Critical Period For Developmental Plasticity Research Articles

Early Life Nutrition and Energy Balance Disorders in Offspring in Later Life.

The global pandemic of obesity and type 2 diabetes is often causally linked to changes in diet and lifestyle; namely increased intake of calorically dense foods and concomitant reductions in physical activity. Epidemiological studies in humans and controlled animal intervention studies have now shown that nutritional programming in early periods of life is a phenomenon that affects metabolic and physiological functions throughout life. This link is conceptualised as the developmental programming hypothesis whereby environmental influences during critical periods of developmental plasticity can elicit lifelong effects on the health and well-being of the offspring. The mechanisms by which early environmental insults can have long-term effects on offspring remain poorly defined. However there is evidence from intervention studies which indicate altered wiring of the hypothalamic circuits that regulate energy balance and epigenetic effects including altered DNA methylation of key adipokines including leptin. Studies that elucidate the mechanisms behind these associations will have a positive impact on the health of future populations and adopting a life course perspective will allow identification of phenotype and markers of risk earlier, with the possibility of nutritional and other lifestyle interventions that have obvious implications for prevention of non-communicable diseases.

Early life nutrition, epigenetics and programming of later life disease.

The global pandemic of obesity and type 2 diabetes is often causally linked to marked changes in diet and lifestyle; namely marked increases in dietary intakes of high energy diets and concomitant reductions in physical activity levels. However, less attention has been paid to the role of developmental plasticity and alterations in phenotypic outcomes resulting from altered environmental conditions during the early life period. Human and experimental animal studies have highlighted the link between alterations in the early life environment and increased risk of obesity and metabolic disorders in later life. This link is conceptualised as the developmental programming hypothesis whereby environmental influences during critical periods of developmental plasticity can elicit lifelong effects on the health and well-being of the offspring. In particular, the nutritional environment in which the fetus or infant develops influences the risk of metabolic disorders in offspring. The late onset of such diseases in response to earlier transient experiences has led to the suggestion that developmental programming may have an epigenetic component, as epigenetic marks such as DNA methylation or histone tail modifications could provide a persistent memory of earlier nutritional states. Moreover, evidence exists, at least from animal models, that such epigenetic programming should be viewed as a transgenerational phenomenon. However, the mechanisms by which early environmental insults can have long-term effects on offspring are relatively unclear. Thus far, these mechanisms include permanent structural changes to the organ caused by suboptimal levels of an important factor during a critical developmental period, changes in gene expression caused by epigenetic modifications (including DNA methylation, histone modification, and microRNA) and permanent changes in cellular ageing. A better understanding of the epigenetic basis of developmental programming and how these effects may be transmitted across generations is essential for the implementation of initiatives aimed at curbing the current obesity and diabetes crisis.

Neuronal cytoskeleton in synaptic plasticity and regeneration

During development, dynamic changes in the axonal growth cone and dendrite are necessary for exploratory movements underlying initial axo-dendritic contact and ultimately the formation of a functional synapse. In the adult central nervous system, an impressive degree of plasticity is retained through morphological and molecular rearrangements in the pre- and post-synaptic compartments that underlie the strengthening or weakening of synaptic pathways. Plasticity is regulated by the interplay of permissive and inhibitory extracellular cues, which signal through receptors at the synapse to regulate the closure of critical periods of developmental plasticity as well as by acute changes in plasticity in response to experience and activity in the adult. The molecular underpinnings of synaptic plasticity are actively studied and it is clear that the cytoskeleton is a key substrate for many cues that affect plasticity. Many of the cues that restrict synaptic plasticity exhibit residual activity in the injured adult CNS and restrict regenerative growth by targeting the cytoskeleton. Here, we review some of the latest insights into how cytoskeletal remodeling affects neuronal plasticity and discuss how the cytoskeleton is being targeted in an effort to promote plasticity and repair following traumatic injury in the central nervous system.

SYNGAP1 Links the Maturation Rate of Excitatory Synapses to the Duration of Critical-Period Synaptic Plasticity

Critical periods of developmental plasticity contribute to the refinement of neural connections that broadly shape brain development. These windows of plasticity are thought to be important for the maturation of perception, language, and cognition. Synaptic properties in cortical regions that underlie critical periods influence the onset and duration of windows, although it remains unclear how mechanisms that shape synapse development alter critical-period properties. In this study, we demonstrate that inactivation of a single copy of syngap1, which causes a surprisingly common form of sporadic, non-syndromic intellectual disability with autism in humans, induced widespread early functional maturation of excitatory connections in the mouse neocortex. This accelerated functional maturation was observed across distinct areas and layers of neocortex and directly influenced the duration of a critical-period synaptic plasticity associated with experience-dependent refinement of cortical maps. These studies support the idea that genetic control over synapse maturation influences the duration of critical-period plasticity windows. These data also suggest that critical-period duration links synapse maturation rates to the development of intellectual ability.

