Endocrinology Vol. 138, No. 9 3804-3810
Copyright © 1997 by The Endocrine Society
Role of Gonadal Steroids in Determining Sexual Differences in Expression of Fos-Related Antigens in Tyrosine Hydroxylase-Immunoreactive Neurons in Subdivisions of the Hypothalamic Arcuate Nucleus1
Sun Cheung,
Yvonne M. Will,
Kenneth Hentschel,
Kenneth E. Moore and
Keith J. Lookingland
Department of Pharmacology and Toxicology, Michigan State
University, East Lansing, Michigan 48824-1317
Address all correspondence and requests for reprints to: Sun Cheung, M.D., Ph.D., Department of Pharmacology and Toxicology, B-440 Life Sciences Building, Michigan State University, East Lansing, Michigan 48824-1317. E-mail: cheungs{at}pilot.msu.edu
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Abstract
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Dual immunohistochemistry was employed to examine the role of gonadal
steroids in determining sexual differences in the expression of Fos and
its related antigens (FRA) in tuberoinfundibular dopaminergic (TIDA)
neurons located in the dorsomedial (DM-) and ventrolateral (VL-)
subdivisions of the arcuate nucleus (ARC). In the DM-ARC, there was no
sexual difference in the number of tyrosine hydroxylase
(TH)-immunoreactive (-IR) perikarya, but the number of these containing
FRA-IR was greater in females than in males in all but the most caudal
region. In the VL-ARC, there were more TH-IR perikarya in males than in
females, but there was no sexual difference in the numbers of those
containing FRA-IR throughout the entire rostrocaudal extent of this
nucleus. Ovariectomy decreased the number of TH-IR perikarya containing
FRA-IR in the DM-ARC, but not in the VL-ARC, whereas orchidectomy
increased the number of TH-IR perikayra containing FRA-IR in both the
DM-ARC and VL-ARC. These gonadectomy-induced effects were reversed by
estrogen and testosterone, respectively. These results reveal gonadal
steroid-dependent sexual differences in the regulation of immediate
early gene expression in anatomically discrete subpopulations of TIDA
neurons. In females, estrogen stimulates FRA expression in TIDA neurons
in the DM-ARC, whereas in males, testosterone inhibits FRA expression
in TIDA neurons in both the DM-ARC and the VL-ARC.
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Introduction
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TUBEROINFUNDIBULAR dopaminergic
(TIDA) neurons located in the hypothalamic arcuate nucleus (ARC)
project to the median eminence, where dopamine released from these
neurons is transported in the hypophysial portal blood to the anterior
pituitary, where it inhibits PRL secretion from lactotrophs (1). Much
of what is known regarding the regulation of TIDA neurons is based upon
neurochemical estimates of dopamine synthesis [i.e.
accumulation of 3,4-dihydroxyphenylalanine (DOPA) after pharmacological
inhibition of DOPA decarboxylase] and metabolism (i.e.
concentrations of 3,4-dihydroxyphenylacetic acid) in axon terminals
converging in the median eminence. Using these indexes, it has been
established that the basal activity of TIDA neurons is 2–3 times
higher in female than in male rats (2, 3, 4), and that this difference is
due to circulating gonadal steroids; i.e. estrogen
stimulates (5), whereas testosterone inhibits (6), the synthesis and
metabolism of dopamine in the median eminence.
More recently, expression of the immediate early gene products Fos and
its related antigens (FRA) in neuronal perikarya in the ARC has been
shown to reflect the activity of TIDA neurons (7, 8). Indeed,
alterations in FRA expression precede changes in the expression of
messenger RNA (mRNA) for tyrosine hydroxylase (TH) in TIDA neurons (7, 9), suggesting a role for these immediate early gene products in the
regulation of this rate-limiting enzyme in dopamine biosynthesis.
Regulation of FRA expression is generally believed to involve
ligand-mediated activation of membrane receptors located on neuronal
perikarya and/or dendrites, which causes second messenger-mediated
Fos-related gene transcription and synthesis of FRA mRNAs and proteins
(10, 11). In TH neurons, FRA proteins are translocated to the nucleus,
where they form heterodimers with constitutively expressed Jun-related
transcription factors that bind to the activating protein-1 promoter
site on the TH gene and facilitate transcription of TH mRNA (12). Thus,
the presence of FRA proteins represents an early neurochemical marker
of activity that permits the identification of TIDA neurons uniquely
responsive to specific stimuli (7, 8).
