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Differential Activation of c-fos Immunoreactivity After Hypophysectomy in Developing and Adult Rats.

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THE ANATOMICAL RECORD 290:1050–1056 (2007)
Differential Activation of c-fos
Immunoreactivity After
Hypophysectomy in Developing and
Adult Rats
Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong,
Hong Kong SAR, China
Department of Pathology & Anatomy, Eastern Virginia Medical School, Norfolk, Virginia
The aim of the present study is to compare c-fos expression in identified hypothalamic vasopressin (AVP) and oxytocin (OT) neurons in developing (PN7 and PN14) and adult rats following hypophysectomy using
dual-labeled immunostaining. Our results showed that hypophysectomy
induced c-fos expression in supraoptic (SON) and paraventricular (PVN)
nuclei in both the developing and adult rats. Few or no positive cells
were observed in the same nuclei in sham-operated animals. Quantitative
analysis for c-fos and either of the above named neuropeptides revealed
that almost all AVP and OT neurons in the adult and PN14 groups
expressed c-fos in response to hypophysectomy. In PN7, hypophysectomy
also induced all AVP neurons to express c-fos in SON and PVN. However,
few OT neurons in the SON and PVN produced c-fos after hypophysectomy. In addition, the time course of c-fos expression was different in the
developing and adult rats after hypophysectomy. The c-fos expression in
the developing rats exhibited a more prolonged induction in which staining for c-fos persisted for at least 3 days after hypophysectomy compared
with that in the adult in which c-fos immunoreactivity disappeared
within 24 hr post-lesion. This study demonstrates that c-fos expression
after hypophysectomy is regulated differently during development. Anat
Rec, 290:1050–1056, 2007. Ó 2007 Wiley-Liss, Inc.
Key words: hypothalamus; hypophysectomy; neuronal death;
immediate early genes
Long-lasting adaptive changes in the mammalian
central nervous system (CNS) may depend on the activation of a specific group of programmed response genes
(Goelet et al., 1986). The protooncogene c-fos is among the
genes that have been implicated in such processes (Sheng
and Greenberg, 1990; Morgan and Curran, 1991b).
The c-fos is induced in neurons by a variety of extracellular stimuli in the CNS. Many investigations have analyzed Fos expression in the hypothalamic magnocellular neurons of the SON and PVN. Expression of c-fos is
induced by acute stimuli such as parturition (Fenelon
et al., 1993; Luckman, 1995; Lin et al., 1998), noxious
stimuli (Smith and Day, 1994), restraint stress (Miyata
et al., 1995), LPS-injection (Matsunaga et al., 2000),
Cholecystkinin injection (Verbalis et al., 1991) and
chronic stimuli such as water deprivation (Miyata et al.,
1994) and salt loading (Miyata et al., 1994, 2001). These
observations, combined with the identification of the
Grant sponsor: University of Hong Kong; Grant sponsor:
Hong Kong Research Grants Council; Grant sponsor: Jeffress
Foundation; Grant number: J531.
*Correspondence to: Wutian Wu, Department of Anatomy,
Li Ka Shing Faculty of Medicine, The University of Hong Kong,
21 Sassoon Road, Hong Kong SAR, China. Fax: 852-281-70857.
Received 5 December 2006; Accepted 18 May 2007
DOI 10.1002/ar.20570
Published online 28 July 2007 in Wiley InterScience (www.
c-fos protein as a transcription factor (Chiu et al., 1988),
have supported the role for the c-fos gene in coupling
extracellular stimuli with transcriptional events leading
to chronic modifications in neuronal function (Sheng and
Greenberg, 1990; Morgan and Curran, 1991b). In the
adult rat, injuries to the hypothalamo-neurohyphyseal
system (HNS) such as hypophysectomy also induce transient c-fos expression (Villar et al., 1991). Hypophysectomy in adult rats induced a series of changes characterized by dramatic changes in peptide expression (Villar
et al., 1990) and up-regulation of NOS as well as robust
regeneration (Wu and Scott, 1993). It has been suggested that the transient and early activation of Fos in
injured magnocellular neurons that precedes the
changes in magnocellular neurons of the HNS, participates in the regulation of those changes (Villar et al.,
1991). Hypophysectomy, however, elicits different reactions in magnocellular neurons of the HNS in pups,
including no or unremarkable up-regulation of NOS
expression as well as no significant regeneration on the
floor of the third cerebral ventricle (Yuan et al., 2006).
These different responses led us to try to compare the
pattern of c-fos induction following hypophysectomy in
postnatal rats with that of adults.
