Social deficits induced by peripubertal stress in rats are reversed by resveratrol

Adolescence is increasingly recognized as a critical period for the development of the social system, through the maturation of social competences and of their underlying neural circuitries. The present study sought to test the utility of resveratrol, a dietary phenol recently reported to have mood lifting properties, in modulating social interaction that is deficient following early life adversity. The main aims were to 1) pharmacologically restore normative social investigation levels dampened by peripubertal stress in rats and 2) identify neural pathways engaged by this pharmacological approach. Following peripubertal (P28–42) stress consisting of unpredictable exposures to fearful experiences, at adulthood the subjects' propensity for social exploration was examined in the three-chamber apparatus, comparing time invested in social or non-social investigation. Administered intraperitoneally 30 min before testing, resveratrol (20 mg/kg) normalized the peripubertal stress-induced social investigation deficit seen in the vehicle group, selectively altering juvenile but not object exploration. Examination of prefrontal cortex subregion protein samples following acute resveratrol treatment in a separate cohort revealed that while monoamine oxidase A (MAOA) enzymatic activity remained unaltered, nuclear AKT activation was selectively increased in the infralimbic cortex, but not in the prelimbic or anterior cingulate cortex. In contrast, androgen receptor nuclear localization was increased in the prelimbic cortex, but not in the infralimbic or anterior cingulate cortex. This demonstration that social contact deficits are reversed by resveratrol administration emphasizes a prosocial role for this dietary phenol, and evokes the possibility of developing new treatments for social dysfunctions.

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

Role of the HPA axis in the long-term programming of social behaviors by peripuberty stress

Vandana Veenit

Stress during childhood and adolescence enhances the risk of psychopathology later in life. In fact, exposure to stress during this period is known to predispose individuals to the development of psychopathologies such as depression and anxiety disorders later in life. Similarly, individuals subjected to fearful experiences or abuse during childhood and puberty exhibit violent behaviors in adulthood, as revealed in both human literature and animal studies. Previous work from our laboratory has shown that exposing peripuberty rats to fear experiences (such as synthetic fox odor and exposure to an elevated platform) following an unpredictable schedule, on a range of 7 specific days across P28 to P42 in male Wistar rats leads to reduced sociability, increased aggression, anxiety- and depression-like behaviors in adulthood. The hypothalamic pituitary adrenal (HPA) axis is one of the main physiological stress systems and various components of the HPA axis like corticotropin releasing hormone (CRH), glucocorticoids are modulated in response to early life experience. We therefore sought to investigate the role of HPA axis in long term programming of social and emotional behaviors as a result of peripuberty stress(PPS). We addressed this by manipulating (i) glucocorticoid system by two approaches, and, (ii) corticotropin releasing hormone (CRH) system. First, using male Wistar rats, we evaluated the consequences of administration of corticosterone following the same experimental schedule as for stress administration in our peripuberty stress paradigm (without actual stress exposure) on play behavior on postnatal day 44 (P44) and on behavioral tests of anxiety, aggression, sociability and depression in adulthood. Corticosterone response to novelty was also measured in adulthood. Our results show that, as compared to vehicle-, corticosterone-treated animals exhibit higher aggressive play behavior during adolescence, and escalated aggressive behavior in adulthood, while reduced sociability and decreased corticosterone response to novelty in adulthood. No differences were observed between groups on anxiety- and depression-like behavior tested later in life. Next, we examined whether pharmacological blockade of glucocorticoid receptor 30 minutes prior to peripuberty stress would prevent the consequences of peripuberty stress on emotional, social behavior and dysregulated gene expression. Our findings showed that administration of glucocorticoid receptor antagonist on days of peripuberty stress prevents the effects of peripuberty stress on behaviors related to the domain of aggression and sociability in adulthood without producing any effect on anxiety- and depression-like behavior tested later in life. Interestingly, administration of GR antagonist in PPS animals also reversed the effects of PPS on increased expression of GR and Trpc5 genes in central nucleus of amygdala. We also observed increased Crhr1 expression in limbic areas in peripuberty stressed animals which was not reversed by administration of GR antagonist in peripuberty stressed animals. Subsequently, we sought to evaluate the consequences of counteracting CRHR1 activation during early post-stress period on long-term behavioral consequences of peripuberty stress in tests for anxiety- and depression-like behaviors. Our results showed that administration of CRHR1 antagonist post peripuberty stress rescued the effects of peripuberty stress on depression-like behavior and to some extent on anxiety- like behavior. Taken together, our studies show that corticosterone administration during peripuberty largely mimics the behavioral alterations observed in peripuberty stressed animals in social realm, administration of glucocorticoid receptor antagonist on days of peripuberty stress prevents the effects of peripuberty on social domain and on increased expression of GR and Trpc5 genes in central nucleus of amygdala, and administration of CRHR1 antagonist post peripuberty stress rescued the effects of PPS on depression-like behavior and to some extent on anxiety-like behavior.

EPFL2013

A Motion Capture Study to Measure the Feeling of Synchrony in Romantic Couples and in Professional Musicians

Joan Llobera Mahy, Pierre Magistretti, Delphine Preissmann

The feeling of synchrony is fundamental for most social activities and prosocial behaviors. However, little is known about the behavioral correlates of this feeling and its modulation by intergroup differences. We previously showed that the subjective feeling of synchrony in subjects involved in a mirror imitation task was modulated by objective behavioral measures, as well as contextual factors such as task difficulty and duration of the task performance. In the present study, we extended our methodology to investigate possible interindividual differences. We hypothesized that being in a romantic relationship or being a professional musician can modulate both implicit and explicit synchronization and the feeling of synchrony as well as the ability to detect synchrony from a third person perspective. Contrary to our hypothesis, we did not find significant differences between people in a romantic relationship and control subjects. However, we observed differences between musicians and control subjects. For the implicit synchrony (spontaneous synchronization during walking), the results revealed that musicians that had never met before spontaneously synchronized their movements earlier among themselves than control subjects, but not better than people sharing a romantic relationship. Moreover, in explicit behavioral synchronization tasks (mirror game), musicians reported earlier feeling of synchrony and had less speed errors than control subjects. This was in interaction with tasks difficulty as these differences appeared only in tasks with intermediate difficulty. Finally, when subjects had to judge synchrony from a third person perspective, musicians had a better performance to identify if they were present or not in the videos. Taken together, our results suggest that being a professional musician can play a role in the feeling of synchrony and its underlying mechanisms.

Frontiers Research Foundation2016