The overall aim of the present study was to examine the role of
gonadal steroids in determining sexual differences in the expression of
FRA in TIDA neurons in the dorsomedial (DM) and ventrolateral (VL)
regions of the ARC using dual immunohistochemistry. Initial experiments
compared the distribution of TH-immunoreactive (-IR) neurons and the
number of TH-IR neurons containing FRA-IR in four representative
rostrocaudal levels of the ARC in female and male rats. Follow-up
experiments examined the effects of gonadectomy and gonadal steroid
hormone replacement on the number of TH-IR neurons containing FRA in
both females and males.
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Materials and Methods
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Animals and treatments
Male and female Long-Evans rats, weighing 200–225 g, were
purchased from Harlan Breeding Laboratories (Indianapolis, IN) and
maintained in a temperature (22 ± 1 C)- and light (lights on
between 0500–1900 h)-controlled environment, with food and tap water
provided ad libitum. The estrous cycles of female rats were
monitored by daily vaginal lavage, and only diestrous females
exhibiting two or more consecutive 4- to 5-day cycles were used in
these experiments. In one experiment, cycling female rats were
ovariectomized under diethyl ether anesthesia and allowed to recover
for 1 week before receiving injections of either 17ß-estradiol
benzoate (25 µg/kg·day, sc; Sigma Chemical Co., St. Louis, MO) or
its corn oil vehicle (1 ml/kg·day, sc) for 3 consecutive days (13).
In another experiment, males were orchidectomized under diethyl ether
anesthesia and allowed to recover for 1 week before receiving
injections of either testosterone proprionate (200 µg/kg·day, sc;
Sigma) or its corn oil vehicle (1 ml/kg·day, sc) for 3 consecutive
days (14). Gonadally intact diestrous female and male rats served as
respective controls in these gonadectomy studies.
Tissue collection and preparation
After appropriate treatments, rats were anesthetized with
Equithesin (4 ml/kg, ip) and perfused through the aorta with 0.9%
saline (4 C), followed by ice-cold 4% paraformaldehyde in 0.1
M phosphate buffer. Brains were quickly removed and
postfixed in 4% paraformaldehyde overnight and cryoprotected in 20%
sucrose in 0.1 M phosphate buffer at 4 C until sectioning.
Fixed brains were frozen on aluminum foil placed over dry ice, and
frontal sections (30 µm) were made using a cryostat (IEC Minotome,
International Equipment Co., Needham Heights, MA) through the entire
rostrocaudal extent of the ARC, beginning approximately 2.0 mm
posterior to bregma (15). Sections were processed for dual
immunohistochemical detection of FRA and TH as described below.
Immunohistochemical procedures
Anti-FRA antiserum (OA-11–824, Genosys Biotechnologies, The
Woodlands, TX) was generated in sheep against a synthetic peptide
derived from a conserved region of the c-fos gene common to
all FRA genes, including FOS, FRA1, FRA2, and FOSB (10). The
specificity of antibody for FRA was determined by the manufacturer and
another research group (16). The specificity of the antibody for TH was
characterized by the manufacturer (Incstar Corp., Stillwater, MN).
Preliminary dual immunohistochemical titration studies determined that
the optimal dilutions for FRA and TH antisera were 1:5000 and 1:1000,
respectively.
Sections were incubated for 40 h at 4 C in primary sheep
anti-FRA antiserum diluted in 0.05 M Tris-buffered saline
(TBS) containing 1.5% normal donkey serum and 0.2% Triton X-100 (TX).
