1.3 Neural Development and Neurogenesis

Neural Development and Neurogenesis

The human brain is a structurally and functionally complex organ that demonstrates ongoing modifications in response to diverse experiences and diseases. Understanding how the anatomical and neurochemical systems underlying cognitive, social, emotional, and sensorimotor functions develop from early neuronal and glial cell populations is essential, particularly in psychiatry, as defects in these processes can lead to various brain disorders. Abnormalities in development may contribute to conditions like autism and fragile X mental retardation, but they are also relevant in mature diseases such as schizophrenia and depression. Evidence suggests that these disorders involve underlying ontogenetic factors, evidenced by brain pathology and neuroimaging findings showing volumetric reductions in brain regions, neuron and glial cell numbers, and various interneuron types in schizophrenia at diagnosis.

Evidence in Autism
The early developmental trajectory in autism suggests features such as abnormally increased early brain growth and impaired cell organization arising from disruptions in cell proliferation and migration. Aberrant early brain development creates an atypical population of neurons distinguished by cell type, number, and placement, potentially leading to abnormal neuronal connections. As brain systems mature, they rely on these component neurons to process complex information which may falter if initial conditions of development are disturbed.

Overview of Nervous System Morphological Development

  1. Temporal Generation of Brain Regions

    • Different brain regions and neuron types are formed at specific developmental stages. This phenomenon entails crucial implications regarding the impact of developmental insults. For example, fetal exposure to thalidomide from days 20 to 24 of gestation has been linked specifically to the development of autism.

  2. Abnormalities in Early Development Affect Subsequent Stages

    • The sequence of cellular development suggests that early deficits predict future anomalies, though not all may be clinically measurable. For instance, a deficit in neuron number may result in reduced axonal development and diminished myelin (white matter), which can manifest in neuroimaging even if neurons remain unaffected due to the outnumbering significance of glial cells (which outnumber neurons approximately 8:1).

  3. Role of Molecular Signals in Development

    • Molecular signals, notably extracellular growth factors and transcription factors, play pivotal roles in various developmental stages. For instance, insulin-like growth factor I (IGF-I) and brain-derived neurotrophic factor (BDNF) are critical in promoting neuron survival, migration, and synaptic modifications essential for learning and memory.

Neural Plate and Neurulation

The nervous system begins its development within the human embryo approximately between 2 and 4 weeks of gestation. This development initiates with neuron emergence due to interactions among neighboring cell layers. A significant process in this phase includes:

  • Gastrulation (days 14 to 15): It forms a two-layered embryo, constituting ectoderm and endoderm. The neural plate emerges from the ectoderm with influence from the underlying mesoderm (appearing on day 16), stimulating ectoderm to transform into the neural plate.

  • Neurulation occurs between weeks 3 to 4, with the neural plate's edges rising and fusing to form the neural tube, which is key for the ventricular system. Defects in neurulation, potentially arising from factors like retinoic acid or anticonvulsants (e.g., valproic acid), can lead to conditions like anencephaly and spina bifida.

The neural crest forms as a consequence of neurulation, giving rise to several components of the peripheral nervous system and other structures, such as melanocytes and ganglia, further leading to congenital syndromes.

Regional Differentiation of the Embryonic Nervous System

The neural tube expands radically to form distinct morphological subdivisions:

  • By 4 weeks, the divisions include the prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain). By 5 weeks, these further multiple into five divisions:

    • Prosencephalon: Telencephalon (cortex, hippocampus, basal ganglia), Diencephalon (thalamus and hypothalamus)

    • Mesencephalon: Midbrain

    • Rhombencephalon: Metencephalon (pons and cerebellum), Myelencephalon (medulla)

As development continues, precursor proliferation rates diversify regionally along with their migration and differentiation processes influenced by specific soluble growth factors released by adjacent proliferating cells or signaling centers. The process culminates in specific regional expressions of molecular patterns predictive of neuronal outcome, such that various embryonic regions generate a distinct array of neuronal classes across neurodevelopment.

