Central monoamine activity in genetically distinct strains of mice following a psychogenic stressor:...

Brain Research 892 (2001) 293–300www.elsevier.com/ locate /bres

Research report

Central monoamine activity in genetically distinct strains of micefollowing a psychogenic stressor: effects of predator exposure

a a b a ,*Shawn Hayley , Thomas Borowski , Zul Merali , Hymie AnismanaInstitute of Neuroscience, Carleton University, Life Science Research Bldg., Ottawa, Ontario K1S 5B6, Canada

bSchool of Psychology and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada

Accepted 21 November 2000

Abstract

The effects of psychogenic stressors, rat exposure and fox urine odor, on central monoamine functioning was assessed in two inbredstrains of mice, BALB/cByJ and C57BL/6ByJ, thought to be differentially reactive to stressors. These stressors markedly increased NEutilization, as reflected by MHPG accumulation, in the locus coeruleus, hippocampus, prefrontal cortex and central amygdala. Likewise,the 5-HT metabolite, 5-HIAA, was elevated in hippocampus, prefrontal cortex and central amygdala, and to some extent DOPACaccumulation was increased in the prefrontal cortex. In most brain regions, the neurochemical effects of the stressors were comparable inthe two mouse strains. However, central amygdala 5-HIAA elevations as well as DOPAC increases in the prefrontal cortex elicited by foxodor were greater in C57BL/6ByJ than in BALB/cByJ mice. Although BALB/cByJ mice are more behaviorally reactive thanC57BL/6ByJ mice, and also show greater corticosterone elevations in response to neurogenic and systemic stressors, it was previouslyshown that differential corticosterone changes were not elicited by a predator exposure. Taken together with earlier findings, it appearsthat despite greater behavioral reactivity /anxiety, the strain-specific neurochemical changes elicited may be situation-specific such that theprofile apparent in response to neurogenic and systemic stressors may not be evident in response to predator-related threats. 2001Elsevier Science B.V. All rights reserved.

Theme: Neural basis of behavior

Topic: Stress

Keywords: Stress; Predator stress; Anxiety; Genetic; Norepinephrine; Dopamine; Serotonin

1. Introduction forced swim and footshock, BALB/cByJ mice displayedmuch greater behavioral signs of anxiety and also ex-

Although stressors reliably increase hypothalamic–pitui- hibited greater levels of plasma corticosterone relative totary–adrenal (HPA) functioning and provoke increased the hardier C57BL/6ByJ strain [3,4,8,13,14,17,21,27–central monoamine activity [10,19,24], considerable inter- 30,36]. However, the use of neurogenic stressors does notindividual variability exists in this respect, and pronounced permit the dissociation of effects attributable to physicaldifferences have been observed across strains of rats and stressors relative to those related to the psychologicalmice [5,16,23,26,37]. Interestingly, while some strains of attributes of the stressor. Indeed, unlike the effects elicitedmice can be differentiated on the basis of their behavioral by footshock, in response to a psychogenic stressor, suchand neuroendocrine responses to stressors, such effects are as being exposed to either a predator (the rat) or olfactoryalso dependent upon the characteristics of the stressor cues associated with predators (fox odor), the corticos-employed. In this respect, it is not necessarily the case that terone response in BALB/cByJ mice is actually lessphysically painful (neurogenic) and psychological (psycho- pronounced than in the C57BL/6ByJ strain [3,16]. Ingenic) stressors will lead to the same outcomes. For effect, while this form of psychogenic stressor provokedinstance, in response to neurogenic stressors, such as greater behavioral signs of anxiety in BALB/cByJ mice, a

comparable manifestation of stressor reactivity was notapparent with respect to circulating corticosterone levels.*Corresponding author. Fax: 11-613-520-4052.