The primary antiserum was localized using the avidin-biotin complex
system (ABC Elite Kit, Vector Laboratories, Burlingame, CA). After
three rinses in 0.05 M TBS-TX, sections were incubated for
1 h at room temperature in 1:225 biotinylated donkey antisheep IgG
antiserum. After three rinses in 0.05 M TBS-TX, sections
were incubated in a solution containing 3,3'-diaminobenzidine and
nickel (Vector Laboratories) for 5 min at room temperature. After six
rinses in 0.05 M TBS-TX, sections were incubated for
40 h in primary mouse anti-TH antiserum in 0.05 M
TBS-TX containing 1.5% normal horse serum (Incstar Corp.). The primary
antiserum for TH was detected using 1:225 biotinylated horse antimouse
IgG antiserum and rhodamine-conjugated avidin D (1:500; Vector
Laboratories). The sections were mounted onto gelatin-coated slides,
air-dried, dehydrated using graded concentrations of ethanol and
xylene, and coverslipped.
Quantitative analyses and statistics
Sections were chosen macroscopically and coded to eliminate bias
during analyses. Sections through the ARC were divided into four
regions of approximately equal distance in the rostrocaudal plane in a
manner similar to that described previously (8, 9, 17, 18).
Representative sections from each of these regions are depicted
schematically in Fig. 1
. Region I
included the most rostral extent of the ARC, approximately 2.3 mm
posterior to bregma (15). Regions II and III comprised the middle
portion of the ARC where the lateral apertures of the median eminence
were most prominent; region II was located approximately 2.8 mm
posterior to bregma; region III was located approximately 3.3 mm
posterior to bregma. Region IV included the most caudal portion of the
ARC, approximately 3.8 mm posterior to bregma. During analyses, the
rostrocaudal location of each of the sections was anatomically matched
across treatment groups.
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Figure 1. Schematic representation of the distribution of
TH-IR neurons in the DM-ARC and VL-ARC (shaded areas) in
representative frontal sections through the rostal (region I), middle
(regions II and III), and caudal (region IV) ARC. Approximate distances
relative to the bregma for these sections were -2.3 mm for region I,
-2.8 mm for region II, -3.3 mm for region III, and -3.8 mm for
region IV (15). Filled circles represent TH-IR neurons
in the DM-ARC, VL-ARC, periventricular nucleus, and zona incerta. The
relative number of filled circles in each region of the DM-ARC and
VL-ARC reflects the distribution of TH-IR neurons in male rats. DMH,
Dorsomedial hypothalamic nucleus; F, fornix; INF, infundibular stalk;
ME, median eminence; PeVN, periventricular nucleus; PMV, ventral
premammillary nucleus; VMH, ventromedial hypothalamic nucleus; ZI, zona
incerta.
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On the basis of their neurochemical properties, TIDA neurons may
be subdivided into two anatomically distinct populations of neurons
located in the dorsomedial (DM-) and ventrolateral (VL-) regions of the
ARC (19). TIDA neurons in the DM-ARC contain both TH and DOPA
decarboxylase and synthesize dopamine, whereas those in the VL-ARC lack
DOPA decarboxylase and synthesize the inactive dopamine precursor DOPA.
In the present study, TH-IR neurons in the DM-ARC and VL-ARC were
analyzed separately using a demarcation line extending laterally at an
angle of 30° from the base of the brain (Fig. 1
) (19). The total
numbers of TH-IR neurons and TH-IR neurons containing FRA nuclei in the
DM-ARC and VL-ARC were counted bilaterally in two sections per animal
for each rostrocaudal division of the ARC.
Mean values for each animal were calculated, and the resulting data
were compared between treatment groups by Student’s t test
and across treatment groups using one-way ANOVA followed by
Newman-Keuls post-hoc comparison test. Differences were
considered significant if the probability of error was less than
5%.
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Results
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The distribution of TH-IR perikarya in the DM-ARC and VL-ARC of
female and male rats in four representative rostrocaudal regions of the
ARC is depicted in Fig. 2. There was no
sexual difference in the numbers of TH-IR perikarya in the
DM-ARC, but in both females and males there was a descending
rostrocaudal gradient in the distribution of TH-IR perikarya in this
region. The mean number of TH-IR perikarya in the DM-ARC declined from
region I to region IV in females by approximately 50% (from 74 ±
5 to 33 ± 3 neurons/section) and in males by approximately 40%
(from 76 ± 3 to 47 ± 2 neurons/section). In contrast, in
the VL-ARC there were more TH-IR perikarya/section in males than
females, especially in the middle and caudal regions (regions II–IV),
where the number of TH-IR perikarya per section in males was up to 6
times higher than that counted in females.