The Ventricular and Subventricular Proliferative Zones

Patterns of precursor cell proliferation and migration dictate the radial organization in the nervous system. The final population of specific brain regions results from complex regulation of neurogenesis and programmed cell death (apoptosis). Notably, attention has shifted from the previous notion that excessive cell production is followed by selective cell death toward an understanding that structured neurogenesis occurs at various developmental stages, requiring precise regulatory frameworks. This has implications concerning diseases, particularly in conditions characterized by a lesser-than-normal brain region size, such as schizophrenia, which might indicate failure in early neuronal generation.

Radial and Tangential Patterns of Neurogenesis and Migration

Focusing on the cerebral cortex, it serves as a model for the processes of neurogenesis and migration. The formation of its characteristic six-layer structure occurs via radial migration from the ventricular zone (VZ) outward. In this process:

  • Initial postmitotic cells migrate outward from the VZ, establishing a preplate composed of distinct cell types, including Cajal-Retzius cells and subplate neurons. Later, other postmitotic neurons traverse the preplate, forming the cortical plate's layers.

  • Important findings point to the notion that specific genetic mutations are connected to unique cortical malformations affecting neurogenesis, migration, or cellular organization.

  • The majority of cortical neurons trace back to the forebrain VZ, but critical subsets of inhibitory GABA interneurons arise from the ventral forebrain ganglionic eminences, showcasing the dynamic interplay of radial and tangential movements.

Studies of schizophrenia have noted reduced interneuron density in the prefrontal cortex and contextualized these observations to a potential decreased GABAergic activity model, with implications for understanding etiology and potential intervention strategies.

Neuronal Specification and Cell Differentiation

Progressing from neurogenesis, newly formed neurons then undergo differentiation, during which they expand their dendritic trees and establish synapses. This intricate process is tightly linked with the maturation of functional properties and is a critical period for excess synaptogenesis and pruning that are experience dependent. The development of axons into mature neurons is mediated by molecular cues that dictate both direction and speed of axonal guidance, ultimately establishing appropriate neuronal networks.

The Neurodevelopmental Basis of Psychiatric Disease

Increasingly, neurodevelopmental pathways are regarded as foundational in a range of psychiatric disorders. The hypothesis suggests that disruptions occurring during gestation negatively affect brain development, creating susceptibility to additional factors that later manifest clinically as mental illness. Research implicates numerous genetic and environmental risk factors in illnesses such as schizophrenia and autism. For instance:

  • In schizophrenia, neuroimaging studies indicate structural brain abnormalities, often observing diminished volumes in the prefrontal cortex and hippocampus without concurrent evidence of cell loss or inflammation, leading to questions regarding the adequacy of current etiological models.

  • Autism spectrum disorders (ASDs) are recognized for their heterogeneous manifestations, likely arising from diverse neurodevelopmental disruptions, with evidence suggesting alterations in timing, cell proliferation, and processes linked to synaptic organization. Identifying specific etiological contributors, including hereditary and environmental factors, is pivotal in understanding ASDs and other neurodevelopmental disorders.

Adult Neurogenesis

Recent findings have revolutionized our perspective on neurogenesis, establishing that new neurons continue to arise throughout life, particularly in the hippocampus and olfactory bulb. Important factors modulating this process include:

  • Growth factors like bFGF and IGF-I, which influence neuron production and survival, thus impacting learning and memory functions.

  • The balance of neurogenesis versus neuronal loss becomes a crucial aspect in the context of various psychiatric conditions, with stress and hormonal influences directly impeding neurogenesis and correlating with depressive symptoms.

Neurogenesis may offer potential therapeutic avenues in treating neurodegenerative and psychiatric disorders, as recent insights hint at reactivation of neurogenesis as a strategy for recovery from brain injuries and functional regressions.