Introduction to Neurodevelopment and Brain Plasticity

Fundamental Facts of the Human Brain

• Brain Weight Changes: At birth, the human brain weighs approximately $350\,\text{g}$. In adulthood, the weight increases to approximately $1300\,\text{g}$.
• Neural Composition: The mature brain contains approximately $85$ billion neurons and trillions of synapses.
• Neurogenesis Peak: During the peak of neurogenesis, neurons are born at a rate of $250,000$ per minute.

Prenatal Development Phases

• Germinal Stage ($1-2$ weeks):     * The nuclei of the egg and sperm fuse to form a zygote.     * At $12\,\text{h}$, the zygote begins to divide via a process called cleavage.     * This forms a cluster of homogeneous cells known as a morula.     * The morula continues dividing to form a blastocyst consisting of $200-300$ cells.     * Fertilization occurs at day $0$. Cleavage occurs through days $1-3$ ($2$ cells, then $4$ cells). The morula forms at day $4$. The blastocyst develops at day $7$.     * Once implantation in the uterine wall (endometrium) occurs, the embryonic stage begins.
• Embryonic Stage ($3-8$ weeks):     * Characterized by gastrulation and the formation of major organ systems.     * Major morphological abnormalities typically occur during this period if development is disrupted.
• Fetal Stage ($9-38$ weeks):     * Ongoing development and maturation.     * Disruptions during this stage typically result in functional defects or minor morphological abnormalities.

Gastrulation and the Formation of the Nervous System

• The Embryonic Disc: Initial structure before layer differentiation.
• Primary Germ Layers: Uneven rates of cell development form three distinct layers:     * Ectoderm: The outer layer, which will eventually fold in on itself to become the nervous system and the skin.     * Mesoderm: The middle layer, forming muscles and the skeleton.     * Endoderm: The internal layer, forming the digestive tract and vital organs.
• Neural Tube Formation:     * At approximately $2$ weeks, the neural plate forms.     * At $18$ days, the primitive streak and neural plate are visible.     * At $20$ days, the neural groove forms as the plate folds.     * At $22$ days, the neural folds fuse to form the neural tube. The neural crest cells also begin to differentiate.     * At $24$ days, the neural tube is closed, showing a central canal. The primary brain vesicles (Telencephalon, Diencephalon, Mesencephalon, Rhombencephalon) and the spinal cord begin to differentiate.
• Developmental Timeline:     * $3$ weeks: Forebrain, Midbrain, Hindbrain, and Spinal cord are distinguishable.     * $7$ weeks: Further differentiation of the Forebrain, Midbrain, and Hindbrain.     * $11$ weeks: Forebrain expands significantly; cranial nerves, cerebellum, and medulla are forming.     * At birth: Full structure of the brain is present.

Neural Tube Defects

• Spina Bifida: A failure of the closure of the neural fold at the level of the spinal cord.     * Occurs in approximately $1$ in $1000$ live births.     * Small openings can often be surgically corrected.     * Larger openings can lead to paralysis and limb deformities.
• Anencephaly: A condition where the brain fails to develop entirely. This generally results in a stillborn infant.
• Prevention: Neural tube defects can often be prevented by folic acid supplements during pregnancy.

The Six Stages of Brain Development

1. Cell birth / Proliferation (Neurogenesis and Gliogenesis)
2. Cell migration
3. Cell differentiation and maturation
4. Synaptogenesis and synaptic pruning
5. Cell death
6. Myelination (Myelogenesis)

Stage 1: Cell Birth and Proliferation (Neurogenesis and Gliogenesis)

• Mechanism: This is a massive process occurring at $250,000$ neurons per minute at peak.
• Neural Tube Structure: Initially, the neural tube is one cell thick, touching both the inner and outer ends. As the tube widens, cell extensions elongate while still holding onto the outer wall.
• Stem Cells: Neurons themselves do not divide. Instead, immature cells called stem cells divide to form progenitor (precursor) cells.
• Progenitors: Each progenitor cell can differentiate into either a neuroblast (which becomes a neuron) or a glioblast (which becomes a glial cell).
• The Brain's Nursery: Santiago Ramon y Cajal observed that cells undergoing mitosis (division) were always closer to the inner surface of the neural tube, known as the ventricular zone.
• Ventricular System: The neural tube gives rise to the ventricular system in the mature brain. The lining of the adult ventricles still contains stem cells.
• Abundance: An abundance of neurons is created during early development—more than will exist in the adult brain.

