Trajectories of brain development: point of vulnerability or window of opportunity?

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Abstract

Brain development is a remarkable process. Progenitor cells are born, differentiate, and migrate to their final locations. Axons and dendrites branch and form important synaptic connections that set the stage for encoding information potentially for the rest of life. In the mammalian brain, synapses and receptors within most regions are overproduced and eliminated by as much as 50% during two phases of life: immediately before birth and during the transitions from childhood, adolescence, to adulthood. This process results in different critical and sensitive periods of brain development. Since Hebb (1949) first postulated that the strengthening of synaptic elements occurs through functional validation, researchers have applied this approach to understanding the sculpting of the immature brain. In this manner, the brain becomes wired to match the needs of the environment. Extensions of this hypothesis posit that exposure to both positive and negative elements before adolescence can imprint on the final adult topography in a manner that differs from exposure to the same elements after adolescence. This review endeavors to provide an overview of key components of mammalian brain development while simultaneously providing a framework for how perturbations during these changes uniquely impinge on the final outcome.

Section snippets

Background and theoretical framework

Nearly 22.1% of the adult population of the United States has a diagnosable mental illness. Differences in diagnostic issues may slightly influence this statistic, but the World Health Organization estimates that mental disorders are on the rise [94]. Depression, for example, is projected to become the second leading disorder by 2020 [94]. Despite the complete mapping of the human genome, the genetic culprits that underlie the most prevalent psychiatric disorders in our society remain elusive.

Normal brain development

The trajectory of brain development occurs in multiple stages as reviewed below. Schematically, this timeline is found in Fig. 1. Within the timeline, different brain regions have a unique course of ontogeny. Late developing structures, including the cortex, hippocampus and the cerebellum [77], [103], [107], set the stage for differential periods of vulnerability in a regionally specific manner.

Intrinsic factors of brain development

A number of functional changes occur during the maturation of the brain that serve as important regulators or stabilizers of programmed development [101]. In addition to the structure–function relationships described above, age-dependent changes in intrinsic factors are integral for determining set points in synaptic activity that further define a developmental trajectory. Four categories exist: (1) neurotransmitters serve as trophic factors that directly guide innervation; (2)

Extrinsic factors of brain development

The sculpting of the immature brain is an interactive process between genetic programming, cell function, and the environment. The result of this process is an endophenotype, which refers to heritable traits that increase the risk to develop or manifest a given disease [39], and offers a new approach to elucidating the underlying mechanisms of action of common symptoms across disorders [3]. For example, the endophenotypes of ADHD consist of aberrancies in temporal processing or delay gradients

Extrinsic factors known to influence the vulnerability to insult

This section will highlight supportive data regarding the importance of a number of factors that influence the appearance of any early insult.

Conclusions

The relationship between early insult and resulting psychopathology is still in its infancy. Waves of overproduction and elimination of synapses, receptors, and function may serve as a neural guide or stabilization mechanism during adolescence [101]. Thus, the key to understanding the impact of various risk factors on the emergence of psychopathology is the time course of development of the underlying brain structures and function. In this regard, we know very little about how the brain matures

Acknowledgements

The author wishes to thank Carryl P. Navalta and Kai C. Sonntag for valuable comments and Martin H. Teicher for his continued support (MH-43474). The financial support of the Scottish Rite Schizophrenia Research Program, the Tourettes Syndrome Association, and NARSAD (SLA) is also gratefully acknowledged.

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