E-mail address: [email protected] (H. Anisman). Exposure to neurogenic stressors elicits a series of

0006-8993/01/$ – see front matter 2001 Elsevier Science B.V. All rights reserved.PI I : S0006-8993( 00 )03262-5

294 S. Hayley et al. / Brain Research 892 (2001) 293 –300

central neurochemical alterations, including increased utili- day at which testing was conducted, all procedures werezation of norepinephrine (NE), dopamine (DA), and conducted between 0800 and 1200 h. Mice were placedserotonin (5-HT) in hypothalamic and limbic sites [5,11]. individually in a clear plastic cage and then transported toMoreover, as in the case of the corticosterone changes, at the test area. The mouse cage was placed inside a largerleast some of the monoamine variations are more pro- chamber (45345345 cm) containing a rat (Long Evansnounced in the reactive BALB/cByJ strain than in C57BL/ Hood). The rat could roam freely about the chamber, walk6ByJ mice [27–29]. While not assessed to a comparable around and on top of the mouse cage, and even push itextent, psychogenic stressors, such as predator exposure or about. However, physical contact with the mouse was notcues associated with a predator, lead to behavioral and possible. Thus, the sight and odors of the rat served as theneuroendocrine variations [2,6], as well as marked DA stressor. To maintain interest in the mouse, a rat was notalterations within mesolimbic sites [32]. Interestingly, it exposed to more than four mice over the course of a study,seems that the pattern of neurochemical changes evident and the order of mouse presentations was counterbalancedacross brain regions is dependent on the nature of the for strain. Two groups of mice were exposed to the rat forstressor to which animals are exposed. For instance, air- a 10 min period and then removed from the area. One ofpuff startle provoked a marked activation of forebrain these groups was decapitated 10 min afterward, while thecircuits, whereas brainstem activation predominated in second group was decapitated 20 min later. A third groupresponse to hemorrhage [33]. Likewise, it seems that the of mice was exposed to the rat for a 20 min period,region-specific DA changes associated with neurogenic removed from the area and decapitated 10 min later.stressors [11], as well as conditioned fear cues [20], can be Control mice were likewise transported in a clear cage, butdistinguished from those evident in response to predator were not brought into the vicinity of the rat room norodors [20]. The present investigation was undertaken to placed into any chamber before sacrifice.identify central monoamine changes associated with anaturalistic stressor (rat exposure, as well as fox urine 2.1.1. Neurochemical determinationsodor). Moreover, this experiment assessed whether, in fact, Following decapitation, brains were extracted and spe-a psychogenic stressor would differentially influence cen- cific regions were micropunched from coronal slices (300tral monoamine variations in BALB/cByJ and C57BL/ mm) obtained using a dissecting block fitted with slots,6ByJ mice, as observed with respect to behavioral signs of which served as guides for single edged razor blades. Brainanxiety. sections were placed on glass slides, frozen on dry ice, and

then punches obtained following the mouse brain atlas ofFranklin and Paxinos [12] and that of Palkovits and

2. Experiment 1 Brownstein [22]. The regions assayed included theparaventricular nucleus of the hypothalamus (PVN), me-

Exposing mice to a rat reliably influences plasma dial prefrontal cortex (mPFC), dorsal hippocampus, andcorticosterone levels and may affect immune functioning locus coeruleus. Tissue was stored at 2808C for de-[3,16,17]. Experiment 1 assessed whether this stressor termination of amine and metabolite concentrations. Levelswould also affect NE, DA and 5-HT activity in brain of NE, DA, and 5-HT, and their respective metabolites,regions where stressors typically affect monoamine func- MHPG, DOPAC and 5-HIAA, were determined by high-tioning (e.g., hypothalamus, locus coeruleus, hippocampus, performance liquid chromatography (HPLC) with electro-prefrontal cortex). As the effects of predator exposure on chemical detection using a modification of the method ofcentral amine activity have been used sparingly, fun- Seegal et al. [25]. Tissue punches were sonicated in adamental data concerning the effects of this stressor are not homogenizing solution comprised of 14.17 g monochloro-available. Accordingly, in the initial experiment mice acetic acid, 0.0186 g disodium ethylenediamine tetraace-received either 0, 10 or 20 min of exposure to the rat. tate (EDTA), 5.0 ml methanol and 500 ml H O. Following2

