Extra-hypothalamic oxytocin neurons drive stress-induced social vigilance and avoidance

AbstractOxytocin increases the salience of both positive and negative social contexts and it is thought that these diverse actions on behavior are mediated in part through circuit-specific action. This hypothesis is based primarily on manipulations of oxytocin receptor function, leaving open the question of whether different populations of oxytocin neurons mediate different effects on behavior. Here we inhibited oxytocin synthesis in a social stress-sensitive population of oxytocin neurons specifically within the medioventral bed nucleus of the stria terminalis (BNSTmv). Oxytocin knock-down prevented stress-induced increases in social vigilance and decreases in social approach. Viral tracing of BNSTmv oxytocin neurons revealed fibers in regions controlling defensive behaviors including lateral hypothalamus, anterior hypothalamus, and anteromedial BNST (BNSTam). Oxytocin infusion into BNSTam in stress naïve mice increased social vigilance and reduced social approach. These results show that a population of extra-hypothalamic oxytocin neurons play a key role in controlling stress-induced social anxiety behaviors.

Download Full-text

Extrahypothalamic oxytocin neurons drive stress-induced social vigilance and avoidance

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2011890117 ◽

2020 ◽

Vol 117 (42) ◽

pp. 26406-26413 ◽

Cited By ~ 5

Author(s):

Natalia Duque-Wilckens ◽

Lisette Y. Torres ◽

Sae Yokoyama ◽

Vanessa A. Minie ◽

Amy M. Tran ◽

...

Keyword(s):

Social Stress ◽

Social Contexts ◽

Stria Terminalis ◽

Social Approach ◽

Bed Nucleus ◽

Defensive Behaviors ◽

Oxytocin Infusion ◽

Different Populations ◽

Social Vigilance ◽

Sensitive Population

Oxytocin increases the salience of both positive and negative social contexts and it is thought that these diverse actions on behavior are mediated in part through circuit-specific action. This hypothesis is based primarily on manipulations of oxytocin receptor function, leaving open the question of whether different populations of oxytocin neurons mediate different effects on behavior. Here we inhibited oxytocin synthesis in a stress-sensitive population of oxytocin neurons specifically within the medioventral bed nucleus of the stria terminalis (BNSTmv). Oxytocin knockdown prevented social stress-induced increases in social vigilance and decreases in social approach. Viral tracing of BNSTmv oxytocin neurons revealed fibers in regions controlling defensive behaviors, including lateral hypothalamus, anterior hypothalamus, and anteromedial BNST (BNSTam). Oxytocin infusion into BNSTam in stress naïve mice increased social vigilance and reduced social approach. These results show that a population of extrahypothalamic oxytocin neurons plays a key role in controlling stress-induced social anxiety behaviors.

Download Full-text

Pubertal Androgens Reduce the Effects of Social Stress on Anxiety-related Behaviors in California Mice

10.1101/2020.12.02.408526 ◽

2020 ◽

Author(s):

Emily C. Wright ◽

Hannah I. Culkin ◽

Shwetha Sekar ◽

Amita Kapoor ◽

Cody Corbett ◽

...

Keyword(s):

Social Stress ◽

Neural Circuits ◽

Social Defeat ◽

Developmental Period ◽

Adult Males ◽

Social Approach ◽

Males And Females ◽

Anxiety Behavior ◽

California Mice ◽

Social Vigilance

AbstractAdolescence is an important developmental period during which anxiety-related behaviors differentiate in males and females. In humans anxiety prevalence increases to a greater degree in women than men after puberty, but the mechanism is unknown. We used social defeat stress to model anxiety behaviors in California mouse, a species in which aggressive females allow for comparison of social anxiety behaviors across sex. Adult female California mice show reduced social approach and increased social vigilance after exposure to stress, while these changes are weaker in males. Here we show that in juveniles, social defeat reduces social approach and increases social vigilance in both males and females. Next, we show that prepubertal castration sensitizes adult males to social defeat. However, when pubertal castration was paired with either testosterone or dihydrostesterone replacement, effects of defeat on social approach and vigilance were blunted in adult males. We also showed that effects of defeat on social behavior in juveniles were oxytocin receptor dependent, as has been described for adult females. This work highlights the importance of pubertal testosterone to the development of sex differences in anxiety behavior, and provides evidence that androgen receptors play an important role in the development of neural circuits of anxiety.

