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Department of Psychiatry, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0559
Address all correspondence and requests for reprints to: Dr. Helmer F. Figueiredo, Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0559. E-mail: figueih{at}ucmail.uc.edu.
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Introduction |
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The predator stress model affords an excellent means to resolve central mechanisms responsible for internally generated stress responses. It does not involve stimuli that are frankly painful (e.g. foot shock) and does not expose subjects to artificial situations or environments (e.g. restraint tubes). In addition, predator stress does not invoke reactive responses to physiologic challenges (e.g. immune stimulation, hemorrhage, ether). As such, determining mechanisms underlying predator-related stress responses will be valuable to understanding how endogenous stress-related disease processes are initiated and perpetuated. In the present report, we evaluate the impact of chronic predator exposure on neuronal and hormonal indices of acute and chronic stress. In addition, we present a comparison of the acute stress profile induced by predator stress with that initiated after restraint and hypoxia, representing stressors currently categorized as psychological (or processive) and physical (or systemic), respectively (13, 14, 15). Our results indicate that predator stress engages a unique neurocircuitry that may fuel long-lasting changes in brain stress responsivity.
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Materials and Methods |
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Cat stress procedures
Experiment 1.
Rats were subdivided into four experimental groups (n = 6 animals/group). Cat-exposed rats received either a single 60-min cat exposure (cat group) or daily 60-min exposure to the cat for 7 or 14 consecutive days (7- or 14-d groups, respectively). In addition, a group of rats were not exposed to the cat or chamber and served as the unstressed control group. On the day of testing, the cat was transported to the testing room in a standard cat transporter. Cat-exposed rats were placed in a 23 x 46 x 23-cm Universal Anesthesia Plexiglas chamber (Harvard Apparatus, Holliston, MA) into which 15.0 x 0.5-cm slots were cut at regular intervals. The apparatus allowed the rats access to visual, olfactory, and acoustic stimuli associated with the cat while prohibiting physical interaction or attack. The Plexiglas chamber was then placed in a large dog enclosure (137 x 94 x 114 cm), constructed of 7-gauge zinc-coated steel (Midwest Steel, Muncie, IN; model no. 99). The cat was immediately placed in the enclosure, and a black curtain was placed 5 ft around and 12 in from the cage to prevent the cat from seeing the observer. Throughout the experiments, the cat spent a greater amount of time in the immediate proximity of the cage and had the habit of sitting on it, but did not display any aggressive behavior toward the rats. In the 7- and 14-d groups, the timing of cat exposure varied randomly between morning (0900–1100 h) and afternoon (1500–1700 h). To assess the postexposure time course of CORT secretion in cat-exposed animals, blood samples were collected by tail nicks on the 1st and 6th days from the 7-d exposed group, and on the 1st, 6th, and 13th days from the 14-d group. These samplings were taken in the morning (between 0900 and 1100 h) under light restraint at 60, 120, and 180 min from onset of cat exposure. Finally, all rats were killed by rapid decapitation immediately after the single cat exposure or in the morning of the day after the last cat exposure (7- and 14-d groups). Control rats were killed in the morning, and had no access to any sensory cues associated with the cat. After kill, trunk blood samples were collected in EDTA-coated Vacutainer (BD Biosciences, Franklin Lakes, NJ). Brains were rapidly removed and frozen in isopentane cooled to -45 C on dry ice, and subsequently stored at -80 C until further processing. In addition, adrenal and thymus glands were removed from these animals and weighed.
Experiment 2.
To differentiate the effects of cat exposure from those of novelty, rats were habituated for 3 d to the holding chamber before introduction of the cat. Thus, two groups of rats (n = 6 animals/group) were exposed for 60 min to the predator-testing environment (described above) on 3 consecutive days. On d 4, groups of animals received either an additional 60-min chamber exposure (chamber group) or a 60-min exposure to the cat (cat plus chamber group) between 0900 and 1100 h. The chamber group had no exposure to sensory cues from the cat itself. Animals were killed by rapid decapitation in the morning (between 0900 and 1100 h), immediately after testing, and processed as noted above.
