Ernst Strüngmann Forum

Sylvain Baillet, Yehezkel Ben-Ari, April A. Benasich, Olivier Bertrand, Gyorgy Buzsáki, Alain Chédotal, Sam M. Doesburg, Gordin Fishell, Adriana Galván, Jennifer N. Gelinas, Jay Giedd, Pierre Gressens, Ileana L. Hanganu-Opatz, Rowshanak Hashemiyoon, Takao K. Hensch, Suzana Herculano-Houzel, Mark Hübener, Mark, Matthias Kaschube, Michael S. Kobor, Bryan Kolb, Thorsten Kolling, Jean-Philippe Lachaux, Ulman Lindenberger, Heiko J. Luhmann, Hannah Monyer, Sarah R. Moore, Charles A. Nelson III, Tomáš Paus, Patrick L. Purdon, Pasko Rakic, Urs Ribary, Akira Sawa, Terrence J. Sejnowski, Wolf Singer, Cheryl L. Sisk, Nicholas C. Spitzer, Michael P. Stryker, Migranka Sur, Peter J. Uhlhaas

Abstract

Across development, the coupling and synchronization of oscillations among brain areas are thought to mediate network assembly, coordination, and plasticity, and to play supporting roles in sensorimotor functions and cognition, including perception, language, learning, and memory. Ongoing neural plasticity and sensitivity to environmental cues contribute crucially to this process. To explore the complex mechanisms by which the brain evolves and matures, the Ernst Strüngmann Forum gathered experts to examine collectively how dynamic brain coordination emerges during development. This chapter introduces the extended discourse that transpired and summarizes the perspectives that emerged from multiple disciplines. Background information is provided on the key areas of enquiry (prebirth, childhood, early adolescence, and emerging adulthood), remaining gaps in knowledge are highlighted, and innovative ways forward are proposed to further this evolving area of cross-disciplinary study.

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Abstract
To orchestrate the stepwise assemblage of building blocks in a living system, effective developmental processes are required to establish precise relations among the organism’s components. Particular challenges exist for the development of nervous systems, as their functionality depends critically on highly specific relations among individual neurons. To establish precise connections among neurons, these challenges are met by using both molecular signaling systems and the electrical activity of neurons. Exploiting the exquisite sensitivity of synaptic modification rules for the precise timing of discharge patterns, the temporal correlation structure of both self-generated and environmentally induced activity is used to encode relations, thereby specifying the functional architecture of neuronal networks. Among the multiple mechanisms implemented to generate temporally structured activity, the propensity of microcircuit networks to engage in oscillatory activity plays a prominent role: network oscillations permit precise timing relations between discharges of distributed neurons to be established through synchronization, systematic phase shifts, and cross-frequency coupling. Developmental mechanisms are reviewed that translate temporal relations among neuronal discharges into functional architectures.

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Abstract
Our understanding of the etiology of axon guidance disorders as well as our ability to correct axon guidance defects or treat neuronal network dysfunction is limited. Surgical methods currently employed to improve some forms of strabismus cannot, for example, be readily applied to more complex disorders, although experimental neurosurgery for neuropsychiatric disorders can now successfully target thalamocortical networks. Should aberrant projections be silenced or should the growth of new connections be promoted? This chapter examines the role of axon guidance molecules in the regulation of cell–cell interactions during normative and atypical development. It discusses how this affects the formation of neural circuit connections (normal and pathological) and posits what types of experiments and novel tools are needed to explore these processes. It is recommended that these observations be expanded to derive general rules of network construction and developmental sequences.

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Abstract
Prior to birth, the brain becomes highly developed, and many early events lay the foundations for later maturation. This chapter begins with a focus on the range of normal brain structure and function, with consideration given to how dynamic changes over time can best be studied. It then explores the extent to which the specification of cortical cell types is constrained during development, followed by a review and discussion of what happens to spatiotemporal patterns of waves of activity during early cortical development and their roles in developmental plasticity. Consideration of the central role of activity in organizing the developing nervous system prompted us to ask how changes in activity prefigure development of pathology. Key conclusions and future directions are summarized at the end of this report.

All theories are wrong but some are useful (after George E. P. Box).
If you torture the data long enough, it will always confess (after Ronald H. Coase).

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Abstract
During development, neural circuitry can be profoundly shaped by experience at well-defined periods of time. Using amblyopia as a model of postnatal synaptic plasticity, this chapter reviews the “triggers” and “brakes” that determine the onset and offset of these critical periods. Consideration is given to the molecular constraints that act on plasticity as well as to the physical and sensory environmental factors that impact function and cortical circuit plasticity. Reactivation of plasticity in primary visual cortex suggests that critical periods are not limited to early postnatal development. The extent to which the amblyopia model will generalize at a mechanistic level is discussed. Genetic diversity in mice and humans may provide insight into individual variability and the timing of critical periods and should be pursued. To permit comparison of developmental trajectories more readily across species and disease states, the call is made for better models of critical period plasticity and the identification of biochemical and electrophysiological correlates of these windows.