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Figure 2. Rostrocaudal distribution of TH-IR neurons in the
DM-ARC and VL-ARC of gonadally intact female and male rats. Rats were
perfused, and their brains were processed for immunohistochemical
detection of TH-IR as described in Materials and
Methods. Columns represent the means, and
vertical lines represent the SEM of
determinations of the numbers of TH-IR neurons in six or seven brains
of female (open columns) and male (solid
columns) rats. I–IV represent rostrocaudal divisions of the
DM-ARC and VL-ARC depicted in Fig. 1. *, Values in males that are
significantly different (P < 0.05) from those in
females.
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The expression of FRA in TH-IR neurons located in the DM-ARC of a
gonadally intact female rat is depicted in Fig. 3. TH-IR perikarya containing FRA-IR were
found evenly dispersed among the majority of TH-IR perikarya that did
not contain FRA-IR. Across regions I–IV, an average of 13–16% of all
DM-ARC TH-IR perikarya contained FRA-IR nuclei in females compared with
5–6% in males. As shown in Fig. 4, the
number of DM-ARC TH-IR perikarya containing FRA-IR was greater in
females than in males, especially in regions I–III. In the VL-ARC,
there was no sexual difference in the numbers of TH-IR perikarya
containing FRA-IR in regions I–IV (Fig. 4).
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Figure 3. Fluorescence (left panel) and
brightfield (right panel) photomicrographs of the same
image depicting the expression of FRA in TH-IR neurons in the DM-ARC of
a gonadally intact female rat. Left panel, Numerous
TH-IR neuronal perikarya and processes were found in the DM-ARC
adjacent to the third ventricle (3V). Right panel,
FRA-IR nuclei were found in some (arrowheads), but not
all, TH-IR neurons (left panel). Scale
bar = 10 µm.
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Figure 4. Rostrocaudal distribution of TH-IR neurons
expressing FRA in the DM-ARC and VL-ARC of gonadally intact female and
male rats. Rats were perfused, and their brains were processed for dual
immunohistochemical detection of TH-IR and FRA-IR as described in
Materials and Methods. Columns represent
the means, and vertical lines represent the
SEM of determinations of the numbers of TH-IR neurons
containing FRA in six or seven brains of female (open
columns) and male (solid columns) rats. I–IV
represent rostrocaudal divisions of the DM-ARC and VL-ARC as depicted
in Fig. 1. *, Values in males that are significantly different
(P < 0.05) from those in females.
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Ovariectomy decreased the number of TH-IR perikarya containing FRA-IR
nuclei in regions II and III of the DM-ARC, but had no effect in
regions I or IV of the DM-ARC or in regions I–IV of the VL-ARC (Fig. 5). Estrogen administration reversed the
inhibitory effects of ovariectomy on the number of TH-IR perikarya
containing FRA-IR in regions II and III of the DM-ARC (Fig. 5).
Orchidectomy increased the number of TH-IR perikarya containing FRA-IR
nuclei in regions I–IV of the DM-ARC and in regions II and III of the
VL-ARC (Fig. 6), and testosterone
administration reversed these effects (Fig. 6).
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Figure 5. Comparison of the effects of ovariectomy and
estrogen replacement on FRA expression in TH-IR neurons in the DM-ARC
and VL-ARC of female rats. One week after ovariectomy (OVX), rats were
injected with either 17ß-estradiol benzoate (E2; 25
µg/kg·day, sc) or its corn oil vehicle (1 ml/kg·day, sc) for 3
consecutive days and were perfused 24 h after the last injection.
Columns represent the means, and vertical
lines represent the SEM of determinations of the
numbers of TH-IR neurons containing FRA in seven to nine brains of
gonadally intact (open columns), ovariectomized
(solid columns), and E2-treated
ovariectomized (cross-hatched columns) female rats.
I–IV represent rostrocaudal divisions of the DM-ARC and VL-ARC as
depicted in Fig. 1. *, Values in ovariectomized females that are
significantly different (P < 0.05) from those in
gonadally intact controls.
