Tu Oct 9

1
Tu Oct 9 Development Teaching Assistant
Denise Bolen Office Hours Tuesday 1-2 PM and
Wednesday 1-2 PM - S04-6401 denise.bolen001_at_umb.e
du
2

(a) Day 28

(b) By
Day 60 During embryonic period Neural tube
forms and closes 3 part brain develops Different
iates into the 5 part brain

3
Stages of pregnancy (38 weeks long) 1.
Preimplantation period - days 0-14 2. Embryonic
period - days 15-60 3. Fetal period - days 61
until birth Growth and differentiation of organ
systems - to completion for all organs except
brain
4

• Processes during fetal period neural development
• Proliferation birth of cells
• Migration movement to end location
• Differentiationspecialization into a
  particular cell type
• Elaboration growth of dendrites and axon
• Synaptogenesis formation of synaptic
  connections
• Gliogenesis - formation of glial cells

5

• Brain Development in the Fetal Period
• formation of cortex
• continued proliferation and migration (before
  and after birth)
• specialized neural cells (neurons) form and
  begin to connect with each other involves
  differentiation and elaboration
• apoptosis (cell death) in some areas
• synaptogenesis, gliogenesis, and synaptic
  remodeling
• birth occurs - most processes continue

6
Principles of Neural Development 1. Proceeds from
hindbrain to forebrain (caudal to rostral
gradient) 2. Degree and timing of neurogenesis
and other processes varies across brain areas 3.
Gliogenesis of certain glial cells occurs in
parallel with neurogenesis Radial glia (cells
that form tracks for neuronal migration) and
microglia (clean up debris of dead cells, etc)
4. Other glial cells (myelin) develop after
neuronal differentiation and elaboration 5. 6
cortical layers- layer I is outmost, layer VI is
deepest. VI-I form inside out - deeper layers
form first.
7

Day 28 Day 60 Embryonic Brain


Brain at birth (showing fetal
period development)
8

• Processes during neural development
• Elaboration
• Synaptogenesis
• Gliogenesis
• Apoptosis - programmed cell death
• At 2 developmental stages, apoptosis removes
  about half of all neurons created
• 1st stage - Prior to birth and during infancy
• 2nd stage - Again in adolescence
• Also synaptic remodeling occurs formation and
  elimination creation and pruning of circuits

9

• Human Postnatal Brain Development
• Infancy
• overproduction of neurons and synapses beginning
  in fetal period and continuing to about 18 months
  of age
• apoptosis and pruning of synapses continues to
  about 2 years of age
• Adolescent Period
• another wave of development and apoptosis and
  synaptic remodeling

10

• Postnatal brain development
• Differentiation, synaptogenesis, apoptosis, and
  synaptic remodeling continue
• prefrontal cortex, cerebellum, and hippocampus
  complete development postnatally
• certain fiber tracts serving the prefrontal
  cortex are not complete until after adolescence

11

• Adolescent Brain Development
• overproduction of neurons and their axons
  peaking at 11 years in girls 12 years in boys
• pruning through age 20 with final stages
  occurring in highest brain areas prefrontal
  cortex and lateral temporal lobes
• overproduction then pruning of receptors for
  several systems (DA, 5HT, GABA/BZD, ACh, GLU)
• major decline in excitatory stimulation of
  cortex (from diffuse to focal)

12
Pattern of Apoptosis Neurons die off from back to
front
From Gogtay et al, 2004. 13 children were
scanned at 2 year intervals from 4-20 years. Blue
represents a decline in gray matter density
(neuronal cell body density).
13
All the same parts, but better connected
14
Consequences of Drug Exposures that Occur
Prenatally How are brain development and
behavior effected? Teratology - study of abnormal
development Teratogen - an agent that causes
abnormal development Neurobehavioral
Teratology the study of abnormal brain and
behavioral development due to prenatal exposure
to toxic agents
15

• Endpoints of Abnormal Development
• Death
• Malformation
• Growth Retardation
• Functional Deficit

16
Environment influences development at every
stage 1. Preimplantation - death 2. Embryonic
period - malformation, effects on growth,
functional problems 3. Fetal period - growth,
functional problems, altered differentiation,
synaptogenesis, myelination, apoptosis
17

• Types of environmental influences upon
  development
• maternal health
• maternal nutrition
• infections
• drug use
• environmental chemicals
• physical restrictions or damage

18
Teratogens of the CNS Radiation Antimitotic
agents (cancer treatments) Certain
illnesses Abnormal amounts of certain vitamins or
minerals Prescription drugs - Accutane (treatment
of acne) Anticonvulsants Environmental chemicals
- lead, mercury, PCBs Drugs of abuse -
alcohol Hormonal disruptors Pesticides
19

• Variables Governing Susceptibility
• Gestational Age at Exposure
• Genotype
• Characteristics of Agent
• Mechanism of Action
• Amount
• Route

20

• Potential Neurobehavioral Teratogens
• Psychoactive Agents known to act on the adult
  CNS - drugs, hormones
• Compounds that are harmful to the adult brain
  and behavior - Neurotoxicants

21

• Known Human Neurobehavioral Teratogens
• Rubella
• Cytomegalovirus
• X-Irradiation
• Retinoic Acids
• Anticonvulsant Drugs (Phenytoin Valproic Acid
  Phenobarbital Carbamazepine)
• Drugs of Abuse (Alcohol Heroin Methadone
  Methamphetamine Cocaine)
• Methylmercury
• Lead
• PCBs

22

• Causes of Behavioral Dysfunction
• Reduced Number of Neurons
• Migration Defects
• Abnormalities of Cytoarchitecture synaptic
  connections
• Neurochemical Disturbances

23

• Certain principles
• Some things are evident at birth some are not.
• Generally, neurobehavioral teratogens impair the
  function of more children than the number
  affected with malformations our techniques are
  not yet good enough to detect structural brain
  abnormalities at birth.
• Some agents do not cause detectable structural
  malformations (imaging), but do compromise
  behavior.
• Agents that are harmful during pregnancy may also
  be harmful during childhood brain development.

24

• Accutane pill used to treat cystic acne
• a synthetic Vitamin A (a retinoic acid)
• isotretinoin

25

• Embryonic Exposure to Accutane (Isotretinoin)
• Spontaneous Abortion (40)
• Major Malformations (35)
• Prematurity 16

26

• Accutane interferes with the development of
• Central Nervous System
• Craniofacial structures
• The Heart
• The Thymus and Parathyroid Glands
• Other organ systems

27
(No Transcript)
28
(No Transcript)
29
Figure 1. Mental ability of children exposed to
isotretinoin during embryonic development.
30

• Is vulnerability to the CNS effects of retinoic
  acid seen in adolescence?
• controversial human data suggest that some
  individuals of unspecified ages may experience
  depression, suicidality, or psychosis following
  Accutane treatment (Wysowski, Pitts, and Beitz,
  2001 Bremner, 2003)
• long term effects are unknown
• 2 studies in adolescent mice show that 21 days
  of treatment with 1 mg/kg/day 13 cis RA reduces
  hippocampal cell survival (Sakai et al, 2004) and
  reduces spatial learning (Crandall et al, 2004)
• reduced hippocampal neurogenesis has been shown
  in depression (increased during antidepressant
  treatment)