Physiology & Behavior 146 (2015) 105–110

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Restraint stress and social defeat: What they have in common Simone Cristina Motta, Newton Sabino Canteras ⁎ Departamento de Anatomia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Brazil

a r t i c l e

i n f o

Article history: Received 6 February 2015 Received in revised form 11 March 2015 Accepted 12 March 2015 Keywords: Entrapment Social defeat Restraint Hypothalamus Hippocampus

a b s t r a c t Bob Blanchard was a great inspiration for our studies on the neural basis of social defense. In the present study, we compared the hypothalamic pattern of activation between social defeat and restraint stress. As important stress situations, both defeated and immobilized animals displayed a substantial increase in Fos in the parvicellular part of the paraventricular nucleus, mostly in the region that contains the CRH neurons. In addition, socially defeated animals, but not restrained animals, recruited elements of the medial hypothalamic conspecificresponsive circuit, a region also engaged in other forms of social behavior. Of particular interest, both defeated and immobilized animals presented a robust increase in Fos expression in specific regions of the lateral hypothalamic area (i.e., juxtaparaventricular and juxtadorsomedial regions) likely to convey septo-hippocampal information encoding the environmental boundary restriction observed in both forms of stress, and in the dorsomedial part of the dorsal premammillary nucleus which seems to work as a key player for the expression of, at least, part of the behavioral responses during both restraint and social defeat. These results indicate interesting commonalities between social defeat and restraint stress, suggesting, for the first time, a septo-hippocampal–hypothalamic path likely to respond to the environmental boundary restriction that may act as common stressor component for both types of stress. Moreover, the comparison of the neural circuits mediating physical restraint and social defense revealed a possible path for encoding the entrapment component during social confrontation. © 2015 Elsevier Inc. All rights reserved.

1. Introduction Newton Canteras first met the Blanchard couple in 1999 at a Society for Neuroscience Meeting, when he felt very honored to have the opportunity to discuss with Bob and Caroline his ideas on the hypothalamic circuits mediating anti-predatory fear responses. Newton and the Blanchard couple continued their interaction over subsequent years, and established a very fruitful collaboration. In 2001, Bob and Caroline invited Newton to visit their lab at the University of Hawaii, and during this visit, Bob introduced Newton to his data on social agonistic behavior. One afternoon during this visit, Bob spent quite a lot of time demonstrating what happens during social confrontation, and Newton was fascinated. Bob was inspiring enough to convince Newton to run a circuit analysis study for intruders exposed to social defeat, following the same line of the studies that Newton had previously performed in animals exposed to natural predators. After returning to Brazil, Newton started establishing the resident–intruder paradigm in his laboratory, and at that time, Simone Motta had just started her PhD in Newton's lab characterizing the neural circuits mediating social defense. We were able to show that social and anti-predatory defense are mediated by distinct hypothalamic circuits, and found that socially defeated animals recruited, in the medial zone of the hypothalamus, a circuit ⁎ Corresponding author at: Av Prof. Lineu Prestes 2415, Cidade Universitária, 05508000, São Paulo, SP, Brazil. E-mail address: [email protected] (N.S. Canteras).

http://dx.doi.org/10.1016/j.physbeh.2015.03.017 0031-9384/© 2015 Elsevier Inc. All rights reserved.

also engaged in other forms of social behaviors, the so-called social responsive circuit, composed by the medial preoptic nucleus, the ventrolateral part of the ventromedial nucleus and the ventral premammillary nucleus, in addition to recruiting a particular region of the dorsal premammillary nucleus (i.e., its dorsomedial part). We have further shown that dorsal premammillary nucleus (PMD) lesions block the passive components of social defense (i.e., freezing and sustained on the back position) seen during confrontation with the dominant aggressor [23]. Considering that social defeat represents an important stress, we have started exploring other forms of stress, and began to examine the pattern of hypothalamic activation in response to an acute restraint stress. The comparison between the pattern of hypothalamic activation found in physical restraint stress and social defense revealed interesting potential commonalities, which will be explored in the present publication. Briefly, we were particularly surprised to see that the dorsomedial part of the PMD showed a substantial Fos expression in both forms of stress, and that parts of the pathway relaying septo-hippocampal information to the PMD were also mobilized in both social defeat and restraint. Taking into account that the hippocampus provides a spatial map of the environment and that, in both situations, the animals are restricted to a certain location within the environment (either by the restraining apparatus or by a dominant conspecific), we hypothesized that this environmental boundary restriction would serve as a stressor component for both situations and, perhaps, processed by this common septo-hippocampal–PMD pathway, found to be recruited in both

