Neural organization under hormonal versus direct-genetic effects

Cynthia J. Gill, Ph.D.Asst. Professor of Physiology

Hampshire CollegeSchool of Natural Sciences

• essential brain area controlling female-typical sexual behavior

• sexually dimorphic in adult male and female whiptails

• site of estrogen sensitivity

Ventral medial hypothalamus

(VMH)

PC

V M H

DH

LTP

VE

TECT

Receptor mRNA expression in the adult VMH

0

5

10

15

20

25

30

35

40M

ean

in s

itu g

rain

s/ce

ll (+

SEM

)PR FemalesPR MalesER FemalesER Males

Progesterone Receptor Estrogen Receptor

Modified from Godwin and Crews, 1995

**

/ +E / +E / +E / +E

Injection blank(/) or estrogen (+E)

QuestionQuestion

Since adult males have higher testosterone levels than adult females...

is chronic testosterone exposure responsible for the steroid receptor expression differences observed between adult males and females?

testosteronetestosterone estrogenestrogen

malesmales

femalesfemales

6 week exposure 1 week recovery

injection

Experimental procedure:

measure ER & PR mRNA expression in VMH by in situhybridization

PC

VMH

DH

LTP

VE

TECT

Gdx

SSV

SSV + estrodiol benzoate

SSV + estrodiol benzoate (high magnification)

FemalesMales

b

a' a'

b

a

c

0

15

5

10

25

20

30M

ean

in s

itu g

rain

s/cl

uste

r (+S

EM)

Progesterone receptor mRNA expression in the adult VMH

T/- T/E -/E T/- -/E -/- 6 week exposure/injection

Modified from Wennstrom, Gill and Crews, 1998

a a

b

a

b

c

FemalesMales

0

15

5

10

25

20

30M

ean

in s

itu g

rain

s/cl

uste

r (+S

EM)

Estrogen receptor mRNA expression in the adult VMH

T/- T/E -/E T/- -/E -/-

6 week exposure/injection

a

b

b

Gill, Crews & Wennstrom, 2004

• Estrogen-induced progesterone receptor mRNA is fixed in an adult female, but responsive to testosterone environment in an adult male

• Estrogen-induced estrogen receptor mRNA is fixed in an adult male, but responsive to testosterone environment in an adult female

ConclusionsConclusions

….like behavioral sensitivity.

.…like brain morphology.

Testosterone ...

• directly regulates expression of some genes

• can be converted to estrogen by aromatization to regulate other genes

• affects synaptic connectivity

• affects the size of cells

• affects cell survival

E PR

-

POA VMH

Male +T

Male, no T

FemaleE PR

cell death

Model: Variation in cell survival early and cell connectivity later

QuestionQuestion

Since adult males and females differ in hormone receptor induction...

is the sensitivity the result of hormonal or direct-genetic effects during development?

Sexual, parthenogenic and sex-reversed whiptails

C. inornatus

C. inornatus

C. costatusor C. burti

C. uniparens

F1 parthenoform

X

X

C. uniparens - created by blocking estrogen production in the embryo

C. inornatus

Sexual &

Parthenogen &(‘male’ is genetically female,hormonally male)

Progesterone receptor mRNA expression in the VMH

0

5

10

15

20

25

30M

ean

grai

ns/c

lust

er (+

SEM

)SSVEB

One day old Thirty days old

female male female "male"__________________ sexual

__________________ sexualfemale male female "male"

__________________ parthenogen

__________________ parthenogen

Estrogen receptor mRNA expression in the VMH

0

2

4

6

8

10

12M

ean

grai

ns/c

lust

er (+

SEM

)SSVEB

One day old Thirty days old

female male female "male"__________________ sexual

__________________ sexualfemale male female "male"

__________________ parthenogen

__________________ parthenogen

**

*

*

• Estrogen-induced progesterone receptor mRNA expression is not sexually dimorphic at one and thirty days of age

• Estrogen-induced estrogen receptor mRNA is sexually dimorphic at one and thirty days of age

• The sex dimorphism in estrogen receptor mRNA expression is reversed in very young animals and it is hormone dependant.

Conclusions IIConclusions II

.…like brain morphology.

….like behavior.

Undergraduate research assistants: Michelle Embleton

Molly Fant Jen Lui Kavita Juneja Laura Young

Drs. David Crews and Kira Wennstrom

AcknowledgementsAcknowledgements

BEHAVIOR

OVARY

OVIDUCT

HORMONES

Female-like Male-like Female-like Male-like

Ovulation Ovulation

Estradiol

Progesterone

BRAIN mRNA

POA

VMH

PR

ER

Sexually dimorphic Fos responses to mating stimuli

Female response to chemosensory cues and mating

Male response to chemosensory cues and mating

0

5

10

15

20

25

30 JGDataFemalesJGDataMales

Mea

n in

situ

gra

ins/

clus

ter (

+SEM

)Progesterone receptor mRNA expression in the adult VMH

T/- T/E -/E -/- -/E T/- -/E -/- T/- T/E

a

aa

b

b

c

0

5

10

15

20

25

30 JGdataFemalesJGdataMales

Mea

n in

situ

gra

ins/

clus

ter (

+SEM

)Estrogen receptor mRNA expression in the adult VMH

T/- T/E -/E -/- -/E T/- -/E -/- T/- T/E

b

a

b