Defects in neural tube closure. Location and extent of neural tube defects (NTD) vary Causes: Some genetic predisposition Teratogens Alcohol

Nervous System Development Flashcards by Quynh Tran

Primary Vesicles

Appears during the 4th week of development.

Rostral ⇒ Caudal

Prosencephalon → forebrain
Mesencephalon → midbrain
Rhombencephalon → hindbrain

Two flexures present in the neural tube at this stage:

Cephalic flexure
- Occurs at the level of the future midbrain
- Retained in bipedal organisms
Cervical flexure
- Occurs between the rhombencephalon and caudal spinal cord
- Straigtens out later in development

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Secondary Vesicles

Appears during 5th week of development.

Two primary vesicles become subdivided.

Rostral ⇒ Caudal

Prosencephalon:
- Telecephalon (cerebrum)
  - Cerebral hemispheres
  - Basal ganglia
- Diencephalon
  - Thalamus
  - Hypothalamus
  - Retina
Mesencephalon: does not become subdivided
- Midbrain
Rhombencephalon
- Metencephalon
  - Cerebellum
  - Pons
- Myelencephalon
  - Medulla Oblongata

A third flexure develops in additional to the previous two:

Cephalic → ventral mesencephalon
Pontine → dorsal surface between Metencephalon and Myelencephalon
- Is not retained
- Important in development of caudal brainstem
Cervical → ventral surface between Myelencephalon and spinal cord

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Major Developmental Events

Neurulation
- The process by which the neural tube is formed
- Includes formation of the neuraxis (flexures)
- Occurs between 3-8 weeks
Neuronal Proliferation and Migration
- Occurs between 8-16 weeks
Synapse Formation and Myelination
- Occurs between 16-40 weeks
- Under a significant amount of environmental influence

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Primary Neurulation

Occurs during 3rd and 4th week of embryonic development.

Band of ectoderm thickens
Ectodermal cells form the neural plate
Neural plate folds in medially to form neural groove between neural folds
Neural groove fuses to form the neural tube
- Closure starts in the center ⇒ both rostral and caudal
Neural tube develops into the CNS
- Cavity becomes the ventricular system
- Group of cells from crest of each neural fold dissociates from the neural tube ⇒ neural crest cells
  - Cells develop into a variety of cell types including:
    - sensory neurons of ganglia of spinal nerves
    - postganglionic neurons of the ANS
    - Schwann cells of the PNS

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Three Vesicle Brain

During the 4th week of development:

Neural tube enlargements appear forming the three primary vesicles ⇒ three vesicle brain
- Proencephalon
- Mesencephalon
- Rhombencephalon
Cephalic and cervical flexures develop

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Five Vesicle Brain

During the 5th week of development:

Proencephalon and rhombencephalon become subdivided forming the five secondary vesicles ⇒ five vesicle brain
1. Telencephalon
2. Diencephalon
3. Mesencephalon
4. Metencephalon
5. Myelencephalon
Pontine flexure develops dorsally
Dorsal and ventral segments of neural tube thicken disproportionately
A longitudinal fissure appears along the lateral wall of the neural tube ⇒ Sulcus limitans
- dorsal portion ⇒ alar plate
  - mainly sensory (afferent) derivatives
- ventral portion ⇒ basal plate
  - mainly motor (efferent) derivatives
- Specific neural modalities (visceral, somatic, special) have characteristic locations within alar/basal plates and subsequent dorsal/ventral horns of spinal cord
- Similar orgainziation exists in the brain stem
  - Sensory nuclei lateral
  - Motor nuclei medial
Sensory ganglia, basal ganglia, thalamus, and hypothalamus begins to develop

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Neural Tube Closure

Closure begins in the region of the 4th to 6th somites at around day 22
Proceeds both cranially and caudally
Rostral neuropore (cranial opening) closes by ~ day 25
Caudal neuropore (caudal opening) closes by ~ day 27

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Rachischisis

Defects in neural tube closure.

Location and extent of neural tube defects (NTD) vary
Causes:
- Some genetic predisposition
- Teratogens
- Alcohol

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Anencephaly

Failure of rostral neuropore to close
Results in subsequent brain under-development and incomplete skull formation
Fetus rarely survive and frequently terminated

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Spina Bifida

Developmental defects in caudal vertebral column, meninges, and/or spinal cord.