PN7, PN14, or adult male SD rats (200–220 g) were used
in the present experiments. They were housed in a temperature-controlled room under daily light and dark cycle
(12:12) with free access to laboratory chow and tap water.
Animals at age of PN14 and adults were performed by
removing both the anterior and posterior pituitary by
the peripharyngeal approach (Thorngren et al., 1973;
Wu and Scott, 1993). Briefly, animals were anesthetized
with intraperitoneal injections of ketamine (80 mg/kg)
and xylazine (8 mg/kg) and mounted upside-down in a
stereotaxic apparatus. The skin on the ventral aspect of
the neck was incised and the infrahyoid musculature
separated on the midline and retracted to either side.
The sella turcica was approached by blunt separation,
and a hole was drilled at the basal occipital suture to
allow visualization of the pituitary gland. The anterior
and posterior pituitaries were removed by suction. The
wound was packed with gelfoam, and the skin incision
closed with suture. The animals in the control group
received sham operation, which involved the entire surgical procedure with the exception of neural lobe ablation.
In PN7 animals, hypophysectomy was performed according to Glasscock’s method (Glasscock, 1980). Briefly, after
pups were anesthetized with ice, the pup’s head was
held between the thumb and index finger so that the
skull was parallel to the tabletop. A needle 20-G tip
with a length of 15 mm was probed into the region of
the ear where the ear canal develops and then the needle was pushed through the skull. Once the needle penetrated the skull, the syringe was elevated approximately
45 degrees (from the horizontal plane) until the needle
was parallel to the floor of the skull. The needle was
then pushed toward the midline until its movement was
stopped by the needle against the ear. The plunger of
the syringe was withdrawn slightly (approximately 0.1
ml), removing the pituitary without disrupting the diaphragma sella. The needle was withdrawn from the
pup’s head and the aspirated anterior and posterior
pituitaries were examined to confirm the completeness
of hypophysectomy. Sham-operated pups were anesthetized and probed with the needle, but once the top had
reached the pituitary region, it was withdrawn without
damage to the gland. After surgery, animals were
allowed to survive 3 (n 5 5), 12 (n 5 5), 24 (n 5 5) hr,
and 1 (n 5 5), 3 (n 5 5), 7 (n 5 5), 14 (n 5 5) days.
Perfusion and Tissue Processing
After survival, animals were anesthetized with an
overdose of ketamine and xylazine and perfused transcardially with 4% paraformaldehyde in 0.1 M phosphate
buffer (pH 7.4). The brains were removed and post-fixed
overnight at 48C. The sella turcica was examined at autopsy to ensure that hypophysectomy was complete.
Forty-micrometer-thick frozen sections of hypothalamus were collected in wells containing phosphate-buffered saline (PBS). After rinsing, sections were treated
for fluorescence immunostaining. The primary antibodies used included (1) rabbit IgG polyclonal antibody
against c-fos (1:1,000, Oncogene) and (2) rabbit IgG polyclonal antibodies against AVP (1:6,000, Peninsula Labs)
and OT (1:3,000, Peninsula Labs).
For c-fos, primary antibody (1:1,000, Oncogene) was
incubated with the sections overnight followed by incubation with the Alexa Fluor 568-conjugated goat antirabbit immunoglobins (1:400) for 2 hr. For double-labeling experiments, some sections were completely washed
with PBS for several times and then incubated with either the rabbit polyclonal antibody against AVP or a polyclonal antibody against OT overnight and followed by
incubation with the Alexa Fluor 488-conjugated goat
anti-rabbit immunoglobins (1:400) for 2 hr. Procedures
for immunohistochemistry carried out under room temperature. Sections were then mounted on slides and
observed under a confocal laser scanning microscope.
Two lines emitting at 488 and 568 nm were used for
exiting Alexa Fluor 488 and Alexa Fluor 568 secondary
antibodies, respectively. To test the specificity of the
immunoreactions, we have performed several tests.
First, a few sections from each animal were incubated
without the primary antibodies, and all sections showed
negative immunoreactions. Second, to test the specificity
of AVP and OT, we incubated sections which contain
only AVP or OT neurons with both antibodies against
AVP and OT, and the results showed that only the right
type of neurons stained. For example, incubation of sections from suprachiasmatic nucleus with both antibodies
against AVP and OT produced only AVP labeling, which
is consistent with previous studies (Nylen et al., 2001;
Van den Pol and Tsujimoto, 1985; Hou-Yu et al., 1986).