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restraint and social stress. Curiously, during our last meeting with Bob, when he visited Brazil for the last time in 2012, we had the chance to discuss these ideas on the commonalities between social entrapment and physical constraint, and he said that the idea was very nice but hard to prove. We hope that the findings reported here start addressing these issues. 2. Materials and methods 2.1. Animals A total of 20 adult Wistar male rats (three months of age) were used in accordance to the Ethical Guides of the Instituto de Ciências Biomédicas — Universidade de São Paulo. Animals were kept on a 12/ 12 h light cycle (lights on at 2 am and off at 2 pm) and had free access to food (Nuvilab®) and fresh water. Animals were isolated 24 h before the test in a cage measuring 30 × 20 × 19 cm and light, food and water were maintained under the same conditions as before. Animals were returned to this cage after the behavioral test. All tests were conducted during the first hour of the dark period under red light illumination. 2.2. Behavioral tests 2.2.1. Restraint After 24 h isolation, animals were restrained for 30 min in an acrylic tube measuring 20 cm in length with an internal diameter of 5.3 cm (volume = 450 ml, Beiramar Ind. e Com. Ltda., Brazil) as previously described [9]. After this period, animals were returned to the same cage in which they had been previously been housed. 2.2.2. Resident–intruder paradigm On the day of the test, subjects were placed singly in the home cage of a dominant, Long Evans rat. During the encounter, an initial investigation period was followed by the resident attacks. The dyad was separated 5 min after the first attack. Defensive behaviors were clearly observed in the intruders, i.e. upright and on-the-back postures, boxing, flight and freezing, for most of the time after being attacked [2,23]. Animals that did not display such submission were excluded from the analysis. As the restrained animals, after the social defeat, animals returned to their home cage. For a control group, rats were handled identically to the other two groups and left undisturbed in a cage. 2.3. Fos immunostaining Ninety minutes after the behavioral test, animals were deeply anesthetized with sodium pentobarbital (40 mg/kg, i.p.) and perfused transcardially with a solution of 4% (w/v) paraformaldehyde in 0.1 M phosphate buffer at pH 7.4; the brains were removed and left overnight in a solution of 20% sucrose in 0.1 M phosphate buffer at 4 °C. The brains were then frozen and 5 series of 40-μm-thick sections were cut with a sliding microtome in the frontal plane. One series was processed for immunohistochemistry with anti-Fos antiserum raised in rabbit (Ab-5; Calbiochem) at a dilution of 1:20,000. The primary antiserum was localized using a variation of the avidin–biotin complex system. In brief, sections were incubated for 90 min at room temperature in a solution of biotinylated goat anti-rabbit IgG (Vector Laboratories) and then placed in the mixed avidin–biotin horseradish peroxidase (HRP) complex solution (ABC Elite Kit; Vector Laboratories) for the same period. The peroxidase complex was visualized by a 5-min exposure to a chromogen solution containing 0.02% 3,3′ diaminobenzidine tetrahydrochloride (DAB; Sigma) with 0.3% nickelammonium sulfate in 0.05 M Tris buffer (pH 7.6), followed by incubation for 20 min, in chromogen solution with hydrogen peroxide (1:3000) to produce a blue–black product. The reaction was stopped by extensive washing in potassium PBS (KPBS; pH 7.4). Sections were

