Neurobiology Chapters 23 and 25: Construction of Neural Circuits and and Plasticity in the Developing Brain

__________ __________ plays a primary role in the process that leads to changes in neural circuit structure and function during a critical period.

Synaptic activity.

What is the Hebb's postulate?

Synaptic terminals strengthened by correlated activity during development will be retained and sprout new branches. Synaptic terminals that have activity that is not correlated with post-synaptic activity will be removed.

Slit and robo are available immediately off the midline and are thought to do what?

Terminate the growth con'e sensitivity to netrin once it has crossed from one side of the CNS to the other.

What is a critical period?

The time during which a given behavior is especially susceptible or requires specific environmental influences in order to develop normally.

Why might temporal retinal axons be repulsed by the posterior tectal membranes?

There's a repulsion factor located on the surface of the posterior tectal cells that causes growth cone collapse.

Describe this graph.

NGF influences the survival of newborn rat sympathetic ganglion cells grown in culture for 30 dyas.

What was the first neurotrophic factor to be discovered? How was it discovered?

Nerve growth factor (NGF). If was discovered as an "activity" that elicited growth of neuronal processes in cell culture.

Specialized adhesion molecules link pre- and postsynaptic domains so that the synapse emerges as a discrete, relatively stable intracellular specialization for local electrical or chemical signaling. Among this list of molecules that initiate synaptogenesis, ____________ is an essential regulator of expression and localization of postsynaptic receptors and other proteins.

Neuregulin (Nrg1)

Describe this diagram.

Neurotrophic factors have distinct effects on different target cells.

When growth cones are examined in vitro, lamellipodia can be seen clearly, as can numerous fine processes called __________ that extend from each lamellipodium.

Fliopodia

Microtubule-binding proteins such as kinesin and dynein are essential for what?

For moving molecules and organelles (cargo) up and down neuronal processes.

The ________ cytoskeleton regulates changes in lamellipodial and filopodial shape for directed growth.

Actin

________ is the primary molecular constituent of a network of cellular filaments found in the lamellipodida and filopodia of growth cones.

Actin

Growth cone motility reflects rapid, controlled rearrangement of the cytoskeleton. The force to move the axon is genertaed by ATP-dependent modification of the __________ and ___________ cytoskeletons.

Actin and microtubule

The dynamic behavior of growth cones depends on what?

Adhesive, attractive, and repulsive molecular signals in the embyronic environment. Signals can be non-diffusable or diffusable.

Describe the opposing activities of netrin and slit at the ventral midline of the spinal cord.

At first, the neuron is attracted by netrin and insensitive to slit and semaphorins (both repulsive) because it doesn't express receptors for them. When the neuron enters the floorplate, slit silences netrin attraction. After it has crossed the midline, it is repelled by slit and semaphorins and is insensitive to netrins.

Explain this diagram.

Axons must exhibit target selection. In the mammal visual system, they must maintain topographic maps as they cross in the optic chiasm and project into the LGN and visual cortex.

___________ signals selectively attract growth cones to useful destinations.

Chemoattractant

__________ signals discourage axon growth toward inappropriate regions.

Chemorepellent

Describe this diagram.

Comissural axons express robo 1/2 which is the receptor for slit (chemorepellent) and DCC which is the receptor for netrin (chemoattractant). When the axon nears the midline, it expresses robo 3 which inhibits robo 1/2. The neuron can then cross the midline because it responds to netrin. After crossing the midline, robo3 is no longer expressed and robo 1/2 inhibits netrin to prevent the cell from turning around. Non-commissural axons only express robo 1/2 to keep them from crossing the midline.

Once the normal population has been determined, the formation of synapses is regulated by what?

Competitive trophic and activity-dependent mechanisms.

Explain this diagram.

Concentration gradients of Eph receptors and ephrins cause different mapping of axons. Retinal growth cones with a high concentration of of Eph receptors are more likely to recognize a lower concentration of ligand (ephrins). A growth cone with low Eph receptor concentration recognizes a higher concentration of ligand.

What is amblyopia? Does this condition go away or persist with time?

Cortical blindness. It is permanent.

