Neuroscience/Objectives/Lectures 9-10

From PhysioWiki

Development, plasticity, and regeneration

Understand which major adult structures arise from which embryonic compartments.

• Prosencephalon (forebrain)
  • Telencephalon
    • Cerebral cortex
    • Hippocampus
    • Basal ganglia
    • Basal forebrain
  • Diencephalon
    • Dorsal thalamus
    • Hypothalamus
• Mesencephalon (midbrain)
  • Ventral midbrain colliculi
• Rhombencephalon (hindbrain)
  • Metencephalon
    • Cerebellum
    • Pons
  • Myelencephalon
    • Medulla
• Spinal cord

Understand the temporal sequence of events during nervous system development.

1. Segmentation of the nervous system, development of rostral-caudal and dorsal-ventral axes
2. Birth of all cells (neurons and glia) from neuroepithelial stem cells in ventricular zone
3. Migration of neurons and glia to their final, mature positions
4. Differentiation of cells into mature phenotypes, sending of axon collaterals to form functional circuits
5. Connectins are refined by mechanisms involving neurotrophic factors and experience-dependent plasticity

Know which clinical syndromes are associated with deficits in neural tube closure.

Anencephaly

Results from incomplete closure of the anterior (rostral, cranial) neuropore.

Spina bifida

Results from incomplete closure of the posterior (caudal) neuropore.

Understand the mechanism by which the nervous system becomes patterned along the rostral-caudal and dorsal-ventral axes.

Morphogens are secreted by organizing centers in the developing embryo and act in a concentration-dependent manner. The orientation of the concentration gradient often determines the plane in which an axis will develop. This is accomplished through the differential activation of transcription factors.

Rostral-caudal axis There are rostral anterior visceral endoderm) and caudal (Henson's node) organizing centers. The anterior center secretes Cerberus, Dickkopf, and Tlc, which antagonize effects of caudal proteins. The caudal center secretes retinoic acid, FGF, and Wnt.

Dorsal-ventral axis The development of the dorsal spinal cord is largely governed by bone morphogenic proteins (BMPs), while the ventral spinal cord is regulated by sonic hedgehog (Shh). Shh is secreted by the ventral mesoderm (e.g. notochord). Its diffusion induces the basal plate and produces the ventral-dorsal concentration gradient. Motor neurons are formed in the presence of high Shh; sensory neurons form in low Shh concentrations.

Understand the role of Shh in the spinal cord and forebrain during development, and the associated clinical disorder that results in mutations in the Shh gene.

The morphogen Shh plays a key role in the development of the dorsal-ventral axis of the spinal cord. Shh is a ventralizing agent, being secreted by the ventral mesodermal tissue and having a ventralizing effect on tissues that respond to it. As discussed above, high Shh concentrations yield motor neurons, while low concentrations give sensory neurons.

Produced by the floor plate and associated cells in the ventral telencephalon, Shh has ventralizing effects in forebrain development similar to its effects on the spinal cord. High concentrations of Shh in the ventral prosencephalon induce the production of medial (MGE) and lateral ganglionic eminences (LGE) from telencephalic progenitors. The LGE gives rise to local inhibitory projections of the striatum, whereas the MGE yields cortical interneurons. Ventral telencephalic neurons (i.e. from the MGE and LGE) are inhibitory (GABAergic) while dorsal neurons are excitatory (glutamatergic).

Mutations in the Shh gene can result in holoprosencephaly, in which the prosencephalon fails to develop.

Understand how cerebral cortical interneurons and excitatory neurons are generated during development.

Cortical interneurons are derived from the medial ganglionic eminence of the telencephalon. They are GABAergic and therefore inhibitory. These neurons reach the cortex through tangential migration where they meet with excitatory neurons generated locally in neocortical ventricular (germinal) zones.

Excitatory neurons are generated in the ventricular zones of the developing neocortex. They migrate along radial glia (as opposed to migrating tangentially) to generate the cortical plate. This plate differentiates into the six-layered neocortex, with layer 1 superficial and layer VI deep. Neurogenesis is inside-out, with the earliest neurons generated in layer VI (most deep) and the latest generated neurons in layer I (most superficial). Neurons in each layer have similar morphologies and projections.

