Development of the brain

Question 1

How does the brain develop?

Answer 1

The prenatal brain start developing at 2 weeks, when the dorsal surface thickens, forming the neural tube. The neural tube - embryonic brain - is segmented along its AP axis (rostocaudal axis) in 6 prosomeres, which will develop in the forebrain, 1 midbrain segments, and 8 rhombomeres (PAX and HOX genes control their regulation), which will develop into the hindbrain. These segments are determined by spatiotemporal gradient of retinoic acid, which is induced by Hox gene expression.
A migration of pseudostratified epithelial cells causes the differentiation of the embryonic nervous system: the neural crest will develop into the PNS, the neural tube will develop into the CNS and the somites in the vertebrae.
The forward part of the neural tube, which will develop into the brain start to enlarge forming three vesicles (4 weeks): forebrain, midbrain and hindbrain. These vesicles will differentiate again, forming five vesicles: the forebrain will form the telecephalon and the diencepphalon, the midbrain will form the mesencephalon, and the hindbrain will form the metencephalon and myelencephalon.

At week 7, neurons are forming rapidily.
At week 14, the brain is divided in two halves.
At month 6, the nerve cell generation is complete, which cause the cortex to wrinkle and the myelination of the axons.
At month 9, the cortex keeps wrinkle, forming sulci and gyri in a process called cephalisation

Question 2

How is the adult brain structured?

Answer 2

1. Hindbrain/ rhombocephalon:
   
   • cerebellum and pons/ metencephalon (efferent)
     
     • (C) coordination
     • (C) balance
     • (P) relay centre
   • medulla oblongata/ myelencephalon (afferent)
     
     • cranial nerve
       *spinal cord
     • heart, reflexes, breath
       Contain both afferent (receptors or sensory fibers that bring information to CNS) and efferent (bring information to muscles) nerves.
2. Midbrain/ mesencephalon
   
   • tectum and tegmentum/ substantia nigra
     *neuromelanin
   • red nucleus
     
     • hemoglobin/ferritin
       It contains two sensory neurons:
       I. superior colliculus
     • ocular reflex
       II. inferior colliculus
     • auditory reflexes
3. Forebrain/ prosencephalon:
   
   • thalamus, hypothalamus and pineal gland/ diencephalon
     
     • (T) hormones secretion
     • (HT) regulation of ANS, goal-directed behaviour, pituitary gland
     • (PG) circadian rhythm
   • cortical areas, cerebral cortex (outmost layer of grey matter), basal nuclei and limbic system/ telencephalon
     
     • (CA) primary motor neurons
     • (CA) primary sensory neurons
     • (CA) association areas (interpret sensory inputs and put together a motor response)
     • (CC) wernicke’s area = general interpretive center
     • (CC) broca’s area = speech center
     • (CC) prefrontal cortex = high cognitive, intellectual functions
     • (BN) subconscious control of muscle tone and coordinate learned movement pattern
     • (LS) hippocampus = memory expression
     • (LS) amigdala = emotional expression

The cortex is divided in :

1. visual cortex = high level visual processing
2. parietal cortex = sensory integration and visual-motor processing
3. temporal cortex = auditory and visual processing
4. frontal cortex = high level cognition, motor control, expressive language

The nuclei of the brain are cluster of neuronal cell bodies, which are also called grey matter; the tracts, which connect pathways between different parts, are also called white matter; the cortex is a dense rid of grey matter the cover all the brain.

On the surface of the brain sulci, fissures and gyri can be found.

The brain is surrounded by meninges, three membranes:
1. dura mater
2. arachnoid mater
3. pia mater
Between 2. and 3. the subarachnoid space contain the cerebrospinal fluid .

Question 3

What are neurons? How can they be classified?

Answer 3

Neurons are message transmitting cells. The rely on chemical signals, or neurotransmitters, that are released upon an action potential, which needs multiple synaptic impulses, from the pre-synaptic neuron and taken up from the post-synaptic neuron thanks to its receptors.

