The Developing Brain: Comprehensive Notes

The Developing Brain

Questions to Keep in Mind

• How is the brain changing across early development?
• How do experiences/INPUTS impact brain development (age- vs experience-related changes)?
• Are there regional changes in brain development, and if so, how do they relate to behavior?
• Can we accelerate, delay, extend, or prevent a critical period?
• What are critical periods of development?
• What triggers critical periods?
• What closes critical periods (brakes)?
• Why would we want to close critical periods?
• How might critical periods inform disease models or aging?

Fetal Development

• Nervous systems of mammals, birds, reptiles, and fish all develop according to a similar plan.
• Almost all animals initially form 3 germ layers (groups of cells in the embryo).
  • Exception: Cnidarians (aquatic animals) form 2 layers – no mesoderm (bone and muscle).
• Germ layers develop through gastrulation, during which a blastula (hollow cluster of cells) reorganizes into:
  • Endoderm (inner layer)
  • Mesoderm (middle layer)
  • Ectoderm (outer layer)

Germ Layers and Tissue Development

• Within a week of conception, the human embryo forms three distinct tissue layers:
  • Endoderm: Inner layer that gives rise to digestive and respiratory systems (lungs, liver, pancreas).
  • Mnemonic: Endoderm: inner layer, respiration, digestion
  • Mesoderm: Middle layer that gives rise to bone, muscle, and connective tissue.
  • Mnemonic: Mesoderm: middle layer, muscle
  • Ectoderm: Outer layer that gives rise to skin and the nervous system.
  • Mnemonic: Ectoderm: external/outer layer, nervous system, skin
  • The ectoderm layer closes in upon itself to form the neural tube, which is the precursor to the brain and spinal cord.

Neural Tube Development

• By the fourth week after fertilization, one end of the neural tube begins to show three swellings that will become the forebrain, midbrain, and brainstem and cerebellum.
• The other end of the tube closes and forms the spinal cord.
• Review:
  • The brainstem connects the cerebrum of the brain to the spinal cord and cerebellum and consists of midbrain, pons, and medulla.
  • The midbrain includes inferior and superior colliculi and dopamine cell bodies.

Neuronal Development Phases

• Neurons pass through five developmental phases:
  1. Cell birth
  2. Migration
  3. Differentiation
  4. Axon Growth
  5. Cell death

1) Cell Birth

• The ventricular zone (inner portion of the neural tube wall) contains newly born cells that give rise to neurons and glia of the nervous system.
• These “soon-to-be brain cells” are called neural progenitor cells.

2) Migration

• Neural progenitor cells leave the ventricular zone and migrate through an intermediate zone of the neural tube before reaching their destination in the brain.
• The marginal zone, along with the cortical zone, make up the 6 layers that form the cortex.
• Cells migrate to the cortex, guided by the radial glial cells.

3) Differentiation

• Once a cell has arrived at its destination, it takes on the shape (morphology) and function of other cells in the region.
• As it becomes a particular type of cell, it undergoes differentiation.
• Because cells differentiate and take on the appearance of other nearby cells, the different layers of the cerebral cortex are filled with cells that all share a relatively similar size and shape.
  • One layer of the cortex contains neurons with very small cell bodies.
  • Another layer has medium-sized neurons.
  • Another contains very large neurons in the shape of pyramids.

4) Axon Growth

• To find its targets, axons also rely on the growth cone (purple) located at the tip of the developing axon (green).
• Chemoattractants (+) and chemorepellents (–) signal to the developing axon which direction to move and which to avoid.
• The chemorepellents prevent the developing axon from veering off course.

4) Axon Growth (Continued)

• The growth cone temporarily adheres to the cell adhesion molecules (CAMs).
• Chemoattractant and chemorepellent signals combine with cell adhesion molecules to guide the movement of the growth cone and its axon.

5) Cell Death

• During brain development, a large number of cells are created and then several are lost through programmed cell death (apoptosis).
• Without apoptosis, the brain would grow too large to fit in the skull (e.g., interference with apoptosis in mouse fetus).
• We create more neurons than needed.
• Then remove extra ones just like when we plant many seeds and then remove excess plants that sprout up leaving only a few to best thrive in the environment.

Neurotrophic Factors

• Nerve growth factor (NGF) is a protein that prevents apoptosis and also promotes neuronal growth
• When added into a dish containing clumps of developing neurons, the cells undergo explosive growth of axons and dendrites.
• In the absence of NGF, the neurons died.

Prenatal/Fetal Brain Development

• Includes diagrams showing brain development at 25 days, 35 days, 40 days, 50 days, 100 days, 5 months, 6 months, 7 months, 8 months, and 9 months.