Third, we incubated sections with two polyclonal antibodies against c-fos and AVP and found that there was
not cross-reaction because c-fos is located in nucleus and
OT/AVP is located in cytoplasm. Therefore, these antibodies were used in the present study.
Quantitative Analysis
Sections in the medial level of the SON were observed
under laser confocal microscope because of its cellular
homogeneity (the SON is composed essentially of magnocellular AVP and OT neurons and almost all of them
project to pituitary). In this study, a quantitative analysis of the PVN was not performed because it contains
numerous parvocellular elements, which project to the
brainstem or median eminence (ME) and thus would not
be lesioned by hypophysectomy. The quantitative analysis was performed on at least four sections in each animal of five rats in each age group. The percentage of
Fos-positive nuclei in the OT- or AVP-positive neurons
in the medial level of SON was compared between different age groups and between OT- and AVP-positive neurons with one-way analysis of variance and Tukey–
Kramer multiple comparisons test.
In sham control adult rats, few or no c-fos–positive
cells were found in the SON or PVN (Fig. 1A,B). Expression of c-fos was induced following hypophysectomy (Fig.
1). Intensive nuclear staining for c-fos was already
observed by 3 hr in both SON (Fig. 1C) and PVN (Fig.
1D) post-lesion and sustained in the group of animals up
to 12 hr survival time (Fig. 1E for SON and 1F for
PVN). The c-fos expression diminished at 24 hr (Fig. 1G,
H), which was comparable to that of controls. These
findings are consistent with a previous report of transient c-fos induction in rat magnocellular hypothalamic
neurons after hypophysectomy (Villar et al., 1991).
Similar to adult rats, c-fos–immunoreactive nuclei
were not detected in the SON or PVN in the sham control PN14 and PN7 rats (Fig. 2A,B, 3A,B). After hypophysectomy, intensive c-fos induction was observed in
the above areas (Figs. 2, 3) in both PN7 and PN14
groups. The time course of c-fos expression was significantly prolonged compared with the adult. The intensive
c-fos stained nuclei were observed by 3 hr after hypophysectomy (Figs. 2C,D, 3C,D) and maintained up to 3
days post-lesion (Figs. 2E,F, 3E,F). Occasional c-fos
immunoreactivity was still detected in both the SON
and PVN at 1 week after hypophysectomy (Figs. 2G,H,
Double-labeling experiments showed that almost all
magnocellular neurons in both populations of AVP and
OT neurons in the SON and PVN were induced to
express c-fos in PN14 and in the adult as well (Figs. 4,
5, 7). Hypophysectomy also induced almost all AVP neurons in the SON and PVN to express c-fos in the PN7
group (Fig. 6C,D), but there was little evidence of c-fos
induction in OT neurons in either PVN or SON after
hypophysectomy (Figs. 6A,B, 7).
These results demonstrate that hypophysectomy induces c-fos in both immature and adult rats in magnocellular neurons of the PVN and SON. This finding is in
striking contrast to the observations in other models in
the brain that some stimuli such as kainic acid (KA)
treatment (Schreiber et al., 1992), cortical brain injury
(Herrera et al., 1993), and hypobaric hypoxia (Luo et al.,
2000), which could elicit intense c-fos expression in the
adult, do not induce significant c-fos at neonatal rats.
Schreiber et al. (1992) explained their results of age-dependent induction of c-fos in hippocampal and cortical
neurons after KA treatment by several mechanisms.
One of the explanations is that perhaps hippocampal
and cortical neurons do not participate in KA-related
seizure activity during the early postnatal period,
reflected by changes in metabolic activity following systemic KA injection. If this is the case, it would suggest
that the magnocellular neurons, at least the AVP neurons, as early as PN7 participate in the response to
hypophysectomy. However, so far there is no report
about changes in peptide expression in magnocellular
hypothalamic neurons in the PVN or SON in postnatal
rats after hypophysectomy. Induction of c-fos in OT neurons after hypophysectomy did not occur until PN14,
suggesting that these neurons only become engaged in
the response to hypophysectomy after further maturation. Indeed, it is well documented that maturation of
OT neurons is delayed compared with that of AVP neurons (Choy and Watkins, 1979; Lazcano et al., 1990).
