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Section on Endocrine Physiology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health (X.-M.M., G.A.), Bethesda, Maryland 20892; Dorothy Crowfoot Hodgkin Laboratories, Department of Medicine, University of Bristol (S.L.L.), Bristol, United Kingdom BS2 8HW
Address all correspondence and requests for reprints to: Greti Aguilera, M.D., Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262, Bethesda, Maryland 20892. E-mail: greti{at}helix.nih.gov
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Using intronic hybridization, previous studies have shown that transcription of both CRH and VP is activated by acute stress (9, 11, 12, 13, 14, 15, 16), whereas an increased proportion of cells that cosecrete CRH and VP (17, 18, 19) and a preferential activation of VP rather than CRH (10, 11, 18) are observed after repeated stress. Depending on the stress paradigm, repeated stress can result in an adaptation or desensitization of the hypothalamic-pituitary-adrenal (HPA) axis to the homotypic stressor (10, 20, 21, 22, 23). However, exposure of repeatedly stressed animals to a novel stress usually results in a greater ACTH response than that seen in naive control animals (4, 21, 24, 25). In the current studies we have investigated how adaptation of the hypothalamic response to a homotypic stressor affects plasma corticosterone and the hypothalamic CRH and VP hnRNA and mRNA responses to a novel heterotypic stressor.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Rats were divided into two groups. One group was left undisturbed (naive rats), and a second group was subjected to daily restraint for 60 min for 14 days by placing the rats into 2.5 x 6-in. plastic restrainers. On day 15, 24 h after the last restraint, groups of six rats from each group were killed undisturbed or 15 min, 1 h, 2 h, or 4 h after a novel stress, ipHS (1.5 M NaCl, 1.5 ml/100 g BW), a painful stress paradigm with an osmotic component (26, 27). Additional groups of six naive and repeatedly restrained (RR) rats were subjected to an additional 60-min restraint episode and killed 3 h later. All experimental manipulations were performed between 0900–1200 h.
Rats were killed by decapitation between 0900–1200 h. Trunk blood was collected into ice-cold tubes containing EDTA and centrifuged, and plasma was stored at -20 C for corticosterone RIAs using a rat corticosterone kit (Diagnostic Products, Los Angeles, CA) with a sensitivity of 7.5 ng/ml. Brains were removed, frozen on dry ice, and stored at -80 C. Twelve-micron sections were cut through the medial parvocellular subdivision of the PVN, thaw mounted on poly-L-lysine (Sigma Chemical Co., St. Louis, MO)-coated slides, and stored at -80 C.
In situ hybridization histochemistry
The rat CRH intron (CRHin) probe (supplied by Dr. Robert
Thompson, University of Michigan, Ann Arbor, MI) was a 530-bp
PvuII fragment of the CRH gene subcloned into pGEM-3
(Promega Corp., Madison, WI) and linearized with
XbaI. The rat CRH (CRHex 2) complementary DNA (Dr. Robert
Thompson) was a 770-bp BamHI fragment subcloned in pGEM-3Z
(Promega Corp.), linearized by HindIII. The VP
exonic probe was a 230-bp fragment of exon 3 of the rat VP
complementary DNA (VPex) cloned into pGEM-4Z (provided by Drs. Susan
Wray and Harold Gainer, NINDS, NIH, Bethesda, MD) and linearized with
BamHI. The VP intronic probe (VPin; supplied by Dr. Thomas
G. Sherman, Georgetown University, Washington DC) was generated from a
735-bp PvuII fragment of VP intron I subcloned into pGEM-3
and linearized by HindIII. High specific activity antisense
complementary RNA probes for CRHin, CRHex, VPin, and VPex were produced
using [35S]ATP and [35S]UTP as previously
described (28). In situ hybridization was performed as
previously described (28). Briefly, before hybridization, sections were
air-dried at room temperature, fixed with 4% formaldehyde for 5 min at
room temperature, washed three times with PBS, and then acetylated in
0.25% acetic anhydride in 0.1 M triethanolamine-0.9% NaCl
(pH 8.0) for 10 min at room temperature. Sections were transferred
through 70% (1 min), 80% (1 min), 95% (2 min), and 100% ethanol (1
min); 100% chloroform (5 min); and 100% (1 min) and 95% ethanol (1
min) and dried. Sections were hybridized overnight at 55 C with 2
x 106 cpm labeled CRHin, CRHex, VPex, or VPin probe per
slide containing four sections, respectively. Nonspecifically
hybridized probe was removed by washing with 50% formamide-250
mM NaCl at 60 C for 10–15 min and ribonuclease A treatment
for 30 min at 37 C, followed by three washes with 0.1 x SSC
(standard saline citrate) at 50 C for 15 min. Finally, slides were
dipped in 70% ethanol and air-dried before exposure to film. All
control and experimental sections were hybridized at the same time.
