Actions of Steroid Hormones in the Brain Prof. Bruce S. McEwen · Department of Cell Biology and...

Actions of Steroid Hormones

in the Brain

Prof. Bruce S. McEwen

The screen versions of these slides have full details of copyright and acknowledgements 1


in the Brain

Bruce S. McEwen, Ph.D.Alfred E. Mirsky Professor

Head, Harold and Margaret Milliken Hatch

Laboratory of Neuroendocrinology

The Rockefeller University

New York, NY. 10021

USA

2A. A. Berthold 1849

Hormones and the brain

Testosterone

3

Some actions of steroid hormones in brain - 1

Estradiol – neuroendocrine regulation and sexual behavi or; attention, mood,

memory; induction of synaptic connecti ons in hippocampus,

cortex and hypothal amus; neuroprotecti on from stroke, Parkinson’s,

Alzheimer’s diseaseMcEwen, B. S. and Alves, S. H., Estrogen actions in the central nervous system,

Endocrine Rev. 1999, 20: 279-307

Testosterone – neuroendocri ne regulation; sexual and aggressive behavi or;

synapses in hippocampus; gap junctions in spinal cord motor neuronsBecker, J. B., Breedlove, S. M., Crews, D., and McCarthy, M. M., Behavioral Endocrinology,

Second Edition ed. Cambridge, MA: The MIT Press; 2002;

Leranth, C., Petnehazy, O., and MacLusky, N. J., Gonadal hormones affect spine synaptic density

in the CA1 hippocampal subfield of male rats, J. Neurosci., 2003, 23: 1588-1592

Progesterone – neuroendocrine regulation and sexual behavi or;

neuroprotecti on; mood regulationStein, D. G., Brain damage, sex hormones and recovery: a new role for progesterone and estrogen?

TRENDS in Neurosci., 2001, 24: 386-391;

Wagner, C. K., The many faces of progesterone: a role in adult and developing male brain,

Front. Neuroendocrin., 2006, 27: 340-359


in the Brain



4

Some actions of steroid hormones in brain - 2

Glucocorticoids – neuroendocrine regulation;

acute enhancement of memory; mediate

chronic stress effects on neuronal remodelingMcEwen, B. S., The physiology and neurobiology of stress and adaptation: central role of the brain,

Physiol. Rev., 2007

Mineralocorticoids – regulate salt appetite;

mineralocorticoid receptors play a key role in excitabilityJoels, M., Corticosteroid effects in the brain: U-shape it, Trends Pharmacol. Sci. 2006, 27: 244-250

Vitamin D – increases expression of NGF and p75,

influences mood; developmental deficiency may increase risk

for schizophrenia, multiple sclerosisMcGrath J. et al ., Trends in Neuroscience 24: 570-571, 2001

5

Steroid receptors in the brain

Receptor type

Estrogen

Androgen

Progestin

Glucocorticoi d

Mineralocorticoi d

Vitamin D

Methods used to detect them

Steroid autoradi ography

Immunocytochemistr y

In situ hybridizati on

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Adrenal steroid receptors in hippocampus


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Estrogen receptors in hypothalamus, amygdala

Steroid autoradiography

Immunocytochemistry

Pfaff and Keiner, 1973

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Vitamin D nuclear binding to neurons of the septal, substriatal

and amygdaloid area in the Siberian hamster (Phodopus sungorus) brainMusiol IM, Stumpf WE, Bidmon HJ, Heiss C, Mayerhofer A, Bartke A

Department of Cell Biology and Anatomy, University of North Carolina,

Chapel Hill 27599-7090, USA

Department of Physiology, Southern Illinois University School of Medicine,

Carbondale, Illinois, USA

Abstract - Autoradiographic experiments were performed on brains of Siberian hamsters

(Phodopus sungorus) injected with tritiated 1,25-dihydroxycholecalciferol. Nuclear labeling

was prevented in the presence of excess unlabeled hormone. Strong nuclear concentration

of radioactivity was observed in neurons of the nucleus basalis of Meynert,

the medial septal nucleus, the nucleus of the diagonal band of Broca and the central amygdaloid

group. The latter has been defined as consisting of the central nucleus of the amygdala,

its extension into the sublenticular part of the substantia innominata of Reichert,

and the lateral division of the bed nucleus of the stria terminalis.

