Exhaustive Overview of Brain Plasticity and Behavior in the Developing Brain

General Principles of Brain Development and Plasticity

• Historical Context of Development: Approximately $2,000$ years ago, Roman philosopher Seneca proposed that a human embryo was simply an adult in miniature, and development was merely growing larger. This view persisted until the $19^{th}$ century. Modern neurobiology identifies that brain development is a series of stages divided into two primary phases.

  • Phase One: A genetically determined sequence of events occurring in utero, which can be modulated by the maternal environment.

  • Phase Two: Occurring pre- and postnatally in humans, this phase is characterized by brain connectivity being highly sensitive to the environment and patterns of activity produced by experience.

• Definition of Epigenetics: These are changes in developmental outcomes, including the regulation of gene expression, based on mechanisms other than the DNA sequence itself. Experiences can alter gene expression, leading to organizational changes in the nervous system.

• Conceptual Overview: Brain development reflects a "complex dance" of genetic and experiential factors rather than a simple genetic blueprint. Pre- and postnatal factors, including sensory stimuli, drugs, diet, hormones, and stress, sculpt the emerging brain.

The Sequential Stages of Brain Development

• Cell Formation Timelines:

  • Neural Tube Formation: Cells destined for the nervous system begin forming approximately $3$ weeks after fertilization.

  • Subventricular Zone: The neural tube later becomes the subventricular zone, referred to as the "brain's nursery."

  • Cerebrum Development: Cell division for the cerebrum begins at about $6$ weeks; by $14$ weeks, the cerebrum appears distinctly human.

  • Sulci and Gyri: These structures do not begin to form until approximately $7$ months of gestation.

• Neurogenesis: Most neurogenesis is complete by $5$ months.

  • Exception: The hippocampus continues to form neurons throughout the lifespan.

  • Numerical Specifics: Each human cerebral hemisphere requires approximately $10,000,000,000$ ($10$ billion) cells. At the peak of formation, an estimated $250,000$ neurons are produced per minute.

• Cell Migration: Neurons migrate along fibrous pathways created by radial glial cells extending from the subventricular zone to the cortical surface. The subventricular zone contains a primitive map of the cortex, guiding cells to specific locations.

• Cell Differentiation: Migrating cells have unlimited potential until তারা reach their destination, where genes, maturation, and environmental factors steer them into specific cell types.

• Cell Maturation:

  1. Dendrite Growth: Provides surface area for synapses. Growth is slow, at a rate of several $\mu m$ per day.

  2. Axon Extension: Axons grow approximately $1,000$ times faster than dendrites, at a rate of roughly $1\,mm$ per day. This allows axons to contact targets before dendrites are fully formed, influencing circuit differentiation.

• Synaptogenesis:

  • The human cerebral cortex contains more than $100,000$ trillion ($10^{14}$) synapses.

  • Peak synapse formation occurs between $1$ and $2$ years of age.

• Pruning and Cell Death: The brain overproduces neurons and connections. Unneeded elements are removed via cell death and synaptic pruning, acting as a "metaphorical chisel" shaped by epigenetic signals, experience, hormones, and stress.

• Myelination: The birth of astrocytes and oligodendrocytes begins after neurogenesis. While axons can function before myelination, adult levels of function are reached only after myelination is complete, which occurs after $18$ years of age in the prefrontal, posterior parietal, and anterior temporal cortex.

Special Physiological Characteristics and Synaptic Categories

• Stem Cells: Cells lining the subventricular zone remain active throughout life, producing neural or glial progenitor cells that can migrate into adult white or gray matter. These can be activated by injury.

• Adult Neurogenesis: The mammalian brain generates new neurons in adulthood for the olfactory bulb and hippocampal formation.

• Experience-Expectant vs. Experience-Dependent Synapses (Greenough, Black, and Wallace, 1987):

  • Experience-Expectant: Early-forming, diffuse synapses that "expect" experience to prune them back.

  • Experience-Dependent: Later-forming, focal synapses localized to regions processing specific experiences. These are added or pruned based on specific learning and memory processes.

Eight General Principles of Plasticity in the Normal Brain

1. Multiple Levels of Analysis: Plasticity can be observed via global imaging (MRI), anatomical measures (cell morphology), physiological measures (cortical stimulation), or molecular changes (gene expression/calcium channels).

2. Independent Measurability: Different neuronal changes, such as spine density and dendritic length, do not always move in tandem; they can vary independently or in opposite directions.

3. Focal Experience-Dependent Changes: Chronic plastic changes (e.g., from drugs) are often surprisingly localized (e.g., to the prefrontal cortex or nucleus accumbens) rather than widespread.

4. Time-Dependency: Changes can be transient or permanent. Rats in complex housing show increased dendritic length in the prefrontal cortex at $4$ days that disappears by $14$ days, while sensory cortex changes only appear after $14$ days.

5. Interaction of Experiences: Prior experiences modulate later ones. Exposure to psychomotor stimulants (e.g., methylphenidate or amphetamine) can block expected plastic changes from later enriched environments.