Analysis and quantification
For quantification of CRH hnRNA and CRH mRNA in the PVN as well
as VP hnRNA and VP mRNA in the magnocellular division of the PVN,
sections were exposed to Kodak BIOMAX film (Eastman Kodak Co., Rochester, NY) together with 14C-labeled
standards (American Radiochemical, St. Louis, MO) for 10 h
(CRHex), 15 days (CRHin), 20 min (VP mRNA), and 40 h (VP hnRNA).
For cellular localization of VP and CRH hybrids, slides were
subsequently dipped in nuclear emulsion diluted 1:1 in distilled water
(NTB2, Eastman Kodak Co.), exposed for appropriate times
(CRHin, 40 days; CRHex, 3 days; VPex, 12 days; VPin, 42 days) and
counterstained with cresyl violet acetate (Sigma Chemical Co.). The optical density of film autoradiographic images of
parvocellular CRH mRNA and CRH hnRNA as well as magnocellular VP hnRNA
and mRNA in the PVN and supraoptic nuclei (SON) were measured in a
computerized image analysis system (Imaging Research, Inc., St. Catherine, Canada), using the public domain NIH Image
program (developed at the NIH and available over the internet at:
http://rsb.info.nih.gov/nih-image). Optical densities obtained in two
consecutive sections per rat were averaged and used to calculate group
means. The results are presented as the mean and SE of the
percent change from the basal level in naive rats. Analysis of grain
density levels of VP hnRNA and mRNA and of the number of cells
containing VP hnRNA and VP mRNA in the medial parvocellular of the PVN
was carried out in the cresyl violet-counterstained sections using a
x40 objective with brightfield condenser as previously described (9, 16). Medial parvocellular VP neurons in the PVN were differentiated
histologically from magnocellular neurons on the basis of their overall
size, their relatively low level of VP expression, and their small,
dense-staining nuclei. The relative grain density levels of VP hnRNA
and VP mRNA were quantified in the medial parvocellular subdivision of
PVN using computerized densitometry, as described above, after
subtracting background from the proximity of the measured cells. The
grain density measurements for parvocellular VP hnRNA and VP mRNA were
made on individual cells identified as parvocellular after excluding
scattered magnocellular cells in the medial parvocellular subdivision
of the PVN. For each animal, at least two sections were measured
bilaterally, and the average value for each rat was used to calculate
group means. The results of grain density measurements are presented as
the mean and SE of the percent change from the basal level
in naive rats.
Statistical analysis was performed by one-way ANOVA, followed by Fisher’s least significant difference procedure (PLSD) test to assess statistical significance between control and experimental groups at each time point. P < 0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), but were unaffected by daily restraint for 14 days, and
transcripts failed to increase in response to the last restraint
episode (Fig. 2B). However, the pattern
of CRH hnRNA responses to a novel stress, ipHS, in RR rats was
identical to that in naive rats, showing a marked increase at 15 min
and returning to the basal level 1 h after acute HS injection
(Figs. 2, C and D, and 3A).