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Figure 6. Comparison of the effects of orchidectomy and
testosterone replacement on FRA expression in TH-IR neurons in the
DM-ARC and VL-ARC of male rats. One week after orchidectomy (ORX), rats
were injected with either testosterone proprionate (T; 200
µg/kg·day, sc) or its corn oil vehicle (1 ml/kg·day, sc) for 3
consecutive days and were perfused 24 h after the last injection.
Columns represent the means, and vertical
lines represent the SEM of determinations of the
numbers of TH-IR neurons containing FRA in seven to nine brains of
gonadally intact (open columns), ORX (solid
columns), and testosterone-treated ORX (cross-hatched
columns) male rats. I–IV represent rostrocaudal divisions of
the DM-ARC and VL-ARC as depicted in Fig. 1. *, Values in ORX males
that are significantly different (P < 0.05) from
those in gonadally intact controls.
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Discussion
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TH-IR perikarya comprising the TIDA neuronal system are
somatotopically distributed throughout the entire rostrocaudal extent
of the ARC and adjacent periventricular nucleus (20, 21); axons of
these neurons course ventrally through the mediobasal hypothalamus to
terminate in close proximity to capillaries of the corresponding
rostrocaudal level of the external layer of the median eminence (22, 23). TH-IR neurons in the DM-ARC predominantly innervate the medial
portion of the median eminence (24, 25) and are generally believed to
be the primary inhibitors of pituitary PRL release (26, 27);
physiological changes in PRL secretion that occur during proestrus,
pregnancy, pseudopregnancy, and lactation have been correlated with
reciprocal changes in immediate early gene expression by these neurons
(7, 8). TH-IR neurons in the VL-ARC innervate the more lateral aspects
of the median eminence (28), but as these neurons lack DOPA
decarboxylase and do not synthesize dopamine (19), their function is
unknown. The results of the present study support the conclusion that
these subdivisions of the ARC contain separate populations of TIDA
neurons with distinct gender-specific characteristics.
In the DM subdivision of the ARC there were differences in the
rostrocaudal distribution of TH-IR perikarya that were not related to
gender. In both females and males, there were higher numbers of TH-IR
neurons in the rostral DM-ARC compared with the more caudal regions,
which corresponds with the distribution of TH-IR neurons in the entire
(i.e. DM plus VL) ARC in males (20, 21). Although not
addressed in the present study, the higher numbers of TH-IR neurons in
the rostral DM-ARC may be due in part to the presence of a
subpopulation of TH-IR neurons comprising the tuberohypophysial DA
neuronal system that project to the neurointermediate lobe of the
pituitary rather than to the median eminence (22, 23). Nevertheless, as
the DM-ARC provides the major source of dopamine-containing fibers to
the median eminence (19), the finding that there are similar numbers of
TH-IR neurons in females and males in all rostrocaudal levels of the
DM-ARC is consistent with indirect neurochemical evidence
(i.e. dopamine concentrations) of a lack of a sexual
difference in the numbers of TIDA neurons terminating in the median
eminence (1).
On the other hand, there are sexual differences in the activities of
TIDA neurons associated with neurotransmitter release and its
replenishment via de novo synthesis. Indeed, the synthesis,
release, and metabolism of dopamine in the median eminence are all
elevated in females compared with males (2, 3, 4, 29) due in part to
higher levels in females of TH mRNA in perikarya in the ARC (30) and TH
in terminals in the median eminence (31). In agreement, the results of
present study reveal that the number of TH-IR neurons expressing FRA is
2–3 times higher in females than in males in all but the most caudal
region of the DM-ARC. As expression of FRA in neuronal perikarya in the
ARC has been shown to reflect the activity of TIDA neurons (7, 8),
these results suggest that sexual differences in neurochemical
estimates of TIDA neurons in the median eminence may be due in part to
greater numbers of active TIDA neurons in females in the DM-ARC.