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Abstract
Epigenetic mechanisms are critical to the developing brain. This chapter reviews epigenetic mechanisms, their involvement in the processes of brain development, and the literature suggesting that epigenetic mechanisms may account for the enduring effects of environmental factors on the brain and behavior in human development. Epigenetic factors guide the expression of the genome in response to the intrinsic signals inherent to the processes of embryogenesis, neurogenesis, cell migration, synaptic transmission, and the timing of developmental windows. Moreover, evidence suggests that epigenetic regulators may account for the embedding of early social experiences within neurobiology. These early modifications to the epigenetic code are hypothesized to have consequences for developing neural structures and function. Epigenetic changes might also channel or moderate the effects of genetic variation on emotional and cognitive processes, and psychiatric conditions. Thus, the study of the epigenetic consequences of early-life environments may shed light on the biological pathways of environmentally induced risk.

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Abstract
During the first years after birth, infants face the enormous task of building a comprehensive and predictive internal model of the external world, allowing them to navigate and interact successfully with their environment. This chapter explores the frontiers involved in understanding the neural bases of this process and how such knowledge could be leveraged to treat and prevent neurodevelopmental disorders. It begins by describing how developing brains form dynamical networks that integrate genetic, epigenetic, and sensory information, emphasizing the interplay between molecules and neural activity. Strategies are highlighted that the brain uses to tightly control the impact of sensory input onto its developing networks, which are manifest at the molecular, neural activity, and behavioral levels, and which appear pivotal as the brain strives to maintain a fine balance of flexible yet stable configuration. While suitable animal models have greatly contributed to our basic understanding of neural development, revealing the neural basis of cognitive development in humans remains a challenge. To overcome this barrier, new directions are discussed that combine animal and human studies. Finally, this chapter discusses implications of the complexity of the human brain and highlights the potential of data-driven formal models of neurodevelopmental trajectories to enable early detection and individualized treatment of developmental disorders.

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Abstract
Adolescence is characterized by maturation of reproductive and other social behaviors and social cognition. Although gonadal steroid hormones are well-known mediators of these behaviors in adulthood, the role these hormones play in shaping the adolescent brain and behavioral development has only come to light in recent years. This chapter reviews the organizational effects of pubertal hormones on sex-specific behaviors that mature during adolescence and the neurobiological mechanisms of structural organization of the adolescent brain by pubertal hormones. Important questions are identified to direct further study of the relationship between pubertal hormones, the adolescent brain, and experience.

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Abstract
Adolescence is a time of enhanced neural plasticity, including both experience-expectant plasticity and experience-dependent plasticity. Experience-expectant changes are likely related to socioaffective behaviors, including play, sex, and social interactions, all of which come to dominate the life of adolescents. The most likely candidates driving plasticity in adolescence include the generation of new neurons and/or glia, the formation of connections either by axon extension or synapse formation, pruning or growth of dendrites and thus synapses, thinning of the cortex, epigenetic changes, and changes in the excitatory–inhibitory balance. A range of factors influence plasticity in the adolescent brain (e.g., play, drugs, sensorimotor experiences, stress, diet, cerebral injury, and the immune system). The onset of the sensitive period is around the onset of pubertal gonadal hormone production, but may or may not be triggered by the hormone release. The offset of the sensitive period may be related to myelination, which reduces plasticity, and the timing of the offset likely varies in different cortical regions.

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Abstract
GABAergic inhibition mediates many crucial aspects of brain development, including the development of structural connections, critical period plasticity, and functional synchronization across large-scale networks via gamma-band oscillations. Disturbances in the development of GABAergic circuits are thought to underlie neurodevelopmental disorders such as schizophrenia and autism. Characterizing the developmental trajectory of these circuits in humans is a vitally important problem, but a challenging one. Current approaches in humans include postmortem studies and noninvasive imaging. These methods can provide highly specific information about GABA circuits in older children, and in-depth functional information in younger children, albeit with only indirect links to GABA circuit function. An ideal characterization in humans would map the continuous trajectory of GABA circuit function from infancy through adulthood with a common set of tools, alongside detailed measurements of sensory, cognitive, and language function. In this chapter it is proposed that studies of anesthesia-induced oscillations could be used to characterize and track the development of GABAergic oscillatory circuits from infancy through adulthood. The most commonly used anesthetic drugs in both pediatric and adult practice are powerful positive allosteric modulators of GABA receptors. These drugs induce large, stereotyped oscillations in the unconscious state that are likely generated by the same GABAergic circuits responsible for gamma oscillations in the conscious state. In the United States alone, these anesthetic drugs are administered to tens of millions of patients each year, under conditions of both neurotypical and atypical development. By harnessing this anesthetic experiment of nature, it may be possible to develop detailed developmental trajectories of GABAergic circuit function in humans.