Restraint and hypoxia stress procedures
Additional groups were included to provide a qualitative comparison of c-fos mRNA induction after hypoxia or restraint stress. Hypoxia causes dose-dependent ACTH release that is accompanied by activation of ascending pathways known to be selectively involved in transmission of interoceptive stressors (13, 16, 17, 18). On the day of testing, animals were placed in a 23 x 46 x 23-cm Universal Anesthesia Plexiglas chamber (Harvard Apparatus), and a 9% oxygen/91% nitrogen mixture permeated the chamber for 60 min. Animals were then removed from the chamber and killed by rapid decapitation. Restraint stress is a widely used model of acute stress. Animals were placed into plastic restrainers for 60 min, and subsequently removed from the chamber and killed by rapid decapitation. Brains from each group were harvested and processed for in situ hybridization analysis of c-fos mRNA expression.
In situ hybridization
Brains were sectioned at 14 µm on a Zeiss (Kalamazoo, MI) Microm cryostat. In the preparatory phase of hybridization, the sections were fixed in 4% phosphate-buffered paraformaldehyde for 10 min, then rinsed twice (5 min each) in each of the following: 5 mM potassium PBS (KBPS), 5 mM KPBS with 0.2% glycine, and again in 5 mM KBPS. The slides were then acetylated with 0.25% acetic anhydride (made in 0.1 M triethanolamine (pH 8.0)] for 10 min, rinsed twice in 0.2x saline citrate (SSC) for 5 min each, and then dehydrated through graded alcohols (2 min each) and chloroform for 5 min.
The hybridizations used antisense cRNA probes complementary to rat c-fos (700 bp) and CRH (300 bp) mRNAs. Probes were labeled by in vitro transcription using [35S]UTP. The c-fos fragment (original full-length cDNA from T. Curran, St. Jude Children’s Research Hospital, Memphis, TN) was cloned into pGem4Z vector, linearized with AvaII, and transcribed with SP6 RNA polymerase. The CRH fragment was cloned into a pGem4 vector, linearized with AvaII, and transcribed with T7 RNA polymerase. The labeling reaction for c-fos and CRH consisted of 5x transcription buffer, 125 µCi 35S, 200 µmol of a mixture of nucleoside 5'-triphosphate (33% GTP, 33% CTP, 33% ATP, and 1% UTP), 100 mM dithiothreitol, 50 U ribonuclease inhibitor, 40 U SP6 or T7 RNA polymerase, and 2 µg linearized DNA. The probes were incubated at 37 C for 90 min, precipitated with ammonium acetate, and reconstituted in diethylpyrocarbonate-treated nanopure water.
Probes were diluted in hybridization buffer [50% formamide, 20 mM Tris-HCl (pH 7.5), 1 mM EDTA, 335 mM NaCl, 1x Denhardt’s, 200 µg/ml salmon sperm DNA, 150 µg/ml yeast tRNA, 20 mM dithiothreitol, and 10% dextran sulfate] to yield 1,000,000 cpm per 50 µl buffer. An aliquot of 50 µl was added to each slide and coverslipped. The slides were then hybridized overnight at 55 C in a polystyrene chamber lined with blotting paper and saturated with 50% formamide. The next day, the slides were briefly soaked in 2x SSC, and the coverslips were removed. The slides were then rinsed in 2x SSC for 20 min, and then incubated at 37 C in 100 µg/ml ribonuclease A for 30 min. The slides were then rinsed three times in 0.2x SSC for 15 min each, and incubated in 0.2x SSC at 65 C for 1 h. The slides were taken through graded alcohols, dried, exposed to Kodak Biomax MR-2 film for 14 d (Packard Instrument Co., Inc., Meriden, CT) for 14–21 d, and subsequently dipped in Kodak NTB2 liquid emulsions.
Hormone assays
Serum CORT assays were performed using 125I RIA ICN kits (ICN Biochemicals, Inc., Cleveland, OH). ACTH assays were performed using 125I RIA from DiaSorin, Inc. (Stillwater, MN). For both assays, all samples were tested in the same run.