mounted on gelatin-coated slides and then dehydrated and coverslipped with DPX (Sigma). An adjacent series was always stained with thionin to serve as a reference series for cytoarchitectonic purposes. 2.4. Quantification of Fos-labeled cells Density of Fos-immunoreactive neurons were evaluated by an observer without knowledge of the animal's experimental treatment and were generated for selected brain regions using the 10× objective of a Nikon Eclipse 80i (Nikon Corporation, Chiyoda-Ku, Tokyo-To, Japan) microscope equipped with a Nikon digital camera DXM1200F (Nikon Corporation). For the quantification of the density of Fos labeling, we first delineated, in a given section, the borders of a region of interest, as defined in adjoining Nissl-stained sections, and Foslabeled cells were counted therein. Only darkly labeled oval nuclei that fell within the borders of a region of interest were counted. The density of Fos labeling was determined by dividing the number of Fosimmunoreactive cells by the area of the region of interest. Both cell counting and area measurements were performed with the aid of a computer program (Image-Pro Plus, version 4.5.1; Media Cybernetics, Silver Spring, MD, USA). Cell densities were obtained on both sides of the brain and averaged for each individual. The brain regions examined in the present investigation were selected before the analysis following the criterions discussed below, and the employed parcellation followed The brain maps: structure of the rat brain [32]. The selection of the hypothalamic sites to be analyzed followed specific criterions. First, considering that both social defeat and physical restraint represent strong stressors, in the periventricular zone of the hypothalamus, we have focused our analysis on the paraventricular nucleus, both the parvicellular and magnocellular parts [9,27,28,34], and in the dorsomedial nucleus, which is a key component of a visceromotor pattern generator network, thought to control the neuroendocrine motor neurons [33]. In the medial zone, we analyzed the elements of the conspecific-responsive circuit, namely, the medial preoptic nucleus, the ventrolateral part of the ventromedial nucleus and the ventral premammillary nucleus, likely to respond to social cues [23], and the dorsal premammillary nucleus, a key site that integrates crucial threats that challenge the individual (i.e. social aggressor and predator, [8,23]). In the lateral zone, we focused on two specific regions, the juxtaparaventricular and juxtadorsomedial regions, which represent critical nodes to convey septo-hippocampal information to the dorsal premammillary nucleus [16]. 2.5. Statistical analysis A multivariate analysis of variance (MANOVA) was applied to the experimental data, followed by univariate analyses and Tukey HSD post hoc tests for pairwise comparisons. The significance level employed in the univariate ANOVAs was adjusted downward by a Bonferroni's correction (alpha = 0.005). In spite of possible departures of normality and homogeneity of variance assumptions by the present data set, our choice of a parametric analysis relies on the fact that ANOVA is relatively robust to such departures [36], thus preserving the statistical power of the analysis. 3. Results During the social confrontation, we observed that all the resident rats, after a short latency (less than 30 s), started vigorously attacking the intruders. After the first attack, intruders were left for 5 min with the resident male, and remained passively frozen most of the time, usually presenting the typical ‘on-the-back’ position. During the attack, intruders also presented active forms of defense by trying to push the resident away, assuming an upright position with sparse boxing, and occasionally fleeing from the resident. During the acute restraint stress