The results of the present study also reveal that like the
neurochemical activity of these neurons in the median eminence (1),
sexual differences in FRA expression in TIDA neurons in the DM-ARC are
dependent upon circulating gonadal steroids. In females, ovariectomy
decreases the number of TH-IR neurons containing FRA in the middle
region of the DM-ARC, and this effect is reversed by estrogen. In
males, orchidectomy increases the number of TH-IR neurons containing
FRA throughout the entire rostrocaudal extent of the DM-ARC, and this
effect is reversed by testosterone. As immediate early gene regulation
is mediated by ligand-induced activation of membrane receptors (11), it
is unlikely that the effects of these steroids are mediated by a direct
action on these neurons. Rather, these results suggest that
steroid-dependent sexual differences in TIDA neurons are mediated by
hormone and/or neurotransmitter receptors located on perikarya and/or
dendrites of these neurons. In females, the stimulatory effect of
estrogen on the neurochemical activity of TIDA neurons occurs primarily
via a PRL-dependent mechanism (1); i.e. estrogen stimulates
the synthesis and release of PRL from pituitary lactotrophs, which, in
turn, activates TIDA neurons. PRL (like estrogen) also increases the
numbers of TH-IR neurons containing FRA in the DM-ARC (32), suggesting
that the stimulatory effect of estrogen on FRA expression in DM-ARC
TH-IR neurons observed in the present study is mediated by PRL. In
males, the inhibitory effect of testosterone on TIDA neurons is PRL
independent (6), possibly occurring via a mechanism involving
inhibitory afferent dynorphinergic neurons (33, 34). The results of the
present study are consistent with the conclusion that testosterone
inhibits the activity of TIDA neurons via an indirect transynaptic
afferent neuronal regulatory mechanism.
In contrast to the DM-ARC, the rostrocaudal distribution of TH-IR
neurons in the VL-ARC was sexually dimorphic. In males, there are fewer
numbers of TH-IR neurons in the rostral compared with the more caudal
regions of the VL-ARC, where the number of TH-IR neurons is 2- to
3-fold higher. In females, the number of TH-IR neurons does not vary
throughout the rostrocaudal regions of the VL-ARC and is consistently
lower than that in males. Thus, a prominent population of TH-IR neurons
is present in the VL-ARC of males that is absent or undetectable in
females. There was no sexual difference in the actual numbers of TH-IR
neurons containing FRA in the VL-ARC, but due to greater numbers of
TH-IR neurons in males, a lower percentage of these neurons expressed
FRA than in females. Neither ovariectomy nor estrogen has any effect on
FRA expression in TH-IR neurons in the VL-ARC in females, revealing
that TH-IR neurons in this region are regulated by different mechanisms
than neurons in the DM-ARC (8). In contrast, orchidectomy increases the
number of TH-IR neurons containing FRA in the middle region of the
VL-ARC, and this effect was reversed by testosterone. These results
reveal a population of TH-containing neurons in the VL-ARC of males
that is regulated by a testosterone-dependent mechanism similar to
neurons in the DM-ARC. As TH-IR neurons in the VL-ARC lack DOPA
decarboxylase and synthesize only the inactive dopamine precursor DOPA
(19), the functional significance of these neurons is not known. One
intriguing hypothesis is that VL-ARC TH-IR neurons may mediate the
delayed inhibitory effects of chronic hyperprolactinemia on GnRH
release from the lateral median eminence (35, 36), possibly via a
mechanism involving PRL-induced induction of DOPA decarboxylase and
dopamine synthesis in these neurons.
In summary, the results of the present study reveal gonadal
steroid-dependent sexual differences in the regulation of FRA
expression in TH-IR perikarya in the DM-ARC that reflect similar
differences in the neurochemical activity of TIDA neurons terminating
in the median eminence (1). Estrogen stimulates, whereas testosterone
inhibits, the expression of FRA in TH-IR neurons in the DM-ARC of
females and males, respectively. In addition, a unique population of
TH-IR neurons was identified in the VL-ARC of males (but not females)
in which FRA expression is also inhibited by testosterone. In
conclusion, these results confirm the heterogeneous distribution of
TH-IR neurons in the ARC and highlight the utility of using FRA
expression as a neurochemical marker of activity of subpopulations of
TIDA neurons.
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Acknowledgments
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The authors acknowledge Erika Bronz for technical
assistance.
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Footnotes
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1 This work was supported by NIH Grant MH-42802. 
Received April 16, 1997.
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Abstract
Introduction