Postnatal Development

• Difference between a 1-year-old and a 40-year-old brain.

Changes in Brain Weight with Age

• Brain weight:
  • 400 g (newborn)
  • 1100 g by 3 years (toddler)
  • 1350 g by 6 - 7 years (child)
  • 1459 g by 20s (adult)

Dynamic Changes in Brain Organization with Age

• Even though brain mass reaches ~adult levels by roughly childhood, there are still big changes in the rewiring of brain circuitry and myelination, etc.

Imaging the Developing Brain

• Uses noninvasive MRI techniques.
  • Structural MRI: Gray matter, white matter.
  • Gray Matter Plasticity: Axon sprouting, Dendritic branching, Neurogenesis
  • White Matter Plasticity: (Myelin formation), Oligodendrocyte, Axons, Myelin
  • Diffusion Weighted Imaging: Provides information about direction of fibers and cell density (diffusion inside vs outside cells) and cell density (restriction spectrum imaging).
  • Task-based Brain Activity: based on changed in blood oxygenation
  • Functional Connectome: Correlated activity across regions of the brain during rest or tasks

Brain Maturity

• Is there a neural signature of maturity?
• Estimated age of developmental asymptote varies by brain region:
  • Frontal: 20-25 years
  • Temporal: 15-20 years
  • Parietal: 15-20 years
  • Occipital: 10-15 years
  • Whole brain
• Changes in peak cortical thickness from 5 to 20 years of age.
• Regional changes in Peak Cortical Thickness from Childhood to Early Adulthood
  • Sensorimotor cortex reaches peak cortical thickness before association cortex (e.g., prefrontal cortex).

Multimodal Quantitative Anatomical Prediction of Age

• Age-varying contribution of different Imaging Measures in Prediction of Age
  • Cortical area is the strongest predictor in childhood, whereas subcortical volume is a strong predictor during adolescence.

Functional Connectome-based Prediction

• Functional connections within the brain are like a fingerprint, with an individualized pattern that makes each of us distinct from one another.
• The Functional Connectome becomes more distinct with increasing age

Maturity of Functional Networks

Brain Maturity

• Continued changes well into adulthood (i.e., the brain is plastic) but stabilization of circuits begins to emerge by adolescence.
• Is there a brain maturity index that could be used like height and weight growth charts?
• Heroic attempts.
• Developmental asymptote (change that levels off or plateaus) varies by brain region/circuit, imaging modality, and other factors (sex, emotional state).

Regional Changes in Brain Development

• Sensorimotor cortex reaches peak cortical thickness before association cortex (e.g., prefrontal cortex).
• Changes also occur in deep subcortical limbic regions during adolescence
  • Subcortical limbic regions involved in desire, rage, fight & flight Focus has typically been on prefrontal cortex (PFC)
• Imbalance in the development of primitive circuits involved in desire, fear, rage, and those involved in self-control (peak dev of subcortical emotional circuits during mid to late teens while emotional control circuits continue to develop into 20s)
• Development of the emotional brain as hierarchical from subcortical to cortical circuitry
• Development of lower-level circuits instantiates the development of subsequent circuits.

Synaptogenesis and Synaptic Pruning

• Synaptogenesis is the formation of synapses, the points of contact where information is transmitted between neurons and is integral for creating brain networks, and for the overall architecture of brain connectivity.
• An explosive increase in synapses occurs in the early postnatal period, mostly peaking within the first few years after birth
• Synaptogenesis and the subsequent pruning of synapses appears to be region-specific (peaks and then decreases in the primary visual cortex earlier than in the prefrontal cortex).
• This pattern is paralleled by cortical thickness changes observed in humans with MRI, but MRI does not have the spatial resolution to detect individual synapses.

Synaptogenesis Experiments

• Is the surge in synapses (synaptogenesis) due to all the input at birth?
• Does premature visual stimulation affect the rate of synaptic over-production?
  • The # of synapses in the visual cortex was compared in monkeys born prematurely (3 weeks early) versus those born full term controlling for gestational age (tested at 1 day or 1, 2, or 3 weeks postconception).
  • There was no significant difference in # of synapses between preterm and full-term animals.
  • So surge in synapses early in development is not time-locked with birth itself.
• Does preventing retinal input to the visual cortex affect the rate and number of synaptic over-production?
  • Measured # of synapses in the visual cortex in animals with embryonic removal of eyes and control animals at 3 months or 3 years
  • There was no difference in # of synapses in the visual cortex between animals with no visual input compared to control animals.
• There is a thick overgrowth of synapses at birth (full-term).
• The brain becomes more receptive to input.
• Experiences prune less relevant synapses and strengthen relevant ones.
• Neurons that fire together wire together.
• Neurons out of sync lose their link.
• No effect of experimental manipulations (premature birth, removal of visual input) on the absolute # of synapses in the visual cortex.
• The findings suggest that the initial formation of synaptic contacts is dominated by intrinsic mechanisms, whereas subsequent pruning of synapses is influenced more by evoked activity and experience.
• Even in the immature system, see spontaneous activity that can facilitate wiring of the brain as shown in the visual system by Carla Shatz.