Moreover, among mice that received the 10 min rat centrifugation, the supernatants were used for the HPLCexposure, decapitation was undertaken either 10 or 20 min analysis. Using a Waters M-6000 pump, guard column,after the treatment. radial compression column (5 m, C reverse phase, 818

mm310 cm), and a three cell coulometric electrochemical2.1. Methods detector (ESA Model 5100A), a 20 ml aliquot of the

supernatant was injected into the column at a flow rate ofMale BALB/cByJ and C57BL/6ByJ mice (n 5 32/ 1.5 ml /min (1400–1600 PSI). The mobile phase used for

strain) that were bred in our facility from parent stock the separation was a modification of that used by Chiueh etobtained from the Jackson Laboratory, Bar Harbor, Maine, al. [9]; each liter consisted of 1.3 g of heptane sulfonicserved as experimental subjects. Mice were housed in acid, 0.1 g disodium EDTA, 6.5 ml triethylamine, 35 mlgroups of four in standard polypropylene cages, permitted acetonitrile. The mobile phase was then filtered (0.22 mmfree access to food and water, and tested at 80–90 days of filter paper) and degassed, following which the pH wasage. To avoid potential effects associated with the time of adjusted to 2.5 with phosphoric acid. The area and height

S. Hayley et al. / Brain Research 892 (2001) 293 –300 295

of the peaks were determined using a Hewlett-Packard the levels of MHPG (irrespective of stressor condition)integrator. The protein content of each sample was de- were somewhat higher in the C57BL/6ByJ strain,termined using bicinchoninic acid with a protein analysis F(1,51) 5 3.61, P 5 0.063.kit (Pierce Scientific, Brockville, Ontario, Canada) and a Within the hippocampus the concentrations of NE andspectrophotometer (Brinkman, PC800 colorimeter). 5-HT were comparable in the strains and across the

stressor conditions, while the accumulation of both MHPG2.1.2. Statistical analyses and 5-HIAA increased significantly as a function of the

The data were subjected to a two-way analysis of stressor treatment, F’s(3,51) 5 7.82 and 6.57, P’s , 0.01.variance (Strain3Stressor treatment). Between-group As seen in Table 1, the stressed groups all exhibitedcomparisons maintaining family-wise error at 0.05 were metabolite concentrations that significantly exceeded thoseachieved using Bonferroni corrections. During the course of nonstressed mice. Once again, the MHPG and 5-HIAAof the experiment several tissue samples were lost, and as a concentrations did not differ as a function of the Strainresult the degrees of freedom varied across brain regions variable or as a function of the Strain3Stressor inter-and neurotransmitter being assessed. action.

The concentration of NE within the PFC was unaffected2.2. Results by the stressor, whereas the accumulation of MHPG varied

as a function of the stressor treatment, F(3,56) 5 5.70,Within the PVN the concentrations of NE and MHPG, P , 0.01. The multiple comparisons indicated that the

as well as 5-HT and 5-HIAA, were not affected by the stressor significantly increased the metabolite accumula-stressor treatment. In contrast, accumulation of MHPG tion, such that 20 min of exposure to the rat provoked anwithin the locus coeruleus was influenced by the stressor increase of the metabolite concentrations. In contrast, 10treatment, F(3,51) 5 8.23, P , 0.01 (see Table 1). Multiple min of such treatment did not provoke significant eleva-comparisons revealed elevated MHPG accumulation tions of MHPG (see Table 1). The concentrations of theamong mice that had been stressed for either 10 or 20 min 5-HT were unaltered, while the metabolite, 5-HIAA, wasand then decapitated 10 min later. When mice were affected by the stressor, F(3,49) 5 6.66, P , 0.01. Spe-sacrificed 20 min after stressor termination, MHPG con- cifically, 5-HIAA concentrations were elevated 20 mincentration were comparable to those of nonstressed mice. after a 10 min exposure session, but not 10 min afterThis precise profile was apparent in both strains, although stressor application.. Although DA activity within the