Cortical GABAergic Interneurons in Cross-Modal Plasticity following Early Blindness

Early loss of a given sensory input in mammals causes anatomical and functional modifications in the brain via a process called cross-modal plasticity. In the past four decades, several animal models have illuminated our understanding of the biological substrates involved in cross-modal plasticity. Progressively, studies are now starting to emphasise on cell-specific mechanisms that may be responsible for this intermodal sensory plasticity. Inhibitory interneurons expressing γ-aminobutyric acid (GABA) play an important role in maintaining the appropriate dynamic range of cortical excitation, in critical periods of developmental plasticity, in receptive field refinement, and in treatment of sensory information reaching the cerebral cortex. The diverse interneuron population is very sensitive to sensory experience during development. GABAergic neurons are therefore well suited to act as a gate for mediating cross-modal plasticity. This paper attempts to highlight the links between early sensory deprivation, cortical GABAergic interneuron alterations, and cross-modal plasticity, discuss its implications, and further provide insights for future research in the field.

Sensory Deprivation and Brain Plasticity

Early experience plays a key role in the development of the central nervous system as the brain has to adapt continuously to environmental changes that threaten its harmonious development. This adaptation phenomenon is called brain plasticity and refers to the lifelong changes in the structure of the brain that accompany experience (experience-dependent plasticity). Brain plasticity implies that the brain is pliable and can be remolded in response to challenges that interfere with its normal development such as sensory deprivation, brain injury, or abnormal development. Indeed, several regimens of visual deprivation such as dark rearing, enucleation, or eye-lid suturing lead to alterations of the visual system. Conversely, environmental enrichment also produces regional changes in brain anatomy such as increased dendritic space for synapses, increased cortical thickness, and elevated gene expression. Sensory deprivation at birth or perinatally has dramatic effects on the organization of the brain circuitry, leading to a takeover of the deprived cortex by other sensory modalities. This phenomenon is known as cross-modal plasticity and is mediated by the development of new inter-modal connections or by strengthening or unmasking of already existing connections. Cross-modal plasticity has been demonstrated following visual and auditory deprivation since birth. In both cases, the deprived cortex becomes activated by one or more of the remaining senses, touch, audition, and olfaction in the case of blindness and visual stimulation in the case of deafness. There is a large body of evidence, based upon anatomical, metabolic, and behavioral findings, that the deprived sensory cortex acquires multiple sensory and cognitive functions, transforming itself therefore into a multimodal cortex. In this issue, we have gathered a number of review and original papers on the topic of brain plasticity in humans and in animal models of unimodal sensory deprivation. We have welcomed not only papers dealing with various sensory systems such as vision, audition, touch, and olfaction but also those dealing with basic mechanisms of brain plasticity. Several papers present results on cross-modal plasticity and sensory substitution in humans and in animal models of sensory deprivation. Using elegant methodologies, these studies highlight how other sensory modalities take over the deprived visual or auditory cortices in blind and deaf subjects, respectively. Brain plasticity can also be triggered by changes in sensory experience. Neural reorganization will take place if the environment is modified during the early stages of development as is the case following cortical lesions of the visual cortical areas, visual deprivation through eyelid suturing, or dark-rearing (M. W. Burke et al.; H. Bengoetxea et al.). As shown by J. F. Maya-Vetencourt and N. Origlia, visual cortex plasticity results from a complex interplay between the individual's genetic background and the environment. M. Pietrasanta and coworkers describe how the interhemispheric connectivity between the visual cortices can be altered by visual deprivation. The corpus callosum therefore seems to have a pivotal role in plasticity of the visual cortex. The papers by G. Dormal and colleagues and M. Ptito and colleagues provide evidence that the functional segregation of the efferent projections of the primary visual cortex into a dorsal and a ventral stream is preserved in congenitally blind humans. A. Leo and colleagues focus on the purported role of the parietooccipital connections in conveying nonvisual information to the deprived visual cortex. Two papers focus on auditory deprivation and cross-modal plasticity. M. A. Meredith and B. L. Allman show how the auditory cortex of deaf ferrets is reorganized by the somatosensory modality, whereas P. Hirst and colleagues use a primate model to highlight cross-modal plasticity. D. M. Coppola describes a model of olfactory system plasticity through unilateral naris occlusion. The author points to the role of the spared ipsilateral olfactory pathway in olfactory plastic responses and also discusses several methodological caveats. The papers by K. Lehmann and colleagues and S. Desgent and M. Ptito address the role of GABAergic inhibitory interneurons in brain maturation and brain plasticity. These papers describe the important role of GABAergic inhibitory interneurons in maintaining the appropriate dynamic range of cortical excitation, in establishing critical periods of developmental plasticity, in receptive field refinement, and in the cortical processing of sensory information. This interneuron population is very sensitive to sensory experience during development, and visual deprivation studies emphasize the important contribution of these inhibitory interneurons in cross-modal plasticity. We hope that this special issue will shed light on the various mechanisms involved in cross-modal plasticity and sensory substitution and contribute to the development of new tools that will boost training-induced plasticity. Maurice Ptito Ron Kupers Steve Lomber Pietro Pietrini

