Neural Development

Embryonic Development
Neurogenesis
Cell migration
! Radial glia

Cell differentiation
! Cell autonomous
! Induction

Synapse formation
Cell death
! Neurotrophic factors

Synaptic remodeling

Increase in human brain weight

Our brains grow a lot during the first 5 years of life

Brain Development
Adult human (~ 100 billion neurons) but we
start as just one cell the zygote

Embryonic Development

Development begins

with fertilization of egg

(sperm & egg unite =
zygote)
Within one week, the
embryo has three
distinct layers
The nervous system
develops from the
outer layer called the
ectoderm

Embryonic Development

Cell layers thicken to a

flat neural plate

Ridges of the ectoderm
continue to thicken
and the middle portion
forms the neural
groove
The top of the neural
ridge come together to
form the neural tube

Embryonic Development
Anterior portion of neural tube develops into the
forebrain, midbrain, and hindbrain

Embryonic Development
Posterior tube develops into spinal cord
The interior of the neural tube develops into the
cerebral ventricles

Brain Development
Brain size increases massively in utero
In 8th week, head is half the size of entire embryo

Birth

Brain Development
Brain size also increases massively
after birth

! Rapid increase first 5 years

! Peak b/w 18 & 30
! Gradual decline thereafter

Stages of Cellular Activity

What are the cellular processes that contribute

to the morphological development of the brain?

Stages of Cellular Activity

1. Neurogenesis
! mitotic division of non-neuronal cells to produce neurons

(occurs in neural tube)

2. Cell migration
! movement of cells to establish distinct populations
3. Differentiation
! transformation of neuron into distinct types
4. Synaptogenesis
! establishment of synaptic connections as axons and
dendrites grow
5. Cell death
6. Synaptic remodeling
! loss/growth of synapses to refine connectivity

1. Neurogenesis- birth of new neurons

Cells on the inner

surface of the neural

tube divide (mitosis)
and form a densely
packed ventricular
zone
These cells arent
neurons yet, they are
progeny cells
This ventricular
mitosis is the source
of all neurons and glia

1. Neurogenesis- birth of new neurons

Shown here is a small

section of the wall of the

neural tube at an early
stage of embryonic
development
At this early stage there is
a ventricular zone (the
location of cell birth, i.e.
ventricular mitosis)
Progeny cells (still not
differentiated cells yet)
migrate from ventricular
layer to the marginal layer
(labeled M on right)

1. Neurogenesis- birth of new neurons

Later in embryonic

development the wall of the

neural tube thickens and
an intermediate layer forms
(labeled I on diagram to
the right
Again, all neurons and glia
are derived from these
progeny cells, so the hope
is one day we can identify
the birth and life span of
every cell

2. Cell Migration
Cells migration,
Neural Tube

movement of
progeny cell away
from ventricular
zone to their final
destination
Cells travel along a
particular type of
glia cell (radial glial
cells)

2. Cell Migration
Radial glial cells act as a series of guide wires
Newly formed cells creep along these radial glia
Cell adhesion molecules guide cell migration

3. Cell Differentiation
Many different types of neurons

3. Cell Differentiation
Migrating cells are not

differentiated (no neuronal

phenotype)
When cells reach
destination genes that make
neuronal proteins are
expressed
Cells differentiate into those
appropriate for brain region
(e.g., motor neurons in
ventral horn, sensory
neurons in dorsal horn)

3. Cell Differentiation
Purkinje cells develop like this even if they are removed

and put in a dish. Thus, the development is independent

of neighboring cells (called cell-autonomous)

3. Cell Differentiation
Some cells will only develop

into the appropriate cell if they

get a specific signal from a
neighboring cell
In this case, the neighboring
cell secretes a chemical that
changes the gene expression
and the phenotype of the
developing cell this is called
induction
Cell-cell interactions are
necessary for the development
of motor neurons (gold) must
encounter a specific protein
(sonic hedgehog) to become a
motor neuron

Chick spinal cord

4. Synapse Formation
Dendrites and axons grow out to make synaptic

connections
Possess growth cones (comprised of lamellipodia and
filopodia), specialized structures that seek out the
target

4. Synapse Formation
Filopodia pull the growth

cone towards target

Target cells secrete
chemical that guides
growth cones (chemotropic
guidance)
There both
chemoattractants attract
certain growth cones
And chemorepellents- repel
certain growth cones
Synapses formed when
cone contacts target

Chemorepellent (red)
Repels most, but not all,
axons. Example from
Fruit Fly

5. Programmed Cell Death (Apoptosis)

Programmed cell death is a critical

phase of embryonic brain

development
In chick spinal cord, more motor
neurons are made that are needed
and then over 50% undergo
apoptosis
Specific cellular machinery mediates
apoptosis (death genes, caspases)
Machinery is ancient, present in C.
elegans
Dont need to know the details on
this image

