Chapter 23: Wiring the Brain
Neurodevelopment
Adult Brain
Precise interconnections among 85 billion neurons
Brain Development
Ectoderm → tube → CNS
Neurogenesis, synaptogenesis, pathway formation connections formed and modified
Wiring
Establishing correct pathways and targets
Fine-tuning based on experience
The Genesis of Neurons
Neuronal structure develops in three major stages:
Cell proliferation (making cells)
Cell migration
Cell differentiation
Cell Proliferation
Two layers of vesicle walls:
Ventricular zone - lines the inside of each vesicle (where cell proliferation occurs)
Marginal zone - faces the overlying pia
Five “positions” of cell proliferation
First Position - a cell in the ventricular zone extends a process that reaches upward toward the pia
Second Position - the nucleus of the cell migrates upward from the ventricular surface toward the pial surface; the cell’s DNA is copied
Third Position - the nucleus, containing two complete copies of the genetic instructions, settles back to the ventricular surface
Fourth Position - the cell retracts its arm from the pial surface
Fifth Position - the cell divides
Symmetrical - becomes another radial glia
Asymmetrical - becomes another cell type (ex: neural precursor cell)
Radial Glial Cells - neural progenitors that give rise to all the neurons and astrocytes of the cerebral cortex
Multipotent - can become other cell types when they divide
Primates have a second proliferative layer of cells, the subventricular zone
Neurons from the layer make up the upper layers of the cortex (layers 2 and 3)
In the adult brain, this layer of cortex is the source of corticocortical connections that connect cytoarchitecturally distinct areas
Cell Migration
Neural Precursor Cells - immature neurons that slide along the thin fibers emitted by radial glial cells from the ventricular zone to the surface of the brain
Including future pyramidal cells & astrocytes
1/3 of these cells migrate laterally on their way to the cortex
Future inhibitory interneurons & oligodendroglia
Neural precursor cell destined to become the adult cortex cross the subplate and form the cortical plate
The first cells to migrate away from the dorsal ventricular zone are destined to reside in the subplate, which eventually disappears as development proceeds
Layers form from the “inside out”
Cell Differentiation
Cell differentiation is the process by which a cell takes on the appearance and characteristics of a neuron
The consequence of a specific spatiotemporal pattern of gene expression
Differentiation of neural precursor cell into a neuron:
Neurites sprout off the cell body
Differentiation is programmed well before the neural precursor cell arrives at its final resting place
The protein semaphorin 3A is secreted by cells in the marginal zone
Repels growing pyramidal cell axons to stream them away from the pial surface and attract the dendrites to stream toward the brain surface
The apical dendrites grow in the direction of the higher concentration
Axons are repulsed by high concentrations, so it grows in the opposite direction of the apical dendrites
Begins when cells arrive in cortical plate
Differentiation of Cortical Areas
Radial Unit Hypothesis - the entire radial column of cortical neurons originates from the same birthplace in the ventricular zone
Neurons in different regions of cortex have distinct molecular identities
Emx2 (posterior) and Pax6 (anterior) are two complementary gradients of transcription factors along the anterior-posterior axis of the ventricular zone of the developing neocortex
Helps in cell differentiation from a limited number of genes
Experiment: Remove gradients to test if transcription factors affect the placement of cell development
Loss of EMX2: increased motor and somatosensory cell densities
Loss of PAX6: increased visual cell densities
For neurons that migrate laterally
Subplate neurons attract the appropriate thalamic axons to different parts of the developing cortex
The axons innervate distinct populations of subplate cells
They invade the cortex when the overlying cortical plate grows to a sufficient size
The subplate layer of earliest born neurons contain the instructions for the assembly of the cortical quilt
Atomic Bomb Adult Neurogenesis - granular cells of the dentate gyrus C-14 suggests continual neurogenesis post adolescence
BrdU → integrates into new cells undergoing mitosis
Using immunocytochemistry
Could also be non-neuronal cells (like glial cells)
NeuN makes cells green, both make it yellow; neurons showed neurogenesis with BrdU
Activity: Relationship between depression, BDNF, and adult neurogenesis
decreased Adult Neurogenesis → low Hippocampal BDNF → Depression
Depression → decreased Adult Neurogenesis → low Hippocampal BDNF
low Hippocampal BDNF → decreased Adult Neurogenesis → Depression
The Genesis of Connections
As neurons differentiate, they extend axons that must find their appropriate targets
This pathway formation occurs in three phase:
Pathway selection - which direction to go
Target selection - where to go
Address selection - which area to go
Each of the three phases of pathway formation depends on communication between cells:
Direct cell—cell contact, contact between cells and the extracellular secretions of other cells, and communication between cells over a distance via diffusible chemicals
The Growing Axon
Growth Cone - the growing tip of a neurite; identifies an appropriate path for neurite elongation
Lamellipodia (flat membrane) → filopodia (sense and grip ECM) → laminin (using integrins, or gripping proteins)