(Non-diffusable signals for axon guidance) Where are CAMs and cadherins found?

On growth cones and growing axons as well as on surrounding cells and targets.

The role of ECM molecules in axon guidance is particularly important in the (CNS/PNS).

PNS

Once the basic pattern of brain connections is established, what modifies synaptic circuitry in the developing brain?

Patterns of neuronal activity.

After ephrins, calcium dependent CAMs, and the cadherin families of calcium dependent adhesion molecules allow growth cones to recognize suitable post-synaptic sites on dendrites and cell bodies, what happens next? What is implicated in this process?

Pre- and post-synaptic specialization must be elaborated. Several soluble or secreted signals have been implicated in the process, including growth factors and neurotransmitters.

(True/false) A certain level of chemorepulsion will step axon growth.

True

(True/false) In some vertebrates like frogs, correct retinotopic connections can be made after the optic nerve is severed.

True

(True/false) Target cells initially synapse with multiple presynaptic cells.

True

(True/false) The early stages of synapse formation are relatively non-selective.

True

__________ is the primary molecular constituent of the microtubules that run parallel to the axis of the axon and give it both structural integrity and a means for transporting proteins from the nerve cell body to the axon terminal.

Tubulin

(Non-diffusible signals for axon guidance) What kind of receptors are Eph receptors?

Tyrosine kinase receptors

How do kinesis and dyneins generate force to "walk" along microtubules with their cargo proteins?

ATP hydrolysis

Neurons that fail to interact successfully with their target undergo ___________. What does this suggest?

-Apoptosis -This suggests a competition for some trophic factor

The assembly and disassembly of actin and tubulin is regulated via __________ proteins that rely upon enzymatic cleavage of second messengers like ________ and _______ to generate energy.

-Capping -cAMP and cGMP

Netrin chemoattractant signals are transduced by specific receptors, including the molecule ________. A different receptor, ________, mediates netrin-dependent chemorepulsion.

-DCC -Unc5

What two things modify the developing brain? When are these influences most important?

-Environment and experience -Critical period

Which protein is the negative guidance signal for temporal axons in the posterior tetcum? Which protein is the repulsive signal?

-Eph receptors -Ephrins

What are some experiments that support the fact that NGF promotes growth?

-Injection of NGF antiserum results in loss of NGF-dependent neurons -Injection of endogenous NGF in newborn mice results in enlargement of sympathetic region - NGF is produced by target cells and other target cells produce different neurotrophins

What are the ECM adhesion molecules that act as non-diffusible signals for axon guidance?

-Laminins, fibronectin, collagen -Integrin receptors

What are the potential consequences of a mutation in a chemoattractant or chemorepellent molecule?

-Misguided neurons -Absent synapses -Disrupted circuits

Give an example of a chemoattractant and an example of a chemorepellant.

-Netrins -Semaphorins

What are the two groups of neurons that have cell bodies in the peripheral nervous system?

-Neurons in the autonomic nervous system -Sensory ganglion cells

NGF belongs to the family of related trophic molecules referred to as ____________, which are also called growth factors. Name a member of this family that is made by muscle cells.

-Neurotrophins -NT-3

Actin filaments will (polymerize/depolymerize) in response to an attractive cue and (polynmerize/depolymerize) in response to a repulsive cue.

-Polymerize -Depolymerize

What happens if netrin bound to DCC and Unc5 are both present?

-Repulsion -Growth stimulation

What two kinds of cells to NGF promote the growth of

-Sensory cells -Sympathetic ganglion cells

The secreted factor _________ and its receptor _________ are important for preventing an axon from straying back over the midline once it has crossed initially in response to netrin.

-Slit and robo

In the frog, axons from the temporal region of the retina innverate what part of the tectum? What about axons from the nasal part of the retina?

-The anterior pole -The posterior pole

What happens if netrin bound to DCC and slit bound to robo are both present?

-The attractive netrin response is silenced and the neurons stops moving -The neuron will mature

What are the major classes of non-diffusible axon guidance molecules?

