Background and Significance
Studying social defeat as a way to understand human psychopathology: Background and Significance
Our current treatment strategies for psychiatric disorders such as depression and posttraumatic stress disorder (PTSD) are woefully inadequate. One reason that these disorders are so intractable is that they likely stem from evolutionarily adaptive behavioral states produced in response to social stress or defeat (Blanchard et al., 2001; Sloman et al., 2003; Taylor et al., 2011). Social stress is known to have pervasive effects on health and to be a primary risk factor for the development of mood disorders and drug abuse (Furukawa et al., 1999; Heim and Nemeroff, 2001; Miczek et al., 2008). Similarly, in many non-human species, exposure to social defeat produces persistent physiological and behavioral responses that closely mimic the symptoms of depression and PTSD (Huhman, 2006; Neumann et al., 2011). What is desperately needed is an improved understanding of how social stress affects the brain and shifts behavior from one stable state to another. My lab has developed an ethologically relevant model in hamsters termed conditioned defeat (CD) wherein even a single exposure to social defeat stress causes a striking behavioral shift from social investigation/aggression to social avoidance/submission. The overarching goal of our work is to define the neural mechanisms of social stress-induced behavioral changes and to discover how these changes might be prevented or reversed.
Social defeat as an ethologically relevant stressor: Why Syrian hamsters?
Syrian hamsters readily exhibit rich and varied agonistic behavior (defined as a range of behaviors – from aggression to defense and submission – that are seen in conflict situations) in the laboratory. When hamsters are singly housed, resident animals routinely attack and defeat intruders placed into their home cages. Another advantage of using hamsters is that their agonistic behavior is ritualized, and the severity of encounters in terms of bites/tissue damage is usually quite low, particularly when compared with aggressive strains of mice. Thus, our animals suffer little to no tissue damage. Agonistic behavior in hamsters has been well characterized and is easily quantified. Hamsters that lose in an agonistic encounter, but not those that win, display a “classical” hormonal stress response (Huhman et al., 1990; Huhman et al., 1991). Importantly, this stress response is not dependent on actual contact between the animals because exposure of a previously defeated hamster to a dominant opponent stimulates a similar hormonal response in the loser even if the opponents are separated by a barrier (Huhman et al., 1992). Thus, social defeat in hamsters is readily obtainable, ethologically relevant, and is a potent psychological stressor.
Why conditioned defeat?
A particularly valuable model for the investigation of social stress-induced behavioral change is a phenomenon called conditioned defeat (CD) that was first demonstrated in hamsters by the PI (Potegal et al., 1993). In this model, a hamster is defeated in the home cage of a larger, more aggressive male. When the defeated hamster is later paired in its own home cage with a smaller, non-aggressive opponent, the previously defeated hamster does not display normal territorial aggression but instead produces only defensive and submissive behavior. This behavioral response in hamsters is reliably observed even after a single experience of social defeat. Similar defeat-induced changes have been reported in rats and mice but only following repeated exposure to defeat (Berton et al., 2006; Bolhuis et al., 1984; Siegfried et al., 1984). In rats, however, agonistic behavior is usually quite low unless the animals are housed in complex social conditions, and in aggressive strains of mice the level of fighting and wounding is often quite high. CD in hamsters is also produced by a social defeat experience from which the subject can escape, further emphasizing the ethological relevance of this phenomenon (McCann and Huhman, 2012). Finally, CD is persistent in that many male hamsters will continue to exhibit CD for at least one month (Huhman et al., 2003). Thus, CD offers a unique opportunity to explore how multiple brain systems that mediate fear/anxiety, emotional learning, social behavior, and motivation interact to control complex behavior in a social context and to “shift” or “switch” individuals among stable behavioral states. The nature of such “switches” is a fundamental unanswered question in behavioral neuroscience, and the underlying neurobiology must be elucidated if we are to develop more effective treatment strategies to prevent and treat stress-induced psychopathology in humans.
Neural circuit mediating conditioned defeat: A brief “progress report”
During the first funding period of our NIH grant on conditioned defeat, we demonstrated that the BLA and the central amygdala (CeA) are critical components the neural circuit mediating CD (Jasnow et al., 2004a; Jasnow and Huhman, 2001). We also tested hypotheses about what neurochemical signals (e.g., glutamate, gamma aminobutyric acid (GABA), corticotropin releasing factor (CRF)) mediate or modulate conditioned defeat (Cooper and Huhman, 2005; Cooper and Huhman, 2010; Day et al., 2011; Jasnow et al., 2004a; Jasnow et al., 2004b; Jasnow and Huhman, 2001; Jasnow et al., 2005). In the second funding period, we proposed to expand the CD neural circuit by testing whether the medial nucleus of the amygdala (MeA) (Markham and Huhman, 2008), the bed nucleus of the stria terminalis (BNST) (Markham et al., 2009), and the nucleus accumbens (NAcc) (Luckett et al., 2011) are also components of the circuit mediating the acquisition or expression of CD. We have gone beyond what we proposed to test the role of the medial prefrontal cortex (mPFC) (Markham et al., 2011), the lateral septum (McDonald et al., 2011), the dorsal raphe (DR) (Cooper et al., 2009; Cooper and Huhman, 2007; Cooper et al., 2008), and the hippocampus (both dorsal (DH) and ventral (VH)) (Markham et al., 2010). We have demonstrated that each of these brain regions (with the exception of DH) mediate the acquisition only, the expression only, or both the acquisition and expression of CD (see Fig 1). Our current grant examines the role of neurotrophic factors such as BDNF and NGF in social stress-induced behavioral changes.
Figure 1. Simplified unilateral diagram illustrating some of our
progress towards defining the components of the neural circuit
mediating conditioned defeat.
Green = Necessary for Acquisition and Expression (BLA, CeA, MeA, DR)
Blue = Necessary for Acquisition but not Expression (mPFC, VH)
Yellow= Necessary for Expression but not Acquisition (NAcc, lateral septum, BNSTpl)
Red = Neither Acquisition nor Expression (DH)