Development and Function in the Nervous System: Neuronal Development, Neuroplasticity, and Recovery

Learning Objectives for Nervous System Development and Function

• Describe the prenatal development of the nervous system.

• Explain the five stages of neuronal development: proliferation, migration and aggregation, differentiation, myelination, and synaptogenesis.

• Discuss the mechanisms of neuroplasticity and the occurrence of adult neurogenesis.

• Explain how epigenetics serves as a link between experience and gene expression.

• Evaluate the causes, mechanisms, and limitations of recovery following brain damage.

• Explain the phenomenon of the phantom limb.

The Nature-Nurture Interaction in Brain Development

• Brain development is a continuous interaction between two primary factors:

  • Maturation (Nature): Genetically programmed processes that unfold according to a biological timetable.

  • Learning (Nurture): The shaping of neural circuits through experience, particularly during critical periods.

• A refined understanding of this interaction involves learning how neurons develop and survive, how axons navigate to correct targets, and how experience modifies the brain's structure and function.

• Core Principle: Maturation "opens the windows," while experience determines the specific wiring of the brain.

Embryology and Prenatal Development

• The development begins from a single cell: the zygote ($1 \, \text{day}$ post-conception).

• Multiplication occurs via mitosis; reproduction begins with the fusion of an ovum and sperm (each carrying $23$ chromosomes through meiosis).

• Initial Development Stages:

  • Multiplication: Rapid cell division.

  • Induction of the Neural Plate: Occurs at approximately $2-3 \, \text{weeks}$.

• The Neural Tube:

  • The dorsal surface thickens, forming a neural tube surrounding a fluid-filled cavity.

  • This cavity, filled with cerebrospinal fluid (CSF), eventually becomes the central canal of the spinal cord and the four ventricles of the brain.

  • The Neural Crest develops into the Peripheral Nervous System (PNS).

• Developmental Timeline:

  • $2-3 \, \text{weeks}$: The Central Nervous System (CNS) begins to form.

  • $5-6 \, \text{weeks}$ ($40 \, \text{days}$): Bulges become visible on the neural tube differentiating into the hindbrain, midbrain, and forebrain.

  • $7 \, \text{weeks}$: Regional differentiation becomes evident.

  • $11 \, \text{weeks}$: The brain resembles a mature structure, though the cortex remains smooth with few convolutions.

  • $39-40 \, \text{weeks}$ (Birth): Significant increase in cortical surface area characterized by extensive convolutions.

The Five Stages of Neuronal Development

1. Proliferation:

   • The production of new cells. After the neural tube forms, cells lining the ventricles divide rapidly.

   • Some become stem cells (which continue to divide), while others become neurons or glia (astrocytes, oligodendrocytes, or microglia).

   • Peak production rate is approximately $250 \, \text{million}$ ($2.5 \times 10^{8}$) neurons per minute.

   • The brain overproduces neurons, many of which are later eliminated. Health at this stage is critical; toxins, infection, or malnutrition have severe consequences.

2. Migration and Aggregation:

   • Newly formed neurons move to their final destinations, guided by chemicals: immunoglobulins (which attract) and chemokines (which repel).

   • Movement is slow; a short migration can take approximately $1.5 \, \text{hours}$.

   • Aggregation: Once arrived, neurons align with neighbors to form structures, mediated by Neural Cell Adhesion Molecules (NCAMs).

   • Errors in migration are linked to lissencephaly (smooth brain) and epilepsy.

3. Differentiation:

   • A primitive neuron initially resembles any other cell. Differentiation occurs as it develops its distinctive shape.

   • Axons grow first, followed by dendrites.

   • The growth cone at the tip of the axon navigates using chemical signals.

4. Myelination:

   • The process where glia produce the fatty sheath covering axons to speed up neural impulse transmission.

   • It starts in the spinal cord and proceeds to the hindbrain, midbrain, and forebrain.

   • This process continues gradually for decades.