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test (RST), animals presented clear signs of stress and intense vocalization. Following a significant multivariate analysis of variance (MANOVA, Wilks lambda b 0.001, F(20,10) = 69.64, P b 0.001), we proceeded to univariate ANOVAs for each dependent variable. As shown in Table 1, univariate ANOVAs yielded significant group effects for all hypothalamic sites analyzed (F(2,14) N 10.15; p b 0.0019), even after employing Bonferroni's correction to adjust the significance level. In the periventricular zone, post hoc pairwise comparisons (Tukey HSD) revealed that, compared to the control group, both defeated and immobilized animals up-regulated Fos expression in the dorsomedial nucleus (DMH, p b 0.002) and in the parvicellular part of the paraventricular nucleus (PVH, p b 0.02), whereas in the magnocellular part of the paraventricular nucleus, only the immobilized animals differed from the controls (p = 0.0015). Notably, in the parvicellular part of the paraventricular nucleus, Fos-labeled cell counting was significantly greater in the immobilized than in the defeated animals (p = 0.003), and in both groups, Fos labeled cells were mostly distributed to the dorsal zone of the medial parvicellular part, in the region that contains the CRH cell group (Fig. 1B,C). In the medial zone, post hoc pairwise comparisons (Tukey HSD) revealed that, compared to the control group, Fos expression in the elements of the conspecific responsive medial hypothalamic circuit (namely the medial preoptic nucleus, the ventrolateral part of the ventromedial nucleus and the ventral premammillary nucleus, Fig. 1G–I) was significantly increased in the defeated animals (p b 0.0003), but not in the immobilized animals (p N 0.4359). In addition, post hoc pairwise comparisons (Tukey HSD) also revealed that the dorsal premammillary nucleus presented a significant increase in Fos expression in both defeated and immobilized animals when compared to the control group (p b 0.0027). In the PMd, Fos-labeled cell counting was significantly greater in the defeated than in the immobilized animals (p = 0.0025), and curiously, in both groups, Fos-labeled cells tended to be distributed in the dorsomedial part of the PMD (Fig. 1H,I). Finally, in the lateral hypothalamic zone, post hoc pairwise comparisons (Tukey HSD) revealed that both defeated and immobilized animals had increased Fos expression in the juxtaparaventricular and juxtadorsomedial regions when compared to the control group (Fig. 1D–F, p b 0.0035). 4. Discussion The present results provide an interesting comparison of the hypothalamic pattern of activation between two forms of stressors (i.e. social defeat and restraint), showing interesting commonalities particularly helpful to clarify some of the complexities of the neural system responding to agonistic social confrontations. As important stress situations, both defeated and immobilized animals presented a substantial

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increase in Fos expression in the parvicellular part of the paraventricular nucleus, mostly in the region that contains CRH neurons. In addition, as summarized in Fig. 2, both defeated and immobilized animals presented a clear increase in Fos expression in the juxtaparaventricular and juxtadorsomedial regions of the LHA, which are likely to convey septo-hippocampal information related to spatial restraint, and in the dorsomedial part of the PMD, which, as we shall discuss below, seems to work as a key player for the expression of, at least, part of the behavioral responses during both restraint and social defeat stress. Moreover, socially defeated animals, but not physically restrained animals, recruited elements of the medial hypothalamic conspecific-responsive circuit. In the periventricular zone of the hypothalamus, our results were in accordance with the literature. As expected, for restrained animals, in the PVH, a strong activation was observed mostly in the region that contains CRH neurons in the dorsal parvicellular region [9,27,28,34], in addition to a small activation of the magnocellular part [9,34]. The involvement of the PVH in the organization of stress-related neuroendocrine and autonomic responses has been widely studied (see [25, 26] for review). Thus, for acute restraint stress, CRH mRNA is increased in the PVH [19], together with increased plasma ACTH levels [15,34], which are markedly reduced after knife lesions of the PVH [37]. Along the same lines, the presently observed Fos induction in the DMH after restraint is consistent with previous reports [9,21]. The DMH has been suggested to have a modulatory effect, both excitatory and inhibitory, over PVH actions on the HPA axis [17,18,21,30]. Conversely, in intruders, corticosterone and ACTH levels have been reported to be greatly increased after social defeat [1,5,10], consistent with increased PVH activation [22,23]. Similarly, DMH activation during social defense has also been reported [23], and its role on heart rate alterations after social stress described [29]. In the medial zone of the hypothalamus, conspecific intruders, but not restrained animals, up-regulated Fos expression in the elements of the conspecific-responsive circuit, comprising the medial preoptic nucleus, the ventrolateral part of the ventromedial nucleus and the ventral preammillary nucleus. This finding is in general agreement with previous studies in rats [23] and hamsters [20], where Fos activation has also been reported in the anterodorsal and posteroventral parts of the medial amygdalar nucleus [20,23]. The medial amygdalar nucleus plays an important role in social recognition, as well as in learning and memory for socially relevant cues [3,35], and its parts, here discussed as mobilized during social confrontation, provide substantial inputs to the elements of the medial hypothalamic social-responsive circuit [7]. Notably, elements of the social-responsive circuit have a key role in a number of reproductive and social behaviors, including maternal behavior, mating and social aggression; and for all these behavioral responses, the functional role of each component of the socialresponsive circuit has been largely explored (see [6]). In sharp contrast,