-The extracellular matrix molecules and their integrin receptors -The calcium independent cell adhesion molecules (CAMs) -The calcium dependent cell adhesion molecules, or cadherins -The ephrins and Eph receptors

What is the difference between tropic and trophic factors?

-Tropic factors guide growing axons toward a source -Trophic molecules support the survival and growth of neurons and their processes once an appropriate target has been contacted

Describe how you can get attraction, short-range and long-range repulsion by changing the interactions between netrin and DCC and Un5c5.

-Two netrins interacting with two DCC's causes attraction -A netrin interacting with the Un5 receptor causes short-range repulsion -A netrin interacting with DCC and Unc5 causes long-range repulsion

What is strabismus?

A condition in which the two eyes can no longer be aligned.

Explain how trophic interactions regulate neuronal connections.

A functional nervous system requires that the neuronal population match the target population. Many more cells are born than survive, and their survival and differentiation depends on the establishment of a contact with the target cell. The dependency between a neuron and target is a trophic interaction mediated by neurotrophic factors released on small quantities by target cells.

What is this photo?

A sensory ganglion grown in culture with NGF.

Explain these diagrams.

A shows ocular dominance in a normal cat and B shows ocular dominance in a cat with strabismus. In B, most of the cells are driven exclusively by stimulation of one eye or the other.

Explain these diagrams.

A) Chemoattractants, or tropic signals, can operate from a distance and reorient growth toward the source of a cue. Chemorepellant signals can also act from a distance to orient growth away from the source of a cue. B) The netrin/slit family of attractive and repulsive secreted signals acts through two distinct receptors, DCC, which binds netrin, and robo, the receptor for slit. C) Semaphorins are repulsive cues that can either be bound to the cell surface or secreted. D) Semaphorin causes growth cone to collapse and is dependent on calcium.

Explain this diagram.

A) ECM molecules including fibronectin and laminin and collagen serve as ligands for multiple integrin receptors. Integrins transduce ECM signals by interacting with cytoplasmic protein kinases and activating calcium channels. B) Homophilic calcium independent cell adhesion molecules (CAMs) are both ligands and receptors. Homophilic binding activates intracellular kinases, leading to cytoskeletal changes. C) Calcium dependent adhesion molecules, or cadherins, are capable of homophilic binding. They signal via activation of beta-catenin, which influences gene expression. D) Ephrins, which can be either transmembrane or membrane-associated, signal via the Eph receptors, which are receptor tyrosine kinases.

Explain these diagrams.

A) This is a neuromuscular junction. At first, there are two neurons at the synapse. One neuron then retracts. B) These are purkinje cells and the red are climbing fibers. The climbing fiber initially contacts multiple purkinje cells and then it starts to concentration on just one. These diagrams show elimination of multiple innervations in both the CNS and PNS.

Describe this experiment.

B) One eye of a newborn kitten was closed from one week after birth until 2.5 months of age. After 2.5 months, the eye was opened and the kitten matured normally to 38 months. Light shined on both eyes caused no electrical responses in visual cortical neurons. The only visual responsive cells responded to the ipsilateral (non-deprived eye). C) A much longer period of monocular deprivation in an adult cat showed little effect on ocular dominance, although overall cortical activity diminished. Most responsive cells were driven by both eyes.

Which non-dissusable signal(s) for axon guidance is associated with the bundling, or fasiculation, of groups of axons, as well as determination of final target selection in the transition from growing axon to synapse.

CAMs and cadherins

The effects of activity-dependent developmental change are transduced by signaling pathways that modify the levels of __________ which then modifies neurotransmission and gene expression.

Calcium

Calcium is a major mediator of actin and microtubule dynamics in the growing axon. What may cause a rise in intracellular calcium levels?

Calcium enters the cell through voltage regulated calcium channels, transient receptor potential (TRP) channels activated by second messengers, or second messenger pathways that mobilize intracellular calcium stores.

The initial distinction of the characteristic single axons from the multiple dendrites of a neuron depends on ___________ ____________, a process that reflects interactions among proteins found in different regions of a neuron's cytoskeleton.

Cellular polarization

Netrins are similar to what kind of molecules? Where are they secreted from?

ECM molecules. They are secreted from the source cell.

