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 aren’t 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,

movement of progeny cell away from ventricular zone to their final destination • Cells travel along a

particular type of glia cell (radial glial cells)

Neural Tube

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 • Don’t 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 don’t 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 person’s 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 anti-

Mullerian 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 mullerian system) Wolffian duct

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 don’t 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 ‘neuro-endocrine’ signaling that occurs within the brain (or from brain to pituitary)

Early evidence for testosterone

32  The First Experiment in Behavioral Endocrinology, Figure 7.3

Biological Psychology, by Rosenzweig, Leiman, and Breedlove © 1996 Sinauer Associates, Inc.

Group 1Appearance ofimmature roosters

Appearance ofadult roosters

Comb and wattles:Mount hens?Aggressive?Crowing?

Manipulation None

NormalYesYesNormal

SmallNoNoWeak

NormalYesYesNormal

Remove testes

Remove testes and reimplant one in abdomen

Group 2 Group 3

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

Early evidence for testosterone

32  The First Experiment in Behavioral Endocrinology, Figure 7.3

Biological Psychology, by Rosenzweig, Leiman, and Breedlove © 1996 Sinauer Associates, Inc.

Group 1Appearance ofimmature roosters

Appearance ofadult roosters

Comb and wattles:Mount hens?Aggressive?Crowing?

Manipulation None

NormalYesYesNormal

SmallNoNoWeak

NormalYesYesNormal

Remove testes

Remove testes and reimplant one in abdomen

Group 2 Group 3

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

Types of Chemical Communication • Synaptic communication- chemical released by

one neuron to act on another

33 (Part 1)  Chemical Communication Systems, Figure 7.4

Biological Psychology, by Rosenzweig, Leiman, and Breedlove © 1996 Sinauer Associates, Inc.

(a)—Synaptic transmission function

(b)—Autocrine function (c)—Paracrine function

Neuron

Autocrine cell

Paracrinecell

Types of Chemical Communication • Autocrine communication- hormone released by

a cell which then affects its own activity

• Paracrine communication- hormone released by a cell to affect nearby target cells

33 (Part 1)  Chemical Communication Systems, Figure 7.4

Biological Psychology, by Rosenzweig, Leiman, and Breedlove © 1996 Sinauer Associates, Inc.

(a)—Synaptic transmission function

(b)—Autocrine function (c)—Paracrine function

Neuron

Autocrine cell

Paracrinecell

Types of Chemical Communication

• Endocrine communication- hormone released into bloodstream to act on distal target tissues

34  Neuroendocrine Cells Blend Neuronal and Endocrine Mechanisms, Figure 7.6

Biological Psychology, by Rosenzweig, Leiman, and Breedlove © 1996 Sinauer Associates, Inc.

(a)

Endocrine cell

Signal molecule

Presynapticneuron

NeurotransmitterPostsynapticneuron

Hormone

Blood

Neuron BloodHormones

Neuroendocrinecell

(b)

Target cell

Target cell

Target cell

(c)

Action potential

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

(strings of amino acids) ! e.g., vasopressin

• Amine hormones (single amino acids) ! e.g., thyroid hormone

• Steroid hormones (four carbon rings) ! e.g., testosterone,

estrogen

(c)—Amine hormone(b)—Steroid hormone

HO

H2N

COOH

Adrenocorticotropic hormone (ACTH)

ThyroxineEstradiol

CH2CHCOOH

NH2

HO

CH3OH

O

I I

I

(a)—Protein hormone

Different amino acids

I

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 ‘non-genomic’ activation (previously thought to only work via genomic effects)

• Estrogen is a steroid hormone that has these ‘non-genomic’ effects (in addition to its classic genomic effects)

Major Endocrine Glands

Don’t 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 hypothalmic-pituitary 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

x

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