All these structures have been reported to be involved in memory and other cognitive processes,

and to be affected by age-dependent neurodegenerative disorders such as Alzheimer's disease.

Corresponding localization of 1,25-dihydroxycholecalciferol receptor sites in these select basal

forebrain nuclei of the Siberian hamster may implicate vitamin D (soltriol),

the steroid hormone of sunlight, in memory processing.

Neuroscience Vol. 48, No. 4, pp. 841-848, 1992

Vitamin D receptors in forebrain

Steroid autoradiography

Fig. 7. Schemata a-f provide outline maps of the basal forebrain based on the atlas of the rat brain by Paxinos and Watson adapted for the septal substriatal and amygdaloid region

of the Siberian hamster; Dots represent [3H]-1,25-D3

labeled cells, increasing diameters according to increasing numbers of labeled cells

(small: 1-3 labeled cells; medium: < 5; large: < 10)

7a

b

c

d

e

f

Fig. 4. Photomicrographic montage demonstrating labeled magnocellular neurons of the nucleus basalis of Meynert and the area of the substantia innominata in overview

(a; scale bar – 50 µm); arrows point out areas shown in detail (b-d; scale bar – 20 µm)

Lordosis behavior

• Steroid hormones coordinate brain function

with rest of body to ensure reproduction

appropriate to environment

• The lordosis response is triggered by touch

on the back; It is primed by the actions

of estradiol and progesterone acting sequentially on neurons in the ventromedial hypothalamus

• The surge of progesterone at the time of ovulation

not only primes lordosis but also the hopping, darting and ear wiggling of the female known

as “proceptivity”

Pfaff, “Drive”, MIT Press, 1999


in the Brain



Neural circuit for lordosis behavior;From Estrogens & Brain Function(Pfaff, Springer-Verlag, 1980)

Neural circuit

11

Cell nuclear ER alpha in ventromedialnuclei of rat hypothalamus (VMN)

Estrogen induction of oxytocin receptors

The ventromedial nuclei of hypothalamus (VMN) are the sites of E regulationof female sexual behavior

Estrogen regulation of female sexual behaviorin the rat: genomic actions via ERE

E-inducible progestin receptors in VMN

Regulation of lordosis involvesactions of ER alpha via the ERE

12


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13

Glucocorticoi d receptors (GR) facilitate Morris water maze learning;

Defective GR prevent the beneficial action

Rat/mouse learns by finding shortest

path to platform using either global

spatial cues or local contextual clues

Morris water maze - finding hidden platform

14PNAS, Vol 98, No 22, pp. 12790-12795, 2001

15

Key transformations

of steroids in the nervous

system

Schumacher M et al., Steroid hormones and neurosteroids in normal

and pathological aging of the nervous system, Progress in Neurobiology71: 3–29, 2003


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Limited capacity for steroid hormone synthesis

Cholesterol to pregnenolone and pregnenolone sulfate

Actions: regulation of NMDA, GABA receptors

Ref. Gibbs TT, Russek SJ, Farb DH, Sulfated steroids as endogenous neuromodulators,

Pharmacology Biochemistry Behav., 84: 555-567, 2006

17


Cholesterol to progesterone

Actions: neuroprotection; myelin formation

Koenig, H. L. et al., Schumacher, M., Ferza, B., Do Thi, A. N., Progesterone synthesis

and myelin formation by Schwann cells, Science, 1995, 268: 1500-1503

Schumacher M. et al., Steroid hormones and neurosteroids in normal and pathological aging

of the nervous system, Progress in Neurobiology 71: 3–29, 2003

Stein, D. G., Brain damage, sex hormones and recovery: a new role for progesterone and estrogen?