5. Cell Death (Apoptosis)

Pattern of cell death in

motor neurons in chicks

and humans is very similar
Neural darwinism
! Neurons are
overproduced
! Neurons compete for
connections with target
! Those that make stable
connections survive
! Those that do not perish
! Why? Because those
without connections
dont get trophic factors

Chicks

Humans

Neurotrophic factors
Neurotropic factor- is the
target derived chemical
that affects the growth of
neurons because it is a
chemical that feeds
neurons attempting to
connect
There are many types of
nerve growth factors
including brain-derived
neurotrophic factor
(BDNF) which is also
important for
neuroplasticity in adults

6. Synaptic rearrangement
Synaptic remodeling takes place for the remainder of
the organisms life
Synaptic connectivity regulated by neuronal activity
(use it or lose it)
This is essential for learning and memory

Sexual Differentiation
Final block of the course will cover lots of social behavior
Important sex differences in brain and behavior

Genetic Sex
Genetic sex is determined at the time of fertilization
But this is just the first in a series of steps that culminate in the

development of a male or female

Each cell contains 23 pairs of chromosomes (excluding sperm cells
and ova; which are haploid)
Production of these gametes entails a special form of cell division
that produces cells with one member of each chromosome

Gametes and Genetic Sex

Development begins at the time of fertilization when a

single sperm and ovum join

They share their 23 single chromosomes to reconstitute
the 23 pairs
A persons genetic sex is determined at he time of
fertilization of the ovum
22 chromosome pairs determine physical development
independent of sex
The final pair consists of two sex chromosomes which
contain genes that determine whether the offspring will be
a genetic male or female
Two types of sex chromosomes: X and Y
All ova contain X; Sperm contain X or Y XX (female) XY
(male)

Development of Gonads
Initially, during first 6

weeks of development,
all individuals have the
same undifferentiated
(indifferent, bipotential)
gonad
If your genetic sex is
male the Y
chromosome has sry
gene
SRY protein binds to
DNA in cells within the
undifferentiated gonad
and develop into testes

Gonad development

If genetic sex is

female no SRY
protein
Therefore,
undifferentiated
gonads become
ovaries
Female is the default
SRY = sex
determining region
of the Y
chromosome

Gonadal Hormones
Gonadal hormones direct

sexual differentiation of the

body
Developing testes produce
several hormones
Developing ovaries produce
very little
Bodies are preset to
develop female but fetus is
masculinized if testes are
present and secrete
testosterone

Organizational VS Activational
Once gonads in genetic

males develop into testes

they secrete androgens:
testosterone and
dihydrotestestone
These masculinize the
fetus i.e. cause Wolffian
system to develop
Testes also secrete antiMullerian hormone and
this hormone defeminizes
the fetus (i.e. prevents the
Mullerian system from
developing)

Wolffian and Mullerian systems

The early fetus has a

genital tubercle that

can form either a
clitoris or a penis
As well as two ducts
that connect the
indifferent gonads to
the out body wall the
wolffian ducts and the
mullerian ducts
In females, the
mullerian ducts
develop into fallopian
tubes, uterus and inner
vagina

Wolffian and Mullerian systems

In males, hormones

secreted by the testes

cause the wolffian ducts
to develop into the
epididymis, vas deferens,
and seminal vesicles
This system is
masculinized by
testosterone (which
promotes the development
of the wolffian system)
And anti-mullerian
hormone (which induces
regression of the
Wolffian duct
mullerian system)

Wolffian and Mullerian systems

In the absence of

testes, these
hormones are not
present and the
genital tract develops
into a feminine pattern
(i.e. the wolffian ducts
regress and the
mullerian ducts
develop into
components of the
female internal
reproductive tract;
fallopian tubes,
uterus)

Mullerian duct

Androgens masculinize
Testosterone masculinizes

non-wolffian derived
structures
Testosterone is converted
to dihydrotestosterone and
this causes tissue around
the urethra to form the
prostrate gland, scrotum
and penis

Androgens masculinize
Testosterone masculinizes

non-wolffian derived
structures
Testosterone is converted
to dihydrotestosterone and
this causes issue around
the urethra to form the
prostrate gland, scrotum
and penis
If androgens are absent,
the prostrate fails to form
and the external skin
grows into the labia and
clitoris

Hormones guide sexual differentiation

So the chromosomes

determine the sex of the

gonad
The gonadal hormornes
then drive sexual
differentiation for the rest
of the body
Later in life, both
hormones and experience
guide sexual
differentiation and the
development of gender
identity