Image analysis
Semiquantitative analyses of CRH and c-fos mRNA expression were performed using Scion Image 1.62 software (Scion, Frederick, MD). CRH mRNA expression was assessed in the paraventricular nucleus (PVN) and central nucleus of the amygdala (CeA), whereas c-fos mRNA expression was assessed in the somatosensory cortex, insular cortex, and ventrolateral septum. Background signal was determined over a nonhybridized area (white matter) for every region measured and subtracted from specific signal to obtain corrected gray level units per pixels.
Statistical analysis
To allow direct comparisons among treatment groups in experiments 1 and 2, all plasma samples were tested in single CORT or ACTH assays, and all in situ hybridizations were performed in the same test run. To avoid differences in blood sampling methods (tail nicks vs. trunk blood), only trunk blood samples were analyzed across experiments 1 and 2. The tail nick results (60, 120, and 180) in experiment 2 were analyzed separately. The effect of treatments (cat exposures, chamber, and controls) on hormone plasma levels (CORT and ACTH) or CRH mRNA expression was determined by one-way ANOVA. The effect of cat exposure on the time course of CORT secretion (60, 120, and 180 min) was analyzed by repeated-measures ANOVA. Significant overall effects and interactions were further analyzed by planned comparisons [Fisher’s projected least significant difference (PLSD)]. Statistical analyses were performed using Statview 5.0 software (SAS Institute, Inc., Cary, NC) and GB-STAT (Dynamic Microsystems, Inc., Silver Spring, MD). Statistical significance was taken as P 
0.05.
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0.05) (Fig. 1
). Notably, CORT levels were significantly elevated in both 60-min cat-exposed and chamber-habituated 60-min cat cohorts relative to all other groups (P < 0.05; Fisher’s PLSD test). Interestingly, the chamber-naive cat-exposed group (60-min cat group) showed an elevated CORT response relative to the chamber-habituated group. Furthermore, overall ANOVA revealed a significant effect of cat exposure on ACTH levels (F(5,35) = 3.74; P 0.05) (Fig. 1); however, in this analysis, ACTH was significantly elevated only in the chamber-exposed group. In combination, the data suggest that chamber preexposure alters the kinetics of HPA responses to predator stress.
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). Notably, the enhanced adrenal weight was associated with body weight loss, because changes in raw adrenal weight were not significant. To evaluate whether repeated exposure to the cat resulted in habituation of the HPA axis, we determined the time course (60, 120, and 180 min) of CORT levels in the repeated-exposure animals. Thus, blood samples were collected immediately after 60-min exposure to the predator on d 1 and 6 from the 7-d group, and on d 1, 6, and 13 from the 14-d groups. Repeated-measures ANOVA revealed that CORT levels in the 7-d group of animals were significantly affected by time (F(2,32) = 8.97; P 0.05), and, in the 14-d group, were significantly affected by time (F(2,47) = 8.48; P 0.05), day of exposure (F(2,47) = 7.27; P 0.05), and time x day interaction (F(4,47) = 2.68; P 0.05) (Fig. 2). Further analysis revealed that, in the 14-d group, rats exposed for 6 and 13 d displayed significant enhancement of CORT secretion (P 0.05; Fisher’s PLSD test), indicating that these animals did not habituate to the cat. Furthermore, overall CORT secretion (area under the curve) was elevated on d 6 (P < 0.05; repeated-measures ANOVA), and on d 13 after cat exposures (P < 0.05; repeated-measures ANOVA) (Fig. 2). Enhanced secretion at the 6- and 13-d sampling points was largely due to prolonged CORT secretion, because peak secretion (60-min time point) did not distinguish the groups.
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. Results from both experiments 1 and 2 (see Materials and Methods) were normalized to the appropriate control group to allow comparisons across the two studies. Overall, there was a significant effect of predator exposure on CRH mRNA levels in both the PVN (F(5,25) = 4.63; P 0.05) and CeA (F(5,26) = 8.63; P 0.05). In the PVN, elevations in CRH mRNA were seen 60 min after stress exposure in both chamber-naive and chamber-habituated predator-exposed groups, relative to control and chamber-only groups. Elevated PVN CRH mRNA was also observed after 2 wk of daily 1-h exposures (P 0.05; Fisher’s PLSD test). The CeA effect was carried predominantly by the chamber-habituated, predator-exposed animals, which showed elevated CRH mRNA levels relative to all other groups (P 0.05; Fisher’s PLSD test). No other groups differed significantly from control or chamber-only animals.
