1. Week beginning Monday 21 October 2013 Lecture 10 Development & Aging
Lecturer: Dr Lucy Patston

2. Reading Lundy: Chapter 5 Tortura: Chapter 14 – see Moodle pdf
Lundy-Ekman. Neuroscience: Fundamentals for Rehabilitation, 4th Edition. W.B. Saunders Company, 2013.
Kandel et al. Principles of Neural Science, 5th Edition. McGraw Hill,
Tortura & Derrickson. Principles of anatomy and physiology, 13th Edition. Wiley

3. Overview Fetal brain development Development at cellular level
Normal development
Developmental disorders

4. Learning Objectives
Understand and be able to reproduce (Ha!) the process of brain development during the three stages of fetal development
Have an appreciation of normal brain development in the wider context of the person
Have an understanding of the types of disorders that can occur during fetal development and know a little bit about each of these

5. Introduction
Genetic and environmental influences act on cells throughout development of nervous system
Processes: cell growth, migration, differentiation
Even cell death, axonal retraction help to create the mature brain
Some processes completed in utero, others in first years after birth (by no means “ready to go” at birth! Gazelle anecdote)

6. Developmental Stages in Utero
We will only be considering the brain development of babies
Humans undergo 3 developmental stages:
Pre-embryonic
Embryonic
Fetal (Major brain development occurs very early in this stage)

7. Pre-embryonic Stage Conception to day 14
Fertilization (usually fallopian tube)
Cell begins divisions -> solid sphere cells
Blastocyst (D) opens into a cavity
Outer layer becomes placenta, inner cell mass becomes embryo
Implants in uterus (day 7), inner cell mass forms embryonic disk of ectoderm and endoderm (future brain)!

9. Embryonic Stage Day 15 to end of 8th week Organs are formed
Ectoderm develops into sensory organs, epidermis and nervous system
Mesoderm develops into dermis, muscles, skeleton, excretory and circulatory systems
Endoderm develops into gut, liver, pancreas and respiratory system

10. Fetal Stage Beginning of 9th week to birth
Nervous system develops more and myelination begins

11. Formation of Nervous System
During embryonic stage nervous system tissue coalesces to form a neural tube running down the back of the embryo
When tube closes (right to the ends) brain formation begins
Neural tube formation (Day 18-27)
Brain formation (Day 28 ->)

12. Neural tube formation (Day 18-27)
NS begins as longitudinal (head to “tail”) thickening of ectoderm – the neural plate
In contact with amniotic fluid

13. Neural tube formation
Midline of neural plate moves toward interior, creating the neural groove
Somites begin to form

14. Somites Somites spherical clusters of cells adjacent to mesoderm
Anteromedial part (sclerotome) becomes vertebrae and skull (e.g., “somite 10” becomes C6 & “somite 1 becomes occipital bone)
Posteromedial part (myotome) becomes skeletal muscle
Lateral part (dermatome) becomes dermis

16. Neural tube formation When folds touch, neural tube is formed
The neural crest separates from the tube and from the remaining ectoderm
The neural crest is a mass of tissue that differentiates into: dorsal root ganglia, spinal nerves, ganglia of cranial nerves, cranial nerves, ganglia of ANS, adrenal medulla and meninges

18. Neural tube formation
Neural tube first closes in cervical region then zips up rostrally and caudally, leaving open ends (neuropores)
(Superior neuropore closes Day 27, inferior neuropore Day 30)

20. Developing Structures
By Day 26 the tube differentiates into:
Mantle layer: which will become gray matter
Marginal layer: which will become axons of cells in mantle layer and glial cells
Ependymal layer: which will become the lining of the central canal of spinal cord and ventricles
When tube and crest have developed both move inside embryo, remaining overlying ectoderm will become skin

21. Developing Structures
Cells of mantle layer proliferate inside neural tube and start to separate into dorsal and ventral sections (look familiar?!)
Axons from cells in motor plate grow out of neural tube and innovate myotome region of a somite
Leads to the formation of a myotome: a group of muscles derived from one somite and innervated by a single spinal nerve.
NB: two meanings of “myotome”, embryonic and post-embryonic

22. Motor/basal plate becomes ventral horn of the mature spinal cord
Somite
Neurons with cell bodies in motor plate become motor neurons (innervate muscles) and interneurons
Motor/basal plate becomes ventral horn of the mature spinal cord
Neurons with cell bodies in motor plate become motor neurons (innervate muscles) and interneurons
Motor/basal plate becomes ventral horn of the mature spinal cord
Association plate becomes dorsal horn of mature spinal cord