Neurons an be classified based on:

1. number of neurites
   
   • pseudounipolar
   • bipolar
   • multipolar
2. dendritic tree
   
   • pyramidal cells
   • stellate cells
   • purkinje cells
3. length of axon
4. function
   
   • afferent/sensory
   • efferent/motor
5. transmitter secretion
6. activating/inhibiting

Question 4

What are glial cells? What is their function?

Answer 4

Glial cells are cells that maintain neurons and neuronal communication. They are microglia, astrocytes and oligodendrocytes in the CNS, and schwann cells in the PNS.

Oligodendrocytes and Schwann cells produce myelin, which surround the axons of neurons increasing the speed of electrical transmission.

Question 5

How does the brain develop at the cellular level?

Answer 5

All 8 stages of formation of neurons/glial cells occur simultaneously in different parts of the brain.

1. Mitosis/Proliferation
   The proliferation of stem cells occur in the ventricular zone of the brain, and generates radial glial cells and neuroblasts. Under neural induction, the ectoderm differentiate into epidermis and neuroectoderm, which differentiate again in the neural tube. At this point all neural cells are forming, following the processes of neurogeensis, oligodendrogenesis and astrogliogenesis: neuroepithelial cell undergo asymmetrical division, forming one nIPCs, which will give rise to neurones, and one undifferentiated cell; this undifferentiated cell will undergo asymmetrical division again, forming one oIPC, which will give rise to the olygodendrocytes, and one undifferentiated.
2. Migration
   Neurons use radial glia cells as guide wires to crawl to their correct position. They use both extrinsic, chemicals in the environment, and intrinsic, proteins, to direct themselves to the target place.
3. Differentiation
   After mitotic division, neurons become fixed and specialized: they develop processes (axons/dendrites), neurotransmitter-making abilities (electrical conductivity). The differentiation is dictated by their cell fate.
4. Aggregation
   Neurons aggregates into columns to give rise to a function.
5. Synaptogenesis
   This is the process of formation of synapses, the sites where neurons/neuron-tissues are connected: they can be axo-dendritic, axo-somatic or axo-axonic, depending on the pre- and post-synaptic neuron.
   The pre-synaptic part is attracted to the target cell due to theformation of a chemical gradient, which orient the growth of the synapse. The first contact between the cells involve in the synapse is meidated by proto-cadherins which create specificity.
   The maturation of the synapse is accompanied by changes in spine shape, size and number.
6. Neuron death
   40-75% of the neurons formed during embryonic/fetal development fail to make optimal synapses.
7. Synapse re-arrangement
   Active synapses take up neurothrophic factors; inactive synapses are too unstable and die.
8. Myelination
   In this process, glial cells wrap themselves around axons in primary motor and sensory neurons: this increase the speed of neural conduction.

Question 6

What are the diseases that damage on a specific area of the brain can cause?

Answer 6

1. defects in the migration of cells during synaptogenesis:
   
   • flamin/arfgef2 = microcephaly
   • lis1/Dcx = lissencephaly or double cortex
   • reelin/apoer2 = inverted cortical layer
   • DCX = double cortex
2. defects in the cerebral acqueduct:
   
   • hydrocephaly = no circulation of CSF
3. defects in the rhombocephalon:
   
   • korsakoff’s psychosis
   • wernicke’s encephalopathy
   • cerebellum medulloblastoma
4. defects in mesencephalon:
   
   • fetal valproate syndrome
5. defects in association cortex:
   
   • agnosia
   • apraxia
   • aphasia
6. defects in basal nuclei:
   
   • huntington’s disease
   • hemibalism
   • parkinson’s disease
7. defects in limbic system:
   
   • asperger’s syndrome
   • urbacht-wiethe disease
   • alzheimer’s disease
8. defects in diencephalon:
   
   • eating disorders
   • feritility/reproductive disorders
   • growth disorders
   • disturbance homeostasis