Spina bifida occulta
- Bony vertebral defect only seen via XR or MRI
- Skin dimpling or hairy patch may appear at base of spine
- 5-10% of general population
Open spina bifida
- Meninges, spinal nerves, or spinal cord connected to overlying skin
- 50/100,00 births
- Two types:
  - Meningocele
    - Meninges are fused with overlying skin in pouch containing CSF
    - Can usually be surgically repaired
  - Myelomeningocele
    - Failure of caudal neuropore closure
    - Pouch also contains spinal nerves or spinal cord in most severe cases
    - Surgical repair difficult
    - Most non-ambulatory

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Holoprosencephaly

Failure of the prosencephalon to differentiate into forebrain and diencephalon
Occurs during 2nd month of gestation
Rostral neuropore closure was normal
Very rare

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Secondary Neurulation

Begins during 4th week and completed 6-7th week of development:

After neural tube closes, secondary cavity forms at the caudal end of the neural tube ⇒ secondary neurulation
Develops into the scaral spinal cord
During this time enlargement of specializations of neural tube also occurs
- telencephalon
- cerebellum

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Fourth Ventricle Formation

Pontine flexure development forces walls of the neural tube apart forming a diamond shaped cavity
Only thin membranous roof covers future site of 4th ventricle
Alar and basal plates rest at the floor of the 4th ventricle
Eventually forms part of the adult brainstem ⇒ rostral medulla & caudal pons
- Sensory nuclei laterally located
- Motor nuclei centrally located

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Neurulation

Late Stage

Occurs during the 8-12th weeks of development:

Reflexes appear caudally
- Suggests interconnection of sensory and motor pathways in spinal cord
Major development of complex structures at rostal end
- Neuronal proliferation and migration in the cerebral and cerebellar cortex
- First cortical sulci appear
- Glia begin to differentiate

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Neuronal Proliferation and Migration

Occurs during the 8th - 16th weeks of development

Timing of a neuron’s final division (birthday) determines migratory site.

Location determines function.

Migration guided by radial glial cells which extend from ventricular zone to surface of the marginal layer.

Thalamus
- Occurs in an “outside-first” order
- First neurons to reach their birthday migrate to outermost portion of the thalamus and mature there
- Neurons with later birthdays migrate to more medial locations
Cerebral & Cerebellar Cortices
- Occurs in an “inside-out” pattern
- First cells to migrate located in ventricular zone
- Cerebral cortex formed by expansion of superficial part of intermediate zone into the subplate and cortical plate.
- Final neuroblasts located closer to pial surface.

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Neuron Death

During first 24 weeks of gestation:
- Twice as many neurons generated than found in mature brain
- Large number of degenerating neurons undergoing apoptosis appears during this period
Reason for overproduction then elimitation unclear
- May be related to strict requirements for specific connectivity patterns during different stages of development
- Cells with potential problems eliminated
Mature patterns of required for function dependent on:
- final location of neurons
- early synapse formation
- dendritic development
- formation of axonal branches

Factors Determining

Neuron Connectivity and Function

Mature patterns of connectivity required for neuronal function dependent on:
- final location of neurons
- early synapse formation
- dendritic development
- formation of axonal branches

Microcephaly

Decreased brain size due to defect in neuronal proliferation.

Skull is also smaller due to brain size.

Lissencephaly

“Smooth Brain”

Decrease or absence of sulci and gyri in the cerebral cortex
Normally associated with microcephaly
Due to defect in neuronal migration

Pachygyria

“Thick Gyri”

Gyri are broad, shallow, and decreased in number
Due to defect in neuronal migration

Polymicrogyria

Characterized by numerous small gyri

Due to interference in neuronal migration

Cortical Heterotopias

Misplaced neural tissue.