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Abstract

How does lifetime experience shape cognitive and neural development? This chapter considers this question from the perspective of early adolescence. Plasticity in the adolescent brain may occur on three possible time courses: adolescent brains may be no more plastic than adult brains; adolescence could mark the end of critical periods which began in infancy; or adolescence might constitute its own, distinct critical period. In humans, all these time courses likely coexist. Many functional properties of the brain continue to change well into adolescence (e.g., regional cortical information selectivity, neural network correlations, oscillatory activity). Determining how these developmental changes are influenced by genes and/or experience in humans is challenging. Some insight comes from studies with individuals who have different developmental histories (e.g., individuals who grow up blind). These investigations suggest that experience plays a fundamental role in determining the functional specialization of cortical networks and patterns of functional connectivity. Studies with animal models provide crucial insight into the causal factors that drive brain development because they allow direct manipulation of experience and genetics as well as more direct measurements of neural function. However, work is needed to bridge the gap between measurements of brain function in animals and humans. At present, work with animal models has focused on plasticity in sensory systems, whereas much of the developmental change that occurs in early adolescence is in higher cognitive systems. Bridging these gaps is an important goal for future research.

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Abstract
Late adolescence is associated with the emergence of major brain disorders, such as schizophrenia and affective disorders, thus raising the question of the underlying biological vulnerability and mechanisms that confer risk for psychopathology. This chapter presents evidence which shows that during late adolescence, dynamic brain coordination undergoes major modifications in specific circuits involved in cognition and affective regulation. These data are consistent with emerging findings from physiology and anatomy that physiological and anatomical underpinnings of brain coordination are characterized by profound changes during the transition from adolescence to adulthood. This chapter posits that the expression of psychopathology may be intimately linked to ongoing modifications in brain coordination, which occur during adolescence, and that these could confer a biological vulnerability for disturbances in affect and cognition.

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Abstract

Applying insights from research on critical periods in early development, this chapter outlines a life-span research agenda on human plasticity and uses it as the conceptual foundation for a set of research hypotheses and open questions. Plasticity is defined as the capacity for lasting changes in brain structure associated with expansions in behavioral repertoire. As a complement to plasticity, flexibility refers to the instantiation and reconfiguration of the existing behavioral repertoire during periods of stability that are characterized by the absence of structural change. Mammalian and avian brains evolve through cycles of plasticity and stability, with a general trend toward stability. Animal work on critical periods in motor and sensory development substantiates three hypotheses that can serve as guideposts for research on plasticity in later age periods: First, likelihood, rate, and magnitude of plastic changes decrease after maturity. Second, when triggered, plastic changes often entail an overproduction of new synaptic connections, followed by pruning. Macroscopically, this sequence is associated with a pattern of gray matter volume expansion, followed by renormalization. Third, earlier plastic changes provide a structural scaffold for later learning. These hypotheses await empirical testing in humans, engender research design recommendations, and are related to fundamental open issues in research on human plasticity.

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Abstract

Over the past two decades there has been an explosion of research on the human adolescent brain. This research has demonstrated that the brain continues to mature during the second decade of life, due to ontogeny and experience. The majority of this work has focused on changes that occur in regulation and affective circuitry; in particular, on how these neurobiological changes relate to characteristic adolescent behavior. This chapter summarizes existing understanding and speculates about agents of change that impact neurobiological development in the adolescent brain. It begins with a discussion of what adolescence refers to and reviews the prevailing neurobiological models of adolescent brain development. Factors are considered that contribute to adolescent brain development (e.g., puberty, sleep, social relationships, adolescent risk-taking). Open questions are posed to aid further consideration and research.

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Abstract
Adolescence is a critical stage of brain development prior to the attainment of a more mature state. The neurobiological underpinnings of this transition have been difficult to characterize, contributing to the challenges in diagnosing, treating, and preventing the neuropsychiatric diseases that commonly emerge during this developmental epoch. This chapter proposes a multidisciplinary approach with a focus on the changing patterns of both physiologic and pathologic brain dynamics across adolescence. The intellectual merit and scientific promises of combining multiple research modalities are discussed: longitudinal studies in humans and animal models are encouraged as are potential for contributions from computational models, including artificial neural systems. Adolescence represents a nonlinear, discrete period of perturbation during which specific brain systems for higher cognitive, emotional, and social functions are highly, and often irreversibly, modified. Identifying the neural processes that underlie these developmental modifications will help facilitate their normal expression during adolescence and ultimately prevent their disruption and onset of neuropsychiatric disease.

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