Week beginningMonday 21 October 2013

Lecture 10

Development & Aging

Lecturer: Dr Lucy Patstonlpatston@unitec.ac.nz

Lundy: Chapter 5 Tortura: Chapter 14 – see Moodle pdf

Reading

Lundy-Ekman. Neuroscience: Fundamentals for Rehabilitation, 4th Edition. W.B. Saunders Company, 2013.

Kandel et al. Principles of Neural Science, 5th Edition. McGraw Hill, 2012.

Tortura & Derrickson. Principles of anatomy and physiology, 13th Edition. Wiley. 2012.

Fetal brain development Development at cellular level Normal development Developmental disorders

Overview

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

Learning Objectives

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)

Introduction

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)

Developmental Stages in Utero

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)!

Pre-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

Embryonic Stage

Beginning of 9th week to birth Nervous system develops more and

myelination begins

Fetal Stage

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 ->)

Formation of Nervous System

NS begins as longitudinal (head to “tail”) thickening of ectoderm – the neural plate

In contact with amniotic fluid

Neural tube formation (Day 18-27)

Midline of neural plate moves toward interior, creating the neural groove

Somites begin to form

Neural tube formation

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

Somites

When folds touch, neural tube is formed The neural crest separates from the tube

and from the remaining ectoderm

Neural tube formation

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

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)

Neural tube formation

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

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

Developing Structures

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

Somite

Neurons with cell bodies in motor plate become motor neurons (innervate muscles) and interneuronsMotor/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

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

Developing Structures

Somite

Adult nervous system

Fetal nervous system

Developing Structures

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

Brain Formation (Day 28 ->)

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

Brain Formation

Midbrain (mesencephalon): develops as the midbrain

Central canal becomes the cerebral aqueduct (connects the third and fourth ventricles)

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

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

Brain Formation

Ventricle 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

Brain Formation

insula

Primary Brain Vesicles

Secondary Brain Vesicles Mature Brain

Forebrain (Prosencephalon)

TelencephalonCerebral Hemispheres

Basal NucleiLateral Ventricles

DiencephalonThalamus

HypothalamusThird Ventricle

Midbrain (Mesencephalon) Mesencephalon Midbrain

Cerebral Aqueduct

Hindbrain (Rhombencephalon)

MetencephalonPons

CerebellumFourth Ventricle

Myelencephalon Medulla OblongataFourth Ventricle

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…)

Cellular Development

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

Neurogenesis

Time lapse images of neural migration

http://www.neuralimages.org/ Number 6 and 7 are good

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”)

Neurogenesis

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

Cephalocaudal: From head, downward

Principles of Growth

• 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!

Cephalocaudal Principle

Development proceeds from the head to the feet.◦ From birth to adulthood

Head doubles Trunk trebles Arms/hands quadruple Legs/feet grow fivefold

Head is one-fourth of body

Head is one-twelfth of body

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

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”)

Myelination

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

Developmental Disorders

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)

Critical Periods

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)

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)

Neural Tube Defects

Level of foramen magnum

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

Neural Tube Defects

Four types of Spina bifida:1. Spina bifida occulta “Spina bifida cystica” (umbrella term for

when meninges protrude causing cyst-like sac)2. SB with meningocele (men-IN-go-

seal)3. SB with meningomyelocele (men-IN-go-

my- el-o-seal)4. SB with myeloschisis (my-o-LOS-

ka-sis)

Neural Tube DefectsG

reate

r se

verity

Neural tissue does not protrude through bony defect

Spinal cord function usually normal Usually L5 or S1

Spina bifida occulta

Only meninges protrude through defected vertebrae

Spinal cord function may be impaired

SB with meningocele

Neural tissue also protrudes

Abnormal growth of spinal cord and some degree of lower extremity dysfunction

Bowel & bladder dysfunction

Higher cognitive deficits

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

SB with meningomyelocele

Malformed spinal cord open to the surface of body

Neural folds fail to close Intellectual disability Paralysis of lower limbs and no sensation

SB with myeloschisis

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

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.

Developmental Disorders

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.

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

The Aging Brain

• The Aging Brain◦ 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