Table 1Accumulation of MHPG, 5-HIAA and DOPAC in response to predator (rat) exposure

Duration of rat exposure and time following treatment (min)

No stress 10110 10120 20110

MHPGLocus coeruleusC57BL/6ByJ 2.3360.21 4.3660.51* 2.1560.25 3.6460.72*BALB/cByJ 1.9960.25 3.0160.66* 2.2760.40 2.7160.35*

HippocampusC57BL/6ByJ 2.7060.19 5.5861.20* 5.3060.47* 6.1360.67*BALB/cByJ 2.6160.43 4.9360.78* 6.2760.84* 5.1660.99*

Prefrontal cortexC57BL/6ByJ 2.5960.19 3.8260.38 5.0860.81 5.5760.70*BALB/cByJ 3.2160.39 4.0960.61 3.7660.60 5.7760.70*

5-HIAAHippocampusC57BL/6ByJ 4.5960.41 8.4261.03* 7.0960.61* 5.6160.40*BALB/cByJ 4.3060.80 6.2960.70* 5.9760.70* 6.1360.45*

Prefrontal cortexC57BL/6ByJ 4.1361.38 3.2560.51 7.3861.12* 2.8060.48BALB/cByJ 3.8260.39 5.4561.31 5.9760.62* 3.5860.42

DOPACPrefrontal cortexC57BL/6ByJ 1.7260.35 1.8960.26 2.7060.60 1.9160.19BALB/cByJ 2.0160.24 2.7560.65 2.3560.27 1.6860.21

*P , 0.05 relative to nonstressed mice.


mPFC has been shown to be sensitive to stressors, the tion mice were decapitated, brains frozen in isopentane,effects of rat exposure did not significantly affect the and stored for subsequent monoamine determinations asconcentration of the DA metabolite, DOPAC, although a described in Experiment 1.modest rise was apparent (P , 0.10).

3.1.2. Statistical analysesThe monoamine and metabolite levels were analyzed as

3. Experiment 2 a 2 (strain)33 (Stressor treatment) analysis of variance.Between group means, and the simple effects of significant

Although rat exposure influenced monoamine utilization interactions, were compared using Newman–Keuls multi-much in the same way as other stressors provoke such ple comparisons (a 5 0.05). Amines and metabolites with-effects, NE activity was not affected within the PVN. in the left and right amygdala were likewise analyzed as aMoreover, as previously observed in the case of plasma 233 factorial, but the two amygdala punches were treatedcorticosterone [3,16], it was clear that this particular as a within group variable.stressor did not differentially influence monoamine activityin these strains. Yet, neurogenic stressors have been found 3.2. Resultsto have a greater effect on monoamine activity in BALB/cByJ mice than in similarly treated C57BL/6ByJ mice. As in the case of rat exposure, the analysis of varianceWhile it is certainly possible that the differences between indicated that within the PVN the fox odor provoked onlythe strains may occur exclusively in response to neuro- a small rise of MHPG concentrations, which did not reachgenic stressors, it is also possible that rat exposure was statistical significance, F(2,61) 5 2.40, P 5 0.09. However,simply not sufficiently potent to provoke potential strain the accumulation of 5-HIAA was markedly affected by thedifferences. Accordingly, a second experiment assessed stressor, F(2,61) 5 7.41, P , 0.01. The multiple compari-monoamine activity in response to yet another naturalistic sons indicated that while placing the animals in the novelstressor, namely the odor of fox urine. In this experiment, open field provoked a modest, nonsignificant, increase ofmonoamine determinations were made in mice that had 5-HIAA, exposure to the fox odor appreciably increasedbeen placed in a novel environment (a modest stressor the metabolite concentration (see Fig. 1). The magnitude ofitself), or were placed in a novel environment after which the increase was, however, comparable in the two strainsthe fox urine odor was introduced. As the central amygdala of mice.may be associated with fear and anxiety, metabolite The accumulation of MHPG within the prefrontal cortexconcentrations were assessed within this region, as well as was influenced by the stressor treatment, F(2,61) 5 3.50,the PVN and PFC. In view of the possibility that stressors P , 0.05. The multiple comparisons indicated that expo-may differentially influence neuronal functioning in the left sure to the novel environment did not affect MHPGand right amygdala [1], the amine concentrations were accumulation, whereas the fox odor resulted in a signifi-assessed independently in the two hemispheres. cant elevation of the metabolite (see Fig. 2). The con-