Trends in Neurosci . 24: 386-391, 2001

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Cholesterol to dehydroepiandrosterone

Actions: precursor of androgens, estrogens and other potentially

neuroactive steroids

Schumacher M. et al., Steroid hormones and neurosteroids in normal and pathological aging of the nervous system, Progress in Neurobiology 71: 3–29, 2003


in the Brain



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Limited capacity for steroid hormone synthesisCholesterol to estradiol

Actions: neuroprotection in ischemia, seizures

The Journal of Neuroscience, September 24, 2003, 23(25): 8701-8705

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Important transformations of steroid hormones in the nervous system

11 hydroxysteroid dehydrogenase 2Action: inactivation of active glucocorticoid

11 hydroxysteroid dehydrogenase 1Action: reactivation of active glucocorticoid

Funder J. W., Krozowski Z., Myles K., Sato A., Sheppard K. E., Young M.,

Mineralocorticoid receptors, salt, and hypertension, Recent Prog. Horm. Res. 1997, 52: 247-60

Masuzaki, H., Paterson, J., Shinyama, H., Morton, N. M., Mullins, J. J., Seckl, J. R., and Flier, J. S.

A transgenic model of visceral obesity and the metabolic syndrome, Science, 2001, 294: 2166-2170

Yau, J. L. W., Noble, J., Kenyon, C. J., Hibberd, C., Kotelevtsev, Y., Mullins, J. J., and Seckl, J. R.

Lack of tissue glucocorticoid reactivation in 11b-hydroxysteroid dehydrogenase type 1 knockout mice ameliorates age-related learning impairments, Proc. Natl. Acad. Sci. USA. 2001, 98: 4716-4721

21


Aromatase and 5 alpha reductase

Androgen

receptor

ER alpha

ER beta


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22


Paul, S. M. and Purdy, R. H., Neuroactive steroids, FASEB Journal, 1992, 6: 2311-2322

Smith, S. S., Gong, Q. H., Hsu, F. C., Markowitz, R. S., Ffrench-Mullen, J. M. H., and Li, X., GABAA receptor a4

subunit suppression prevents withdrawal properties of an endogenous steroid, Nature, 1998, 392: 926-930

Rogawski, M. A. and Reddy, D. S. Neurosteroids: endogenous modulators of seizure susceptibility,

New York: Marcel Dekker, 2004, pp. 319-355

Maguire, J. L., Stell, B. M., Rafizadeh, M., and Mody, I., Ovarian cycle-linked changes in GABAA receptors

mediating tonic inhibition alter seizure susceptibility and anxiety, Nature Neurosci., 2005, 8: 797-804

A-ring reduction of progesterone or deoxycorticosterone

Steroid modulation of GABAa receptor

23

Limitation of steroid access: e.g., synthetic glucocorticoids

Multi-drug resistance p glycoproteinMeijer OC et al., Penetration of dexamethasone into brain glucocorticoid targets is enhanced

in mdr1A P-glycoprotein knockout mice, Endocrinology 1998, 139: 1789-1793

Figure 3. In situ hybridization of the GR mRNA in hippocampus of wild-type and mdr1a mutants; There is no

difference in GR mRNA expression in the hippocampus or other brain regions between the genotypes;a, Hippocampus of wild-type mouse;b, Hippocampus of mutant mouse

a

b

Figure 1. Representative autoradiograms of 10-µm coronal sections of the brain of wild type and mdr1a (-/-) mice;

Autoradiograms show labeling with [3H]-dexamethasone of the following groups; a, Wild type treated with [3H]-dexamethasone, hippocampus level; The dark spots

represent transversal section of the cerebroventricular space and adjacent ventricular walls;b, Mutant treated

with [3H]-dexamethasone, hippocampus level; c, Mutant treated with [3H]-dexamethasone, PVN level, note the pituitary mounted on top

of the brain; d, Mutant treated with [3H]-corticosterone, hippocampus level; Note the pituitary mounted on top of the brain

Figure 2. Quantification of the autoradiograms of [3H]-dexamethasone in wild type and mdr1a (-/-); There are no differences between the wild types

and mutants for pituitary; Brain nuclei that contain GR show an increased cell nuclear retention of [3H]-dexamethasone; Data are of n = 5 animals ± SEM; Four brain sections per animalwere measured

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Rapid non-genomic actions of steroids in brain