Growth occurs only if the extracellular matrix contains the appropriate proteins
Fasciculation - a mechanism that causes axons growing together to stick together
Due to the expression of specific surface molecules called cell-adhesion molecules (CAMs), which bind neighboring axon membrane tightly to one another, causing the axons to grow in unison
Axon Guidance
Pioneer axons stretch as the nervous system expands and guides their later developing neighbor axons to the same targets
Guidance cues and growth cone membrane molecules determine the direction and amount of growth via guidance cues being attractive or repulsive (must be coordinated to get the correct response)
Chemoattractant - a diffusible molecule that acts over a distance to attract growing axons toward their targets
Netrin - a protein secreted by neurons in the ventral midline of the spinal cord, whose gradient attracts the axons of dorsal horn neurons (w/ netrin receptors) that will form the spinothalamic tract
Chemorepellent - a diffusible molecule that chases axons away
Slit - a protein that sends a signal to growth cones to express more slit receptor (robo), so axons grow away from the midline
Chemoaffinity Hypothesis - chemical markers on growing axons are matched with complementary chemical markers on their targets to establish precise connections
Ex: In frogs, retinotopy is established when the nasal retina projects to the posterior tectum and the temporal retina projects to the anterior tectum
Synapse Formation
When the growth cone comes in contact with its target, a synapse is formed
The first step is induction of a cluster of postsynaptic receptors under the site of nerve—muscle contact
Synapse Formation:
Dendritic protrusion (filopodium) reaches out and touches an axon passing by
A preassembled presynaptic active zone is deposited at the site of contact
Recruitment of NT receptors to the postsynaptic membrane
Specific adhesion molecules are expressed by presynaptic and postsynaptic membranes that serve to glue the partners together
The Elimination of Cells and Synapses
The development of proper brain function requires a careful balance between the genesis and elimination of cells and synapses
Cell Death
Entire populations of neurons are eliminated during pathway formation by a process known as programmed cell death
Reflects competition for tropic factors, life-sustaining substances that are provided in limited quantities by the target cells
Produces the proper match in the number of presynaptic and postsynaptic neurons
Taken up retrogradely (reverse)
Neurotrophins - a family of related trophic proteins (ex: nerve growth factor [NGF])
Promotes neuronal survival by switching of the genetic programmed cell death
Signal through Trk receptors
Apoptosis - the systematic disassembly of the neuron; organelles are still functional
Ex: can result in Alzheimer’s
Necrosis - damaged cells that explode
Ex: can result from head trauma
Changes in Synaptic Capacity
Synaptic Capacity - the finite number of synapses a neuron can receive on its dendrites and soma
This peaks early in development and then declines as the neurons mature
Synaptic capacity declines sharply during adolescence (synaptic pruning)
In muscle fibers, the initial polyneuronal innervation is replaced by synaptic input from a single alpha motor neuron
The first change during synapse elimination is the loss of postsynaptic AChRs, followed by the disassembly of the presynaptic terminal and retraction of the axon branch
Caused by insufficient receptor activation in an otherwise active muscle
Spontaneous retinal waves in development form the organization of the LGN (Hebbian modification)
Look at images
Coordination of synaptic activity is preferred
Hubel and Wiesel
Ocular dominance columns
cells responding to signals in a specific eye
some from left and some from right (look at monkey study)
Ocular deprivation studies
(study covering one eye)
columns shrink w/ visual deprivation (during critical period)
Activity-Dependent Synaptic Rearrangement
Synaptic rearrangement (competition), a change from one pattern of synapses to another, is widespread in the immature brain
Ex: Two presynaptic neurons providing 3 synapses each to a target cell vs. one providing 1 synapse and the other providing 5 synapses
Occurs as a consequence of neural activity and synaptic transmission
Also experience dependent because it relies on the quality of the sensory environment
Occurs after birth and is influenced by sensory experience during childhood
Critical Period - specific times when developmental fate is influenced by the environment
Elementary Mechanisms of Cortical Synaptic Plasticity
Rules for Synaptic Modification:
Neurons that fire together wire together (Hebb’s Law)
Neurons that fire out of sync lose their link
Long-Term Synaptic Potentiation
Long-Term Potentiation (LTP) - a strengthening of synaptic transmission from strong NMDA receptor activation and resulting flood of Ca2+ into the postsynaptic dendrite
Results in the insertion of new AMPA receptors into the synaptic membrane
Long-Term Synaptic Depression
Long-Term Depression (LTD) - active synapses are decreased in effectiveness from the lower level of NMDA receptor activation and less Ca2+ influx
Results in a loss of AMPA receptors from the synapse and synapse elimination over time
Why Critical Periods End
Three Current Hypotheses:
Plasticity diminishes when axon growth ceases
Due to changes in the ECM or the myelination of the axons by oligodendroglia
Plasticity diminishes when synaptic transmission matures
Plasticity diminishes when cortical activation is constrained