Table 1 Density of Fos-labeled cells in brain regions of control, socially defeated and immobilized group. Level

MPN PVHparv PVHmag VMHvl LHAjp LHAjd DMH DMH PMv PMd

21 26 26 28 26 30 30 31 32 33

Experimental groups Control (n = 5)

Defeated (n = 5)

Immobilized (n = 7)

5.67 ± 1.02 31.40 ± 8.65 30.61 ± 17.38 12.88 ± 9.26 24.38 ± 7.98 6.36 ± 2.31 35.35 ± 12.29 14.57 ± 4.25 5.30 ± 2.31 12.17 ± 6.97

263.80 ± 51.90⁎ 947.20 ± 133.87⁎ 367.21 ± 61.52 511.31 ± 105.02⁎ 483.16 ± 42.59⁎ 621.87 ± 90.61⁎ 418.25 ± 62.73⁎ 711.99 ± 101.22⁎ 1693.75 ± 145.96⁎ 882.68 ± 122.52⁎

54.12 ± 12.75# 2009.22 ± 280.40⁎,# 749.85 ± 152.40⁎,# 96.54 ± 16.63# 397.92 ± 59.03⁎ 510.53 ± 38.44⁎ 486.50 ± 68.32⁎ 740.29 ± 74.14⁎ 145.03 ± 40.95# 445.92 ± 57.90⁎,#

Statistic F(2,14); p

22.28; b0.0001 10.92; =0.0014 10.15; =0.0019 21.96; b0.0001 23.29; b0.0001 34.20; b0.0001 16.23; =0.0002 28.91; b0.0001 129.26; b0.0001 30.00; b0.0001

Values represent the number of Fos-labeled cells per mm2. Data are expressed as mean ± SEM. The table column entitled ‘Level’ refers to plate numbers in brain maps [32], to indicate the approximate rostrocaudal levels at which the measurements were taken. ⁎ Differs significantly from control group, p b 0.05 (Tukey HSD). # Differs significantly from socially defeated group, p b 0.05 (Tukey HSD). (p value of ANOVA adjusted by correction of Bonferroni, p b 0.005).

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Fig. 1. Photomicrographs of transverse Fos-stained sections at the levels of paraventricular (A–C), dorsomedial (D–F) and premammillary nuclei (G–I) of representative cases of the control (A, D and G), socially defeated (B, E and H) and immobilized groups (C, F and I). Abbreviations: DMH, dorsomedial hypothalamic nucleus; fx, fornix; LHAjd and -jp, lateral hypothalamic area, juxtadorsomedial and juxtaparaventricular regions; PMDdm and -vl, dorsal premammillary nucleus, dorsomedial and ventrolateral parts; PMV, ventral premammillary nucleus; PVHdp, -mpd, -mpv, -pml and -pv, paraventricular hypothalamic nucleus, dorsal parvicellular part; medial parvicellular part, dorsal zone; medial parvicellular part, ventral zone; posterior magnocellular part, lateral zone and periventricular part. Scale bars, 100 μm.

