Phosphorylated cyclic AMP response element binding protein expression induced in the periaqueductal gray by predator stress: its relationship to the stress experience, behavior and limbic neural plasticity

Abstract

Electrophysiological studies in cats and recently in rats implicate neuroplasticity in the periaqueductal gray (PAG) and its afferents in stressor-induced increases in fearful behavior and anxiety-like behavior (ALB). Such increases may model aspects of affective changes following traumatic stress in humans. The present study explored the role of neuroplasticity in PAG and its connection with the central nucleus of the amygdala (ACE) in male rodent anxiety-like response to predator stress. In the first of two studies, the effects of predator stress on the induction of phosphorylated cyclic AMP response element binding protein (pCREB) were investigated. pCREB expression in the PAG and ventromedial hypothalamus (VMH) was examined immunohistochemically. Predator stress increased the degree of pCREB expression in PAG cells (measured densitometrically) but did not increase the number of cells expressing pCREB (measured stereologically). Moreover, predator stress-specific increase in pCREB-like immunoreactivity (lir) was restricted to the right lateral column of the PAG. In addition, pCREB lir in the right lateral column likely reflects aspects of the stress experience because the stressor (cat behavior) and the response to the stressor (rat defensive behavior) are highly predictive of degree of pCREB expression. There was no effect of predator stress on pCREB lir in the VMH. Because pCREB expression has been associated with long-lasting potentiation (LLP) of neural transmission, we examined the effects of predator stress on transmission in the ACE-PAG pathway in a second study. Predator stress elevated evoked potential measures of ACE-PAG transmission in the right hemisphere but not in the left hemisphere 11–12 days after predator stress. This finding is consistent with the longer-lived effects of pharmacological stress on amygdalo-PAG transmission in the right hemisphere but not in the left hemisphere in cats. Of interest is the fact that the same aspects of the stressor experience and reaction to it, which are predictive of the degree of pCREB expression, are also highly predictive of the degree of potentiation of measures of ACE-PAG transmission. Behavioral analyses revealed that the most consistent effects of predator stress are on behavior in the plus maze (open arm exploration and risk assessment) and on startle. In addition, covariance analysis suggests that ACE-PAG potentiation mediates some but not all of the changes in ALB produced by predator stress. Because pCREB expression may be a precursor to neuroplastic changes in certain forms of memory and LLP, the present findings complement studies in the cat, showing that neuroplastic changes in the PAG underlie changes in affect following stress. Furthermore, these findings suggest that neuroplastic changes in PAG may be important mediators of predator stress-induced changes in affective behavior in rodents. Finally, consistent with cat and human studies, the right hemisphere appears particularly important in long-term response to stress.