Controllable stress elicits circuit-specific patterns of prefrontal plasticity in males, but not females

Abstract

Actual or perceived behavioral control during a traumatic event can promote resilience against future adversity, but the long-term cellular and circuit mechanisms by which this protection is conferred have not been identified. Clinical outcomes following trauma exposure differ in men and women, and therefore it is especially important in preclinical research to dissect these processes in both males and females. In male adult rats, an experience with behavioral control over tail shock ("escapable stress", ES) has been shown to block the neurochemical and behavioral outcomes produced by later uncontrollable tail shock ("inescapable stress", IS), a phenomenon termed "behavioral immunization." Here we determined whether behavioral immunization is present in females. Unlike males, the stress buffering effects of behavioral control were absent in female rats. We next examined the effects of ES and IS on spine morphology of dorsal raphe nucleus (DRN)projecting prelimbic (PL) neurons, a circuit critical to the immunizing effects of ES in males. In males, IS elicited broad, non-specific alterations in PL spine size, while ES elicited PL-DRN circuit-specific spine changes. In contrast, females exhibited broad, non-specific spine enlargement after ES but only minor alterations after IS. These data provide evidence for a circuitspecific mechanism of structural plasticity that could underlie sexual divergence in the protective effects of behavioral control.

Sex differences in auditory fear discrimination are associated with altered medial prefrontal cortex function

“…These disorders are characterized by impaired inhibition of learned fear, are associated with mPFC dysfunction, and are more prevalent in women than in men, therefore these results may also have important translational relevance. Future studies examining the potential neuronal 33 , neural circuit 31,34,35,[49][50][51] , and gonadal hormone 52 mechanisms underlying sex differences in fear discrimination, both over the course of extended training and during later retrieval testing, may lead to a better understanding of why women are so much more vulnerable to developing anxiety-related disorders than men. www.nature.com/scientificreports www.nature.com/scientificreports/ Methods Animals.…”

Activity of a vmPFC-DRN Pathway Corresponds With Resistance to Acute Social Defeat Stress

“…Given that acute stress-induced activation of serotonergic cells is positively correlated with stress susceptibility ( Amat et al, 2005 ; Cooper et al, 2008 , 2017 ; Paul et al, 2011 ), activation of vmPFC-DRN projections is thought to functionally suppress the DRN’s response during acute stress and buffer its negative consequences. Indeed, vmPFC-DRN cell recruitment is associated with indices of resilience to non-social laboratory stressors such as tail shock ( Baratta et al, 2009 , 2019 ), elevated plus maze ( Faye et al, 2020 ), and forced swim ( Warden et al, 2012 ). In sum, selectively engaging the vmPFC-DRN circuit appears to promote resistance to the effects of acute stress, perhaps by gating proactive behavioral coping strategies.…”

“…Recruitment of this pathway during trauma is thought to promote resistance by suppressing stress-induced serotonergic activity. For instance, in a model of learned controllability, rats who exert control over the duration of a tail shock more readily recruit vmPFC-DRN projections when compared with those not having learned control ( Baratta et al, 2009 , 2019 ). Importantly, learning controllability affords resistance to the effects of tail-shock stress seen in those without control, such as learned helplessness, downward mobility of social dominance, decreased aggression, anhedonia, neophobia, and various impairments of fear learning ( Maier and Seligman, 2016 ).…”

A Distinctive Pattern of Hippocampal-Prefrontal Cortical Network Activity during Stress Predicts Learned Resistance

“…Although fruitful, this approach seldom considers predisposing factors that prone individuals to distinct consequences of stress, making it challenging to link biological findings to specific variables. In contrast, the triadic design of learned helplessness discriminates the effects of the degree of control over stress, a well-established modulator of behavior (Eisenstein and Carlson, 1997;Maier and Watkins, 1998;Weiss, 1968), neurochemistry (Amat et al, 2005;Bland et al, 2003;Weiss et al, 1981), circuit activation (Baratta et al, 2009(Baratta et al, , 2019, and neural plasticity (Christianson et al, 2014;Shors et al, 1989Shors et al, , 2007. We contribute to such a framework by reporting the effects of stressor controllability on network dynamics.…”