Spinal Cord Transplants Support the Regeneration of Axotomized Neurons after Spinal Cord Lesions at Birth: A Quantitative Double-Labeling Study

After spinal cord lesions in newborn rats, transplants of fetal spinal cord tissue rescue immature axotomized neurons, support the growth of axons into and through the site of injury and prolong the critical period for developmental plasticity. Both late-developing (uninjured) and regenerating axons contribute to this transplant-induced anatomical plasticity. After lesions in the mature CNS, transplant-induced axonal elongation is spatially restricted. The current study was designed (1) to determine the magnitude of transplant-induced regeneration, (2) to test the hypothesis that the long distance growth beyond the site of injury is mediated by late-developing axonal pathways, whereas axonal elongation by regenerating pathways is spatially restricted as it is in the adult, and (3) to determine if particular nuclei have a greater inherent capacity for regeneration than others. We used temporally spaced retrograde tracing with the fluorescent dyes fast blue and diamidino yellow to address this issue. Fast blue was placed into the site of a spinal cord over hemisection in rat pups <48 h old to label those neurons which were axotomized by a neonatal lesion. The tracer was removed and a transplant of Embryonic Day 14 fetal spinal cord tissue was placed into the lesion site. Three to six weeks later a second tracer (diamidino yellow) was injected bilaterally into the host spinal cord caudal to the transplant. We counted the number of double-labeled (regenerated), single diamidino yellow-labeled (late-growing), and single fast blue-labeled (nonbridging) neurons in the cortex, red nucleus, raphe nuclei, and locus coeruleus. By systematically varying the distance of the diamidino yellow injection site caudal to the transplant, we were able to compare the distance which injured axons regenerate with the distance that late-growing axons extend. When the diamidino yellow in injection was placed within 5 mm caudal to the transplant 28% of the axotomized neurons in the red nucleus, 32% of the axotomized neurons in the locus coeruleus, and 37% of the axotomized neurons in the raphe nuclei were double-labeled (regenerating). Although the percentage of double-labeled neurons decreased as the distance beyond the transplant increased, a substantial population of regenerating neurons was identified in each of the brain stem nuclei examined following diamidino yellow injections up to 15 mm caudal to the transplant. Thus, after spinal cord lesions and transplants at birth, both regenerating neurons and late-developing neurons extended axons long distances (up to 15 mm) caudal to the lesion site. The capacity for regenerative growth was similar in each of the nuclei examined.

Extension of the critical period for developmental plasticity of the corticospinal pathway.

The corticospinal tract (CST) of the rat undergoes a prolonged period of postnatal development. Lesions of the presumptive CST pathway at birth are followed by the aberrant rerouting of the developing corticospinal axons around the lesion site through adjacent undamaged CNS tissue. This developmental plasticity becomes severely restricted by 5-6 days of age, so the axons are no longer capable of growth around the site of injury. The aim of the current study was to determine whether altering the environment at the site of injury by filling the lesion with transplanted fetal spinal cord tissue could prolong the critical period for developmental plasticity of the corticospinal pathway. The spinal cord was damaged (overhemisection) at three stages in the development of the corticospinal (CS) pathway: 1) prior to the arrival of CS axons, 2) after the axons elongated through the cord but prior to synaptogenesis, and 3) after both axonal elongation and synaptogenesis were completed. One to 9 months later, anterograde neuronal tracing with horseradish peroxidase was used to assess the growth of the corticospinal pathway with or without a fetal transplant at the site of injury, and the pattern of labeling was compared with that observed in adult nonlesioned control animals. Our results indicate that the presence of a transplant prolongs the critical period for developmental plasticity of the CST. Transplants elicited growth of CST axons throughout the postnatal period examined. CST axons damaged prior to synaptogenesis exhibited more robust growth than those lesioned after synaptogenesis had been completed. These results suggest that both environmental and neuronal factors interact to regulate the response of immature CS neurons to injury.

Chapter 26 Effect of target and non-target transplants on neuronal survival and axonal elongation after injury to the developing spinal cord

Publisher Summary This chapter determines: (1) whether transplants of fetal spinal cord tissue at the lesion site can prolong the critical period for developmental plasticity of the corticospinal system, and (2) whether the requirements for survival of immature axotomized neurons are target specific, or whether a variety of immature tissues can substitute for the normal target and support these neurons after injury. Target-specific transplants extend the critical period for developmental plasticity of the corticospinal pathway beyond that seen after lesions alone are demonstrated in the chapter. The corticospinal (CS) axons damaged prior to synaptogenesis are found to exhibit a greater degree of growth than those injured after synaptogenesis is completed, suggesting that an interaction of environmental and neuronal factors regulate the capacity of immature corticospinal neurons for growth. Many immature CNS neurons undergo massive retrograde cell loss in response to target removal by axotomy. At acute survival times, both target and non-target transplants are able to support the temporary survival of axotomized red nucleus (RN) neurons, perhaps by providing a diffusable trophic support for the injured neurons. However, their permanent survival is supported only by target-specific transplants, and they may require axonal elongation and synaptogenesis.