Neuroanatomy 3 -- development of nervous system 2 Histogenesis in the neural tube –

Histogenesis steps in the neural tube –

• 1. Interkinetic nuclear migration

• 2. Symmetric vs asymmetric division

• 3. Formation of 3 layers

• 4. Differentiation of nerve cells

• 5. Myelination 

Neural tube histology

From a simple columnar epithelium to a mitotically active pseudostratified epithelium (neuroepithelium)

Methods for cell number increase in the neuroepithelium

• Interkinetic nuclear migration in the neuroepithelium –

  • Consisting of a Pial/basal and a ventricular/apical side

    • Nucleus moving between sides w/ cell cycle

  • Process in which nucleus migrates in the cytoplasm of elongated neuroepithelial progenitor cells (in phase with mitosis)

  • Thus pseudostratified — nuclei @ different heights & mitotically active

• Symmetric cell division –

  • Generates two morphologically similar daughter cells that are both likely to be stem cells, thus increasing the precursor cell population — creates radial glial cells

Evolution of primary neural precursor cells into ventricular radial glial cells

• Called this because these projections of the cytoplasm seems like rays in the tube (originally thought to be glial cells but then discovered to be precursor cells) – simple precursor cells that become radial glial cells that — (at this point due to symmetric cell division, but now) —

  • Ventricular radial glial cells undergo an asymmetric mitotic division — generate a progenitor cell and a differentiating cell 

    • Thus increasing cell #

    • In symmetric division —  mitotic spindle (pulling them apart) parallel to axis of epithelium — in asymmetric — perpendicular

  • Differentiating cells migrate to their final position using radial glia (wraps around cytoplasmic projections of radial glia cells and uses them to migrate to its final position) 

    • Defects in migration can cause lissencephaly — ex. remain where they are & thus cause much bigger ventricles

Generation of neurons and glial cells and organized in the wall of the neural tube into 3 zones –

• Ventricular/Ependymal layer —

  • Innermost, lined by ependymal cells

• Mantle layer 

  • Presumptive gray matter — most of the body’s neurons

• Marginal layer 

  • Presumptive white matter — made of axons

This organization is evident in the beginning, but over time its remnants are only visible in the spinal cord

Differentiation of nerve cells and neural circuits is a long process (neurons) –

• At the beginning called neuroblasts, but then differentiate into much more complex structure, growing dendrites in all different directions, then into full fledged neuron 

• Takes place in many phases – both prenatally and postnatally 

  • Production of neurons & glia, cell migration, and onset of molecular differentiation & connectivity occur prenatally

  • Unique cellular patterns & neurochemical maturation — around time of birth

  • Extensive neuronal growth, synaptic formation & refinement postnatally

Image showing amount of synapses and connections over time (pre & post natally)

• 8 month premature, 1 month, 3 month, 6 month

• 15 month, 2 years, 4 years, 6 years 

  • Between 2 & 6 synaptic pruning

Myelination –

• Due to schwann cells in PNS and oligodendrocytes in CNS –

  • In PNS all axons have coverage by schwann cells, only myelinated if cytoplasm of schwann cell wraps around axon more than once. (Each schwann cell only for 1 axon) 

  • In CNS oligodendrocytes wrap themselves around more than one axon, which means there is more damage from loss of one oligodendrocyte than one schwann cell 

Myelination over time

• Myelination occurs not as much in fetal months (only upper in cortex), then in months of first year very much, and in 2-10 years lower down develops –

• This shows up to down down corticospinal tract (cortex → spine)

Babinski/Plantar reflex –

• Normal reflex in infants after the sole of the foot has been firmly stroked – the big toe then moves upward or toward the top surface of the foot, the other toes fanning out. 

  • Normal in children up to 2 years old, disappears as child gets older as early as 12 months – if doesn’t disappear could be indicator of some issue (damage to corticospinal tract) 

OTHER REFLEXES ASWELL — not sure if need to know?

