Viral Vector Induction of CREB Expression in the Periaqueductal Gray Induces a Predator Stress-Like Pattern of Changes in pCREB Expression, Neuroplasticity, and Anxiety in Rodents

Robert Adamec,Waleed Abdul Razek,Olivier Berton

doi:10.1155/2009/904568

Abstract

Predator stress is lastingly anxiogenic. Phosphorylation of CREB to pCREB (phosphorylated cyclic AMP response element binding protein) is increased after predator stress in fear circuitry, including in the right lateral column of the PAG (periaqueductal gray). Predator stress also potentiates right but not left CeA-PAG (central amygdala-PAG) transmission up to 12 days after stress. The present study explored the functional significance of pCREB changes by increasing CREB expression in non-predator stressed rats through viral vectoring, and assessing the behavioral, electrophysiological and pCREB expression changes in comparison with handled and predator stressed controls. Increasing CREB expression in right PAG was anxiogenic in the elevated plus maze, had no effect on risk assessment, and increased acoustic startle response while delaying startle habituation. Potentiation of the right but not left CeA-PAG pathway was also observed. pCREB expression was slightly elevated in the right lateral column of the PAG, while the dorsal and ventral columns were not affected. The findings of this study suggest that by increasing CREB and pCREB in the right lateral PAG, it is possible to produce rats that exhibit behavioral, brain, and molecular changes that closely resemble those seen in predator stressed rats.

Highlights

Study of the neurobiology of long-lasting changes in affect occurring after stressful events is of interest, an interest heightened by the fact that fearful events may precipitate affective psychopathologies [1, 2]
Viral vectoring to induce CREB expression in the right lateral column of the periaqueductal gray (PAG) produced behavioral effects resembling those seen in predator stressed rats
The present study demonstrated that directly inducing CREB expression in the right lateral PAG reproduced behavioral, brain, and molecular changes that closely resemble those seen in predator stressed rats

Summary

Introduction

Study of the neurobiology of long-lasting changes in affect occurring after stressful events is of interest, an interest heightened by the fact that fearful events may precipitate affective psychopathologies [1, 2]. Animal models are useful to enhance understanding of the impact of stress on brain and behavior, permitting simulation of a human condition in a controlled setting allowing study of disorder development. Conditioned fear paradigms, behavior in unfamiliar situations that are fear or anxiety provoking, and more recently, predator stress, are all models used to understand the neurobiology of the impact of fearful events on affect. Parallel path analytic studies using data from Vietnam veterans suffering from PTSD and predator stressed rodents find that in both humans and rodents, features of the stressor predict the level of anxiety [6]. Similar lasting changes in startle and habituation of startle are seen in both predator stressed rats and humans with PTSD [6, 15,16,17,18]

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