Stage 2: Cell Migration

• Definition: The movement of newly formed cells from the ventricular zone toward the outer layers.
• Inside-Out Pattern: The cortex develops in an "inside-out" manner across species; early-born neurons settle in deep layers, while later-born neurons migrate past them to form outer layers.
• Primitive Map: Cells are predisposed by a primitive map to migrate to specific locations (Rakic et al., $2009$).
• Guidance Mechanisms:     * Chemical Signals: Immunoglobulins and cytokines.     * Physical Support: Radial glia. These cells act like wheel spokes that neurons "climb" using extensions toward the brain surface.
• Tangential Migration: While most cells climb glial poles, some migrate tangentially (like "Tarzan" moving from one vine to another) to form structures like the basal ganglia and amygdala.
• Postnatal Migration: Extensive migration continues into the infant frontal lobe, most prominent in the first $3$ months of life (some persisting to $7$ months). Most of these become inhibitory GABAergic interneurons (Paredes et al., $2016$).

Stage 3: Differentiation and Maturation

• Differentiation: Once at their destination, immature neurons begin to express specific genes to become a particular cell type.
• Morphological Development:     * Axons: Grow at a rate of millimeters ($\text{mm}$) per day.     * Dendrites: Grow at a rate of micrometers ($\mu\text{m}$) per day.
• Dendritic Development: Involves dendritic arborization (branching) and the growth of dendritic spines.
• Induction: Ongoing cell-cell interactions via the secretion of chemicals where cells influence the fate of neighboring cells.
• Pluripotency: Immature cells are pluripotent (can become any cell type based on local environment), which has therapeutic potential for diseases like Parkinson's. Maturation results in the loss of this property.

Stage 4: Synaptogenesis and Synaptic Pruning

• Synaptogenesis: The formation of synapses, guided by cues and signals. The majority of synapses form after birth and rearrange Throughout life.
• Growth Cone: Discovered by Santiago Ramon y Cajal ($1890$), described as a "battering ram" with chemical sensitivity and amoeboid movements.     * Growth cones extend by adding microtubules to the tip.     * They develop thin extensions called filopodia.
• Guidance Cues:     * Chemotropism: Growth cones are attracted or repelled by chemicals (Tropic molecules, Cell Adhesion Molecules/CAMs) released by target sites (Roger Sperry, $1943$).     * Contact Guidance: Physical contact with other cells.
• Synaptic Pruning: Successful/active synapses are strengthened; unsuccessful ones are eliminated. This follows the "use it or lose it" principle, driven by experience.

Stage 5: Cell Death (Apoptosis)

• Discovery: Viktor Hamburger ($1900-2001$) noticed motor neurons in chick embryos dropped from $20,000$ to $12,000$ during incubation.
• Apoptosis vs. Necrosis: Apoptosis is Programmed Cell Death (PCD). It is an active, gene-driven process involving "death genes" called caspases.
• Neural Darwinism: Axons form synapses with several cells in overabundance. Those that do not form active synapses are eliminated.
• Survival Signals: Neurons require neurotrophic factors from target cells and active communication with other neurons to survive.     * Neurotrophins: Nerve Growth Factor (NGF), discovered by Rita Levi-Montalcini and Stanley Cohen (Nobel Prize $1986$). Other factors include Brain-Derived Neurotrophic Factor (BDNF) and Neurotrophin-$3$ (NT-$3$).