Incomplete migration leads to classical lissencephaly, in which there are few gyri and widespread heterotopias, resulting in mental retardation.

Understand the mechanisms by which axons find their targets.

Sprouting axons navigate by means of a growth cone, which is the leading tip of the growing axon. The growth cone responds to various cues, both contact- and non-contact-mediated. Contact-mediated cues include laminins, cadherins, and ephrins/Eph receptors. Non-contact-mediated (also called chemical or diffusible) cues include neurotrophins, netrins (an attractive cue), and semaphorins. Both types of cues (contact- and non-contact-mediated) may be either attractive or repulsive; in the case of chemical cues, these are termed chemoattraction and chemorepulsion, respectively.

Examples of axon guidance include:

• Lower motor neuron findings its target muscle
  • Neurotrophic factors are secreted by muscle: GDNF, FGF, HGF
• Axonal pathfinding of spinal commissural spinal cord neurons
  • Dorsal neurons attracted to netrin-1 from the floor plate move ventrally and cross the midline
  • Decussated fibers ascend as they are repulsed from the midline by slit from the floor plate
• Retinotectal axon pathfinding from retina to mesencephalic optic tectum
  • Mediated by Eph and ephrins
  • Nasal retina projects to posterior tectum
  • Temporal retina projects to anterior tectum

Understand the role of neurotrophic factors in development and be able to list the subclasses of these factors.

Development of the nervous system results in an excess of neurons and a particularly large excess of synaptic contacts between neurons. Refinement of neuron populations and their connections is mediated by cell death and axonal loss. The survival of neurons and axons is regulated by neurotrophic factors typically secreted by targets of axons (e.g. muscle or other neuron). A limited amount of neurotrophic factors are secreted by the target such that only a limited number of inputs can be supported. Neurons and axons without sufficient access to neuotrophic factors will degenerate.

Known classes of neurotrophic classes include

• Neurotrophins
  • Nerve growth factor (NGF)
  • Brain-derived neurotrophic factor (BDNF)
  • Neurotrophin-3 (NT3)
  • Neurotrophin-4, neurotrophin-5 (NT4/5)
• TGF-β
  • TGF-β3
  • GDNF
  • Neurtruin
• IL-6 cytokines
  • CNTF
  • LIF

Know the processes by which synapses are refined during development.

In addition to the neurotrophic factor-dependent mechanism mentioned above, the refinement of neuronal connections also proceeds by four other major mechanisms.

Transient axonal targets

Transient axonal targets initially develop and are then refined by elimination. These targets are not the intended final targets of the axons, but rather attempts by the axon to find its intended target. Axons to inappropriate targets are eliminated, while the appropriate axons are retained.

Axon collateral elimination

Some axons sprout collaterals to inappropriate targets in an attempt (as above) to find their appropriate targets. These inappropriate collaterals are eliminated.

Synapse elimination*

Instead of eliminating complete axons or collaterals, individual synapses can be eliminated for more refinement.

Synaptic rearrangement*

Rarrangement of synapses results from synaptic activity coupled with release of neurotransmitters. This is an example of activity-dependent synaptic modification regulated by competition.

* Only synapse elimination and synaptic rearrangement occur continuously in the mature individual as part of learning and memory.

Know the types of stem cells that persist in the adult nervous system.

Postnatal neurogenesis is limited to the hippocampus and olfactory bulb. The purpose of postnatal neurogenesis is unclear, but may have to do with learning and memory as these regions have a high degree of plasticity.

In both cases, new neurons are derived from adult stem cells that are pluripotent and capable of self-renewal. Newly generated cells in the hippocampus and olfactory bulb are typically GABAergic inhibitory interneurons.

Stem cells can also be derived from inner cell mass of blastocysts (at the 256-cell stage of the embryo). These embryonic stem cells can be manipulated to differentiate into several cell types including spinal cord motor neurons and midbrain DAergic cells (as well as other non-neuronal cells). Importantly, stem cells cannot simply be implanted in a patient as doing so would likely result in a tumor.