Effects of Social Defeat on Brain Chemistry and Behavior

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TS-Si News Service

Wednesday, 13 April 2011 09:00

New York, NY, USA. Life at the bottom of the social hierarchy has measurable effects on

brain chemistry, contributing to long-term social anxiety at the molecular level.

Researchers found that mice persistently bullied by dominant males grew unusually nervous around new company, accompanied by heightened sensitivity to vasopressin, a

hormone involved in a variety of social behaviors.

Yoav Litvin and colleagues set up a rough-and-tumble school yard scenario in which a young mouse is placed in a cage with a series of larger older mice — a different one in each of 10 days. The mice, being territorial, fight it out in a contest that the new arrival invariably loses.

Yoav Litvin, M.S., is a Postdoctoral Fellow in Mind, Brain and Behavior at Rockefeller University.

He worked on this research with colleagues in Donald Pfaff's Laboratory of Neurobiology and Behavior.

"We found that chronic social stress affects neuroendocrine systems that are paramount for adaptive mammalian social behaviors such as courtship, pair-bonding and parental behaviors."

"Changes in components of these systems have been implicated in human disorders, such as social phobias, depression, schizophrenia and autism."

The study team reported their findings in the journal Physiology & Behavior.Following the 10-minute battle, the mice were separated in the same cage by a partition that keeps them physically apart but allows them to see, smell and hear one another, a stressful experience for the loser. Given a day to rest, the test mice are then put in the company of nonthreatening mice of comparable size and age.

The biggest change in behavior was that the traumatized mice were more reluctant to socialize with their fellow mice, preferring to keep their distance compared to their unbullied counterparts.
The mice that had lost their battles were also more likely to "freeze" in place for longer periods of time and to frequently display "risk assessment" behaviors toward their new cage-mates, behaviors that have been shown to be valid indices of fear and anxiety in humans.
The researchers also gave a group of mice a drug that blocked vasopressin receptors, which partly curbed some of the anxious behavior in the bullied mice.

The researchers then examined the brains of the mice, particularly sections in the middle of the

forebrain known to be associated with emotion and social behavior.

They found that mRNA expression for vasopressin receptors — specifically V1bRs — had increased in the bullied mice, making them more sensitive to the hormone, which is found in high levels in rats with innate high anxiety.
In humans, the hormone is associated with aggression, stress and anxiety disorders.
The surge of vasopressin receptors was especially notable in the amygdala.

How long these effects last remains an open question. Other studies have found, for instance, that chronic stress can impair some cognitive functions in rodents and people, but that their brains can bounce back, given time to recuperate.

Still, many studies in rodents, primates and people have shown that early psychological trauma can have ill effects on health throughout life. Litvin says his study suggests that victims of bullying may have difficulty forming new relationships, and it identifies the possible role for a specific vasopressin receptor.

"The identification of brain neuroendocrine systems that are affected by stress opens the door for possible pharmacological interventions," Litvin says. "Additionally, studies have shown that the formation and maintenance of positive social relationships may heal some of the damage of bullying. These dynamic neuroendocrine systems may be involved."

CitationEffects of chronic social defeat on behavioral and neural correlates of sociality: Vasopressin, oxytocin and the vasopressinergic V1b receptor. Yoav Litvin, Gen Murakami, Donald W. Pfaff. Physiology & Behavior 2011; 103(3-4): 393-403. doi:10.1016/j.physbeh.2011.03.007

Highlights

• We examine the behavioral and neural effects of chronic social defeat (SD).
• SD produces anxiogenesis that may be mediated by the AVP V1B receptor.
• SD enhances activation of the paraventricular nucleus of the

hypothalamus.
• SD enhances V1b and oxytocin receptors in brain areas involved in sociality.
• The AVP V1b receptor is a potential candidate for treating anxiety related disorders.

Abstract

Chronic social stress in rodents produces behavioral and neuroendocrine patterns analogous to symptoms associated with psychopathologies in humans. Chronic social defeat in mice has been used to study the genetic and epigenetic precursors of stress-related social disorders. The neuropeptides arginine vasopressin (AVP) and oxytocin (OT) are released in central targets to modulate anti- and pro-social behaviors, respectively. AVP binds to V1a and V1b receptors (V1bRs) in discrete brain regions related to anxiety, depression and affiliative behaviors. Recent evidence suggests that V1bRs are involved in stress and anxiety and may be an attractive target for the treatment of associated disorders.

In the present series of experiments, we aimed to evaluate the effects of chronic social defeat stress on: 1) anxiety-related behaviors in a social investigation paradigm and their potential modulation by an acute dose of SSR149415, a V1bR antagonist; 2) AVP and Fos protein levels in the paraventricular nucleus of the hypothalamus (PVN) and; 3) AVP- and OT-receptor (OTR) mRNA levels in brain regions associated with sociality. When compared to undefeated animals, socially defeated mice exhibited an anxiogenic behavioral profile towards a novel male conspecific, with SSR149415 partly attenuating these effects. Histochemistry using immunofluorescence showed defeat produced significant elevations of Fos and double labeling of AVP and Fos proteins in the paraventricular nucleus of the hypothalamus (PVN). SSR149415 attenuated the effects of defeat on Fos and AVP/Fos double labeling, consistent with an anxiolytic effect. Defeated mice showed elevated levels of OTR mRNA levels in the

lateral septum (LS) in addition to increased V1bR and OTR mRNA in the medial amygdala (MeA). We suggest the involvement of V1bRs and OTRs in a circuit involving the PVN, MeA and LS in the effects of defeat on sociality. SSR149415 attenuated anxiogenesis in the social investigation model and both Fos and AVP/Fos labeling, suggesting V1bRs are an attractive target for the treatment of anxiety in general and disorders of sociality in particular.

Keywords: stress, anxiety, ssr149415, ot, avp, fos.

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TS-Si is dedicated to the acceptance, medical treatment, and legal protection of individuals correcting the misalignment of their brains and their anatomical sex, while supporting their transition into society as hormonally reconstituted and surgically corrected citizens.

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Last Updated on Monday, 11 April 2011 20:13

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