centrations of the NE were also modestly, but significantly3.1. Methods

3.1.1. Predator odorA total of 34 male C57BL/6ByJ and 33 BALB/cByJ

mice served as experimental subjects. The subject spe-cifications and housing conditions were the same as thoseof Experiment 1. Mice were individually placed in a clearplastic holding cage and transported to the test area, wherethey were transferred to a small open field (60360330cm) covered with a Plexiglas lid. Over the course of theensuing 10 min period, mice of one group had the odor offox urine sprayed into the cage on 10 occasions at 1 minintervals. This was accomplished by placing one drop offox urine (Foxpert Inc., St. Benjamin, Que., Canada) on asmall piece of cotton, which was placed within a 50 mlsyringe. Depressing the plunger thus sprayed 50 ml ofurine-infested air into the test chamber. Mice of a secondgroup were treated identically, except that the odor was notpresented, while mice of a third group were neither placed Fig. 1. Mean (6S.E.M.) 5-HIAA concentrations within the PVN ofin the novel environment, nor exposed to the fox odor. C57BL/6ByJ and BALB/cByJ mice following placement in a novelFive minutes after being removed from the stressor situa- environment, fox odor, or no treatment.


elevated by the fox odor, F(2,61) 5 3.42, P , 0.05. Theconcentration of 5-HT within the prefrontal cortex wasunaltered by the stressor treatment, while 5-HIAA accumu-lation was affected, F(2,58) 5 9.87, P , 0.01. Althoughrelatively variable, exposure to fox odor induced a substan-tial increase of 5-HIAA accumulation. Finally, the ac-cumulation of DOPAC within the prefrontal cortex variedas a function of the Stressor treatment, F(2,58) 5 3.44,P , 0.05, indicating that Fox odor significantly elevatedthe metabolite levels. The Stressor treatment3Strain inter-action did not reach significance; however, as a prioripredictions had been made concerning this interaction,multiple comparisons were conducted of the simple ef-fects. These comparisons indicated that among C57BL/6ByJ mice the fox odor significantly increased the levels ofDOPAC relative to that seen in nonstressed mice. A smallincrease was also evident in BALB/cByJ mice, but thiseffect did not approach significance.

The analysis of MHPG concentrations within the leftand right amygdala indicated only a main effect of theStressor treatment, F(2,59) 5 6.20, P 5 0.01. The multiplecomparisons confirmed that exposure to the novel environ-ment was without effect, whereas fox odor provoked asignificant elevation of the NE metabolite (see Fig. 3). Theanalysis of variance likewise revealed that the stressortreatment influenced 5-HIAA concentrations within theamygdala, F(2,54) 5 6.05, P , 0.01, which was attribut-able to increased metabolite concentrations in response tothe fox odor. As seen in Fig. 3, in both instances theeffects were comparable in the two hemispheres. However,while not statistically significant, the effect appeared to besomewhat more pronounced in the C57BL/6ByJ strainthan in the BALB/cByJ mice. In fact, when separateanalyses were conducted of the left and right amygdala itwas found that fox odor significantly affected 5-HIAAaccumulation among C57BL/6ByJ mice, while not sig-nificantly affecting metabolite concentrations in BALB/cByJ mice. Likewise, MHPG accumulation was increasedin both hemispheres among C57BL/6ByJ mice, whereas inBALB/cByJ mice the increase of MHPG was only in-creased by fox odor in the left amygdala.