23. Developing Structures
Neural crest separates into two columns (each side of tube)
Some neural crest cells become peripheral sensory neurons and grow two processes, one connects to spinal cord, one to dermatome of somite

24. Fetal nervous system
Somite
Adult nervous system

25. Developing Structures

26. Brain Formation (Day 28 ->)
Once the superior neuropore closes the neural tube forms 3 enlargements called primary brain vesicles:
Forebrain
Midbrain
Hindbrain
Hollow cavities -> ventricles
During 5th week of development, secondary brain vesicles begin to develop

27. Brain Formation Forebrain divides into:
Telencephalon: develops into the cerebral hemispheres housing the lateral ventricles and the basal nuclei
Diencephalon: develops into the thalamus and hypothalamus and houses the third ventricle

28. Brain Formation Midbrain (mesencephalon): develops as the midbrain
Central canal becomes the cerebral aqueduct (connects the third and fourth ventricles)

29. Brain Formation Hindbrain divides into:
Metencephalon: develops into the pons, cerebellum, and houses part of the fourth ventricle
Myelencephalon: develops into the medulla oblongata and houses the remainder of the fourth ventricle

30. Brain Formation
The cerebral hemispheres expand so extensively that they envelop the diencephalon. As they expand ventrolaterally they attain a C shape (temporal lobes)
As a result internal structures like caudate nucleus and lateral ventricles also attain a C shape

31. Ventricle Formation

32. Brain Formation
Lateral areas of cortex do not grow as much as other areas, resulting is covered region – insula
Edges of temporal and parietal lobes meet to form lateral sulcus
During this time the sulci and gyri are formed
insula

33. Primary Brain Vesicles Secondary Brain Vesicles
Mature Brain
Forebrain (Prosencephalon)
Telencephalon
Cerebral Hemispheres
Basal Nuclei
Lateral Ventricles
Diencephalon
Thalamus
Hypothalamus
Third Ventricle
Midbrain (Mesencephalon)
Mesencephalon
Midbrain
Cerebral Aqueduct
Hindbrain (Rhombencephalon)
Metencephalon
Pons
Cerebellum
Fourth Ventricle
Myelencephalon
Medulla Oblongata

35. Cellular Development
Cell growth, migration, and myelination are balanced by regressive processes that act to “remodel” the nervous system (cf. development of spastic cerebral palsy: inappropriate connections not eliminated, hence abnormal synergy of muscles)
Neurons migrate to their final location and then differentiate appropriately
Not genetically determined, but location- specific (omnipotent… hence, stem cells…)

36. Neurogenesis
Axons develop from the cell body with a “growth cone” on the end
Growth cone samples/“smells” the environment and “wiggles” its way to a target cell, toward and away from chemical and substrate properties

37. Time lapse images of neural migration
Number 6 and 7 are good

38. Neurogenesis
When growth cone contacts its target, NTs are released repeatedly and postsynaptic receptors are developed accordingly
Hence, synapse is created & strengthened
Neuronal death occurs during these processes as normal “survival of the fittest”
Due to failing to establish an optimal connection
Too inactive
Thus, development dependent on activity (“use it or lose it”)

39. The Nervous System Brain Development
Largest, most developed part at birth
Weight compared to adult brain
25% at birth
75% at age 2
90% at age 5
Normal experience, stimulation, result in normal brain

40. Principles of Growth
Cephalocaudal: From head, downward
Because of its importance to the functioning of the entire body, the brain is rapidly developed prenatally. For the next few years our bodies slowly catch up!

41. Cephalocaudal Principle
Head is one-twelfth of body
Head is one-fourth of body
Development proceeds from the head to the feet.
From birth to adulthood
Head doubles
Trunk trebles
Arms/hands quadruple
Legs/feet grow fivefold

42. Principles of Growth Procession of growth is orderly
Cephalocaudal: From head, downward
Proximodistal: From the center, outwards
Organs/muscles in trunk develop first, then extremities
Gross motor function comes before fine motor function

43. Myelination Begins in fourth fetal month
Near completed around 4yo (but continues well into adulthood!)
Different rates in different systems
Motor roots of spinal cord myelinated at 1mo, tracts from cortex to spinal cord at 2yo
“growing into deficit” is when problems cannot be detected until normal development would have occurred normally – CP not “diagnosed” in babyhood for this reason (frustrating for parents who “know” something is not right”)

