Overlapping neurobiology of learned helplessness and conditioned defeat: implications for PTSD and mood disorders

Abstract

Exposure to traumatic events can increase the risk for major depressive disorder (MDD) as well as posttraumatic stress disorder (PTSD), and pharmacological treatments for these disorders often involve the modulation of serotonergic (5-HT) systems. Several behavioral paradigms in rodents produce changes in behavior that resemble symptoms of MDD and these behavioral changes are sensitive to antidepressant treatments. Here we review two animal models in which MDD-like behavioral changes are elicited by exposure to an acute traumatic event during adulthood, learned helplessness (LH) and conditioned defeat. In LH, exposure of rats to inescapable, but not escapable, tailshock produces a constellation of behavioral changes that include deficits in fight/flight responding and enhanced anxiety-like behavior. In conditioned defeat, exposure of Syrian hamsters to a social defeat by a more aggressive animal leads to a loss of territorial aggression and an increase in submissive and defensive behaviors in subsequent encounters with non-aggressive conspecifics. Investigations into the neural substrates that control LH and conditioned defeat revealed that increased 5-HT activity in the dorsal raphe nucleus (DRN) is critical for both models. Other key brain regions that regulate the acquisition and/or expression of behavior in these two paradigms include the basolateral amygdala (BLA), central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST). In this review, we compare and contrast the role of each of these neural structures in mediating LH and conditioned defeat, and discuss the relevance of these data in developing a better understanding of the mechanisms underlying trauma-related depression. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

Figure 1

Rats were infused into the BNST with 1 µg PACAP or equivolume (0.5 µg) vehicle. 24-hr later, rats were tested in a shuttlebox escape task for the latency to escape footshock (FR-2 schedule). Prior BNST PACAP infusion produced a learned-helplessness like behavioral phenotype; 2-way analysis of variance revealed a main effect of drug F(4,132) = 8.588, p < 0.05, and time F(4,132) = 8.046, p < 0.05.

Figure 2

Hypothesized circuits for A. Learned helplessness and B. Conditioned defeat. Abbreviations: 5-HT, serotonin; BLA, basolateral amygdala; BNSTal, anterolateral bed nucleus of the stria terminalis; CeA, central nucleus of the amygdala; CRH, corticotropin-releasing hormone; dPAG, dorsal periaqueductal gray; DRN, dorsal raphe nucleus; Glu, glutamate; mPFC, medial prefrontal cortex.

Figure 3

Male Syrian hamsters received 3 social defeats in a neutral arena at 3-min intervals. Subjects were able to jump out of the arena during social defeats, and individuals were removed from the arena by the experimenter after 3 failed jumps. Subjects escaped from the arena more quickly during the 2nd and 3rd defeats compared to the 1st (ANOVA, p < .05). No defeat controls received corresponding exposure to an empty neutral arena. Subjects were tested for conditioned defeat 24-hours later in a 5-min social encounter with a non-aggressive intruder. * indicates that defeated subjects showed increased submissive and defensive behavior and reduced social behavior during conditioned defeat testing compared to no defeat controls (t-tests, p < .05).

Figure 4

A review of the literature investigating the brain regions that mediate both learned helplessness and conditioned defeat suggest that interactions between the dorsal raphe nucleus, basolateral amygdala and bed nucleus of the stria terminalis are critical for both behavioral paradigms. Activity within this hypothesized circuit is tightly regulated by projections from the medial prefrontal cortex.