Temporal association of elevated cholecystokininergic tone and adolescent trauma is critical for posttraumatic stress disorder-like behavior in adult mice

Abstract

Adolescent trauma (AT) is a common risk factor for adult-onset posttraumatic stress disorder (PTSD). However, the vulnerability to AT among different individuals varies dramatically, indicating that other cofactors are important. Despite extensive studies, the identification of those cofactors has had little success. Here, we found that after subjected to traumatic stress at postnatal day 25 (P25), a stage that is comparable to the human adolescent period, inducible/ reversible forebrain-specific cholecystokinin receptor-2 transgenic (IF-CCKR-2 tg) mice exhibited a significantly higher level of PTSD-like behavior at a later life (adult) stage compared with their wild-type littermates. Moreover, in these traumatized IF-CCKR-2 tg mice, both the glucocorticoid negative feedback inhibition and spatial learning and memory were impaired. Interestingly, if the CCKR-2 transgene was specifically suppressed during the time of AT exposure, these observations were largely diminished, indicating that a temporal association of the elevated CCKergic tone and AT is pathogenically critical. Treatment of traumatized IF-CCKR-2 tg mice with fluoxetine, a selective serotonin reuptake inhibitor, for a period of 4 wk significantly attenuated the PTSD-like behavior and the impaired glucocorticoid negative feedback inhibition, but not the memory deficit, implying that the memory deficit is an independent post-AT clinical entity and not a consequence of PTSD. Taken together, these results reveal a dynamic role of the CCKergic system in the development of post-AT psychopathologies and suggest that a timely antagonism of CCKR-2 activity during AT exposure is a potential preventive strategy for post-AT psychopathologies including PTSD and cognitive dysfunction.anxiety disorder | animals model | face validity | constructive validity | predictive validity P osttraumatic stress disorder (PTSD), as a predominant form of anxiety disorders, affects 7.8% of people of ages between 15 and 54 y in the United State (1). This prevalence goes up to 32-36% in people who have a history of trauma (2). Particularly, over half of the victims who experienced a preadult trauma such as childhood physical or sexual abuse eventually develop PTSD (3). Given that children, especially early adolescents, have a higher possibility of exposure to traumatic attacks (4), adolescent trauma (AT) is an important risk factor for PTSD. However, the vulnerability among different individuals to AT is different, and this variability may at least partially be attributed to genetic variations (5). Another important factor is pretrauma stress (6). Stress may dysregulate various neurotransmitter systems in the brain, among which the CCKergic system, including cholecystokinin (CCK) peptides and their receptors, is of a significant importance, based on its dynamic regulation in response to stress (7,8). Actually, the CCKergic system has long been recognized as an anxiogenic factor (7), and CCK peptides were commonly used to induce anxiety in volunteers (9, 10). CCK peptides and CCK re...

Therapeutic Action of Fluoxetine is Associated with a Reduction in Prefrontal Cortical miR-1971 Expression Levels in a Mouse Model of Posttraumatic Stress Disorder

“…To analyze the impact of traumatic stress on miRNA profiles in mouse PFC, we employed a well-established mouse model for PTSD that we (28, 29, 41–43) and also other research groups used, at least in slightly modified ways (44–46), for previous experiments. The electric footshock-elicited murine PTSD-like syndrome can be effectively counteracted by the orally administered SSRI antidepressant fluoxetine (28, 29) and, as we published recently, lasts at least until day 60 after shock application (28).…”

Interaction between the Cholecystokinin and Endogenous Cannabinoid Systems in Cued Fear Expression and Extinction Retention

“…There are two CCK receptor isoforms-CCKAR and CCKBR (IUPHAR-CCK1/2) (Hill et al, 1987;Mercer and Beart, 2004). A number of studies demonstrate a role for CCK in fear and anxiety, primarily through activation of G q -coupled CCKBR (de Montigny, 1989;Bradwejn et al, 1991;Rasmussen et al, 1993;Josselyn et al, 1995;Frankland et al, 1996Frankland et al, , 1997Areda et al, 2006;Joseph et al, 2013). Interestingly, CCK and the endocannabinoids seem to engender opposite fear responses.…”

The 5-HT3A receptor is essential for fear extinction

“…In addition, it was reported that the 5-HT 3 receptor is colocalized with cholecystokinin (CCK) immunoreactivity, and that CCK neurotransmission is highly regulated by the 5-HT 3 receptor (Paudice and Raiteri 1991;Férézou et al 2002). Moreover, it was recently shown that CCK is involved in fear extinction (Joseph et al 2013). Therefore, CCK transmission may also contribute to the 5-HT 3A receptor-mediated extinction of fear memory.…”