Nrg1 is a transmembrane protein usually made in presynaptic cells and can be released following proteolytic cleavage of outside portion of the protein. This cleaved, mature form of Nrg1 then diffuses and binds to specific receptors. What are these receptors and where are they found?

ErbB epidermal growth factor-like receptors, found on thes surfaces of many developing central neurons as well as on muscle cells and other targets of peripheral neurons.

The directed growth of axons and recognition of appropriate synaptic targets depend on __________ _________, the specialized endings of growing axons.

Growth cones

(Non-diffusible signals for axon guidance) What is the function of ephrins and Eph receptors?

Immature axons use them to recognize appropriate pathways for growth as well as appropriate sites for synaptogenesis.

What is the result of Nrg1 signaling?

Increased synthesis and insertion of neurotransmitter receptors at a new postsynaptic site.

Mature synaptic input is from a single pre-synaptic cell, but the number of synaptic contacts (increases/decreases).

Increases

Explain this diagram.

Information from both retinas are mapped separately in the LGN. When axons project from the LGN to the striate cortex, they form ocular dominance columns. The cells in these columns respond to information in either the right or left eyes. Cells on on the border of the columns respond equally to both eyes.

(Non-diffusable signals for axon guidance) What are integrins? How do they contribute to axon growth and elongation?

Integrins are surface receptors that bind to laminin, collagen, or fibronectin. This binding triggers a cascade of events - perhaps via interactions between the cytoplasmic domains of integrins with non-receptor cytoplasmic kinases and other signaling molecules, as well as calcium channels - that can stimulate axon growth and elongation.

The primary morphological characteristic of a growth cone is a sheetlike expansion of the growing axon at its tip called a ___________.

Lamellipodium

Chemoattraction and chemorepulsion can be either long-range or short-range. Explain the difference.

Long range signals tend to be diffusible molecules secreted by cells whereas short range signals are non-diffusible and bound to cell surfaces or the extracellular matrix

Axons with a high concentration of receptors will stop migrating at a (high/low) concentration of ephrin.

Low

Explain this graph.

Many more neurons are produced than the amount that actually survive. This is mediated by neurotrophic factors.

Explain this diagram.

Membranes from anterior (A) and posterior (P) optic tectum of chicks were laid down on a glass coverslip. Pieces of either temporal or nasal retina were placed on the stripes. Temporal axons prefer to grow on anterior membranes and are repulsed by posterior membranes. Nasal retinal axons grew equally well on both stripes.

The _________ cytoskeleton is responsible for elongation of the axon itself.

Microtubule

In experiment B, the eye of a kitten was sutured closed early in life and the animal then matured to adulthood. Once the eyelid opened, electrophysiological recordings showed that very few cortical cells could be driven from the deprived eye. What did recordings from the retina and LGN show? What changes occurred in the visual cortex?

Recordings from the retina and LGN layers in response to direct electrical stimulation in the deprived eye indicated that these more peripheral stations in the visual pathway worked normally. However, the deprived eye had been functionally disconnected from the visual cortex.

Blocking synaptic activity results in loss of synapse __________ and __________.

Refinement and elimination

What are the two types of Robo? How do they interact? When are they expressed?

Robo 1/2 and robo 3. Robo 3 inhibits robo 1/2. Robo 3 is expressed when an axon nears the midline and robo 1/2 is always expressed.

Once neurons have been generated and have migrated to their correct position in the CNS, what must they do?

Send out axons and form synapses with the appropriate targets.

Netrins influence the directed growth of neurons in the __________ tract that mediate temperature and pain.

Spinothalamic

How are receptors and channels localized and concentrated to the lamellopodial or filopodial membrane?

The actin cytoskeleton is the anchor for multiple protein scaffolding molecules that in turn localize or concentrate receptors and channels to the lamellipodial or filopodial membrane.

In this experiment, what was the period of susceptibility?

The critical period for ocular dominance development. Eye closure is effective only if the deprivation occurs during the first 3 months of a kitten's life, so this critical period is 0-3 months of age.

What sets the direction of growth cone movement by generating local forces that orient the growth cone toward or away from substrates?