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illustrates the distribution of c-fos mRNA expression in the forebrain after cat exposure, emphasizing regions that are differentially induced by the predator stimulus. These include neurons in the interfascicular division of the bed nucleus of the stria terminalis (Fig. 4A), the perifornical nuclei (B), the dorsomedial cap of the ventromedial hypothalamic nucleus (C), the dorsal premammillary nucleus (D), and the thalamic precommissural nucleus (E). These regions express very low levels of c-fos mRNA after restraint or hypoxia (data not shown). Areas showing a more graded response include the insular cortices, the nucleus of the olfactory tract, and the anterior hypothalamus, including the peri-PVN region (see Fig. 5B). The induction pattern displayed by these regions after cat exposure was identical in chamber-naive and chamber-adapted cat-exposed animals. c-fos expression was not observed in corresponding regions of rats receiving repeated exposure to the chamber alone. Surprisingly, although c-fos is strongly expressed in the PVN of restrained (Fig. 5C) and hypoxic animals (D), its induction is nearly absent in the cat-exposed animals (B).
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and 7, respectively), where c-fos mRNA expression could be observed after 1 h of either cat or restraint exposure (but not in rats receiving repeated chamber placement). A few regions showed differential induction with restraint, including the anterodorsal lateral hypothalamic region and somatosensory cortex (data not shown). Distinct c-fos mRNA expression patterns were also seen after hypoxia. Exposure to hypoxia revealed induction of c-fos in the lateral division of the CeA, in the oval subnucleus of the bed nucleus of the stria terminalis, and in magnocellular neurons in the supraoptic and paraventricular nuclei (cf. Fig. 6). In contrast with restraint and cat exposure, disproportionately low c-fos mRNA induction was observed in the medial amygdaloid nucleus and lateral septum (Figs. 6D and 7D, respectively).
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), prefrontal, orbital, and piriform cortices; and midline thalamic nuclei, including the paraventricular thalamus. To compare the extent of cortical activation after chamber placement with that of cat exposure, we performed a densitometric analysis of c-fos mRNA expression in two cortical areas (somatosensory cortex and insular cortex) showing c-fos activation in both chamber- and cat-exposed animals, and in the lateral septum, a region that appeared to be selectively activated upon predator exposure. There was a significant effect of treatment on c-fos mRNA expression in all three regions (somatosensory cortex, F(2,15) = 17.80, P 0.05; insular cortex, F(2,15) = 6.01, P 0.05; lateral septum, F(2,15) = 45.09, P 0.05) (Fig. 9). Notably, in somatosensory and insular cortices, post hoc analysis revealed that c-fos expression level was significantly higher in both chamber- and cat-exposed groups compared with controls. In the lateral septum, induction in the chamber group was minimal; however, the 60-min group differed significantly from both control and chamber-exposed animals (P 0.05; Fisher’s PLSD test). Thus, it is apparent that c-fos induction can be induced in a subset of stress-responsive brain regions after repeated exposure to the same evocative stimulus.
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Discussion |
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Notably, PVN CRH mRNA expression is up-regulated after repeated predator exposure. Elevated CRH expression is a common result of prolonged or intermittent stress exposure (e.g. Refs. 21, 22, 23, 24), and is indicative of PVN activation. Unlike other stress regimens, the predator stress paradigm can produce PVN CRH up-regulation in the absence of basal (resting) CORT hypersecretion (see Ref. 23); thus, stress sensitization may be related to enhancement of CRH synthesis in the absence of an increased feedback signal, resulting in a net enhancement of HPA output after discrete stressors.