the functional role of the elements of the medial conspecific-responsive circuit in intruders during social agonistic encounters remains to be clarified. In agreement with previous findings in the literature, another component of the medial zone of the hypothalamus that presents a significant increase in Fos expression in both socially defeated and physically restrained animals is the dorsal premammillary nucleus [9, 23]. As previously reported by our group, PMD Fos-labeled cells in the conspecific intruder tended to be mostly distributed in the dorsomedial part of the nucleus [23]. Interestingly, here we have found the same pattern of distribution of Fos-labeled cells in the PMD of the restrained animals. The dorsomedial part of the PMD receives strong projections from both the juxtaparaventricular and juxtadorsomedial regions of the lateral hypothalamic area [16], which, as we shall discuss below, are likely to convey information from the septo-hippocampal system. In addition, the PMDdm is greatly influenced by the medial hypothalamic conspecific-responsive circuit (likely to be mediated via projections from the subfornical region of the lateral hypothalamus, [13]), giving further support to the present data that this nucleus presented a significantly higher activation in the socially defeated than in the restrained animals. As previously reported, PMD lesions disrupt fear responses during social agonistic encounters, such that PMD-lesioned

intruders lose passive defensive postures such as freezing, and the stereotypical, sustained on-the-back position, and do not try to escape from the resident [23]. Moreover, preliminary data from our lab indicates that PMD lesions in physically restrained animals drastically reduces the stressful behavioral responses observed during restraint procedures, such as the vigorous attempts to escape from the restraining apparatus and vocalization, rendering the animals very quiet throughout the restraining procedure. Therefore, the PMD seemingly works as a key player for the expression of, at least, some of the behavioral responses during both restraint and social defeat stresses. Interestingly, during social confrontation, resident aggressors up-regulate Fos expression in regions of the conspecific-responsive circuit, but show only a marginal PMD Fos increase distributed throughout the nucleus [23]. This finding gives further support to the idea that the PMD activation seen in intruders and restrained animals should be compatible with the distress situation related to the social defeat and physical restraint. Both socially defeated and physically restrained animals displayed a significant increase in Fos expression in the juxtaparaventricular and juxtadorsomedial regions of the lateral hypothalamic area (LHA). As discussed above, these LHA regions convey information to the dorsomedial part of the PMD from the septo-hippocampal system [16]. The septo-hippocampal system has been proposed to play a pivotal

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Fig. 2. Schematic diagrams comparing putative circuits related to the medial and lateral hypothalamic areas involved in processing social defeat and physical restraint stress. Abbreviations: LHAjd and -jp, lateral hypothalamic area, juxtadorsomedial and juxtaparaventricular regions; MEAad, and -pd, medial amygdalar nucleus, anterodorsal and posterodorsal parts; MPO, medial preoptic area; PMDdm and -vl, dorsal premammillary nucleus, dorsomedial and ventrolateral parts; PMV, ventral premammillary nucleus; VMHvl, ventromedial nucleus, ventrolateral part.

role in anxiety in response to conflict situations, by interrupting ongoing behavior and increasing the level of arousal and attention to enhance gathering information [14]. In fact, the hippocampus may work as a context analyzer providing a spatial mapping of the environment derived from two sets of information: one based on the external environment and the other based on self-motion [4,24]. Of particular relevance to the present study, the hippocampus contains a special kind of cell, the boundary vector cell (BVC), which codes for environmental boundaries (irrespective of their sensory nature, [31]). Interestingly, the distribution of the BVCs and the cells that project to the juxtaparaventricular and juxtadorsomedial regions of the LHA seem to overlap, at least partially, in the dorsal and intermediate parts of the subiculum [16, 31]. A BVC fires whenever an environmental boundary intersects a receptive field located at a specific distance from the animal in a specific allocentric direction, depending solely on the animal's location relative to the environmental boundaries and is independent of the animal's heading direction [31]. The concept of an environmental boundary is somewhat abstract, and represents a behaviorally significant obstacle to locomotion that does not necessarily need to actually prevent movement to be effective as a boundary stimulus (see [31]). In the present case, both restraint and social confrontation set clear environmental boundaries, constraining the animals either physically (by the restraining apparatus) or behaviorally (as imposed by the dominant male). As it stands, both the physical constraint and the animal's entrapment during a social confrontation are likely to represent a common source of stress in both situations and may be signaled by the hippocampus. Although the entrapment component of social defense in animals has not yet been explored, in humans, entrapment is largely acknowledged and separately assessed from the defeat itself, and both components have clear influence in social psychopathologies [11,12]. Overall, our results on the neural systems involved in processing physical restraint and social defeat stress confirm previous findings of the literature (particularly the involvement of the paraventricular and dorsomedial nuclei in the periventricular zone of the hypothalamus in both forms of stress, and the activation of the social-responsive medial hypothalamic circuit for the social confrontation), and point out, for the first time, to a septo-hippocampal–hypothalamic pathway likely to respond to the environmental boundary restriction, which may act as a common stressor component for both forms of stress. Interestingly, the comparison of the neural circuits mediating restraint and social defense revealed a possible pathway for encoding the entrapment