Schreiber et al. (1992) also suggested that alteration of
the transcriptional apparatus that facilitates stimulustranscription coupling occurs between the second and
third week of postnatal development. However, our
results show that hypophysectomy induced c-fos expression at as early as PN7 and demonstrate that this is not
a generalized phenomenon. This finding suggests that
even if the stimulus-transcription coupling cascade is
activated, induced c-fos expression is neuronal- and/or
In our present study, many c-fos–positive magnocellular neurons were found in the SON and PVN at 3 hr
and 12 hr but no immunoreactivity was seen at 24 hr
after hypophysectomy in the adult. This result is similar
to the observation made by others that c-fos immunoreactivity was observed in magnocellular neurons for the
first 24 hr after hypophysectomy in the adult (Villar
et al., 1991). In this experiment, however, it was shown
that c-fos immunoreactivity was persistently expressed
for at least 3 days after hypophysectomy in immature
rats. Although there is a hypothesis that c-fos protein is
transiently expressed and is not useful for studying
chronic stimuli (Morgan et al., 1987; Morgan and Curran, 1991a), the later reports demonstrated that c-fos–
positive magnocellular neurons were persistently observed in the SON and PVN of rats that were chronically stimulated by the drinking of hypertonic NaCl
solution instead of water or by water deprivation (Miyata
et al., 1994). These observations are inconsistent with
the hypothesis, suggesting that chronic stimuli cause
persistent expression of Fos expression. It has been
postulated that c-fos is expressed persistently to constitute neural components and/or architectures if animals
require large and gradual changes of neural components
and/ or architectures in the response to stimuli, for
example, in development and/or neuronal plasticity
(Miyata et al., 1994). Indeed, sustained increase of cell
size and the elevation of OT and AVP and dynorphin
mRNA has been demonstrated during chronic stimulation of dehydration and lactation (Theodosis and Poulain, 1984; Sherman et al., 1986). This hypothesis is also
supported by the observation that persistent expression
of c-fos mRNA was found in the spinal cord, forebrain,
cerebellum, and retina in the developing mouse (Caubet,
Fig. 1. Photomicrographs showing the influence of hypophysectomy on c-fos–immunoreactivity in the SON and PVN of adult rats. C–
F: Intensive c-fos–immunoreactive stained cellular nuclei began to be
observed at 3 hr in SON (C) and PVN (D) and sustain at 12 hr (E,F)
after hypophysectomy. A,B,G,H: The c-fos-IR diminished at 24 hr
in both SON (G) and PVN (H), which was comparable to sham control
(A and B, respectively). Scale bar 5 50 mm.
Fig. 2. Photomicrographs showing the influence of hypophysectomy on c-fos–immunoreactivity in the SON and PVN of PN14 rats. A–
D: No c-fos–immunoreactivity could be seen in both SON (A) and PVN
(B) of sham-operated rats. Intensive c-fos–immunoreactive stained
cellular nuclei began to be observed at 3 hr in SON (C) and PVN (D)
after hypophysectomy. E,F: Even at 3 days postlesion, there are
numerous c-fos–immunoreactive stained nuclei in SON (E) and PVN
(F). G,H: C-fos–immunoreactivity diminished at 1 week postlesion, a
small number of c-fos–immunoreactive nuclei are scattered in SON (G)
and PVN (H). Scale bar 5 50 mm.
1989). Hence, c-fos protein was persistently expressed to
enhance the transcription of other genes such as AVP or
OT gene. In the present study, the same stimulus of
hypophysectomy induced different expression of c-fos
between the immature and adult rats. We suggest that
hypophysectomy induces different cellular demands that
correspond to different gene expression in magnocellular
neurons in immature and adult rats qualitatively and
Fig. 3. A–H: Photomicrographs showing the influence of hypophysectomy on c-fos–immunoreactivity in the SON (A,C,E,G) and PVN
(B,D,F,H) of PN7 rats. A,B: No c-fos–immunoreactivity could be seen
in both SON (A) and PVN (B) of sham-operated rats. C,D: intensive
c-fos–immunoreactive stained nuclei began to be observed at 3 hr in
SON (C) and PVN (D). E,F: Even at 3 days, there are numerous cfos–immunoreactive stained nuclei in SON (E) and PVN (F). G,H: Cfos–immunoreactivity diminished at 1 week, a small number of c-fos–
immunoreactive nuclei are scattered in SON (G) and PVN (H). Scale
bar 5 50 mm.
Fig. 4. A–D: Laser scanning confocal microscopy showing double
labeling for OT (green) and c-fos (red nuclear; A,B) or AVP (green) and
c-fos (red nuclear; C,D) in SON and PVN of hypophysectomized adult
rats at 3 hr after hypophysectomy. Almost all OT (A,B) or AVP (C,D)
neurons express c-fos in both SON and PVN. Scale bar 5 50 mm.