Derivatives of the neural crest & the placodes

• The neural crest is the origin of the peripheral nervous system (PNS)

  • The portion of the nervous system not inside dorsal body cavities 

  • Melanocytes not part of PNS but derives from neural crest 

• It also originates components of pharyngeal arches & thyroid parafollicular cells (not necessarily neural)

  • In order to give rise to these derivatives, they need to undergo an epithelial-mesenchymal transition in order to be able to delaminate from the other cells & migrate & colonize these areas

The neural crest can be divided into –

• Cranial

  • Craniofacial bone & cartilage, Cranial neurons & glia, Odontoblasts, Melanocytes

• Cardiac

  • Cardiac septa, Cardiac neurons & glia, Smooth muscle cells, Melanocytes

• Vagal

  • Entering neurons & glia

  • Melanocytes

• Trunk/sacral

  • Sensory neurons & glia

  • Autonomic neurons

  • Chromaffin cells

  • Melanocytes

Placodes –

Localized ectodermal thickenings in the head of vertebrate embryos – involved in formation of sense organs (eye, nose, ear) & cranial sensory ganglia

• Crystalline placode — eye

• Acoustic placode — ear

• Olfactory placode — nose

For formation of sensory ganglia of cranial nerves — contribution of neural crest cells aswell

Sensory ganglia of cranial nerves have a double origin –

Neural crest & placodes contribute to the formation of cranial nerves sensory ganglia

Neurocristopathies –

• Class of pathologies occurring in vertebrates, especially in humans that result from –

  • Abnormal specification, migration, differentiation or death of neural crest cells during embryonic development.

  • Various pigment, skin, thyroid and hearing disorders, craniofacial and heart abnormalities, malfunctions of the digestive tract and tumors can also be considered as neurocristopathies.

• Types —

  • Medullary carcinoma of the thyroid

  • Schwannoma

  • Neurofibromatosis Type I (von Recklinghausen disease)

  • CHARGE association –

  • Pheochromocytoma

  • Neuroblastoma

  • Cleft palate

  • DiGeorge Syndrome

  • Hirschsprung disease 

Medullary carcinoma of the thyroid

Neurocristopathy —

• Parafollicular cells, calcitonin

• Sporadic (80%) or familial (20%) – can be associated with MEN (multiple endocrine neoplasia) – autosomal genetic disorder

Schwannoma

Neurocristopathy —

Benign tumour (PNS, schwann cells), most common: acoustic neurinoma

Neurofibromatosis Type I (von Recklinghausen disease)

Neurocristopathy —

• Dominant genetic disorder, protein neurofibromin (tumorsuppressor gene): originates from Schwann cells 

• Multiple neural tumors (neurofibromas) dispersed in the body originating from peripheral nerves cells (neurites, fibroblasts, Schwann cells), pigmented skin lesions.

CHARGE association –

Neurocristopathy —

• Coloboma of the retina, lens or choroid

• Heart defects (e.g. Tetralogy of Fallot)

• Atresia choanae

• Retardation of growth

• Genital abnormalities

• Ear abnormalities or deafness

Pheochromocytoma

Neurocristopathy —

• Generally in adrenal medulla, containing both epinephrine and norepinephrine. 

• Occurs between 40-60 years old and presents with persistent or paroxysmal hypertension, anxiety, tremor, profuse sweating, pallor, chest pain, and abdominal pain

Neuroblastoma

• Common extracranial neoplasm, containing primitive neuroblasts

• Mainly occurs in children (up to 15 years)

• In sympathetic chain ganglia or in the adrenal medulla – presents wit hmetastasis to bones, bone marrow, and lymph nodes 

Cleft palate, DiGeorge Syndrome, and Hirschsprung disease

Development of the spinal cord –

• Useful prototype for studying the overall structural & functional features of the CNS

• When we observe the neural tube at the spinal cord level we find the typical arrangement into 3 layers –

  • Marginal, mantle, and ventricular 

  • In the wall of the neural tube at the level of the mantle layer (future grey matter) organizes into a dorsal/posterior territory and basal/anterior territory –

    • 2 Alar plates

    • 2 Basal plates

      • These plates will form the horns

  • Lumen becomes spinal/ependymal canal (becoming smaller) , and tiny lateral horns form 

• Gray matter divided into sensory & motor territories, and is all clustered together in dorsal & ventral area (thus easy division – clearly marked – in other places not as clear) —

  • Dorsal — sensory

  • Ventral — motor

Alar & Basal plates

Dorsal/posterior territory and basal/anterior territory of wall of neural tube at level of mantle layer (future grey matter)