component during social confrontation. Further studies are obviously needed to establish whether the dorsal and intermediate subiculum would be able to respond to the shortage of environmental boundaries and transmit this information, via the lateral hypothalamus, to the dorsomedial part of the PMD as an important component of the stress response to both social confrontation and physical restraint. Acknowledgements We are grateful to Dr. Paula J. Brunton for reviewing the manuscript. This research was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Research Grant #2014/05432-9, and Conselho Nacional de Desenvolvimento Científico e Tecnológico (Grant #306207/2014-13 awarded to N.S.C.). SCM was supported by FAPESP fellowship (#2010/05905-3). References [1] D.C. Blanchard, R.R. Sakai, B. McEwen, S.M. Weiss, R.J. Blanchard, Subordination stress: behavioral, brain, and neuroendocrine correlates, Behav. Brain Res. 58 (1993) 113–121. [2] R.J. Blanchard, D.C. Blanchard, T. Takahashi, M.J. Kelley, Attack and defensive behaviour in the albino rat, Anim. Behav. 25 (1977) 622–634. [3] J.J. Bolhuis, R.E. FitzGerald, D.J. Kijk, J.M. Koolhaas, The corticomedial amygdala and learning in an agonistic situation in the rat, Physiol. Behav. 32 (1984) 575–579. [4] N. Burgess, E.A. Maguire, J. O'Keefe, The human hippocampus and spatial and episodic memory, Neuron 35 (2002) 625–641. [5] B. Buwalda, J. Scholte, S.F. de Boer, C.M. Coppens, J.M. Koolhaas, The acute glucocorticoid stress response does not differentiate between rewarding and aversive social stimuli in rats, Horm. Behav. 61 (2012) 218–226. [6] N.S. Canteras, Hypothalamic goal-directed behavior — ingestive, reproductive and defensive, in: C. Watson, G. Paxinos, L. Puelles (Eds.), The Mouse Nervous System, Academic Press, Sidney, 2012, pp. 539–562. [7] N.S. Canteras, R.B. Simerly, L.W. Swanson, Organization of projections from the medial nucleus of the amygdala: a PHAL study in the rat, J. Comp. Neurol. 360 (1995) 213–245. [8] A.F. Cezario, E.R. Ribeiro-Barbosa, M.V. Baldo, N.S. Canteras, Hypothalamic sites responding to predator threats—the role of the dorsal premammillary nucleus in unconditioned and conditioned antipredatory defensive behavior, Eur. J. Neurosci. 28 (2008) 1003–1015. [9] W.E. Cullinan, J.P. Herman, D.F. Battaglia, H. Akil, S.J. Watson, Pattern and time course of immediate early gene expression in rat brain following acute stress, Neuroscience 64 (1995) 477–505. [10] K. Ebner, C.T. Wotjak, R. Landgraf, M. Engelmann, Neuroendocrine and behavioral response to social confrontation: residents versus intruders, active versus passive coping styles, Horm. Behav. 47 (2005) 14–21. [11] P. Gilbert, S. Allan, S. Brough, S. Melley, J.N. Miles, Relationship of anhedonia and anxiety to social rank, defeat and entrapment, J. Affect. Disord. 71 (2002) 141–151.

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Restraint stress and social defeat: What they have in common.

Bob Blanchard was a great inspiration for our studies on the neural basis of social defense. In the present study, we compared the hypothalamic patter...
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