Increased brain glucocorticoid actions following social defeat in rats facilitates the long-term establishment of social subordination

Social rank is frequently established through aggressive encounters between new conspecifics. Despite increasing evidence suggesting that social rank is critical for the well-being of both humans and animals, knowledge about the factors influencing social rank remain scarce. Stress was previously shown to affect the establishment and maintenance of social hierarchies in rats. Likewise, increasing systemic corticosterone levels post-encounter in the emerging subordinate rat facilitates the long-term establishment of social subordination. Here, we investigated whether central corticosterone actions are sufficient to mediate this effect. Our data shows that, indeed, an intracerebroventricular corticosterone injection given to the emerging subordinate rat facilitates the long-term maintenance of the subordinate rank. Next, we attempted to identify a particular brain region in which enhancement of corticosterone actions could be sufficient to exert the facilitation of a long-term maintenance in the emerging subordinate brain. However, post-encounter administration of corticosterone into the basolateral amygdala, medial amygdala, lateral septum and the nucleus accumbens, brain regions selected for their implication in social rank establishment and emotional modulation of memory, did not affect long-term social subordination. Our study highlights the involvement of intracerebral corticosterone actions on the facilitation of long-lasting subordinate behavior, likely by having a modulatory role in the neurobehavioral plasticity engaged in the shaping of social subordination.

The glucocorticoid receptor in the nucleus accumbens plays a crucial role in social rank attainment in rodents

Alexandre Claude Gustave Bacq, Jocelin Grosse, Fiona Hollis, Thomas Didier Larrieu, Maria del Carmen Sandi Perez, Meltem Weger, Ioannis Zalachoras, Olivia Zanoletti

Social hierarchy in social species is usually established through competitive encounters with conspecifics. It determines the access to limited resources and, thus, leads to reduced fights among individuals within a group. Despite the known importance of social rank for health and well-being, the knowledge about the processes underlying rank attainment remains limited. Previous studies have highlighted the nucleus accumbens (NAc) as a key brain region in the attainment of social hierarchies in rodents. In addition, glucocorticoids and the glucocorticoid receptor (GR) have been implicated in the establishment of social hierarchies and social aversion. However, whether GR in the NAc is involved in social dominance is not yet known. To address this question, we first established that expression levels of GR in the NAc of high anxious, submissive-prone rats are lower than that of their low anxious, dominant-prone counterparts. Furthermore, virally-induced downregulation of GR expression in the NAc in rats led to an improvement of social dominance rank. We found a similar result in a cell-specific mouse model lacking GR in dopaminoceptive neurons (i.e., neurons containing dopamine receptors). Indeed, when cohabitating in dyads of mixed genotypes, mice deficient for GR in dopaminoceptive neurons had a higher probability to become dominant than wild-type mice. Overall, our results highlight GR in the NAc and in dopaminoceptive neurons as an important regulator of social rank attainment.

2020

Neurobiological Mechanisms Involved in the Establishment and Maintenance of Dominance Hierarchies and its Modulation by Stress in Rats

Maria del Carmen Sandi Perez, Marjan Timmer

Stress can have a strong and long lasting effect on the establishment and maintenance of dominance hierarchies in rats. When two rats of a pair have not been stressed (non-stressed pair) before a first social encounter, they establish a dominance hierarchy, but the rank that is obtained during this first encounter is not maintained until a second encounter one week later. When one rat of the pair is stressed (stressed pair) before the first encounter, the stressed rat becomes subordinate during the first encounter and the hierarchy that is formed is long lasting and stable. In this thesis, the neurobiological mechanisms underlying the effects of stress on dominance hierarchies were studied. In the first study, we investigated the role of increasing corticosterone levels before or just after a first encounter between two rats of a pair in the establishment and the long-term maintenance of a dominance hierarchy. We show that pre-social encounter corticosterone treatment does not affect the outcome of the hierarchy during a first encounter, but induces a long-term memory for the hierarchy when the corticosterone-injected rat becomes dominant during the encounter, but not when it becomes subordinate. Post-social encounter corticosterone leads to a long-term maintenance of the hierarchy only when the subordinate rat of the pair is injected with corticosterone. This corticosterone effect implicates glucocorticoids in the consolidation of the memory for a recently established hierarchy. Next, we investigated the immediate and long-term changes in mRNA levels of receptors for oxytocin and vasopressin in medial amygdala and lateral septum. In subordinate rats of the stressed pairs, we found a downregulation in oxytocin receptor mRNA in medial amygdala at three hours after the first encounter, and a downregulation in vasopressin 1a receptor mRNA in lateral septum one week after the first encounter. We show that administration of an oxytocin antagonist in the medial amygdala of the subordinate rat immediately after a first encounter induces a long-term memory for the established hierarchy. Administration of a vasopressin 1a receptor antagonist in the lateral septum of the subordinate rat just before a second encounter mimics the effects of exposure to acute stress on the long-term establishment of a dominance hierarchy. These results suggest a role for oxytocin and vasopressin in the effects of stress on the long-term establishment of dominance hierarchies. Finally, we investigated the long-term effects of acute stress and hierarchy formation on the establishment of a second hierarchy with an unfamiliar opponent. We show that the behavior of stressed subordinate rats towards an unfamiliar opponent depends on the previous status of the opponent: when paired with a previously dominant rat they become subordinate, whereas they become dominant when paired with a previously subordinate rat. Furthermore, we show that monoamine oxidase A and androgen receptor mRNA levels are downregulated in the lateral septum of stressed subordinate rats at one week after the first encounter; i.e., at the time when we have observed their flexible social behavior against unfamiliar opponents. The monoamine oxidase A inhibitor clorgyline was injected into the lateral septum to examine whether there was a causal relationship between changes in monoamine oxidase A mRNA levels and offensive behavior towards an unfamiliar subordinate opponent. However, our results did not support this hypothesis. Taken together, we have shown that exposure to acute stress and a social encounter leads to changes in the mRNA levels of receptors for oxytocin, vasopressin and androgens and of monoamine oxidase A. These changes might underlie the effect of stress on the formation of a stable and long-lasting dominance hierarchy. Corticosterone plays a role in the long-term maintenance of the recently established hierarchy and hence it is an ideal candidate to mediate some of the observed neurobiological changes.

EPFL2011

Neurobiological Mechanisms Involved in the Establishment and Maintenance of Dominance Hierarchies and its Modulation by Stress in Rats

Maria del Carmen Sandi Perez, Marjan Timmer

EPFL2011