• 2 Alar plates

  • In between 2 alar plates – roof plate

  • Form sensory portion of neural tube

  • Non-permissive – axons cannot cross 

• 2 Basal plates

  • In between 2 basal plates – floor plate

  • Form motor region of neural tube 

  • Permissive – axons can cross

Gray matter division & patterning

Gray matter divided into sensory & motor territories, and is all clustered together in dorsal & ventral area (thus easy division – clearly marked – in other places not as clear)

• Morphagens and transcription factors specify the dorso-ventral patterning of progenitors in the neural tube – specify what is where (motor ventral, sensory dorsal) 

  • Opposite gradients of SHH and BMPs (bone morphogenic protein) determine the dorsal-ventral cell fates –

    • Floor plate, roof plate, etc produce morphogens, which are more concentrated either to the epidermis or the notochord, with these gradients triggering the transcription of transcription factors of Class I & II homeobox, etc 

  • The notochord has influence on development of floor plate and exit sites of nerves from the spinal cord – issues with notochord will cause issues in neural tube development 

Development of spinal nerves (nerves originating from spine to periphery)

• While alar & basal plate are forming, the neural crest cells on the side that didn’t migrate will form the sensory ganglia along with the placodes — forming the dorsal roots

  • Neurons going outside to periphery centrifugal, going inside from periphery is centripetal  (referring to sensory ganglia but also all neurons in general)

    • Axons of centripetal sensory neurons go in from periphery reaching spinal cord from the dorsal root

    • Axons of centrifugal motor neurons go out to periphery from the ventral root (to the derivatives of a somite)

• In basal plate — origination of motor neurons — innvervate & control muscle fibers originating from somites next to them

  • On each segment of the spinal cord on either side the dorsal root & ventral root come together to form a spinal nerve (spinal nerve = mixed)

    • 2 spinal nerves per segment

Each spinal nerve has 4 components –

• Somatosensory

  • Territory receiving information from soma (skin, muscle, joints, ligaments, bones)

• Viscerosensory

  • Neurons on the spinal cord receiving more visceral (organs) information 

• Visceromotor

• Somatomotor

Describe the difference between somatomotor innervation and visceromotor innervation 

• Innervation of striated voluntary muscles vs innervation of smooth muscle 

  • Visceral –

    • Preganglionic axon & autonomic/ganglionic neuron between neuron and target smooth muscle, so at minimum passes through two synapses 

      • Visceromotor/preganglionic neuron in the CNS has an axon linked outside the CNS via a ventral root, then reaching other neurons on autonomic ganglia, finally innervating smooth muscle/glands in visceral organs

  • Somatic –

    • Directly connects to muscle 

Segments of the spinal cord (+ dermatometric map)

• The spinal cord is divided into segments (somitogenesis) – called neuromeres

  • Each segment contain

    • 2 dorsal roots

    • 2 ventral roots

    • 2 spinal nerves (linkage of 1 dorsal & 1 ventral root)

  • Each segment innervates the cutaneous territory (dermatone), bony territory (sclerotome), and the muscular territory (myotome) originating from the adjacent somite 

  • This connection is maintained even when somites disappear – dermatomeric map – displays stretches of skin whose sensory innervation depends mostly from a single segment of the spinal cord 

    • Innervation and motor control of most muscles depends on more than 1 segment of the spinal cord — not as clear as bone/skin

Spinal (/neural) plexuses

• As a neuromere usually innervates more than one muscle, and one muscle is innervated by more than one neuromere — formation of anastomosis between nerves of different neuromeres — thus forming neural plexuses — bundles of intersecting nerves

• Most spinal nerves (exception — thoracic) form spinal plexuses to exchange fibers with one another

Dorsal & ventral rami of spinal nerves

Rami=branches – not roots

• Some muscles that spinal nerves need to innervate are ventral while others are more posterior (rostral?) — thus each spinal nerve divides into into a dorsal & ventral ramus/branch (very early on in development)

Ascent of the spinal cord –

• Ventral & dorsal roots leave the vertebral canal caudal to the vertebrae with the corresponding number 

  • Meaning that those axons begin to make connections with the periphery

• But then, the vertebral column begins to elongate further, leading the roots to elongate or lose the connection with the periphery 

  • Nerve roots acquire a progressively more oblique course in the vertebral canal – the more developed the more oblique – postnatally appear almost straight