4. Discussion

Commensurate with reports showing that predator expo-sure influences neuroendocrine and central neurotransmit-ter functioning [16,32], exposing mice to a rat or to foxodors markedly influenced central neurotransmitter activi-ty. In this respect, increased amine utilization was apparentin regions where neurogenic stressors (e.g., footshock,forced swim) typically provoke such effects. For instance,

Fig. 2. Mean (6S.E.M.) concentrations of MHPG (upper), 5-HIAA exposing mice to fox odor increased NE utilization within(middle) and DOPAC (lower) within the medial prefrontal cortex of

the locus coeruleus, prefrontal cortex, hippocampus andC57BL/6ByJ and BALB/cByJ mice following placement in a novelamygdala, as well as 5-HT utilization within the prefrontalenvironment, fox odor, or no treatment. *P , 0.05 relative to nontreated

mice of the same strain. cortex, hippocampus and amygdala. In addition, these


Fig. 3. Mean (6S.E.M.) 5-HIAA (upper panels) and MHPG (lower panels) concentrations within the left and right central amygdala (L. CeA and R. CeA)of C57BL/6ByJ and BALB/cByJ mice following placement in a novel environment, fox odor, or no treatment. *P , 0.05 relative to nontreated mice ofthe same strain.

stressors were previously shown to elicit pronounced evaluate stressor effects in vivo over time followingvariations of plasma corticosterone concentrations [3,16]. stressor exposure, using microdialysis or amperometeric

Despite the fact that DA activity within the prefrontal detection.cortex and NE activity in the PVN are ordinarily in- It has been reported that the left and right PFC [32] asfluenced by neurogenic stressors [5,11], in the present well as the left and right aspects of the lateral amygdala [1]investigation the effects of the psychogenic stressor on NE may play different roles in subserving stressor reactivity.and DA utilization in these areas were slight. However, it In this respect, it was suggested that the right amygdala iswas the case that in the PFC an increase of DA activity essential for the enhancement of an acoustic startle re-was apparent in the C57BL/6ByJ mice. As well, the sponse elicited by predator exposure [1]. In the presentutilization of NE and 5-HT was apparent in both strains. It investigation, where the amines were assessed in thewas expected that the increase of DOPAC would be greater central amygdala, the elevations of NE and 5-HT activityin the behaviorally more reactive BALB/cByJ mice, elicited by fox odor were comparable in the left and rightparticularly as DA variations within the PFC have been hemispheres. Of course, amines were determined at only athought to reflect anxiety [15,35]. Of course, it is possible single time, and it is possible that the effects observedthat the monoamine variations within the PFC and PVN following stressor exposure varied over time in the twoare simply less amenable to modification by psychogenic hemispheres.stressors, such as predator exposure. Yet, in studies in The C57BL/6ByJ and BALB/cByJ strains of micewhich rats were exposed to a ferret we observed that the display pronounced behavioral differences in anxiety elicit-utilization of NE and DA were increased within the PVN ing situations, including the response to predators [3]. Asand PFC, respectively [18]. To be sure, numerous indicated earlier, while BALB/cByJ mice also displayprocedural differences existed between the studies, includ- greater plasma corticosterone responses to neurogenicing the species used, the duration of stressor exposure and stressors [3,4,25], a similar effect was not apparent inthe time at which animals were sacrificed following response to predators. In fact, the corticosterone changesstressor termination. Ultimately, it may be essential to elicited by predator exposure were actually more pro-


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