Mechanisms of lasting change in anxiety induced by severe stress

Abstract

Affective disorder may arise from exposure to severe stress (Davidson et al. 2002;Holsboer 2001; Keck and Holsboer 2001; Petty 1995; Shalev et al. 1998). Stressprecipitation of affective disorder is a serious problem given that 50%-60% ofNorth Americans experience traumatic stress in their lifetimes (Kessler et al. 1995),and of those 15% may develop posttraumatic stress disorder (PTSD) (Kessler et al.1994).There are promising animal models of lasting effects of stress on affect. Prominentamong them is classical fear conditioning of freezing. Studies of this form oflearning have uncovered mechanisms of neural plasticity underlying acquisitionand extinction of enhanced fear response to simple and complex sensory stimuli(contextual conditioning) (Blair et al. 2001; Maren et al. 1994; Rogan et al. 1997;Schafe et al. 2001). There is clinical interest in classical fear conditioning as a modelof mechanisms of onset of PTSD to inform poststressor prophylactic interventionin humans (Pitman et al. 2002), and to suggest means to improve therapeutic outcomeof exposure therapies (Myers and Davis 2002). Neural plasticity and longtermpotentiation (LTP) in amygdala circuitry contribute to both conditioning andextinction of fear (Bauer et al. 2001; Blair et al. 2001; Schafe et al. 2000; Schafe etal. 2001; Schafe and LeDoux 2000a; Myers and Davis 2002; Nader et al. 2000a).Moreover, these forms of learning are 7V-methyl-D-aspartate (NMDA) receptor dependent(Baker and Azorlosa 1996; Campeau et al. 1992; Davis 2002; Decola et al.1991; Fanselow et al. 1992; Kim et al. 1991; Lee and Kim 1998; Lee et al. 2001;Stiedl et al. 2000), as are some but not all forms of amygdala neural plasticity associatedwith acquisition and extinction of fear conditioning (Bauer et al. 2002;Davis 2002; Goosens and Maren 2002; Lee et al. 2002; Royer and Pare 2002; Tsvetkovet al. 2002).However, fear conditioning cannot model all affective disorders associated withsevere stress. Sensitized fearfulness manifested as generalized anxiety is also a featureof PTSD (Pitman 1997). Animal models of such changes, therefore, are also relevant to stress precipitation of affective disorder. Moreover, animal models withecological validity with regard to stressors are important to both validate and extendthe findings with conditioning models.Studies of lasting changes in affect following exposure to species-relevant lifethreateningcircumstances provide models of stress-induced affective psychopathologywith ecological validity. Exposure of rodents to predator stimuli (predatorstress) is fear provoking and stressful (Adamec et al. 1998; Blanchard et al. 1998;Dielenberg et al. 2001; McGregor et al. 2002). Moreover, predator stress (exposureto a cat) lastingly increases rodent anxiety when the exposure is unprotected andinescapable (Adamec and Shallow 1993; Adamec 1997). Behavioral changes aredetectable in several tests of anxiety, including elevated plus maze (EPM), lightdarkbox, social interaction, and acoustic startle (Adamec 2003).