44. Developmental Disorders
CNS most susceptible to major malformations day 14 to week 20 (major structures forming in this time)

45. Critical Periods
Times when neuronal projections compete for synaptic sites
Periods that are critical for normal development and (usually) cannot be reversed
Monkeys with one eye stitched closed from birth to 6mo are unable to see from that eye even when opened
Visual cortex did not respond to light information hitting “stitched” retina
(occluding vision for 6mo in adult monkey had no effect)
Absolute pitch by 7yo
Language by 12yo
Non-native speech sounds by 6mo (r and l)

46. Neural Tube Defects
Anencephaly: formation of brainstem without cerebral and cerebellar hemispheres
Occurs when cranial end (superior neuropore) of neural tube remains open
Skull does not form over incomplete brain, leaving brainstem and meninges exposed
Causes: abnormal chromosomal abnormalities, maternal malnutrition, maternal hyperthermia
Survival no longer than one week (but 2yo on YouTube)

47. Neural Tube Defects Arnold-Chiari malformation: deformity of hindbrain
Arnold-Chiari type II: malformation of brainstem and cerebellum leading to extension of medulla and cerebellum through foramen magnum
Type II almost always associated with meningomyelocele (men-IN- go-my-el-o-seal)
Level of foramen magnum

48. Neural Tube Defects
Spina bifida: results when the inferior neuropore does not close
Developing vertebrae do not close around incomplete neural tube -> bony defect at distal end of tube
Less 400mg folic acid per day results in higher incidence of disorder

49. Neural Tube Defects Four types of Spina bifida: Spina bifida occulta
“Spina bifida cystica” (umbrella term for when meninges protrude causing cyst-like sac)
SB with meningocele (men-IN-go-seal)
SB with meningomyelocele (men-IN-go-my- el-o-seal)
SB with myeloschisis (my-o-LOS-ka-sis)
Greater severity

50. Spina bifida occulta
Neural tissue does not protrude through bony defect
Spinal cord function usually normal
Usually L5 or S1

51. SB with meningocele Only meninges protrude through defected vertebrae
Spinal cord function may be impaired

52. SB with meningomyelocele
Neural tissue also protrudes
Abnormal growth of spinal cord and some degree of lower extremity dysfunction
Bowel & bladder dysfunction
Higher cognitive deficits

53. SB with meningomyelocele
Neural tissue also protrudes
Abnormal growth of spinal cord and some degree of lower extremity dysfunction
Bowel & bladder dysfunction
Higher cognitive deficits

54. SB with myeloschisis Malformed spinal cord open to the surface of body
Neural folds fail to close
Intellectual disability
Paralysis of lower limbs and no sensation

55. Developmental Disorders
Tethered spinal cord
When filum terminale adheres to one of lower verebra instead of coccyx
Cerebral palsy
Forebrain Malformation
When only single hemisphere develops
Associated with facial abnormalities (single eye)
Holoprosencephaly

56. Developmental Disorders
Development coordination disorder
ADHD
Autism Spectrum Disorders
Intellectual Disability
Abnormalities in dendritic spines
Fetal Alcohol Syndrome
Fetal Alcohol Syndrome is a pattern of mental and physical problems that may occur in some children whose mothers consumed alcohol during pregnancy.
During gestation the fetus receives nourishment through the placenta. When a pregnant woman drinks, alcohol passes through the placenta to the developing fetus.

57. Fetal Alcohol Syndrome
What is it?
Fetal Alcohol Syndrome is a pattern of mental and physical problems that may occur in some children whose mothers consumed alcohol during pregnancy.
How Does Alcohol Reach The Fetus?
During gestation the fetus receives nourishment through the placenta. When a pregnant woman drinks, alcohol passes through the placenta to the developing fetus.

58. Fetal Alcohol Syndrome
What Are the Neurological Problems?
The absorption of alcohol through the placenta may damage the fetus's developing central nervous system and may result in:
mental retardation
developmental delays
learning disabilities
Aggression
Behavioural problems

60. The Aging Brain The Aging Brain Elderly adults
Gradual and mild degeneration
Elderly adults
Brain weight and volume decrease, esp. after 50yo
5-30% fewer neurons than younger adult
Greater loss in sensory-motor areas
Senile plaques (hard areas surrounding neurons)
Plasticity IS STILL possible (new synapses formed)
Race between degeneration and plasticity!!!
Main result of age is slower processing