Download Full-text

Role of CRF receptor 1 antagonism in the bed nucleus of the stria terminalis of male rats after intermittent social defeat stress

10.1101/784488 ◽

2019 ◽

Author(s):

Mailton Vasconcelos ◽

Dirson J. Stein ◽

Matheus Gallas-Lopes ◽

Luane Landau ◽

Luiza Behrens ◽

...

Keyword(s):

Social Behavior ◽

Social Stress ◽

Social Behaviors ◽

Social Defeat ◽

Corticotropin Releasing Factor ◽

Male Rats ◽

Stria Terminalis ◽

Social Avoidance ◽

Bed Nucleus ◽

Sweet Solution

AbstractWe recently demonstrated that the experience of brief episodes of social defeat caused impairments in social behaviors. Moreover, we provided evidence that the antagonism of corticotropin-releasing factor binding protein (CRFBP) in the bed nucleus of the stria terminalis (BNST) restored social approach in stressed animals. This study aimed to test the relation between corticotropin-releasing factor receptor type 1 (CRFR1) located in the BNST and the establishment of social stress-disrupted behaviors in rats submitted to social defeat in the resident-intruder paradigm. Animals were tested for sweet solution preference, subjected to the elevated-plus maze (EPM), and to the social interaction three-chamber test. Social behavior was tested after BNST drug infusions. The drug used in this study was a CRF receptor 1 antagonist, CP376395 (CP), administered in two doses: 50 ng/0.20 μL/side, and 500 ng/0.20 μL/side. Saline solution was used as vehicle and administered 0.20 μL/side. Socially stressed animals (n = 11) did not differ compared to control animals (n = 11) in the EPM. Stressed animals displayed impaired social behavior, represented by a decrease in time spent in the interaction zone. The lower dose (CP 50 ng/0.20 μL/side) administered intra-BNST restored social behaviors in stressed animals. On the other hand, the higher dose of the CRFR1 antagonist (CP 500 ng/0.20 μL/side) induced social avoidance in rats without a history of agonistic confrontations. These findings implicate BNST CRFR1 signaling in the modulation of social behaviors in rats given the choice to explore an unfamiliar conspecific.

Download Full-text

Chronic social stress in the visible burrow system modulates stress-related gene expression in the bed nucleus of the stria terminalis

Physiology & Behavior ◽

10.1016/j.physbeh.2006.05.046 ◽

2006 ◽

Vol 89 (3) ◽

pp. 301-310 ◽

Cited By ~ 38

Author(s):

D CHOI ◽

M NGUYEN ◽

K TAMASHIRO ◽

L MA ◽

R SAKAI ◽

...

Keyword(s):

Gene Expression ◽

Social Stress ◽

Stria Terminalis ◽

Related Gene ◽

Burrow System ◽

Bed Nucleus ◽

Chronic Social Stress

Download Full-text

Bed nucleus of the stria terminalis regulates fear to unpredictable threat signals

eLife ◽

10.7554/elife.46525 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 15

Author(s):

Travis D Goode ◽

Reed L Ressler ◽

Gillian M Acca ◽

Olivia W Miles ◽

Stephen Maren

Keyword(s):

Conditioned Fear ◽

Stria Terminalis ◽

Conditioned Stimuli ◽

Variable Intensity ◽

Reversible Inactivation ◽

Bed Nucleus ◽

Defensive Behaviors ◽

The Us ◽

Specific Factors ◽

Fear And Anxiety

The bed nucleus of the stria terminalis (BNST) has been implicated in conditioned fear and anxiety, but the specific factors that engage the BNST in defensive behaviors are unclear. Here we examined whether the BNST mediates freezing to conditioned stimuli (CSs) that poorly predict the onset of aversive unconditioned stimuli (USs) in rats. Reversible inactivation of the BNST selectively reduced freezing to CSs that poorly signaled US onset (e.g., a backward CS that followed the US), but did not eliminate freezing to forward CSs even when they predicted USs of variable intensity. Additionally, backward (but not forward) CSs selectively increased Fos in the ventral BNST and in BNST-projecting neurons in the infralimbic region of the medial prefrontal cortex (mPFC), but not in the hippocampus or amygdala. These data reveal that BNST circuits regulate fear to unpredictable threats, which may be critical to the etiology and expression of anxiety.