Glucocorticoid action on mating via G protein coupled

receptors in Taricha granulosa

Rapid, sex and subtype selective effects of androgens,

estrogens and glucocorticoids in electric fish

Signaling via second messenger pathways


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25

Taricha granulosa


Fig. 2. Distribution of putative, membrane-bound [3H]CORT binding sites in the POA; Section (left) showing darkly stained

perikarya of POA neurons; Autoradiogram of identical section (right) shows localization of [3H]CORT-specific binding sites in the ocuropil surrounding perikarya of POA neurons

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Tasker, J. G., Di, S. and Malcher-Lopes, R., Minireview: Rapid glucocorticoid signaling

via membrane-associated receptors, Endocrinology, 2006, 147: 5549-5556

Taricha granulosa

27


Communicati on in teleost fish

The Journal of Neuroscience, January 31, 2007, 27(5): 1114-1122


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Steroid regulation of signaling pathways

Estradiol and CREB phosphor yl aitonZhou, Y., Watters, J. J., and Dorsa, D. M. Estrogen rapidly induces the phosphorylation of the cAMP response element binding protein in rat brain, Endocrinology, 1997, 137: 2163-2166

Estradiol and MAPK activati onBi, R., Foy, M. R., Thompson, R. F., and Baudry, M. Effects of estrogen, age, and calpain

on MAP kinase and NMDA receptors in female rat brain, Neurobiol. Aging, 2003, 24: 977-983

Estradiol and AKT phosphor yl ati onSimoncini, T., Hafezi-Moghadam, A., Brazil, D. P., Ley, K., Chin, W. W., and Liao, J. K.

Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol- 3-OH kinase, Nature, 2000, 407: 538-541

Progesterone and adenyl ate cyclaseFinidori-Lepicard, J., Schorderet-Slatkine, S., Hanoune, J., and Baulieu, E. Progesterone inhibits membrane bound adenylate cyclase in Xenopus laevis oocytes, Nature, 1981, 292: 255-257

See also:Razandi, M., Pedram, A., Greene, G. L., and Levin, E. R. Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERα and ERβ expressed in Chinesehamster ovary cells, Mol. Endocrinol., 1999, 13: 307-319

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Steroid hormones have widespread effectson brain structure and function

Estradiol works in many brain areas via non-genomic

as well as genomic receptors

- e.g., regulation of spine synapse formation by estradiol

Chronic stress affects brain structure and glucocorticoids

play a role along with excitatory amino acids

- e.g., regulation of neurogenesis, dendritic branching

and spine density by chronic stress

30

Extra-hypothalamic brain systems affected by estrogens

Basal forebrain cholinergic

Mesolimbic dopami ne

Nigrostriatal dopamine

Brain stem noradrenergic

Midbrain serotoni n

Cerebellum

Hippocampus

Cerebral cortex

Spinal cord

McEwen, B. S. and Alves, S. H. Estrogen actions in the central nervous system,

Endocrine Rev. 1999, 20: 279-307


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31

Dendritic spine density in stratum

radiatum of CA1 fluctuates

over the estrus cycle

ER α in interneuroncell nuclei

E-induction of spine synapses takes several days;

Progesterone causes rapid-down regulation within 12h;

NMDA receptor blockade prevents synapse formation;

E treatment enhances hippocampal-dependent memory in rodents and humans

32

By EM, ERαααα -I is detected in dendritic spines in the CA1 region of the hippocampus (Teri Milner, W eill College of Medicine, Cornell)

Non-nuclear ER alpha in dendritic spines

33

NG-108-15 cells as a model system

Akama, K. T. and McEwen, B. S. Estrogen stimulates postsynaptic density-95 rapid proteinsynthesis via the Akt/protein kinase B pathway, J. Neurosci., 2003, 23: 2333-2339

Membrane

PSD-95 protein translation

FRAPmTOR

PI3K

eIF4E

Estradiol

AktP

P

4E-BP1

P

P

PP

ICI 182,780

LY294002

Rapamycin


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Estradiol acts via GABA neurons and cholinergic mechanisms to up-regulate NMDA receptors

Estradiol inhibits GAD expression transiently and reduces inhibition on CA1 neuron

