Wiring the Brain

Why does the brain need precise wiring to function?

Because neurons must form specific, correct connections to allow coordinated information processing, behavior, and actions.

What happens if neurons connect to the wrong targets?

Even small wiring errors can disrupt information flow and impair brain function.

What does the brain start as during early development?

A simple neural tube that generates neurons, guides migration, and forms synapses.

Why is wiring not random in the developing brain?

Molecular cues guide axons and neurons to the correct partners, and later experience refines these connections.

What are radial glial cells in early brain development?

Neural progenitors that also act as scaffolds for migrating neurons.

Where does mitosis occur for neural progenitors?

At the ventricular surface of the neural tube.

What is interkinetic nuclear migration?

Movement of the progenitor cell nucleus up and down as it progresses through the cell cycle.

What is symmetrical division in neurogenesis?

A division that produces two progenitors and expands the progenitor pool.

What is asymmetrical division in neurogenesis?

A division that produces one progenitor and one neuron, beginning differentiation.

Why must the developing brain balance symmetrical and asymmetrical divisions?

To maintain enough progenitors while also producing the correct number of neurons.

What role does Notch-1 play in neural progenitors?

It promotes progenitor identity and continued division.

What role does Numb play in neural progenitors?

It inhibits Notch signaling and promotes neuronal differentiation.

How does asymmetrical division influence cell fate?

Unequal distribution of Notch-1 and Numb makes one daughter remain a progenitor and the other differentiate.

What could happen if the Notch/Numb balance is disrupted?

Too much Notch causes too few neurons; too much Numb causes premature depletion of progenitors and brain malformations.

How do excitatory pyramidal neurons migrate?

Vertically along radial glial fibers toward the cortical surface.

Where are inhibitory interneurons generated?

In ventral structures like the ganglionic eminences.

How do inhibitory interneurons reach the cortex?

They migrate laterally (tangentially) across the brain.

What disorder results from severe failure of neuronal migration?

Lissencephaly, producing a smooth cortex.

What is the first temporary layer formed during cortical development?

The subplate.

Why is the cortex built in an “inside-out” manner?

Newer neurons must migrate past older ones to form more superficial layers.

Which cortical layers form earliest?

The deepest layers, such as layer VI.

Which cortical layers receive sensory input?

Middle layers, especially layer IV.

Which cortical layers integrate information across cortical areas?

Superficial layers (II and III).

How does semaphorin 3A influence neuronal orientation?

Dendrites grow toward high semaphorin 3A; axons grow toward low semaphorin 3A.

What two transcription factors create cortical area identity gradients?

Pax6 (high rostral) and Emx2 (high caudal).

What happens in Emx2 mutants?

Posterior regions shrink and anterior motor regions expand.

What happens in Pax6 mutants?

Posterior sensory and visual regions enlarge; anterior motor regions shrink.

Why is thalamic input important for cortical development?

Sensory inputs (e.g., LGN to visual cortex) are required for proper area differentiation.

What is pathway selection in axon guidance?

optic nerve to optic chiasm, axons choose to cross the optic chiasm or not

Why do nasal retinal axons cross at the chiasm while temporal ones do not?

To create binocular vision with contralateral visual field representation.

What is target selection in axon guidance?

Reaching the correct brain structure, such as the LGN.

What is address selection in axon guidance?

Connecting to the correct neurons within specific target layers.

What structure at the tip of a growing axon senses guidance cues?

The growth cone.

What structures in the growth cone help with movement and sensing?

Filopodia (thin probes) and lamellipodia (sheet-like regions).

What ECM molecule promotes axon growth?

Laminin.

What receptors allow axons to bind to laminin?

Integrins.

What is fasciculation?

Axons sticking together and traveling in bundles via adhesion molecules.

What is chemoattraction?

When growth cones turn toward a source of an attractive chemical cue.

What is chemorepulsion?

When growth cones turn away from a repulsive chemical cue.

What does Netrin-1 do for retinal axons?

Attracts them to the optic disc so they exit the eye.

What do Slit proteins do near the optic chiasm?

Repel axons to create “guardrails” that position the chiasm correctly.

What is the role of Netrin-1 in retinal axon guidance?

It attracts RGC axons to the optic disc so they exit the eye.

Does Netrin guide axons to the optic chiasm?

No, it only guides axons out of the eye.

What happens if Netrin-1 is absent near the optic disc?

RGC axons fail to exit the retina properly.

What is the role of Slit proteins in optic pathway development?

They act as repulsive guardrails that funnel axons to the correct chiasm location.

Which receptor mediates repulsion by Slit proteins?

Robo2.

Does Slit determine whether an axon crosses the midline or not?

No, it only determines where the chiasm forms.

What is the main purpose of Slit/Robo guidance in the visual system?

To keep axons within a defined corridor leading to the chiasm.

What molecule at the midline determines whether RGC axons cross?

Ephrin-B2.

Which RGC axons express the EphB1 receptor?

Axons from the temporal retina.

What happens when EphB1-expressing axons encounter Ephrin-B2 at the chiasm?

They are repelled and remain ipsilateral.

Why do nasal retinal axons cross the midline?

They lack EphB1 and therefore are not repelled by Ephrin-B2.

How does the Ephrin-B/EphB system support binocular vision?

It sorts temporal axons to stay ipsilateral and nasal axons to cross contralaterally.

What are the three stages of visual pathway molecular guidance?

Netrin exits the eye → Slit positions the chiasm → Ephrin-B sorts crossing vs. non-crossing.

How does synapse formation begin between neurons?

A dendritic filopodium contacts an axon.

What forms on the axon during presynaptic specialization?

Synaptic vesicles and the active zone.

What forms on the dendrite during postsynaptic specialization?

Clusters of neurotransmitter receptors.

What is the final product of coordinated pre- and postsynaptic specialization?

A functional chemical synapse.

What molecule is released by the motor neuron during neuromuscular junction formation?

Agrin.

What receptor does Agrin bind on the muscle membrane?

MuSK.

Which protein clusters acetylcholine receptors at the neuromuscular junction?

Rapsyn.

Why does ACh receptor clustering occur directly under the nerve terminal?

To ensure efficient response to neurotransmitter release.

Why does the developing nervous system produce excess neurons?

To allow competition for targets and ensure only properly connected neurons survive.

What determines whether a neuron survives during development?

Its ability to obtain sufficient trophic factors.

What is the first discovered trophic factor?

Nerve growth factor (NGF).

How does NGF reach the cell body to promote survival?

It is taken up at terminals and transported retrogradely.

What happens if retrograde NGF transport is blocked?

The neuron dies even if NGF is present.

Which receptor family mediates neurotrophin signaling?

Trk receptors.

What is the purpose of apoptosis in neural development?

To remove excess or improperly connected neurons.

How does apoptosis differ from necrosis?

Apoptosis is regulated and genetic; necrosis results from injury.

What happens to motor innervation at the neuromuscular junction during development?

Polyneuronal innervation is eliminated until each muscle fiber has one motor neuron.

What effect does blocking muscle activity have on synapse elimination?

It slows or prevents synapse elimination.

What happens when AChRs on part of a muscle fiber are blocked?

The corresponding axon branches withdraw.

What is the first step in synapse elimination at the NMJ?

Loss of postsynaptic ACh receptors.

What follows receptor loss in synapse elimination?

Retraction of the presynaptic axon branch.

Where else in the nervous system does synaptic pruning occur?

Throughout the CNS, including the visual cortex.

When does major synapse elimination occur in humans?

During childhood and adolescence.

What is the purpose of synapse elimination?

To refine neural circuits by keeping strong connections and removing weak ones.