Download Full-text

Bed nucleus of the stria terminalis regulates fear to unpredictable threat signals

10.1101/376228 ◽

2018 ◽

Cited By ~ 2

Author(s):

Travis D. Goode ◽

Reed L. Ressler ◽

Gillian M. Acca ◽

Olivia W. Miles ◽

Stephen Maren

Keyword(s):

Conditioned Fear ◽

Stria Terminalis ◽

Variable Intensity ◽

Reversible Inactivation ◽

Bed Nucleus ◽

Defensive Behaviors ◽

The Us ◽

Specific Factors ◽

Fear And Anxiety ◽

Pathological Anxiety

ABSTRACTThe bed nucleus of the stria terminalis (BNST) has been implicated in conditioned fear and anxiety, but the specific factors that engage the BNST in defensive behaviors are unclear. Here we examined whether the BNST mediates freezing to conditioned stimuli (CSs) that poorly predict the onset of aversive unconditioned stimuli (USs) in rats. Reversible inactivation of the BNST selectively reduced freezing to CSs that poorly signaled US onset (e.g., a backward CS that followed the US), but did not eliminate freezing to forward CSs even when they predicted USs of variable intensity. Additionally, backward (but not forward) CSs selectively increased Fos in the ventral BNST and in BNST-projecting neurons in the infralimbic region of the medial prefrontal cortex (mPFC), but not in the hippocampus or amygdala. These data reveal that BNST circuits regulate fear to unpredictable threats, which may be critical to the etiology and expression of anxiety.IMPACT STATEMENTThe bed nucleus of the stria terminalis (BNST) is required for the expression of defensive behavior to unpredictable threats, a function that may be central to pathological anxiety.

Download Full-text

Increased BNST reactivity to affective images is associated with greater α-amylase response to social stress

Social Cognitive and Affective Neuroscience ◽

10.1093/scan/nsaa010 ◽

2019 ◽

Vol 14 (12) ◽

pp. 1263-1272

Author(s):

Walker S Pedersen ◽

Tammi R A Kral ◽

Melissa A Rosenkranz ◽

Jeanette A Mumford ◽

Richard J Davidson

Keyword(s):

Stress Response ◽

Salivary Cortisol ◽

Social Stress ◽

Stress Test ◽

Trier Social Stress Test ◽

Stress System ◽

Cortisol Response ◽

Stria Terminalis ◽

Bed Nucleus ◽

Human Stress

Abstract While rodent research suggests that the bed nucleus of the stria terminalis (BNST) and centromedial amygdala (CM) coordinate the hormonal stress response, little is known about the BNST’s role in the human stress response. The human BNST responds to negatively valenced stimuli, which likely subserves its role in responding to threat. Thus, variation in BNST reactivity to negatively valenced stimuli may relate to differences in the stress response. We measured participants’ blood oxygenated level-dependent response to affective images and salivary cortisol and α-amylase (AA) levels in response to a subsequent Trier social stress test (TSST). Greater BNST activation to emotionally evocative images was associated with a larger TSST-evoked AA, but not cortisol response. This association remained after controlling for CM activation, which was not related to the cortisol or AA response. These results suggest that the BNST response to negatively valenced images subserves its role in coordinating the stress response, a BNST role in the stress response independent from the CM, and highlight the need for investigation of the conditions under which BNST activation predicts the cortisol response. Our findings are critical for the future study of mood and anxiety disorders, as dysregulation of the stress system plays a key role in their pathogenesis.

Download Full-text