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, E and F) and did not change 1 h after acute
restraint in naive or RR rats. For the changes in CRH hnRNA, in naive
and RR rats CRH mRNA levels increased significantly 2 and 4 h
after ipHS (Figs. 2, G and H, and 3B). The increase in CRH mRNA levels
2 h after ipHS in RR rats was significantly higher than the
response in naive rats. (P < 0.05 vs. naive
ipHS 2 h; Figs. 2, G and H, and 3B).
VP hnRNA and VP mRNA responses in the parvocellular PVN
Basal expression of VP hnRNA in the parvocellular neurons of the
PVN in naive rats was very low (Fig. 4A)
and was not affected by daily restraint for 14 days (Fig. 4B). Acute
restraint resulted in a significant increase in the levels of
parvocellular VP hnRNA and the number of parvocellular neurons
containing VP hnRNA in both naive and RR rats. However, the increase
tended to be smaller after repeated restraint. The number of
parvocellular neurons containing VP hnRNA 1 h after the last
period of restraint was about 38% smaller in RR rats than in naive
rats (P < 0.05, by ANOVA), whereas the decrease in
grain density reached statistical significance only when excluding the
responses to ipHS (Fig. 5, A and B). The
patterns of response of parvocellular VP hnRNA responses to the
heterotypic stress (ipHS) were similar in naive and RR rats, starting
to increase at 1 h and remaining significantly elevated up to
4 h after ipHS injection (Fig. 5, A and B). However, the levels of
parvocellular VP hnRNA and the number of parvocellular cells containing
VP hnRNA were significantly higher 60 min after injection in RR rats
compared with those in naive rats (Fig. 4, C and D, and Fig. 5, A and
B).
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). Daily repeated restraint for 14 days
increased basal levels of VP mRNA and the number of parvocellular
neurons containing VP mRNA (Fig. 6B). IpHS injection increased VP mRNA
grain density levels by 4 h in naive rats (P <
0.05 vs. naive basal) and caused a further increase from the
already elevated basal levels at 2 and 4 h in RR rats
(P < 0.01 vs. naive ipHS at 2 or 4 h)
(Figs. 6, C and D, and 7). The number of parvocellular neurons
containing VP mRNA increased by 43.9% at 1 h and remained at
231.1% and 336.5% of the basal levels from 2–4 h after ipHS in naive
rats (Fig. 7). Similar to VP mRNA
grain density, the number of parvocellular neurons containing VP mRNA
increased significantly over the already elevated basal levels in RR
rats 2 and 4 h after ipHS (P < 0.05
vs. naive ipHS at 2 or 4 h).
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and 9A). Although the patterns of response
were similar, the increase in VP mRNA levels in RR rats was
significantly higher than that in naive rats 1 h after the
injection (P < 0.05 vs. naive ipHS at
1 h). No significant changes in magnocellular VP mRNA in response
to ipHS were found at any time point in naive rats, whereas in RR rats
there was a small increase in both the PVN and SON, which reached
statistical significance 2 h after ipHS (P < 0.05
vs. naive ipHS at 2 h; (Figs. 8B and 9B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The ip injection of HS into control animals resulted in a rapid activation of the HPA axis, with a 5-fold increase in plasma corticosterone within 15 min and peak levels at about 2 h. This is associated with a rapid increase in CRH hnRNA, which returns to normal levels by 1 h, and a more gradual increase in CRH mRNA, which peaks at 2 h. VP transcripts responded in a different time frame, with no change in hnRNA at 15 min, a peak response at 2 h, and levels still raised at 4 h. Not only are there changes in the prevalence of VP transcripts in the parvocellular PVN, but there is also a massive increase in the number of parvocellular cells that contain VP hnRNA and mRNA transcripts. It is well recognized that the cells containing VP in the parvocellular PVN represent one population of CRH neurons in which CRH and VP coexist, whereas there is a second population in which CRH exists alone (5). It has previously been described that adrenalectomy (32) or repeated stress (17, 18, 19, 33) results in an increased proportion of CRH cells that coproduce VP. The present demonstration of rapid increases in the number of parvocellular neurons expressing VP after a single ipHS injection suggests that the division of these cells into two separate populations is somewhat artificial, as most, and maybe all, CRH cells can cosynthesize VP in the appropriate circumstances. Thus, the proportion of cells falling into each population probably depends on the sensitivity of the methodology for detecting VP transcripts or peptide.
