching superficial layers in significant numbers by postnatal day 6 (P6). Moreover, most parental axons gave rise to only one or occasionally a small number of closely spaced interstitial branches beneath 18a. Our time-lapse data showed that many filopodium-like branches emerged along parental axons in white matter or deep layers in area 18a. Most of these filopo-dial branches were transient, often disappearing after several minutes to hours of exploratory extension and retraction. These dynamic behaviors decreased significantly from P4, when the projection is first forming, through the second postnatal week, suggesting that the expression of, or sensitivity to, cortical cues promoting new branch addition in the white matter is developmentally down-regulated coincident with gray matter innervation. Together, these data demonstrate that the development of topographically organized corticocortical projections in rats involves extensive exploratory branching along parental axons and invasion of cortex by only a small number of interstitial branches, rather than the widespread innervation of superficial cortical layers by an initially exuberant population of branches

Cellular response to micropatterned growth promoting and inhibitory substrates

BACKGROUND: Normal development and the response to injury both require cell growth, migration and morphological remodeling, guided by a complex local landscape of permissive and inhibitory cues. A standard approach for studying by such cues is to culture cells on uniform substrates containing known concentrations of these molecules, however this method fails to represent the molecular complexity of the natural growth environment. RESULTS: To mimic the local complexity of environmental conditions in vitro, we used a contact micropatterning technique to examine cell growth and differentiation on patterned substrates printed with the commonly studied growth permissive and inhibitory substrates, poly-L-lysine (PLL) and myelin, respectively. We show that micropatterning of PLL can be used to direct adherence and axonal outgrowth of hippocampal and cortical neurons as well as other cells with diverse morphologies like Oli-neu oligodendrocyte progenitor cell lines and fibroblast-like COS7 cells in culture. Surprisingly, COS7 cells exhibited a preference for low concentration (1 pg/mL) PLL zones over adjacent zones printed with high concentrations (1 mg/mL). We demonstrate that micropatterning is also useful for studying factors that inhibit growth as it can direct cells to grow along straight lines that are easy to quantify. Furthermore, we provide the first demonstration of microcontact printing of myelin-associated proteins and show that they impair process outgrowth from Oli-neu oligodendrocyte precursor cells. CONCLUSION: We conclude that microcontact printing is an efficient and reproducible method for patterning proteins and brain-derived myelin on glass surfaces in order to study the effects of the microenvironment on cell growth and morphogenesis

Neurodevelopmental effects of chronic exposure to elevated levels of pro-inflammatory cytokines in a developing visual system

<p>Abstract</p> <p>Background</p> <p>Imbalances in the regulation of pro-inflammatory cytokines have been increasingly correlated with a number of severe and prevalent neurodevelopmental disorders, including autism spectrum disorder, schizophrenia and Down syndrome. Although several studies have shown that cytokines have potent effects on neural function, their role in neural development is still poorly understood. In this study, we investigated the link between abnormal cytokine levels and neural development using the <it>Xenopus laevis </it>tadpole visual system, a model frequently used to examine the anatomical and functional development of neural circuits.</p> <p>Results</p> <p>Using a test for a visually guided behavior that requires normal visual system development, we examined the long-term effects of prolonged developmental exposure to three pro-inflammatory cytokines with known neural functions: interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α. We found that all cytokines affected the development of normal visually guided behavior. Neuroanatomical imaging of the visual projection showed that none of the cytokines caused any gross abnormalities in the anatomical organization of this projection, suggesting that they may be acting at the level of neuronal microcircuits. We further tested the effects of TNF-α on the electrophysiological properties of the retinotectal circuit and found that long-term developmental exposure to TNF-α resulted in enhanced spontaneous excitatory synaptic transmission in tectal neurons, increased AMPA/NMDA ratios of retinotectal synapses, and a decrease in the number of immature synapses containing only NMDA receptors, consistent with premature maturation and stabilization of these synapses. Local interconnectivity within the tectum also appeared to remain widespread, as shown by increased recurrent polysynaptic activity, and was similar to what is seen in more immature, less refined tectal circuits. TNF-α treatment also enhanced the overall growth of tectal cell dendrites. Finally, we found that TNF-α-reared tadpoles had increased susceptibility to pentylenetetrazol-induced seizures.</p> <p>Conclusions</p> <p>Taken together our data are consistent with a model in which TNF-α causes premature stabilization of developing synapses within the tectum, therefore preventing normal refinement and synapse elimination that occurs during development, leading to increased local connectivity and epilepsy. This experimental model also provides an integrative approach to understanding the effects of cytokines on the development of neural circuits and may provide novel insights into the etiology underlying some neurodevelopmental disorders.</p

Activity‐dependent alteration of early myelin ensheathment in a developing sensory circuit

Funder: Montreal Neurological Institute – University of Cambridge CollaborationFunder: Natural Sciences and Engineering Research Council of Canada; Id: http://dx.doi.org/10.13039/501100000038Abstract: Myelination allows for the regulation of conduction velocity, affecting the precise timing of neuronal inputs important for the development and function of brain circuits. In turn, myelination may be altered by changes in experience, neuronal activity, and vesicular release, but the links between sensory experience, corresponding neuronal activity, and resulting alterations in myelination require further investigation. We thus studied the development of myelination in the Xenopus laevis tadpole, a classic model for studies of visual system development and function because it is translucent and visually responsive throughout the formation of its retinotectal system. We begin with a systematic characterization of the timecourse of early myelin ensheathment in the Xenopus retinotectal system using immunohistochemistry of myelin basic protein (MBP) along with third harmonic generation (THG) microscopy, a label‐free structural imaging technique. Based on the mid‐larval developmental progression of MBP expression in Xenopus, we identified an appropriate developmental window in which to assess the effects of early temporally patterned visual experience on myelin ensheathment. We used calcium imaging of axon terminals in vivo to characterize the responses of retinal ganglion cells over a range of stroboscopic stimulation frequencies. Strobe frequencies that reliably elicited robust versus dampened calcium responses were then presented to animals for 7 d, and differences in the amount of early myelin ensheathment at the optic chiasm were subsequently quantified. This study provides evidence that it is not just the presence but also to the specific temporal properties of sensory stimuli that are important for myelin plasticity