5. Synaptogenesis:

   • The formation of synapses. The infant brain forms approximately $1 \, \text{million}$ new synapses per second.

   • Connections are initially overproduced and then refined/pruned based on spontaneous neural activity.

   • Successful synapses receive neurotrophins, such as Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF), which ensure survival. Unsuccessful ones undergo apoptosis.

Axon Guidance and Neuronal Survival

• Axonal Pathfinding: Sperry's ($1954$) research with newts demonstrated that axons follow a chemical trail to reach targets. Growing axons move along a gradient of chemicals that either attract or repel them.

• Survival Determinants:

  • Neurons compete for neurotrophins ($NGF, BDNF$).

  • Apoptosis: Programmed cell death that occurs if a neuron does not receive sufficient neurotrophic support.

  • Clinical Relevance of BDNF: Low levels are linked to depression, Alzheimer's disease, and PTSD. Levels can be increased via exercise, antidepressants, and enriched environments.

Neuroplasticity and Adult Neurogenesis

• Neuroplasticity: The brain's ability to change structure or function in response to experience, injury, or disease. Mechanisms include synaptic/structural plasticity, adult neurogenesis, and cortical reorganization.

• Structural Evidence:

  • Mouse studies show approximately $6\%$ remodeling of dendritic trees per month.

  • Jewelfish and rats raised in enriched environments show more dendritic branching and a thicker cortex compared to those in isolation.

• Human Evidence:

  • London Taxi Drivers: Show enlarged posterior hippocampi.

  • Musicians: Show enlarged auditory and motor cortex.

  • Blind Individuals: The visual cortex is recruited for touch and Braille reading.

• Adult Neurogenesis:

  • Recognized in the $1960s$; accepted in the $1990s$. Professors Perry Bartlett and Linda Richards ($1992$) discovered neural stem cells in the adult mouse brain.

  • In humans, it occurs in the subgranular zone (SGZ) of the dentate gyrus (hippocampus), the subventricular zone (SVZ) of the lateral ventricles, and the amygdala.

  • It is linked to memory and mood; reduced by stress/aging and increased by exercise.

Lifelong Development and Vulnerability

• Major Turning Points: Research suggests shifts at ages $9, 32, 66, \text{and } 83$.

  • $0-9 \, \text{years}$: Early childhood (rapid growth, pruning).

  • $9-32 \, \text{years}$: Adolescence/early adulthood (connectivity peak; maturation continues into the $30s$).

  • $32-66 \, \text{years}$: Adulthood (stability, gradual segregation).

  • $66-83 \, \text{years}$: Early older age (white matter decline, reorganization).

  • $83+ \, \text{years}$: Late life (structural decline).

• Vulnerability factors: Malnutrition, toxins, alcohol, infections, and chronic stress.

• Fetal Alcohol Syndrome (FAS): Alcohol inhibits glutamate (NMDA) receptors and enhances GABA activity, leading to reduced neural activity and decreased neurotrophin signaling, which triggers increased apoptosis.

Brain Damage and Recovery Mechanisms

• Causes: Tumors, infections, toxins, radiation, degenerative diseases, and closed head injuries (e.g., stroke, gunshot wounds).

• Later Mechanisms of Recovery:

  • Diaschisis: A temporary shock in areas connected to the damaged region. Function returns as these areas readjust.

  • Axon Sprouting: Healthy axons grow new branches to fill the vacancies left by lost connections.

  • Denervation Supersensitivity: Remaining neurons become hypersensitive to input to compensate for loss.

Phantom Limb Phenomenon

• A sensation, often including pain, felt in an amputated limb, affecting the majority of amputees.

• Theoretical Explanations:

  • Cortical Reorganization: The brain map changes; for example, the face area expands into the original hand/arm area of the cortex. This explains why touching the face can produce sensations in a phantom arm.

  • Stable Body Maps: Newer evidence suggests hand representations may remain in the brain, and phantom movements activate the same cortical patterns regardless of amputation, with limited evidence for total face-area takeover.