Androgen receptors
Androgen insensitivity

syndrome (AIS)
The gene for the androgen
receptor is located on the X
chromosome
An XY individual that has a
dysfunctional androgen
receptor gene does not
respond to androgen that is
produced by the testes
They have SYR so testes
develop and produce
androgens but the
androgens dont have effect

Organizational VS Activational
Post development Hormones play critical roles for sexual

maturation (puberty) and they continue to regulate behavior

Endocrine Hormones
Hormone- chemical of

communication that is secreted

into bloodstream and carried to
distinct target tissues
Organs in the body that make
and secrete hormones and
called endocrine glands
While hormones are traditionally
defined as traveling through the
blood there is also
neurocrine or neuroendocrine signaling that occurs
within the brain (or from brain to
pituitary)

Early evidence for testosterone

In 1849, Arnold Berthold castrated young roosters
In some, implanted testis into body cavity
Group 1

Group 2

Group 3

Appearance of
immature roosters

Manipulation

None

Remove
testes

Remove testes and

reimplant one in
abdomen

Normal
Yes
Yes
Normal

Small
No
No
Weak

Normal
Yes
Yes
Normal

Appearance of
adult roosters

Comb and wattles:

Mount hens?
Aggressive?
Crowing?

Early evidence for testosterone

Castrated animals were weak and lacked male characteristics
Animals with implanted testis developed normally
Group 1

Group 2

Group 3

Appearance of
immature roosters

Manipulation

None

Remove
testes

Remove testes and

reimplant one in
abdomen

Normal
Yes
Yes
Normal

Small
No
No
Weak

Normal
Yes
Yes
Normal

Appearance of
adult roosters

Comb and wattles:

Mount hens?
Aggressive?
Crowing?

Types of Chemical Communication

Synaptic communication- chemical released by
one neuron to act on another
(a)Synaptic transmission function

Neuron
(b)Autocrine function

(c)Paracrine function
Paracrine
cell

Autocrine

(a)Synaptic
transmission function
Types
of Chemical
Communication
Autocrine communication- hormone released by

a cell which then affects its own activity

Paracrine communicationhormone released by
Neuron
a cell to affect nearby target cells
(b)Autocrine function

(c)Paracrine function
Paracrine
cell

Autocrine
cell

Presynaptic Neurotransmitter
Postsynaptic
neuron
neuron

Types of Chemical Communication

Endocrine communication- hormone released

into bloodstream to act on distal target tissues

(b)
Signal
molecule

Hormone

Endocrine
cell

Blood

Target
cell

Target
cell

(c)
Neuron

Blood

Principles of Hormone Action

1) Slow, gradual action that outlasts hormonal

signal
2) Changes intensity or probability of behavior,
rather than turning behavior on or off
3) Hormones produced in small amounts -- often
secreted in bursts (pulsatile)
4) Hormones affect metabolic processes in most
cells (buildup & breakdown of carbohydrates,
lipids, & proteins)
5) Hormones affect only those cells that have
receptors for the hormone

Chemical Structures of Hormones

Protein hormones
(a)Protein hormone

(strings of amino
acids)

H2N

! e.g., vasopressin

Different
amino acids

Amine hormones

(single amino acids)

COOH

! e.g., thyroid hormone

Steroid hormones

(four carbon rings)

! e.g., testosterone,

Adrenocorticotropic hormone
(ACTH)
(b)Steroid hormone

(c)Amine hormone
OH
CH 3

estrogen

HO

HO

I
Estradiol

CH 2CHCOOH
NH 2
I

Thyroxine

Two Cellular Mechanisms of Action

Hormones either have the

typical ligand/receptor
relationship bind to
metabotropic receptors on
the cell surface
Activate G-protein
mediated second
messenger cascades
Such hormone signaling is
considered fast acting
(seconds to minutes) but
this is still very slow
compared to
neurotransmitters like
glutamate (milliseconds)

Two Cellular Mechanisms of Action

Also Steroid hormones
can pass through cell
membranes
Bind receptors located
inside the cell
The steroid hormone and
receptor form a complex
which then binds to DNA
Then acts as a transcription
factor (alters gene
expression)
Steroid hormones acting
inside the cell take hours to
take effect takes time to
make new protein

Nongenomic effects: steroid hormones

When it was discovered that

steroid hormones can have

more rapid effects by acting
at a different class of
receptors on the cell
membrane, many began
referring to this as nongenomic activation
(previously thought to only
work via genomic effects)
Estrogen is a steroid
hormone that has these nongenomic effects (in addition
to its classic genomic effects)