After 2 weeks of restraint stress there was no change in basal corticosterone, CRH hnRNA, CRH mRNA, or VP hnRNA. There was, however, a very marked increase in both VP mRNA and the number of cells containing VP mRNA. This is consistent with previous studies showing that parvocellular VP mRNA levels rise significantly after repeated immobilization or restraint (14, 19, 29) or repeated foot shock (34). Studies examining CRH and VP peptides have shown that daily repeated immobilization did not affect irCRH stores, but resulted in a progressive increase in VP stores and in the number of CRH nerve endings containing VP in the external zone of the median eminence (33). A further study showed that the VP content in the external zone of the median eminence increased to 160–190% of the control value, but the CRH content remained unchanged (35). In addition, the rate of release of immunoreactive VP from median eminence terminals increased in response to repeated or chronic stress (18, 35). Even more, the transient activation of hypothalamic CRH neurons by a single stressor resulted in a long lasting increase in VP coexpression regardless of the nature of the stressor, which in most cases was not accompanied by changes in CRH (36). Our present data showing an increase in the number of cells with detectable VP mRNA further demonstrates the flexibility of the neurochemical repertoire of these neurons. This change is selective for the parvocellular neurons, as there was no change in basal levels of VP mRNA in the magnocellular neurons of either the PVN or the SON.
Although the present study shows changes in CRH and VP expression at a single time point (60 min), the data confirmed our previous multitime point study (29) that showed that repeated restraint results in adaptation of the CRH transcript response but maintained VP responses to a subsequent episode of restraint. When rats from the same experimental group underwent the heterotypic stress of ipHS injection, CRH hnRNA and mRNA responses, far from being depressed, were very robust, and the peak response of both was greater than that seen in the control naive rats. Parvocellular VP hnRNA responded with a different, and delayed, time course, but again the peak levels achieved were greater than those in the control animals. VP hnRNA also reached peak levels earlier in the RR animals than in the controls. VP mRNA, despite starting at much higher prevalence in the RR animals, increased in a similar proportion to that in the control rats, achieving much higher absolute levels, which were still rising at 4 h. Both control and RR rats showed a similar increase in the number of parvocellular PVN cells containing VP hnRNA transcripts, but the relative increase in the number of cells expressing VP mRNA was greater for the control rats, as the RR animals started from a higher basal level.
The different time courses of CRH and VP transcript responses clearly imply different regulatory mechanisms for the transcription of these genes, as has been suggested in previous studies (17, 36, 37, 38). Differential sensitivity to corticosterone feedback (8, 39), second messengers, and transcription factors (38) may all be involved. The demonstration that there is adaptation of CRH, but not VP, parvocellular neuronal responses to repeated restraint confirms previous observations (10) and provides further evidence that VP is an important mediator of HPA axis activity during repeated stress (3, 4, 14, 17, 21, 33, 40, 41). Furthermore, it is clear from these experiments that animals that have adapted to RR stress maintain normal or increased CRH hnRNA and mRNA responses to a heterotypic stressor. The differential responses of the parvocellular neuron to the repeated homotypic stress and the novel heterotypic stimulus suggest the activation of distinct stimulatory and inhibitory pathways by the different stressors. It is possible that adaptation to the repeated homotypic stress is due to desensitization of the afferent pathways to the PVN at the synaptic levels or at the parvocellular neuron itself, and that the novel stress uses different pathways and neurotransmitters. However, despite the habituation, there is little evidence of desensitization, as VP responses to the repeated stress are preserved (29), and microdialysis experiments have shown that norepinephrine turnover in the PVN is increased, rather than decreased, during repeated immobilization (42). In contrast to restraint, the novel stress used in these experiments, ipHS, does not cause habituation of the HPA axis response to the repeated stimulus (11, 23, 27), arguing for different pathways. Facilitation of the HPA axis response has actually been described for a variety of stress combinations regardless of the ability of the repeated or novel stimulus to cause adaptation during repeated exposure (3, 22, 25), suggesting that the mechanisms of differential responses are more complex than simply different pathways and neurotransmitters.