The elevated PVN CRH mRNA expression in both chamber-naive and chamber-habituated groups is not accompanied by a substantial c-fos response in either group. The limited c-fos response occurs within the context of very pronounced c-fos activation of other brain regions, including regions commonly implicated in stress integrative processes (e.g. medial amygdala, lateral septum) (14) as well as the neighboring perifornical region. There are several possible explanations for this discrepancy: first, the time course of c-fos induction may differ among stressors; peak c-fos activation may occur before (or after) the 60-min time point, and may have been missed by our analysis. This possibility is supported by data showing evidence of modest fos protein induction in PVN after exposure to cat odors (25). Second, the predator stimulus causes activation of stress circuits distinct from those used by restraint or hypoxia, and may therefore use alternative signal transduction mechanisms that can largely bypass c-fos induction. Finally, activation of the PVN by predator stress may stimulate CRH neuronal activity without initiating a c-fos response. Whereas most stressors described to date promote PVN c-fos activation, marked CRH and ACTH release can occur in the absence of substantial c-fos induction [e.g. after adrenalectomy (26)]. Thus, it is clear that the PVN has the capacity to respond to stimuli in the absence of c-fos induction, and therefore, c-fos transcription may not be an immutable concomitant of HPA activation.
Acute predator exposure caused elevated CRH mRNA levels in the CeA only in chamber-habituated models. Priming of the CRH mRNA synthesis response may be due to the dissonance of experiencing a predator in a previously safe environment. These data suggest that this CRH-containing cell population is sensitized by repeated exposure to a strange but safe environment, and responds to a novel perceived survival threat (predation) with enhanced activation of CRH synthesis.
As was the case for the PVN, CeA CRH mRNA increases occurred in the absence of marked c-fos mRNA induction, at least at the 60-min time point. These data support numerous failures to demonstrate substantial CeA c-fos expression after psychogenic stimuli (e.g. Refs. 13 and 27). Thus, it appears that CRH gene expression is effectively initiated despite limited c-fos induction. Given a wealth of data coupling CRH gene transcription with CRE-binding protein phosphorylation, it likely appears that CRH neurons in the CeA (and perhaps PVN) are indeed activated by stress, perhaps in a manner that does not involve c-fos transcription. In this regard, it is believed that in vivo activation of PVN CRH transcription may be elicited by CRE-binding protein phosphorylation events, and is independent of c-fos activation (28), thus providing a mechanism whereby CRH and c-fos expression can be modulated independently. Alternatively, it is possible that CRH transcription may be secondary to inhibition of this cell population, driven by an as-yet-unknown mechanism.
Differential c-fos mRNA expression was observed in the interfascicular division of the bed nucleus of the stria terminalis, the perifornical nucleus, the dorsomedial tip of the ventromedial nucleus, the dorsal premammillary nuclei, and the precommissural thalamic nucleus after predator stress, relative to either restraint or hypoxia. Notably, the dorsal premammillary nucleus, the dorsomedial quadrant of the ventromedial nucleus, and the precommissural thalamus represent prominent components of the hypothesized hypothalamic defensive behavior circuit in the rat (29). These regions are known to be fos-activated by predator stress (30, 31), and are consistent with the notion that predator stress invokes a unique circuitry commensurate with anticipation of a physiological challenge. In addition, predator stress resulted in disproportionate activation of the insular cortex, perirhinal cortex, and the nucleus of the lateral olfactory tract, reflecting strong activation of olfactory sensory pathways.
The commonalities in c-fos expression seen after predator exposure, restraint, or hypoxia are also of substantial interest. All three stimuli produced robust activation of medial prefrontal cortex (particularly infralimbic and prelimbic regions), all orbitofrontal cortices, and the paraventricular thalamic nucleus. Indeed, all regions were activated by chamber exposure in habituated rats. Notably, the medial prefrontal cortex plays a major role in inhibition of psychogenic stressors (32, 33), whereas the paraventricular thalamus is intimately involved in mediating HPA axis responses to repeated stress (34, 35). These data suggest that c-fos induction in these regions does not discriminate among stress modality or repetitive stimulation.
Several regions showed differential c-fos mRNA induction in hypoxic rats relative to restraint- or predator-exposed groups. For example, unlike restraint or predator exposure, hypoxia caused induction of c-fos mRNA expression in the lateral divisions of the CeA, in the oval subnucleus of the bed nucleus of the stria terminalis, and in magnocellular neurons of the PVN and supraoptic nucleus, whereas induction in the medial amygdaloid and lateral septal nuclei was much lower than that seen after restraint or hypoxia. These data are consistent with the interoceptive nature of the hypoxic stimulus, and agree with findings seen in animals subjected to other physiologic challenges, including hemorrhage and immune challenge (13, 14, 15).