Major Endocrine Glands

Dont need to memorize
this list for the test

Pituitary Gland

Base of brain below

hypothalamus the
pituitary gland is a
major endocrine
gland
Consists of two
distinct components,
the anterior pituitary
and the posterior
pituitary (completely
separate in function)

Posterior Pituitary Gland

Connected to hypothalamus

via pituitary stalk (aka

infundibulum)
Oxytocin (OT) and
vasopressin (AVP) neurons
in the hypothalamus project
to the posterior pituitary
These neurons are called
hypothalamic
neurosecretory cells extend
all the way into posterior
pituitary
Terminate on capillaries and
action potentials release OT
and AVP into blood stream

Posterior Pituitary Gland

Neurosecretory cells
in hypothalamus
Oxytocin (OT)

! stimulates uterine

contractions
! triggers milk letdown
! facilitates social bonds
(released during
orgasm)

Vasopressin (AVP)

! acts on kidney to reduce

urine output (water

conservation)
! increases blood
pressure

Anterior Pituitary Gland

Mechanism of release is different than posterior
pituitary

! Neurosecretory cells in hypothalamus produce

releasing hormones
! Releasing hormones are secreted into hypothalmicpituitary portal system
! Releasing hormones circulate to anterior pituitary
endocrine cells to stimulate release of tropic
hormones
! Tropic hormones circulate to target tissues to release
target hormone

Anterior Pituitary Gland

Neuroendocrine cell bodies

in the hypothalamus produce

releasing hormones
Neurons terminate at the
median eminence- a region
above the pituitary stalk that
contains blood vessels (the
hypophyseal portal system)
Releasing hormones travel
through these vessels and
are released in the anterior
pituitary

Anterior Pituitary Gland

In the anterior pituitary,

there are additional hormone

producing cells
These cells produce tropic
hormones
Tropic hormones are
released into the
bloodstream and travel to
and regulate endocrine
glands throughout the body

Kisspeptin GnRH LH & FSH

Kisspeptin cells in the arcuate

nucleus (these cells have leptin

receptors) regulates GnRH
The hypothalamus releases
gonadotropin-releasing hormone
(GnRH) into the anterior pituitary
Anterior pituitary releases
luteinizing hormone (LH) and
follicle stimulating hormone
(FSH)
Which travels through the blood
and acts to release testosterone
from the testes

Gonadal Hormones: Male

Testosterone is produced

in Leydig cells of testes

Testosterone is
responsible for the
development and
maintenance of male
reproductive organs
generates male secondary
sex characteristics
development/differentiation
of reproductive organs
muscle mass

Gonadal Hormones: Female

Estrogens (estradiol)
! produced in ovaries
! secondary sex

characteristics
! development and
differentiation of
reproductive
organs
! reproductive cycle
and sexual behavior
(lordosis) in rats

Gonadal Hormones: Female

Progestins
(progesterone)
!produced in ovaries
!thicken uterine wall
for egg implantation
!reduce uterine
contractility
!fall in progesterone
at childbirth
triggers milk
production

Ovaries
Female gonads, ovaries,

produce mature gametes, ova

(eggs) and sex steroids
Hormone secretion from
ovaries is more complicated
than it is in the testes
Ovarian hormones are
produced in cycles
The duration of the cycle
differs depending on the
species
Human ovarian cycle is 4
weeks
Rat cycle is 4 days

Menstrual Cycle
Reproductive cycle in primates (females of other mammalian

species have estrous cycles; some species do not cycle)

Sequence is controlled by hormonal secretion from pituitary and
ovaries
Begins with secretion of FSH by anterior pituitary stimulates growth
of ovarian follicles (small spheres of epithelial cells surrounding
each ovum) (normally produce 1 per month) (2 can = fraternal twins)
As ovarian follicles mature, they secrete estradiol, this causes
growth of the lining of the uterus (preparation for ovum implantation
if fertilized by a sperm
Feedback from increasing levels of estradiol triggers a surge in LH
from anterior pituitary
LH surge causes ovulation (ovarian follicle ruptures and releases
the ovum) ruptured ovarian follicle becomes corpus luteum which
produces estradiol and progesterone (which promotes pregnancy)

Menstrual Cycle
Progesterone maintains lining of the uterus and inhibits ovaries

from producing another follicle

Meanwhile, the ovum enters one of the Fallopian tubes and begins it
progress towards the uterus
If it meets sperm cells during its travel down the Fallopian tubes
and becomes fertilized it begins to divide and soon attaches to the
uterine wall
If the ovum is not fertilized or if fertilized too late to sufficiently
develop by the time it gets to the uterus the corpus luteum will
stop producing estradiol and progesterone and the lining of the
walls of the uterus will slough off, which commences menstruation