Stimulatory stressful information is conveyed to the PVN through
ascending catecholaminergic projections from the brain stem (43, 44).
In addition, studies based on intermediate early gene expression,
retrograde tracer, and lesioning of selective pathways have revealed
that somatosensory/nociceptive stressors, such as restraint,
immobilization, foot shock, social defeat, and forced swim (and
probably ipHS), activate limbic areas in the brain, including the
hippocampus, neocortical areas, amygdala, bed nucleus of the stria
terminalis, and some hypothalamic and thalamic nuclei (45, 46). This
limbic pattern of activation is similar, although not identical, for
the different somatosensory stressors, but it differs markedly from the
transmission paths of potentially life-threatening systemic stressors,
such as metabolic, cardiovascular, respiratory, and immune stimuli,
directly from the brain stem to the PVN (47, 48). The limbic structures
activated by somatosensory stressors all have direct or indirect
connections to the PVN and contain 
-aminobutyl acidergic neurons
known to inhibit the HPA axis (48). Lesions of the prefrontal cortex,
hippocampus, central amygdala, have been reported to potentiate HPA
axis responses to somatosensory stressors, supporting the idea that
responses to this type of stressor can be modulated by limbic
inhibitory circuitry (48). One possible pathway involved in the
increased responsiveness to the heterotypic stressor is the
parabrachial-posterior paraventricular thalamus-amygdala parvocellular
paraventricular hypothalamus pathway, as lesions of the posterior
paraventricular nucleus of the thalamus increase ACTH responses to
restraint in previously chronically stressed animals, but not in naive
animals (25). Influences from hypothalamic nuclei, such as the arcuate,
ventromedial hypothalamic, and medial preoptic area, may also affect
parvocellular neuronal activity during stress. In addition, other
neurotransmitters and neuropeptides, including CRH itself, could
modulate PVN activity through these pathways. Thus, processing and
integration of somatosensory/nociceptive stimuli in the limbic system
could activate or suppress inhibitory pathways to the PVN, enhancing or
inhibiting parvocellular neuron responses depending on previous
experiences and the type of stimulus. The exact mechanisms of the
differential responses to homotypic and heterotypic stressors remain to
be elucidated, but our data would certainly suggest that the
neurotransmitter repertoire (and pathways) activated by different forms
of stressor must be distinct enough to be distinguished by the
stress-responsive cells in the parvocellular PVN.
Consistent with previous studies (49), VP hnRNA in the magnocellular division of the PVN and SON also increased markedly after HS, but no changes in VP mRNA were detected at any time point after HS injection in the control rats. This is probably due to the masking effect of the very large pool of VP mRNA in these neurons, so that significant changes can be observed only after longer periods of osmotic stimulation (22). It is noteworthy that although acute or repeated restraint had no effect on magnocellular VP hnRNA or VP mRNA, the responses of both magnocellular PVN and SON neurons to ipHS were higher in RR than in naive control rats in terms of grain density. Although this effect was seen only at one time point, it suggests that a chronic physical psychological stress may change the sensitivity of magnocellular neurons to osmotic stimulation. The possible implications of such a mechanism in certain disorders, including idiopathic edema, are unclear.
In conclusion, we confirm that there is a desensitization of CRH, but not VP, transcription responses to repeated restraint and have demonstrated that animals adapted to a chronic homotypical stress show a greater response of CRH and VP gene transcription in the parvocellular PVN after a novel stress (HS injection). The hypothalamus clearly has the flexibility to adapt to homotypic stress while at the same time maintaining its ability to respond to novel stressors.
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Footnotes |
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Received December 29, 1998.
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mez F, Armario A 1994 Direct evidence for chronic stress induced facilitation of the
adrenocorticotropin response to a novel acute stressor.
Neuroendocrinolgy 60:1–7[Medline]
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