Synaptogenesis vs. Synaptic Pruning

• Different mechanisms and developmental patterns dominate synaptogenesis and synaptic pruning
  • Synaptogenesis (more intrinsic)
  • Synaptic pruning (more activity/input)

Critical Periods

• A WINDOW of TIME, typically in early development, during which a system is open to structuring / restructuring on the basis of input from the environment.
• Before and after this period, environmental influences cannot affect the sensitivity or response of that system.
• TIMING of the opening of this window is constrained by the maturation of the underlying circuit (biological readiness).
• INPUT is necessary to trigger the opening (i.e., animals reared in the dark remain open to visual influences until a later maturational age, beyond which there is eventually a closing).

Imprinting

• Unlike altricial birds that remain helpless in the nest for several weeks after hatching, precocial birds quickly start walking around.
• They need to follow a caregiver for their own safety and survival; thus imprinting is vital to their early survival.
• Imprinting occurs early!
• Imprinting occurs between 8 and 24 hours with only a 10-minute exposure.
• Ducklings exposed to a male duck model the first day of life continue to respond to it, even if a louder/closer female model is presented later.
• The object/animal needs to bear some visual resemblance to conspecific (boots, box on train)

Evidence of Critical Periods (Visual System)

• Kittens raised with goggles that contained only horizontal lines over one eye and only vertical lines over the other eye the first 3 months of life.
• As adults, their visual cortex could not respond to lines other than vertical or horizontal lines (didn’t respond to diagonals).

Ocular Dominance Columns

• Afferent pathways from the two eyes project to discrete columns of neurons in the visual cortex.
• Neurons in the primary visual cortex are organized in alternating sets of ocular dominance columns.
• Each column receives input from only one eye.
• Visual deprivation of one eye during critical period reduces ocular dominance column width for that eye.
• Closure of one eye before the visual dominance columns begin to form and throughout the critical period will prevent the formation of columns.
• Hubel, Wiesel & LeVay 1977 Closure at 2, 3, or 6 weeks for 15 weeks each
• Closure has a weaker effect on the formation of ocular dominance columns the later it is done because the columns become more segregated with time.

Neural Plasticity

• Plasticity can allow brain areas to take on new functions, especially during development
• For instance, young children with severe seizures (rare) underwent surgery where one-half of the entire forebrain was removed.
• The remaining hemisphere took over many of the cognitive and motor functions that would normally have been carried out by the other half of the brain.
• Following amputation of an arm, inputs from the neighboring areas (e.g., face) expand into what had been the hand and arm somatosensory areas.
• Now when you touch the individual’s face, there is a perception of touch in the missing arm (phantom limb)

Neurotrophic Factors and Plasticity

• Nerve growth factor (NGF) is a protein that promotes neuronal growth and prevents apoptosis.
• When added into a dish of clumps of developing neurons, the cells undergo explosive growth of axons and dendrites.
• In the absence of NGF, the neurons died.
• BDNF plays a critical role in plasticity and learning.
• Excitatory connections are pruned (especially in PFC throughout adolescence), which is thought to lead to an imbalance during this period in circuitry related to a shift in the E/I balance.

GABA and Critical Periods

• The onset of the critical period is determined by the maturation of particular inhibitory GABA cells (Parvalbumin cells)
• Parvalbumin is a subtype of GABA neuron (large basket cell) that acts as a pivotal plasticity switch underlying Critical Period
• GABA helps to bring order to chaos!
• GABA from Parvalbumin cells tell excitatory cells to basically hush.
• Shift in balance from more excitatory to more inhibitory synapses
• Opening…………………Closing

Stabilization and Closing of Critical Period

• Myelination of axons
  • Formation of myelin creates physical barriers to sprouting/axonal growth
• Perineuronal nets
  • Lattice of molecules consisting of proteins and sugars that wrap around the parvalbumin cells as they mature; coincides with the end of Critical Period (barrier)

Songbird Example

• Critical period for Zebra Finch ~20-90days*
• * varies by species
  1. A songbird must hear vocal sounds of adults during a critical period and then hear its own voice when learning to imitate those sounds (like infant babbling).
  2. Depriving juvenile of adult tutor (isolate) can delay/extend closure of critical period, but not indefinitely.
  3. Social signals can influence songs. Zebra Finch’s song is less complex when alone than with a female (e.g., singing in the shower vs singing below the balcony of their sweetheart).
  • “Bird Brain” more like social brain!