Stage 6: Myelination (Myelogenesis)

• Definition: Glia form a fatty sheath covering axons to speed up transmission via saltatory conduction.
• Cells Involved: Schwann cells ($\text{PNS}$) and Oligodendroglia ($\text{CNS}$).
• Pattern of Myelination: Occurs back-to-front (spinal cord, then hindbrain, midbrain, and finally forebrain/cortex).
• Duration: A slow process continuing through adulthood.

Impact of Experience on Neural Development

• Experience Expectant: Standard development that requires specific species-specific experiences during a critical period (Greenough and Black, $1992$).
• Experience Dependent: Brain changes not predetermined, but generated in response to unique local environments. For example, rats in complex environments have more synapses and new neurons.
• Synaptic Rearrangement: Continues throughout life and is fundamentally related to learning.

Adolescent Brain Development

• Synaptic Pruning: Adolescence is a period of increased pruning in the prefrontal cortex.
• Maturational Imbalance: The limbic system (emotions/rewards) matures earlier than the prefrontal cortex (control/reasoning).
• Structural Changes: Grey matter thickens in childhood and thins in adolescence (Gogtay et al., $2004$). White matter (myelination) peaks in adulthood.
• Gender Differences: The maturation process is generally completed earlier in girls than in boys.

Adult Neurogenesis and the Aging Brain

• Historical View: It was originally believed no new neurons formed in adulthood.
• Songbirds: Show seasonal replacement of neurons in the "singing" area (Nottebohm).
• Adult Neurogenic Regions in Humans:     * Olfactory Epithelium: Continuous division to replace sensory neurons.     * Subventricular Zone (SVZ): Cells migrate via the Rostral Migratory Stream (RMS) to replace interneurons in the olfactory bulb.     * Hippocampus: The granular layer of the dentate gyrus produces new neurons throughout life (Altman & Das, $1965$).
• Cerebral Cortex: Very few adult-born neurons; research into injury-induced neurogenesis is ongoing.

Recovery from Brain Injury

• Age and Location: Recovery is better in younger brains and in the periphery compared to the central nervous system.
• Collateral Sprouting: Non-damaged axons form new branches to attach to vacant spots on dendrites or cell bodies left by damaged axons. This is stimulated by neurotrophin secretion and is very rapid in the first $2$ weeks post-injury.

Neuroplasticity and Sensory Reorganization

• Sensory Substitution:     * Blind individuals recruit the occipital (visual) cortex for tactile (Braille) and auditory tasks (Sadato et al., $1996$; Weeks et al., $2000$).     * Deaf individuals show enhanced touch and vision.
• Cortical Reorganization: In monkeys, after a finger amputation, the cortical area for the missing digit becomes responsive to adjacent fingers and the palm.
• Enriched Environments: Rats in enriched settings show thicker cortices and increased dendritic branching, correlated with improved learning.

Critical Periods and Environmental Vulnerability

• Critical Period: A specific window where the brain is most sensitive to experience.     * Imprinting: Konrad Lorenz ($1930\text{s}$).     * Sensory Senses: Vision and hearing have early, tight windows.     * Higher Cognition: Language and symbols have windows that open later and never close entirely but have peak sensitivity.
• Case Study (Genie): Illustrates the severe impact of social, experiential, and nutritional deprivation on development.

Impact of Maternal and Childhood Adversity

• Prenatal/Maternal Factors:     * Maternal Infection Activation ($\text{MIA}$), stress, malnutrition (folic acid/thiamine deficiency), and substance abuse.     * Leads to epigenetic dysregulation (DNA methylation) of $\text{HPA}$ axis-related genes (e.g., $\text{NR3C1}$, $\text{BDNF}$).
• Childhood Adversity:     * Neglect, abuse, or low socioeconomic status can lead to $\text{HPA}$ axis dysregulation, immune dysregulation, and altered neural development.
• Clinical Outcomes: These factors increase the risk for schizophrenia, autism spectrum disorders, epilepsy, anxiety, depression, and cognitive impairment in later life.