Animals exposed to the chamber without cat exposure still exhibited marked c-fos mRNA induction in numerous regions, including somatosensory (parietal) and cingulate cortices. Exposure to the predator did not change the extent of induction in these regions. However, several limbic regions, most notably the lateral septum, showed induction only in the predator-exposed condition. Selective enhancement of c-fos mRNA induction in limbic regions after predator exposure may reflect 1) recruitment of additional circuits by the subjective intensity of the stressful stimulus, or 2) evocation of distinct circuitry in accordance with the characteristics of the stressor. In support of the former, it is clear that exposure to the cat induces substantially greater CORT responses than chamber placement, and is thus a more potent stressor from this standpoint. However, it is also clear that the three different stressors activate distinct central circuits, and the salience of predator exposure as a psychogenic stimulus may invoke relevant limbic pathways that are not involved in responses to repeated stimuli. Indeed, this possibility is supported by the all-or-none nature of septal c-fos mRNA induction to cat exposure; intensity coding would predict a graded response in this region with chamber exposure, which is not observed in this study.
Preexposure to the testing chamber substantially altered the pattern of HPA activation. Of note, plasma CORT levels were differentially elevated in chamber-naive animals at the 1-h time point, whereas ACTH levels were selectively enhanced in chamber-exposed animals after cat stress. Together, the results imply that chamber placement changes the kinetics of the HPA axis response, perhaps resulting in prolonged ACTH secretion and, therefore, a predicted increase in CORT later in time. Because only one time point was evaluated, it is difficult to draw firm conclusions about such issues; however, the combination of elevated ACTH with enhanced CRH mRNA expression in the PVN and CeA suggests that preexposure to the chamber may prime central stress regulatory pathways to respond to a novel stressor. The data suggest that repeated mild stress may sensitize the animal to subsequent fearful stimuli, in accordance with the concept of HPA facilitation proposed by Dallman and colleagues (36).
Overall, the data suggest that predator stress induces reliable and unique stress-circuit activation in both acute and prolonged time domains. The evidence for sensitization of the HPA axis response suggests that aspects of the response to predation stress can prime the individual to secrete glucocorticoids during subsequent exposures. Glucocorticoid secretion has obvious benefits for animals faced with a natural predator, because the physiological actions of CORT (see Ref. 37) can assist in replenishment of resources expended during fight-or-flight responses and limit the immune response mounted in the event of wounding. Thus, mounting this response in the presence of a predator is of substantial predictive significance.
Equally intriguing is the evidence for limited long-term HPA up-regulation after repeated exposure; unlike other chronic stress regimens [i.e. chronic variable stress (23)], the long-term impact of predator stress is transient. Thus, predator exposure primes the HPA axis to respond, but does not induce chronic activation of the HPA system. It is uncertain whether this transience is related to the perceived intensity of the stressful stimulus, or to the differential stress-circuit engagement elicited by the repeated presence of the predator.
In summary, predator exposure is an ethologically relevant, naturalistic stress model that reliably engages neuroendocrine stress responses. Importantly, it also introduces aspects that differ quite substantially from other stress models (e.g. HPA priming with repeated stimulation). The data point to an intricate interaction between neural and endocrine systems with innate response programs, and likely reflect the diversity of behavioral and physiological mechanisms of stress adaptation.
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Acknowledgments |
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Footnotes |
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Abbreviations: CeA, central nucleus of the amygdala; CORT, corticosterone; HPA, hypothalamo-pituitary-adrenocortical; KBPS, potassium PBS; PLSD, projected least significant difference; PVN, paraventricular nucleus; SSC, saline citrate.
1 We dedicate this work to the memory of B.L.B., who died tragically before its completion. His loyalty, dedication, and friendship are sorely missed. 
Received June 6, 2003.
Accepted for publication August 11, 2003.
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