NMDA receptors and PCREB: their role in brain and behavioral changes after stress

Blundell, Jacqueline (2005) NMDA receptors and PCREB: their role in brain and behavioral changes after stress. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

In this dissertation, we employed the ecologically valid predator stress model to assess the effects of stress on brain and behavior. A five minute unprotected exposure of a rat to a cat induces long-lasting changes in anxiety-like behaviors in the rat (Adamec & Shallow, 1993; Adamec et al., 2001; Cohen et al., 2004). Using this model, we addressed four main questions. First, are the various manifestations of the anxiogenic effects of predator stress N-methyl-D-aspartate (NMDA) receptor-dependent? Second, are the neuroplastic changes that occur after predator stress NMDA receptor-dependent? Third, do neuroplastic changes occur after exposure to other, milder stressors, such as the elevated plus maze (EPM)? Finally, is the neuroplastic response to a mild stressor enhanced in animals that have been previously stressed? -- In Chapter 2, we assessed the effects of a NMDA receptor antagonist [(3-(2-carboxypiperazin4-yl)propyl-l-phosphonic acid) - CPP] on anxiety-like behavior produced by predator stress. An affect test battery including hole board, elevated plus maze (EPM), light/dark box, social interaction, social avoidance, and response to acoustic startle was employed to assess the behavioral response to stress. Doses of 1-10 mg/kg of CPP administered ip 30 min prior to predator stress blocked most anxiety-like behaviors measured eight and nine days after stress. CPP blocked the predator stress-induced reduction in open arm exploration and risk assessment in the EPM, blocked the predator stress-induced decrease in entries into the lighted arm of the light/dark box, and blocked the predator stress-induced delay in habituation of the acoustic startle response. Behaviors in which the effects of predator stress were not blocked by CPP included reduction in unprotected head dips in the EPM and reduced social interaction. In addition, predator stress was without effect on social avoidance as measured with the Haller test. Taken together, these findings add to a body of evidence showing that a syndrome of behavioral changes follows predator stress. Components of this syndrome of behavioral changes likely depend on changes in separable neural substrates initiated by NMDA receptors as well as by other neurochemical means. -- Since phosphorylation of cyclic AMP response element binding protein (CREB) is regulated by NMDA receptors and pCREB-like immunoreactivity (lir) is increased after predator stress, we examined the effects of CPP on predator stress-induced changes in pCREB-lir in Chapter 3. pCREB-lir was assessed using immunocytochemistry in brain areas implicated in fearful and anxious behavior including the amygdala, periaqueductal gray (PAG), bed nucleus of the stria terminalis (BNST), anterior cingulate cortex (ACC), and dorsal medial hypothalamus (DMH). Results showed that CPP blocked the predator stress-induced increase in pCREB-lir in the right lateral column of the PAG, blocked the predator stress-induced increase in pCREB-lir in several amygdala nuclei, and reversed the predator stress-induced suppression of pCREB-lir in the BNST. Importantly, at least in the amygdala and PAG, the pattern of pCREB-lir was hemisphere- and anterior-posterior (AP) plane-dependent. Our results suggest that several amygdala nuclei, the PAG, and the BNST, where predator stress changes pCREB-lir in a NMDA receptor-dependent manner, are candidate areas of neuroplastic change contributing to lasting changes in anxiety-like behavior. However, like predator stress-induced changes in anxiety-like behavior, not all stress-induced changes in pCREB-lir were NMDA receptor-dependent. -- In Chapter 4, we examined pCREB changes in response to other stressors, such as the EPM, in brain areas implicated in fear and anxiety. In addition, we investigated the effects of prior traumatic stress on pCREB-lir in animals exposed to the EPM. In particular, pCREB-lir was examined after exposure to the EPM in rats that had been exposed to a cat seven days earlier and naive (handled) controls. Brain areas investigated for both experiments included the amygdala, PAG, and BNST, which are all areas that show NMDA receptor-dependent pCREB-lir changes after predator stress. Results showed that there were no pCREB-lir differences between naive control rats and rats exposed to the EPM only. However, exposure to the EPM in predator stressed rats elevated pCREB-lir in the right lateral column of the PAG and bilaterally in the dorsal column of the PAG. Findings suggest mechanisms associated with neuroplasticity may be further engaged by relatively mild stresses in animals with a history of severe stress exposure. -- Taken together, these results suggest that most changes in anxiety-like behavior following predator stress are NMDA receptor-dependent. In addition, changes in pCREB-lir in several amygdala nuclei, the right lateral column of the PAG and the BNST may mediate the predator stress-induced increases in anxiety-like behavior. Furthermore, mechanisms associated with neuroplasticity may be further activated by relatively mild stresses in animals with a history of severe stress exposure.

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