6. Interaction Directionality: Mild stress during maximal neurogenesis ($E12-E18$ in rats) leads to stress-related changes in the prefrontal cortex but eliminates drug-related effects.

7. Age-Dependency: The brain responds differently to identical experiences at various ages. Juveniles in complex environments show a decrease in spine density, whereas adults and senescent rats show an increase.

8. Maladaptive Plasticity: Not all plasticity is beneficial. Pathological results include drug addiction behavior, chronic pain, epilepsy, schizophrenia, and dementia. Fetal alcohol spectrum disorder and severe prenatal stress are key examples in development.

Environmental Factors: Sensory and Motor Experience

• Deprivation: Raising animals in darkness, silence, or social isolation retards development.

  • Example: Puppies raised alone are virtually insensitive to pain (Hebb, 1949).

  • Example: Eye-sutured kittens suffer permanent loss of spatial vision (amblyopia) (Wiesel and Hubel, 1963).

• Enrichment/Enhancement:

  • Visual: Rats in a virtual optokinetic system with moving vertical lines showed a $25\%$ enhancement in visual acuity in adulthood (Prusky et al., 2008).

  • Tactile: Stroking infant rats with a brush for $15$ minutes, $3$ times daily, for $10-15$ days leads to enhanced skilled motor performance and spatial learning. This increases Fibroblast Growth Factor-2 ($FGF-2$) in the skin and brain.

  • Complex Environments: Housing rats in enriched spaces for $60$ days increases overall brain weight by $7-10\%$ and cortical synapses by roughly $20\%$.

Environmental Factors: Psychoactive Drugs

• Stimulants: Exposure to amphetamine, cocaine, or nicotine increases dendritic length and spine density in the medial prefrontal cortex ($mPFC$) and nucleus accumbens ($NAcc$), but decreases or does not change these in the orbital frontal cortex ($OFC$).

• Antipsychotics: Haloperidol and Olanzapine (typical and atypical) reduce dendritic length, branching complexity, and spine density in the medial prefrontal and orbital cortex, leading to impaired working memory (Frost et al., 2009).

• Anxiolytics and Antidepressants:

  • Diazepam (Valium): Increases dendritic length and spine density in parietal cortex; associated with enhanced skilled motor functions.

  • Fluoxetine (Prozac): Decreases dendritic measures; correlated with impaired spatial learning in adulthood.

• Permanent Plasticity Changes: Early drug exposure can permanently block the brain's ability to show plastic changes in response to enriched environments later in life.

Social and Biological Factors: Gonadal Hormones, Parent-Child, and Peer Relationships

• Gonadal Hormones:

  • Sexual Dimorphism: Human brain volume asymptotes at age $11$ for females and age $15$ for males.

  • Structural Differences: In rats, $mPFC$ neurons are larger in males, while $OFC$ neurons are larger in females. These differences disappear if animals are gonadectomized at birth.

• Parent-Child Relationships:

  • Maternal care (licking, grooming, high-arched nursing) modifies the hypothalamic-adrenal stress response and hippocampal cell membrane corticosterone receptors.

  • Maternal separation increases dendritic length and spine density in both the $mPFC$ and $OFC$ in adult rats.

• Peer Relationships and Play:

  • Play is essential for adult social competence.

  • The $OFC$ responds to the number of peers present, while the $mPFC$ responds to the amount of play.

  • Abnormal childhood play (as seen in Autism or ADHD) may negatively influence prefrontal development.

Early Physiological Stressors, Intestinal Flora, and Dietary Influences

• Early Stress: Prenatal stress is a risk factor for schizophrenia, ADHD, depression, and drug addiction.

  • Timing effects: Moderate stress in the $3^{rd}$ week of gestation reduces spine density in offspring; mild stress in the $2^{nd}$ week may increase spine density in juveniles but show different patterns in adulthood.

• Intestinal Flora (Gut Microbiota): Lack of normal gut microbiota influences signaling pathways and neurotransmitter turnover in the cortex and striatum, altering motor behavior development (Diaz Heijtz et al., in press).

• Diet:

  • Choline: Perinatal supplementation leads to enhanced spatial memory, increases Nerve Growth Factor ($NGF$) in the hippocampus, and increases dendritic length across the cerebral cortex.

  • Micronutrients: Vitamin/mineral supplements given to lactating rats increase dendritic length in the $mPFC$ and parietal cortex of offspring and can reverse the negative structural effects of mild prenatal stress.

Conclusion and Metaplasticity

• Metaplasticity: The process where experiences interact across a lifetime to alter both brain and behavior.

• Critical Windows: There are specific windows where the brain is more responsive; for example, injury to the motor cortex has a poorer outcome in early adolescence than late adolescence, while the reverse is true for prefrontal cortex injuries.

• Future Challenges: Identifying the specific gene expression changes (among hundreds affected) that are most closely associated with observed behavioral changes remains a primary target for neurodevelopmental research.