Estradiol up-regulates NMDA receptorsvia a mechanism involving cholinergicactivity which is regulated by estrogens

35The Journal of Neuroscience, March 1, 2003, 23(5): 1588-1592

Figure 2. Bar graph shows the result of the unbiased stereological calculation of spine synapse density

in the stratum radiatum of the CA1 subfield of control, gonadectomized (GDX), gonadectomized plus testosterone-treated (GDX+T), gonadectomized

plus dihydrotesterone-treated (GDX+DHT), and gonadectomizedplus estrogen-treated (GDX+E2) male

rats; There is no significant difference

between the density values of spine synapses between the Control, GDX+T, and GDX+DHT animals; However,the spine synapse density of the GDX

and GDX+E2 rats is significantly (p < 0.001) lower (48%) than thatof control animals

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Vulnerable to damage;Dendrites shrink with stress

Mossy fiber terminals:glutamate release

Hippocampal formation: plasticity and vulnerability

Neurogenesisreduced by stress

Entorhinalcortex input


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Repeated stress causes CA3 pyramidal cells to show reversible dendritic shrinkage

Mimicked by chronic glucocorticoi d treatment

Increased extracell ul ar glutamate after stress

Prevented byP.

1. Blocking glucocorticoi d synthesis

2. Blocking NMDA receptors

3. Lithium

4. Dilantin

5. Antidepressants

6. Benzodi azepine

38McEwen, B. S. The physiology and neurobiology of stress and adaptation:

Central role of the brain, Physiol. Rev. 2007

Apical dendrites

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Testes

Ovaries

XY

XX

Human

RatBirth

Puberty

Birth

Puberty

Testosterone levels in human and rat male: a comparison

Second trimester

Genetic sex

Testosterone

Estradiol

Note: X and Y linked genes are expressed in many tissues

and contribute to sex differences


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Sexual differentiation and sex differences

41

Summary - 1

Every class of steroid hormones affects the nervous system

Cell nuclear as well as non-nucl ear receptors mediate these effects

Some, but not all, of the non-nucl ear receptors appear to be products

of the same genes that produce the nuclear receptors

The nervous system has a limited capacity for de novo steroid

hormone synthesis , e.g., pregnenol one, DHEA, progesterone and estradiol

The nervous system transforms steroids, e.g., aromatizati on,

5 alpha reductase, A-ring reduction to steroids active on the GABAa

receptor, reactivati on of cortisone to cortisol

The nervous system also excludes some synthetic steroids,

e.g., dexamethasone, via the multiple drug resistance p glycoprotei n

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Summary - 2

Genomic actions of steroids on the brain include the regulation

of female sexual behavi or in the hypothal amus and the modulation

of spatial memor y in the hippocampus

Non-genomic actions of steroids on the brain include G-protein

coupled receptors for glucocorticoi ds , and rapid effects of estrogens,

androgens and glucocorticoids in mating behavi or in fish

A number of second messeng er systems are activated by estrogens

in brain and some of these systems play a role in neuroprotecti on

and in structural plasticity, i.e., synapse formation induced by estradiol

Glucocorticoi ds participate in stress-induced remodeli ng of dendrites,

synapses and the regulation of neurogenesis in the hippocampus ;

They do so by acting in concert with excitator y amino acids

and NMDA receptors and other neurotransmi tters


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Summary - 3

Estrogen actions on synapse formation in the hippocampus involve

a collaboration between genomic and non-genomic actions in a number

of cell types: cholinergic neurons, inhibitory neurons producing GABA,

excitator y neurons producing glutamate, glial cells; NMDA receptors play

a key role

Estrogens have widespread influences on many non-reproduc ti ve functions

throughout the nervous system, along with their effects on reproducti ve

processes; (The same is true for androgens)

Developmentall y programmed sex differences exist throughout the nervous

system and affect non-reproducti ve as well as reproducti ve processes;

Some, but not all, of the sex differences are produced in mammal s

by androgens acting on the devel opi ng brain either as androgens

or after aromatization to estrogens; Genes of the X and Y chromosomes are

also involved

44

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Actions of Steroid Hormones in the Brain Prof. Bruce S. McEwen · Department of Cell Biology and...

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