The dynamic polymerization and depolymerization of actin at the membrane of the lamellipodium as well as within the filopodium.

What is trophic interaction?

The long-term dependency between neurons and their targets.

The brain becomes more refractory to modification with experience as it matures. What does this mean?

The modification of synaptic connections must make activity and experience-dependent modifications permanent within a distinct developmental window. You don't want additional substantial changes to occur once the critical period has ended.

What consolidates the direction of movement of the growth cone by stabilizing the axon shaft?

The polymerization and depolymerization of tubulin into microtubules.

Describe the experiment that showed that targets play a major role in determining the size of the neuronal populations that innervate them.

The removal of a limb bud from a chick embryo results in a reduction in the number of nerve cells in corresponding portions of the spinal cord. They then added to the embryo a limb bud that can be innervated by the same spinal segments that innervate the normal limb. This caused cells to be "rescued" from a neuron population that is overproduced in early development.

Explain this experiment.

These graphs show the consequences of a short period of monocular deprivation at the height of the critical period in the cat. In A, just 3 days of deprivation produced a significant shift of cortical activation in favor of the non-deprived eye. In B, 6 days of deprivation produced a shift of cortical activation in favor of the non-deprived eye that was almost as complete as that elicited by 2.5 months of deprivation.

(Non-diffusable signals for axon guidance) CAMs and cadherins exhibit homophilic binding. What does that mean?

They act as both ligands and receptors, and bind to each other.

At the first stages of synapse formation, ephrins, CAMs and cadherins allow what?

They allow growth cones to recognize suitable post-synaptic sites on dendrites and cell bodies.

Describe how netrins play a role in the developing spinal cord.

They are localized to the floorplate of the neural tube, which defines the central midline in the developing spinal cord as well as sites where axons must cross from one side of the cord to the other.

What are neurotrophic factors?

They regulate differentiation, growth, and survival in nearby cells.

Explain this diagram.

This diagram shows orientation preferences in single cells that have binocular input. In the beginning of development, the cell has an uncorrelated response in the left and right eye in response to a stimulus. After the critical period, these cells have correlated responses. In B, the cell cannot correlate input from the left and right eye in response to a stimulus because one eye was sutured during the critical period. In C, even though one eye was sutured in adulthood, the cell is able to correlate left and right eye activity because the procedure occurred after the critical period.

Describe this diagram.

This diagram shows the ocular dominance distribution of single-unit receptors from a large number of neurons in the primary visual cortex of normal adult cat cells. There were no cells that were not responsive (NR) to light stimulation in the retina.

What is the chemoaffinity hypothesis? What experiment produced this theory?

This hypothesis explains how topographic maps arise during development. In frogs, the terminals of retinal ganglion cells form a precise topographic map in the optic tectum. When the optic nerve is crushed and is allowed to regenerate, retinal axons reestablished the original topographic pattern of connections in the tectum. Even if the eye was rotated 180 degrees, the axons grew back to their original tectal destinations. This caused the frog to view everything upside down. It was proposed that each tectal cell carries a chemical identification tag and that the growing terminals of retinal ganglion cells have tags such that the retinal cells seek out a specific location in the tectum. It was later found out that the behavior of growing axons respond to gradients of molecules.

Explain this diagram.

This is after the optic nerve of a frog was cut. When the eye was rotated 180 degrees, the neurons regenerated and re-established their original connections, causing the frog to see everything upside down.

Explain this diagram.

This is in a mouse. Neurons will the fewest EphA receptors grow to ares with the highest ephrin A and vice verse.

Explain these diagrams.

This is showing the effects of monocular deprivation on arborizations of LGN axons int he visual cortex. In both long term and short term monocular deprivation, axons terminating in layer 4 of the primary visual cortex from LGN neurons driven by the deprived eye have greatly reduced numbers of branches. Long term deprivation does not result in more decreases in arborization that short term deprivation.

(Non-diffusible signals for axon guidance) Ephrin and Eph receptors are considered bidirectional. Why?

When an ephrin ligand from one cell binds to an Eph receptor on another cell, both cells signaling pathways are initiated in both cells.