PNNs and PV neurons during critical period

• The more PNNs & PV neurons the more temporally complex and effective the mating song.
• Isolation from an adult song tutor decreases co-localization and number of PV neurons and PNNs in HVC diminishing effectiveness of song for mating.

Plasticity and Consolidation

• Plasticity is a process by which experiences reorganize neural connections/pathways.
• Long-lasting functional changes in the brain occur when we learn new information (consolidation).
• In the immature brain, learning is susceptible to being lost or “erased”.

Fear Memories

• Preadolescent “fear extinction” is not due to simple degradation but to greater susceptibility to interference from competing inputs

Perineuronal Nets (PNNs) and Fear Memories

• Development of Perineuronal Nets (PNNs) in the Basolateral Amygdala.
• # of PNNs increase across postnatal development.
• > Recovery of cued fear and fear renewal in P23 mice w/ >PNNs
• Loss of PNNs renders fear memory traces susceptible to erasure, but does not interfere with memory consolidation.

Manipulation of GABA and Critical Periods

1. Manipulation of GABA pharmacologically (enhance) with benzodiazepines (Valium, Xanax) can accelerate critical periods.
2. Genetic downregulation of GABA can delay critical periods.

Neural Plasticity Manipulations

• Because GABA levels are so important for critical periods, the manipulation of GABA can impact the onset of a critical period.
• Insufficient input Sufficient input Prevent perineuronal net/myelin forming Knock-down GABA genetically No input during CP Closing eye from birth

PNNs and Aging

• PNNs appear to increase in the prefrontal cortex by adolescent years
• Fewer PNNs in the auditory cortex in 2 strains of mice by old age.
• Loss of PNNs are associated with aging in auditory cortex of 2 strains of mice

Aging Study

• For the 1st time, the old are outnumbering the young (<5 yr).
• Decreased # of children born and increases in life expectancy related to population of aging accelerating
• Individual variation in Age-related Cognitive Decline
• Cognitive Performance can vary widely with age
• Nourishment in utero and during infancy has a direct bearing on the development of risk factors for adult diseases-especially cardiovascular diseases).
• Lapses in memory with Dementia are in sharp contrast to what we call ”senior moments” with relatively healthy aging.
• Alzheimer is the most prevalent of the dementias, affecting over 12% of >65 year olds (risk increases with age)

Alzheimer's Disease

• Marked shrinkage and ventricular enlargement with Alzheimer’s disease
• Regional concentration of neurofibrillary tangles and plaques
• Environmental and genetic factors and their interaction are associated with risk for Alzheimer disease

Alzheimer's Brain Pathology

• Two signs of Alzheimer’s brain pathology
  1. Amyloid plaques are clusters of beta-amyloid protein located within extracellular spaces in the brain
  2. Neurofibrillary tangles are clusters of misfolded tau protein located inside of neurons
• The # of plaques in Alzheimer’s patients does not correlate with cognitive impairment but # of tangles does correlate with both neuronal loss and the degree of the patient’s cognitive decline.

Environmental and Genetic Factors in Alzheimer's

ApoE Gene and Alzheimer's Risk

• Polymorphisms in ApoE gene and risk for Alzheimer’s disease
• Three ApoE alleles (E2, E3, E4)
• ApoE E2 and E4 alleles are rare in the general population
• Increase # of E4 allele (0, 1, 2) increases risk for Alzheimer’s

Lecanemab (Leqembi)

• Lecanemab (Leqembi) that targets β-amyloid protein for people with mild Alzheimer's disease and mild cognitive impairment due to Alzheimer's disease (?clinical significance of small effect?)

Aducanumab

• Aducanumab's efficacy as a treatment for the cognitive dysfunction in Alzheimer's disease cannot be proven by clinical trials with divergent outcomes but FDA approved (2021).

PNNs in Alzheimer's Disease

• -At least 2 studies report reduction of PNNs in the human Alzheimer's brain.
• PNNs localize with both plaques and tangles, so are either instrumental in, a reaction to, or formation of them.
• Alternatively, PNNs may provide protection against excitotoxicity, oxidative stress, and neurofibrillary tangles.