Characterized by islands of neurons in abnormal location along migration route due to arrest in migratory process
Extent of heterotopias determines severity
In mild cases, neurons typically able to find appropriate location eventually
Usually see seizures

Toxic Exposure

During 3rd Month of Gestation

Exposure of embryo during 3rd month to:
- alcohol
- radiation
- drugs which affect monoamines i.e. cocaine
Results in:
- Major abnormalities in lamination
- Decreased cell numbers in cortex
- Subsequent synaptic disorgainzation

Axonal Outgrowth

Synapse Formation

Occurs during 16th-40th weeks of development.

Characterized by prolific synaptogenesis.

Neuron at their final destination extend a single axon with specialized growth cones at the end.
- Many molecular cues guide the growth cone to appropriate destination
  - Tropic factors from the target
  - Trophic factors which sustains the cells
- Axonal branches may be formed in excess
  - Extra or innappropriate branches eliminated
Once growth cone reaches destination, undergoes changes to form presynaptic terminal.
Target neurons begin expressing postsynaptic changes.
- Development of neurotransmitter receptors
- Secondary messenger formation

During this period:
- neuronal migration continues
- Glia proliferate
- myelination begins

Axonal Guidance Cue Relationships

* Cooperation * Crosstalk * Additivity * Synergy * Fine-tuning * Combinatorial signaling * Hierarchical

Fetal Alcohol Syndrome | (FAS)

* **_Neuron survival_** * Triggers **widespread apoptotic neurodegeneration** during the _3rd trimester_ * Occurs via: * Transient blockage of NMDA receptors (glutamate N-methyl-d-aspartate) * Excessive elevation of GABA_A receptors * **_Axon growth_** * Corpus callosum absent in many patients with FAS * Blocks binding of axonal adhesion molecule L1 with substrate (**L1CAM**) * Critical for interactions during axonal growth

Known NMDA antagonist and GABA_A agonists

* Alcohol * Certain sedatives and anesthetics * halothane * isofluorane * nitrous oxide * ketamine * Seizure medications * Anxiolytics * barbiturates and benzodiazepines * Phencyclidine (angel dust)

Effects of Experience

Sensory and motor abilities of the neonate reflect functional pathwyas in sensory and motor systems present at birth. "Fine tuning" of synaptic connectivity occurs late prenatally and postnatally. Dependent on chemical environment and environmental stimuli throughout first years of life.

Binocular Vision Environmental Effects

* **Normal:** * Early, visual axons branch extensively at several points * Later, axon terminals concentrated in a single region * Most axons responsive to stimuli from both eyes * Necessary for binocular vision * **Sensory deprivation:** * One eye is blocked so light seen but not shapes * Deprived eye shows dramatic reduction in axonal arbor development * Once deprivation removed, neurons respond to one eye or the other but not both

Visual Processing Environmental Effects

* City dwellers: * Frequently exposed to buildings with vertical and horizontal lines * Results in higher visual acuity with horizontal and vertical orientations * Cree Indians: * Exposure to curved and oblique orientations * No preferential visual acuity

Developmental Plasticity Auditory System

* Cochlear implants * converts speech to electrical impulses * impulses stimulate auditory nerve * central auditory neurons learn to recognize impulses as words * Efficacy depends on age of implantation * Best before 5.6 y/o * See improved word understanding and comprehesion * Likely related to dendritic development * Increased with environmental stimuli * Decreased with stress

Myelination

* Starts around 6th month of gestation * Continues through 3rd decade of life * Oligodendrocytes responsible for myelination in the CNS * Responds to environmental factors well beyond developmental time frame in adult brain * Degree of myelination measured through water diffusion patterns: * Isotropic = non-myelinated * Anisotropic = myelinated

Environmental Control Emotional Development

**Amygdala** responsible for emotion. **Prefrontal cortex** responsible for control of emotion. * Brain activity in these regions measured in high risk and low risk individuals * High risk = poor familial background * Low risk = good familial background * Participants asked to: * Look at cross hairs = control * Judge emotion * Judge gender * Observe Response: * Cross hair fixation subtracted for baseline activity * High risk individuals showed less activity in the amygdala * Emotion: * Subtracted assign gender for baseline activity * High risk individuals showed greater amygdala but lower prefrontal cortex activity * More emotional and less control Interpretation: Risky childhood leads to establishment of intra-cortical wiring for avoidant coping responses as well as difficulty regulating emotional responses.