Fig. 5. A–D: Laser scanning confocal microscopy showing double
labeling for OT (green) and c-fos (red nuclear; A,B) or AVP (green) and
c-fos (red nuclear; C,D) in SON and PVN of hypophysectomized PN14
rats at 3 hr after hypophysectomy. Almost all OT (A,B) or AVP (C,D)
neurons express c-fos in both SON and PVN. Scale bar 5 50 mm.
quantitatively. Indeed, our previous study showed that
hypophysectomy elicited different reactions in magnocellular neurons of the HNS in pups as compared with
adults. No or unremarkable up-regulation of NOS
expression nor significant regeneration on the floor of
the third cerebral ventricle was observed in pups after
hypophysectomy. In contrast, a marked up-regulation of
NOS expression and a robust regeneration occurred following hypophysectomy in the adults (Yuan et al., 2006).
Thus, in our study, transient c-fos expression corresponds to large changes in NOS expression and neuronal plasticity in the adult. However, persistent c-fos
expression corresponds to no remarkable changes in
NOS expression and neuronal plasticity in developing
rats. We cannot exclude the possibility that the up-regulation of NOS and the structural plasticity are attributed to the activation of c-fos after hypophysectomy in
the adult. However, the persistent expression c-fos is
Fig. 7. Quantitative analysis of the percentage of c-fos–immunoreactive nuclei in AVP- or OT-immunoreactive neurons in SON in 3 hr
after hypophysectomy in PN7, PN14, and adult rats. Data are mean 6
SEM of four rats. *P < 0.01 vs. PN7. **P < 0.01 between OT-immunoreactive and AVP-immunoreactive neurons.
Fig. 6. A–D: Laser scanning confocal microscopy showing double
labeling for OT (green) and c-fos (red nuclear; A,B) or AVP (green) and
c-fos (red nuclear; C,D) in SON and PVN of hypophysectomized PN7
rats at 3 hr after hypophysectomy. Almost all AVP neurons express cfos in both SON (C) and PVN (D) while few OT neurons in SON (A)
and PVN (B) express c-fos. Scale bar 5 50 mm.
induced to enhance other gene expression rather than
NOS expression in the developing rats. This study also
extends the finding that not only chronic stimuli but
also axonal injury induces persistent c-fos expression in
A previous study of ours demonstrated that there was
substantial magnocellular neuronal degeneration in both
immature and adult rats after hypophysectomy as seen
in other systems of the CNS (Yuan et al., 2006). The
c-fos activation has been implicated in the events associated with programmed cell death both during development (Gonzalez-Martin et al., 1991, 1992) and after several experimental brain lesion, including KA-induced
seizure (Popovici et al., 1990; Smeyne et al., 1993; Kasof
et al., 1995) and okadaic acid-reduced apoptosis (Afshari
et al., 1994). Hafezi et al. (1997) further demonstrated
the relationship between programmed cell death and cfos by providing direct evidence that the absence of c-fos
(transgenic mice) prevents light-induced cell death of
photoreceptors. Our quantified results do not support
this model for the following reasons. In PN7 immature
rats, OT neurons underwent a substantial neuronal loss
after hypophysectomy (Yuan et al., 2006) without induction of c-fos. In addition, almost all AVP magnocellular
neurons express c-fos, but significant numbers of AVPIR magnocellular neurons survived hypophysectomy in
PN7. In PN14 and adults, c-fos was present in almost
all AVP and OT neurons that survived after hypophysectomy. These results suggest that not all c-fos–expressing
neurons underwent degeneration, although it has not
yet been demonstrated whether c-fos expression takes
place in regenerating neurons or in those that are
known to degenerate. Therefore, we suggested that c-fos
induction by hypophysectomy is involved in other physiological processes (reviewed in Hughes and Dragunow,
1995) rather than neuronal death.
It is well documented that removal of anterior pituitary can induce a decreased and suppressed negative
feedback of glucocorticoids, resulting in the increased
expression of AVP within neurons producing corticotropin-releasing hormone in PVN (Kiss et al., 1984; Wolfson
et al., 1985). It is thus likely that, after removal of anterior pituitary, AVP neurons producing corticotrophinreleasing hormone in parvocellular neurons of PVN,
whose axons are not lesioned by hypophysectomy, are
activated to enhance AVP expression.
D.E.S. was supported in part by a grant from the
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adults, developing, differential, activation, hypophysectomy, immunoreactivity, rats, fos
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